State of matter (Physical Pharmacy)

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States of Matter

Aseel Samaro

Binding Forces Between Molecules Solids and the Crystalline State Phase Equilibria and the Phase Rule

States of Matter

Objectives of the lecture

After completion of this chapter the students should be able toDescribe the solid state crystallinity solvates and polymorphismUnderstand phase equilibria and phase transitions between the three

main states of matterUnderstand the phase rule and its application to different systems

containing multiple components

Gases are compressible fluids Their molecules are widely separated Liquids are relatively incompressible fluids Their molecules are more tightly packed Solids are nearly incompressible and rigid Their molecules or ions are in close contact

and do not move

Comparison of Gases Liquids and Solids

In order for molecules to exist in aggregates in gases liquids and solids Intermolecular forces must exist

As two atoms or molecules are brought closer together the opposite charges and binding forces in the two molecules are closer together than the similar charges and forces causing the molecules to attract one another

The negatively charged electron clouds of molecules largely govern the balance (equilibrium) forces between the two molecules

Repulsive and Attractive Forces

Ideal Gas Equation

Boylersquos law P a (at constant n and T)1V

Charlesrsquo law V a T (at constant n and P)

Avogadrorsquos law V a n (at constant P and T)

P1V1

T1

=P2V2

T2

PV = nRTR is the gas constant

The conditions 0 0C and 1 atm are called standard temperature and pressure (STP)

Experiments show that at STP 1 mole of an ideal gas occupies 22414 L

PV = nRT

Gaseous state

R = PVnT

=(1 atm)(22414L)(1 mol)(27315 K)

R = 0082057 L bull atm (mol bull K)

9

What is the volume (in liters) occupied by 498 g of HCl at STP

PV = nRT

V = nRTP

T = 0 0C = 27315 K

P = 1 atm

n = 498 g x 1 mol HCl

3645 g HCl= 137 mol

V =1 atm

137 mol x 00821 x 27315 KLbullatmmolbullK

V = 307 L

Gaseous state

1 atm asymp 760001 mm-Hg

P1V1

T1

=

P2V2

T2

Gaseous state

The critical temperature (Tc) is the temperature above which the gas cannot be made to liquefy OR is the temperature above which the liquid cannot longer exist

The critical pressure (Pc) is the minimum pressure required to liquefy a gas at its critical temperature

critical temperature (Tc) of water is 374degC or 647 K and its critical pressure is 218 atm

Liquefaction of Gases

SOLIDS amp CRYSTALLINE STATEPharmaceutical Drugs more than 80 are solid formulations

A crystalline solid possesses rigid and long-range order

In a crystalline solid atoms molecules or ions occupy specific (predictable) positions

An amorphous solid does not possess a well-defined arrangement and long-range molecular order

Solids and the crystalline state

Classification of Solids

Crystalline Amorphous

Amorphous

A unit cell is the basic repeating structural unit of a crystalline solid

latticepoint

Unit Cell Unit cells in 3 dimensions

At lattice points

bull Atoms

bull Molecules

bull Ions

The crystal lattice of sodium chloride NaCl

Na Cl

The various crystal forms are divide to basic 7 unit according to its symmetry

NaCl urea

iodine

sucrose Boric acid

Crystal forms

iodoform

Be3Al2(SiO3)6

CsCl ZnS CaF2

Ionic Crystalsbull Lattice points occupied by cations and anionsbull Held together by electrostatic attractionbull Hard brittle high melting pointbull Poor conductor of heat and electricity

Types of Crystals

diamondgraphite

carbonatoms

Covalent Crystalsbull Lattice points occupied by atomsbull Held together by covalent bondsbull Hard high melting pointbull Poor conductor of heat and electricity

Cross Section of a Metallic Crystal

nucleus ampinner shell e-

mobile ldquoseardquoof e-

Metallic Crystalsbull Lattice points occupied by metal atomsbull Held together by metallic bondsbull Soft to hard low to high melting pointbull Good conductors of heat and electricity

Some elemental substance such as C and S may exist in more than one crystalline form and are said to be allotropic which is a special case of polymorphism

Polymorphism is the ability of a substance to exist in more than one crystal structure

Polymorphism

Polymorphism is the ability of a substance to exist in more than one crystal structure

Polymorphs when two crystals have the same chemical composition but different internal structure (molecular packing ndashmolecular conformation or and inter or intra molecular interactions)modifications or polymorphs or forms

Pseudo polymorphs different crystal forms have molecules of the same given substances and also contain molecules of solvent incorporated into a unique structure (solvates or hydrates (water))

diamond graphite

carbonatoms

High T and p

Diamond is metastable and converts very slowly to graphite

The most common example of polymorphism

Solid State Polymorphs

Mono-component systems Polymorphs

Multi-component systems

Cocrystal

The simplest definition of a cocrystal is a crystalline structure made up of two or more components in a definite stoichiometric ratio where each component is defined as either an atom ion or molecule

Principle of polymorphism

When the change from one form to another is reversible it is said to be enantiotropic

When the transition takes place in one direction onlymdashfor example from a metastable to a stable formmdashthe change is said to be monotropic

Solvates

Pharmaceutical synthesis include purification and crystallization residual solvent can be trapped in the lattice

This result in the formation of cocrystal or solvate

The presence of residual solvent may affect dramatically the crystalline structure of the solid depending on the type of inter molecular forces that the solvent may have with crystalline solid

Melting pointVapor pressureHardnessOptical electrical magnetic

propertiesColorIR spectraNMR spectra

Photochemical reactivityThermal stabilityFiltration and drying characteristicsDissolution rateBioavailabilityPhysical and chemical stability

Solubility and melting point are very important in pharmaceutical processes including dissolution and

formulation

Polymorphism

AMORPHOUS SOLIDS Solids that donrsquot have a definite geometrical shape are known as Amorphous Solids1 In these solids particles are randomly arranged in three dimension2 They donrsquot have sharp melting points3 Amorphous solids are formed due to sudden cooling of liquid4 Amorphous solids melt over a wide range of temperature

Amorphous Solid

An amorphous solid does not possess a well-defined arrangement and long-range molecular order

Amorphous substances as well as cubic crystal are isotropic that is they exhibit similar properties in all direction

The crystalline from of the antibiotic novobiocin acid is poorly absorbed and has no activity where the amorphous form is readily absorbed and therapeutically active due to different dissolution rate

Amorphous or crystalline amp therapeutic activity

General crystallization conditions 1048698Solvents ndashdifferent polarities 1048698Concentration of the solutions (super saturated saturated diluted) 1048698Cooling speed (quenching slow) 1048698Temperature (room or lower than room temperature)

Crystallization

Final Form

Granulation

Drying

Compaction

Tableting

Drug Product

API

Crystallization

Filtration

Drying

Milling

Bulk API

Stability

Polymorphism and Industry Pharmaceutical

Polymorphism and Industry Pharmaceutical

Fluoxetine HCl the active ingredient in the antidepressant drug Prozac

co crystal which will have increased solubility compared to the crystalline form

Celecoxib

CELECOXIB is a nonsteroidal anti-inflammatory drug

However it was found that the higher bioavailability was shown by the amorphous state

The downfall of the amorphous state was its stability

This was due to the structural relaxation

This was enhanced by mixing it with polymers like PVP which helped in stabilizing the amorphous system (Piyush Gupta et al 2004 Piyush Gupta et al 2005)

A new solid state form was developed by Pharmacia

FurosemideTwo forms with significantly differing aqueous solubility and dissolution rateOral bioavailability compromised

Giron lists gt20 excipients that display polymorphism includingndash Lactose (anhydrous also monohydrate)ndash Aspartame (anhydrous hydrate forms)ndash Magnesium stearate (can affect lubrication of tablets)

Bioavailability

The rate and extent to which the active ingredient or active moiety is absorbed from a drug product and becomes available at the site of action

Bioequivalence

The absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study

Carbamazepine

CHLORPROPAMIDEat least six polymorphic white or almost white crystalline powder It exhibits polymorphism Practically insoluble in water soluble in alcohol freely soluble in acetone and in dichlo-romethane dissolves in dilute solutions of alkali hydroxides Protect from light

blood-glucose-lowering drug

AIDS drug ritonavir

Theobroma oil (cacao butter ) is a polymorphic natural fat

Theobroma oil can exist in 4 different polymorphic forms of which only one is Stabile

1 Unstable gamma form melting at 18degC2 Alpha form melting at 22degC3 Beta prime form melting at 28degC4 Stable beta form melting at 345degC

This is important in the preparation of theobroma suppositories

If the oil is heated to a point where it is completely liquified (about 35 C) the crystals of the stable polymorph are destroyed amp the mass does not crystallize until it is cooled to 15 C

The crystals that form are unstable amp the suppositories melt at 24 C

Theobroma suppositories must be prepared below 33 C

Polymorphism and Industry Pharmaceutical

Polymorphism and Industry Pharmaceutical

Anhydrates together with salts form the majority of all drug formulationsAbout a half of all APIs used today are saltsSalts are stable and well soluble in polar solvents (first of all in water) because they contain ionic bondThere is one more essential advantage of salts ndash their solubility is a function of pH Since pH in the gastrointestinal tract (GIT) vary between 1-75

atorvastatin calcium trihydrateEach tablet contains Atorvastatin Calcium Trihydrate equivalent to Atorvastatin 20 mg

Phase Equilibria amp The Phase Rule

Phase diagram ndash Water

Phase Equilibrium A stable phase structure with lowest free-energy (internal energy) of a system and also randomness or disorder of the atoms or molecules (entropy)

Any change in Temperature Composition and Pressure causes an increase in free energy and away from Equilibrium thus forcing a move to another lsquostatersquo

Phase Equilibria amp The Phase Rule Definitions

A phase is defined as any homogeneous and physically distinct part of a system which is separated from other parts of the system by interfaces

A part of a system is homogeneous if it has identical physical properties and chemical composition throughout the part

A phase may be gas liquid or solid A gas or a gaseous mixture is a single phase Totally miscible liquids constitute a single phase In an immiscible liquid system each layer is counted as a separate phase Every solid constitutes a single phase except when a solid solution is formed A solid solution is considered as a single phase Each polymorphic form constitutes a separate phase

Phase Definition

1 Liquid water pieces of ice and water vapour are present together The number of phases is 3 as each form is a separate phase Ice in the system is a single phase even if it is present as a number of pieces

2 Calcium carbonate undergoes thermal decomposition The chemical reaction is CaCO3(s) CaO(s) + CO2 (g) Number of phases = 3 This system consists of 2 solid phases CaCO3 and CaO and one gaseous phase that of CO2

3 Ammonium chloride undergoes thermal decomposition The chemical reaction is NH4Cl(s) NH3 (g) + HCl (g) Number of phases = 2 This system has two phases one solid NH4Cl and one gaseous a mixture of NH3 and HCl

4 A solution of NaCl in water Number of phases = 1

bull Examples

The number of components of a system at equilibrium is the smallest number of independently varying chemical constituents using which the composition of each and every phase in the system can be expressed

Components

Counting the number of components 1 The sulphur system is a one component system All the phases

monoclinic rhombic liquid and vapour ndash can be expressed in terms of the single constituent ndash sulphur

2 A mixture of ethanol and water is an example of a two component system We need both ethanol and water to express its composition

bull Examples

An example of a system in which a reaction occurs and an equilibrium is established is the thermal decomposition of solid CaCO3

In this system there are three distinct phasesSolid CaCO3

Solid CaOGaseous CO2

Though there are 3 species present the number of components is only two because of the equilibrium CaCO3 (s) CaO(s) + CO2(g)

Any two of the three constituents may be chosen as the components

If CaO and CO2 are chosen then the composition of the phase CaCO3 is expressed as one mole of component CO2 plus one mole of component CaO

If on the other hand CaCO3 and CO2 were chosen then the composition of the phase CaO would be described as one mole of CaCO3 minus one mole of CO2

The degrees of freedom or variance of a system is defined as the minimum number of variables such as

temperaturepressureconcentrationwhich must be fixed in order to define the system completely

Degrees of freedom (or variance)

F = C P + 2

1 A gaseous mixture of CO2 and N2 Three variables pressure temperature and composition are required to define this system This is hence a trivariant system

2 A system having only liquid water has two degrees of freedom or is bivariant Both temperature and pressure need to be mentioned in order to define the system

3 If to the system containing liquid water pieces of ice are added and this system with 2 phases is allowed to come to equilibrium then it is an univariant system

Only one variable either temperature or pressure need to be specified in order to define the systemIf the pressure on the system is maintained at 1 atm then the temperature of the system gets automatically fixed at 0oC the normal melting point of ice

bull Examples

Phase Equilibria amp The Phase Rule

A phase diagram (Equilibrium Phase Diagram) summarizes the conditions at which a substance exists as a solid liquid or gas

OR It is a ldquomaprdquo of the information about the control of phase structure of a particular material system

The relationships between temperature and the compositions and the quantities of phases present at equilibrium are represented

F = C P + 2The phase rule

The phase rule JW Gibbs formulated the phase rule which is a general relation

between the variance F the number of component C and the number of phases P at equilibrium for a system of any composition

For a system in equilibrium

F degree of freedom the least number of intensive variable that must be fixed (known) to describe the system completely

Phase Rule relation to determine the least number of intensive variable that can be changed without changing the equilibrium state of the system or alternately

The least number required to define the state of the system which is called degree of freedom F

Intensive variable independent variable that do not depend on the volume or the size egTemp pressure

Independent chemical species which comprise the system These could be Elements Ions Compounds

Eg Au-Cu system Components rarr Au Cu Ice-water system Component rarr H2O

Al2O3 ndash Cr2O3 system Components rarr Al2O3 Cr2O3

Component the smallest number of constituent by which the composition of each phase in the system at equilibrium can be expressed in form of chemical formula or equation

Phase Equilibria amp The Phase RuleComponents of a system

The number of phases in a system is denoted P

(a)A gas or a gaseous mixture is a single phase P=1

(b) For a solid system an alloy of two metals is a two-phase system (P=2) if the metals are immiscible but a single-phase system (P=1) if they are miscible---a homogeneous mixture of the two substances---is uniform on a molecular scale

(c) For a liquid system according to the solubility to decide whether a system consists of one phase or of two For example a solution of sodium chloride in water is a single phase A pair of liquids that are partially miscible or immiscible is a two-phase system(P=2)

Oil in water

Degrees of Freedom = What you can control What the system controls

F = C + 2 P

Can control the no of components added and P amp T

System decided how many phases to produce given the

conditions

A way of understanding the Gibbs Phase RuleThe degrees of freedom can be thought of as the difference between what you (can) control and

what the system controls

F degree of freedom the least number of intensive variable that must be fixed (known) to describe the system completely

Degree of freedom (or variance) F is the number of variables (T p andor composition) that can be changed independently without changing the phases of the system

a) At the triple pointP = 3 (solid liquid and gas)

C= 1 (water)P + F = C + 2

F = 0 (no degree of freedom)

b) liquid-solid curveP = 2

2+F = 1 + 2F= 1

One variable (T or P) can be changed

c) LiquidP =1

So F =2Two variables (T and P) can be varied independently

and the system will remains a single phase

One-component systemsPhase diagram of water

P (

atm

)

Critical point

374

1

=100=0O--Triple point

0006

218

Curve O -CSublimation

Deposition

Curve O-AVaporizationCondensation

Curve O -BMelting

Freezing

F = C P + 2

F = C P + 2

Phase Diagram of Carbon Dioxide

Condensed system System in which the vapor phase is ignored and only the solid andor liquid phases are considered

Two component system For two component system F can be 3 (3D model is needed) eg T p

and concentration usually we fix p = 1atm the vapor phase is neglected and F is reduced to 2

For three component system the pressure and temperature are fixed

Phenol water phase diagram

eg for point d (24)

Two component system containing liquid phase

Tie Line bc line The line at which the system at equilibrium will separate into phases of constant composition termed lsquoconjugate phasesrsquo

Lever Rule a way to calculate the proportions of each phase present on a phase diagram in a two phase field (at a given temperature and composition)

eg for point d (24)

For every 10 g of liquid system in equilibrium in point d

75 g phase A25 g phase B

ExampleMixed 24g phenol +76g water T 50degC

equilibrium75 g phase A 25 g phase B

11 phenol 63 phenol

011 times75 g=825 g phenol

063 times25 g=1575 g phenol

water rich phasecontains water+ phenol(11)

Phenol rich phasecontains Phenol (63)+ water

The Critical Solution Temperature CST

Is the maximum temperature at which the 2-phase region exists (or upper consolute temperature)

In the case of the phenol-water system this is 668oC (point h)

All combinations of phenol and water gt CST are completely miscible and yield 1-phase liquid systems

Systems Showing a Decrease in Miscibility with Rise in Temperature

A few mixtures exhibit a lower critical solution temperature (low CST) eg triethylamine plus water The miscibility with in temperature

Systems Showing Upper and Lower CSTs

The miscibility with temp

a certain temperature miscibility starts to again with further in temperature

Closed-phase diagram ie nicotine-water system

A salol B thymol

53

Two component system containing solid and liquid phase (Eutectic Mixtures)

A salol B thymol

EMLAreg (lidocaine 25 and prilocaine 25) Cream

EMLA Cream (lidocaine 25 and prilocaine 25) is an emulsion in which the oil phase is a eutectic mixture of lidocaine and prilocaine in a ratio of 11 by weight This eutectic mixture has a melting point below room temperature and therefore both local anesthetics exist as a liquid oil rather than as crystals

Eutectic mixture Pharmaceutical Application

Triangular Diagrams for three ndash component systems

Three component system

Birzeit University Physical Pharmacy PHAR 323 Dr Hani Shtaya

1 Binding Forces Between Molecules2 Repulsive and Attractive Forces3 The Gaseous State The Ideal Gas Law Liquefaction of Gases Aerosols4 Solids and the Crystalline State Crystalline Solids Polymorphism Solvates Amorphous Solids5 Phase Equilibria and the Phase Rule Phase Rule Systems Containing One Component Condensed System Two-Component Systems Containing Liquid Phases Two-Component Systems Containing Solid and Liquid Phases Eutectic Mixtures Rules Relating to Triangular Diagrams

Topics that we have covered

  • States of Matter
  • States of Matter (2)
  • Objectives of the lecture
  • Comparison of Gases Liquids and Solids
  • Slide 5
  • Repulsive and Attractive Forces
  • Ideal Gas Equation
  • Gaseous state
  • Slide 9
  • Gaseous state (2)
  • Liquefaction of Gases
  • Slide 12
  • SOLIDS amp CRYSTALLINE STATE Pharmaceutical Drugs more than 80
  • Solids and the crystalline state
  • Classification of Solids
  • Slide 16
  • Slide 17
  • Crystal forms
  • Types of Crystals
  • Slide 20
  • Slide 21
  • Polymorphism
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Cocrystal
  • Principle of polymorphism
  • Solvates
  • Polymorphism (2)
  • Amorphous Solid
  • Amorphous or crystalline amp therapeutic activity
  • Slide 33
  • Slide 34
  • Polymorphism and Industry Pharmaceutical
  • Celecoxib
  • Furosemide
  • Bioavailability
  • Slide 39
  • Slide 40
  • Bioequivalence
  • Slide 42
  • Carbamazepine
  • Slide 44
  • AIDS drug ritonavir
  • Slide 46
  • Slide 47
  • Phase Equilibria amp The Phase Rule
  • Phase diagram ndash Water
  • Phase Equilibria amp The Phase Rule Definitions
  • Phase Definition
  • Examples
  • Components
  • Examples
  • Slide 55
  • Degrees of freedom (or variance)
  • Examples (2)
  • Phase Equilibria amp The Phase Rule
  • The phase rule
  • Slide 60
  • Phase Equilibria amp The Phase Rule (2)
  • The number of phases in a system is denoted P
  • Slide 63
  • Slide 64
  • One-component systems
  • Slide 66
  • Slide 67
  • Slide 68
  • Slide 69
  • Slide 70
  • Two component system containing liquid phase
  • Slide 72
  • The Critical Solution Temperature CST
  • Systems Showing a Decrease in Miscibility with Rise in Temperat
  • Systems Showing Upper and Lower CSTs
  • Two component system containing solid and liquid phase (Eutecti
  • Slide 77
  • Eutectic mixture Pharmaceutical Application
  • Three component system
  • Slide 80
  • Topics that we have covered

    Binding Forces Between Molecules Solids and the Crystalline State Phase Equilibria and the Phase Rule

    States of Matter

    Objectives of the lecture

    After completion of this chapter the students should be able toDescribe the solid state crystallinity solvates and polymorphismUnderstand phase equilibria and phase transitions between the three

    main states of matterUnderstand the phase rule and its application to different systems

    containing multiple components

    Gases are compressible fluids Their molecules are widely separated Liquids are relatively incompressible fluids Their molecules are more tightly packed Solids are nearly incompressible and rigid Their molecules or ions are in close contact

    and do not move

    Comparison of Gases Liquids and Solids

    In order for molecules to exist in aggregates in gases liquids and solids Intermolecular forces must exist

    As two atoms or molecules are brought closer together the opposite charges and binding forces in the two molecules are closer together than the similar charges and forces causing the molecules to attract one another

    The negatively charged electron clouds of molecules largely govern the balance (equilibrium) forces between the two molecules

    Repulsive and Attractive Forces

    Ideal Gas Equation

    Boylersquos law P a (at constant n and T)1V

    Charlesrsquo law V a T (at constant n and P)

    Avogadrorsquos law V a n (at constant P and T)

    P1V1

    T1

    =P2V2

    T2

    PV = nRTR is the gas constant

    The conditions 0 0C and 1 atm are called standard temperature and pressure (STP)

    Experiments show that at STP 1 mole of an ideal gas occupies 22414 L

    PV = nRT

    Gaseous state

    R = PVnT

    =(1 atm)(22414L)(1 mol)(27315 K)

    R = 0082057 L bull atm (mol bull K)

    9

    What is the volume (in liters) occupied by 498 g of HCl at STP

    PV = nRT

    V = nRTP

    T = 0 0C = 27315 K

    P = 1 atm

    n = 498 g x 1 mol HCl

    3645 g HCl= 137 mol

    V =1 atm

    137 mol x 00821 x 27315 KLbullatmmolbullK

    V = 307 L

    Gaseous state

    1 atm asymp 760001 mm-Hg

    P1V1

    T1

    =

    P2V2

    T2

    Gaseous state

    The critical temperature (Tc) is the temperature above which the gas cannot be made to liquefy OR is the temperature above which the liquid cannot longer exist

    The critical pressure (Pc) is the minimum pressure required to liquefy a gas at its critical temperature

    critical temperature (Tc) of water is 374degC or 647 K and its critical pressure is 218 atm

    Liquefaction of Gases

    SOLIDS amp CRYSTALLINE STATEPharmaceutical Drugs more than 80 are solid formulations

    A crystalline solid possesses rigid and long-range order

    In a crystalline solid atoms molecules or ions occupy specific (predictable) positions

    An amorphous solid does not possess a well-defined arrangement and long-range molecular order

    Solids and the crystalline state

    Classification of Solids

    Crystalline Amorphous

    Amorphous

    A unit cell is the basic repeating structural unit of a crystalline solid

    latticepoint

    Unit Cell Unit cells in 3 dimensions

    At lattice points

    bull Atoms

    bull Molecules

    bull Ions

    The crystal lattice of sodium chloride NaCl

    Na Cl

    The various crystal forms are divide to basic 7 unit according to its symmetry

    NaCl urea

    iodine

    sucrose Boric acid

    Crystal forms

    iodoform

    Be3Al2(SiO3)6

    CsCl ZnS CaF2

    Ionic Crystalsbull Lattice points occupied by cations and anionsbull Held together by electrostatic attractionbull Hard brittle high melting pointbull Poor conductor of heat and electricity

    Types of Crystals

    diamondgraphite

    carbonatoms

    Covalent Crystalsbull Lattice points occupied by atomsbull Held together by covalent bondsbull Hard high melting pointbull Poor conductor of heat and electricity

    Cross Section of a Metallic Crystal

    nucleus ampinner shell e-

    mobile ldquoseardquoof e-

    Metallic Crystalsbull Lattice points occupied by metal atomsbull Held together by metallic bondsbull Soft to hard low to high melting pointbull Good conductors of heat and electricity

    Some elemental substance such as C and S may exist in more than one crystalline form and are said to be allotropic which is a special case of polymorphism

    Polymorphism is the ability of a substance to exist in more than one crystal structure

    Polymorphism

    Polymorphism is the ability of a substance to exist in more than one crystal structure

    Polymorphs when two crystals have the same chemical composition but different internal structure (molecular packing ndashmolecular conformation or and inter or intra molecular interactions)modifications or polymorphs or forms

    Pseudo polymorphs different crystal forms have molecules of the same given substances and also contain molecules of solvent incorporated into a unique structure (solvates or hydrates (water))

    diamond graphite

    carbonatoms

    High T and p

    Diamond is metastable and converts very slowly to graphite

    The most common example of polymorphism

    Solid State Polymorphs

    Mono-component systems Polymorphs

    Multi-component systems

    Cocrystal

    The simplest definition of a cocrystal is a crystalline structure made up of two or more components in a definite stoichiometric ratio where each component is defined as either an atom ion or molecule

    Principle of polymorphism

    When the change from one form to another is reversible it is said to be enantiotropic

    When the transition takes place in one direction onlymdashfor example from a metastable to a stable formmdashthe change is said to be monotropic

    Solvates

    Pharmaceutical synthesis include purification and crystallization residual solvent can be trapped in the lattice

    This result in the formation of cocrystal or solvate

    The presence of residual solvent may affect dramatically the crystalline structure of the solid depending on the type of inter molecular forces that the solvent may have with crystalline solid

    Melting pointVapor pressureHardnessOptical electrical magnetic

    propertiesColorIR spectraNMR spectra

    Photochemical reactivityThermal stabilityFiltration and drying characteristicsDissolution rateBioavailabilityPhysical and chemical stability

    Solubility and melting point are very important in pharmaceutical processes including dissolution and

    formulation

    Polymorphism

    AMORPHOUS SOLIDS Solids that donrsquot have a definite geometrical shape are known as Amorphous Solids1 In these solids particles are randomly arranged in three dimension2 They donrsquot have sharp melting points3 Amorphous solids are formed due to sudden cooling of liquid4 Amorphous solids melt over a wide range of temperature

    Amorphous Solid

    An amorphous solid does not possess a well-defined arrangement and long-range molecular order

    Amorphous substances as well as cubic crystal are isotropic that is they exhibit similar properties in all direction

    The crystalline from of the antibiotic novobiocin acid is poorly absorbed and has no activity where the amorphous form is readily absorbed and therapeutically active due to different dissolution rate

    Amorphous or crystalline amp therapeutic activity

    General crystallization conditions 1048698Solvents ndashdifferent polarities 1048698Concentration of the solutions (super saturated saturated diluted) 1048698Cooling speed (quenching slow) 1048698Temperature (room or lower than room temperature)

    Crystallization

    Final Form

    Granulation

    Drying

    Compaction

    Tableting

    Drug Product

    API

    Crystallization

    Filtration

    Drying

    Milling

    Bulk API

    Stability

    Polymorphism and Industry Pharmaceutical

    Polymorphism and Industry Pharmaceutical

    Fluoxetine HCl the active ingredient in the antidepressant drug Prozac

    co crystal which will have increased solubility compared to the crystalline form

    Celecoxib

    CELECOXIB is a nonsteroidal anti-inflammatory drug

    However it was found that the higher bioavailability was shown by the amorphous state

    The downfall of the amorphous state was its stability

    This was due to the structural relaxation

    This was enhanced by mixing it with polymers like PVP which helped in stabilizing the amorphous system (Piyush Gupta et al 2004 Piyush Gupta et al 2005)

    A new solid state form was developed by Pharmacia

    FurosemideTwo forms with significantly differing aqueous solubility and dissolution rateOral bioavailability compromised

    Giron lists gt20 excipients that display polymorphism includingndash Lactose (anhydrous also monohydrate)ndash Aspartame (anhydrous hydrate forms)ndash Magnesium stearate (can affect lubrication of tablets)

    Bioavailability

    The rate and extent to which the active ingredient or active moiety is absorbed from a drug product and becomes available at the site of action

    Bioequivalence

    The absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study

    Carbamazepine

    CHLORPROPAMIDEat least six polymorphic white or almost white crystalline powder It exhibits polymorphism Practically insoluble in water soluble in alcohol freely soluble in acetone and in dichlo-romethane dissolves in dilute solutions of alkali hydroxides Protect from light

    blood-glucose-lowering drug

    AIDS drug ritonavir

    Theobroma oil (cacao butter ) is a polymorphic natural fat

    Theobroma oil can exist in 4 different polymorphic forms of which only one is Stabile

    1 Unstable gamma form melting at 18degC2 Alpha form melting at 22degC3 Beta prime form melting at 28degC4 Stable beta form melting at 345degC

    This is important in the preparation of theobroma suppositories

    If the oil is heated to a point where it is completely liquified (about 35 C) the crystals of the stable polymorph are destroyed amp the mass does not crystallize until it is cooled to 15 C

    The crystals that form are unstable amp the suppositories melt at 24 C

    Theobroma suppositories must be prepared below 33 C

    Polymorphism and Industry Pharmaceutical

    Polymorphism and Industry Pharmaceutical

    Anhydrates together with salts form the majority of all drug formulationsAbout a half of all APIs used today are saltsSalts are stable and well soluble in polar solvents (first of all in water) because they contain ionic bondThere is one more essential advantage of salts ndash their solubility is a function of pH Since pH in the gastrointestinal tract (GIT) vary between 1-75

    atorvastatin calcium trihydrateEach tablet contains Atorvastatin Calcium Trihydrate equivalent to Atorvastatin 20 mg

    Phase Equilibria amp The Phase Rule

    Phase diagram ndash Water

    Phase Equilibrium A stable phase structure with lowest free-energy (internal energy) of a system and also randomness or disorder of the atoms or molecules (entropy)

    Any change in Temperature Composition and Pressure causes an increase in free energy and away from Equilibrium thus forcing a move to another lsquostatersquo

    Phase Equilibria amp The Phase Rule Definitions

    A phase is defined as any homogeneous and physically distinct part of a system which is separated from other parts of the system by interfaces

    A part of a system is homogeneous if it has identical physical properties and chemical composition throughout the part

    A phase may be gas liquid or solid A gas or a gaseous mixture is a single phase Totally miscible liquids constitute a single phase In an immiscible liquid system each layer is counted as a separate phase Every solid constitutes a single phase except when a solid solution is formed A solid solution is considered as a single phase Each polymorphic form constitutes a separate phase

    Phase Definition

    1 Liquid water pieces of ice and water vapour are present together The number of phases is 3 as each form is a separate phase Ice in the system is a single phase even if it is present as a number of pieces

    2 Calcium carbonate undergoes thermal decomposition The chemical reaction is CaCO3(s) CaO(s) + CO2 (g) Number of phases = 3 This system consists of 2 solid phases CaCO3 and CaO and one gaseous phase that of CO2

    3 Ammonium chloride undergoes thermal decomposition The chemical reaction is NH4Cl(s) NH3 (g) + HCl (g) Number of phases = 2 This system has two phases one solid NH4Cl and one gaseous a mixture of NH3 and HCl

    4 A solution of NaCl in water Number of phases = 1

    bull Examples

    The number of components of a system at equilibrium is the smallest number of independently varying chemical constituents using which the composition of each and every phase in the system can be expressed

    Components

    Counting the number of components 1 The sulphur system is a one component system All the phases

    monoclinic rhombic liquid and vapour ndash can be expressed in terms of the single constituent ndash sulphur

    2 A mixture of ethanol and water is an example of a two component system We need both ethanol and water to express its composition

    bull Examples

    An example of a system in which a reaction occurs and an equilibrium is established is the thermal decomposition of solid CaCO3

    In this system there are three distinct phasesSolid CaCO3

    Solid CaOGaseous CO2

    Though there are 3 species present the number of components is only two because of the equilibrium CaCO3 (s) CaO(s) + CO2(g)

    Any two of the three constituents may be chosen as the components

    If CaO and CO2 are chosen then the composition of the phase CaCO3 is expressed as one mole of component CO2 plus one mole of component CaO

    If on the other hand CaCO3 and CO2 were chosen then the composition of the phase CaO would be described as one mole of CaCO3 minus one mole of CO2

    The degrees of freedom or variance of a system is defined as the minimum number of variables such as

    temperaturepressureconcentrationwhich must be fixed in order to define the system completely

    Degrees of freedom (or variance)

    F = C P + 2

    1 A gaseous mixture of CO2 and N2 Three variables pressure temperature and composition are required to define this system This is hence a trivariant system

    2 A system having only liquid water has two degrees of freedom or is bivariant Both temperature and pressure need to be mentioned in order to define the system

    3 If to the system containing liquid water pieces of ice are added and this system with 2 phases is allowed to come to equilibrium then it is an univariant system

    Only one variable either temperature or pressure need to be specified in order to define the systemIf the pressure on the system is maintained at 1 atm then the temperature of the system gets automatically fixed at 0oC the normal melting point of ice

    bull Examples

    Phase Equilibria amp The Phase Rule

    A phase diagram (Equilibrium Phase Diagram) summarizes the conditions at which a substance exists as a solid liquid or gas

    OR It is a ldquomaprdquo of the information about the control of phase structure of a particular material system

    The relationships between temperature and the compositions and the quantities of phases present at equilibrium are represented

    F = C P + 2The phase rule

    The phase rule JW Gibbs formulated the phase rule which is a general relation

    between the variance F the number of component C and the number of phases P at equilibrium for a system of any composition

    For a system in equilibrium

    F degree of freedom the least number of intensive variable that must be fixed (known) to describe the system completely

    Phase Rule relation to determine the least number of intensive variable that can be changed without changing the equilibrium state of the system or alternately

    The least number required to define the state of the system which is called degree of freedom F

    Intensive variable independent variable that do not depend on the volume or the size egTemp pressure

    Independent chemical species which comprise the system These could be Elements Ions Compounds

    Eg Au-Cu system Components rarr Au Cu Ice-water system Component rarr H2O

    Al2O3 ndash Cr2O3 system Components rarr Al2O3 Cr2O3

    Component the smallest number of constituent by which the composition of each phase in the system at equilibrium can be expressed in form of chemical formula or equation

    Phase Equilibria amp The Phase RuleComponents of a system

    The number of phases in a system is denoted P

    (a)A gas or a gaseous mixture is a single phase P=1

    (b) For a solid system an alloy of two metals is a two-phase system (P=2) if the metals are immiscible but a single-phase system (P=1) if they are miscible---a homogeneous mixture of the two substances---is uniform on a molecular scale

    (c) For a liquid system according to the solubility to decide whether a system consists of one phase or of two For example a solution of sodium chloride in water is a single phase A pair of liquids that are partially miscible or immiscible is a two-phase system(P=2)

    Oil in water

    Degrees of Freedom = What you can control What the system controls

    F = C + 2 P

    Can control the no of components added and P amp T

    System decided how many phases to produce given the

    conditions

    A way of understanding the Gibbs Phase RuleThe degrees of freedom can be thought of as the difference between what you (can) control and

    what the system controls

    F degree of freedom the least number of intensive variable that must be fixed (known) to describe the system completely

    Degree of freedom (or variance) F is the number of variables (T p andor composition) that can be changed independently without changing the phases of the system

    a) At the triple pointP = 3 (solid liquid and gas)

    C= 1 (water)P + F = C + 2

    F = 0 (no degree of freedom)

    b) liquid-solid curveP = 2

    2+F = 1 + 2F= 1

    One variable (T or P) can be changed

    c) LiquidP =1

    So F =2Two variables (T and P) can be varied independently

    and the system will remains a single phase

    One-component systemsPhase diagram of water

    P (

    atm

    )

    Critical point

    374

    1

    =100=0O--Triple point

    0006

    218

    Curve O -CSublimation

    Deposition

    Curve O-AVaporizationCondensation

    Curve O -BMelting

    Freezing

    F = C P + 2

    F = C P + 2

    Phase Diagram of Carbon Dioxide

    Condensed system System in which the vapor phase is ignored and only the solid andor liquid phases are considered

    Two component system For two component system F can be 3 (3D model is needed) eg T p

    and concentration usually we fix p = 1atm the vapor phase is neglected and F is reduced to 2

    For three component system the pressure and temperature are fixed

    Phenol water phase diagram

    eg for point d (24)

    Two component system containing liquid phase

    Tie Line bc line The line at which the system at equilibrium will separate into phases of constant composition termed lsquoconjugate phasesrsquo

    Lever Rule a way to calculate the proportions of each phase present on a phase diagram in a two phase field (at a given temperature and composition)

    eg for point d (24)

    For every 10 g of liquid system in equilibrium in point d

    75 g phase A25 g phase B

    ExampleMixed 24g phenol +76g water T 50degC

    equilibrium75 g phase A 25 g phase B

    11 phenol 63 phenol

    011 times75 g=825 g phenol

    063 times25 g=1575 g phenol

    water rich phasecontains water+ phenol(11)

    Phenol rich phasecontains Phenol (63)+ water

    The Critical Solution Temperature CST

    Is the maximum temperature at which the 2-phase region exists (or upper consolute temperature)

    In the case of the phenol-water system this is 668oC (point h)

    All combinations of phenol and water gt CST are completely miscible and yield 1-phase liquid systems

    Systems Showing a Decrease in Miscibility with Rise in Temperature

    A few mixtures exhibit a lower critical solution temperature (low CST) eg triethylamine plus water The miscibility with in temperature

    Systems Showing Upper and Lower CSTs

    The miscibility with temp

    a certain temperature miscibility starts to again with further in temperature

    Closed-phase diagram ie nicotine-water system

    A salol B thymol

    53

    Two component system containing solid and liquid phase (Eutectic Mixtures)

    A salol B thymol

    EMLAreg (lidocaine 25 and prilocaine 25) Cream

    EMLA Cream (lidocaine 25 and prilocaine 25) is an emulsion in which the oil phase is a eutectic mixture of lidocaine and prilocaine in a ratio of 11 by weight This eutectic mixture has a melting point below room temperature and therefore both local anesthetics exist as a liquid oil rather than as crystals

    Eutectic mixture Pharmaceutical Application

    Triangular Diagrams for three ndash component systems

    Three component system

    Birzeit University Physical Pharmacy PHAR 323 Dr Hani Shtaya

    1 Binding Forces Between Molecules2 Repulsive and Attractive Forces3 The Gaseous State The Ideal Gas Law Liquefaction of Gases Aerosols4 Solids and the Crystalline State Crystalline Solids Polymorphism Solvates Amorphous Solids5 Phase Equilibria and the Phase Rule Phase Rule Systems Containing One Component Condensed System Two-Component Systems Containing Liquid Phases Two-Component Systems Containing Solid and Liquid Phases Eutectic Mixtures Rules Relating to Triangular Diagrams

    Topics that we have covered

    • States of Matter
    • States of Matter (2)
    • Objectives of the lecture
    • Comparison of Gases Liquids and Solids
    • Slide 5
    • Repulsive and Attractive Forces
    • Ideal Gas Equation
    • Gaseous state
    • Slide 9
    • Gaseous state (2)
    • Liquefaction of Gases
    • Slide 12
    • SOLIDS amp CRYSTALLINE STATE Pharmaceutical Drugs more than 80
    • Solids and the crystalline state
    • Classification of Solids
    • Slide 16
    • Slide 17
    • Crystal forms
    • Types of Crystals
    • Slide 20
    • Slide 21
    • Polymorphism
    • Slide 23
    • Slide 24
    • Slide 25
    • Slide 26
    • Cocrystal
    • Principle of polymorphism
    • Solvates
    • Polymorphism (2)
    • Amorphous Solid
    • Amorphous or crystalline amp therapeutic activity
    • Slide 33
    • Slide 34
    • Polymorphism and Industry Pharmaceutical
    • Celecoxib
    • Furosemide
    • Bioavailability
    • Slide 39
    • Slide 40
    • Bioequivalence
    • Slide 42
    • Carbamazepine
    • Slide 44
    • AIDS drug ritonavir
    • Slide 46
    • Slide 47
    • Phase Equilibria amp The Phase Rule
    • Phase diagram ndash Water
    • Phase Equilibria amp The Phase Rule Definitions
    • Phase Definition
    • Examples
    • Components
    • Examples
    • Slide 55
    • Degrees of freedom (or variance)
    • Examples (2)
    • Phase Equilibria amp The Phase Rule
    • The phase rule
    • Slide 60
    • Phase Equilibria amp The Phase Rule (2)
    • The number of phases in a system is denoted P
    • Slide 63
    • Slide 64
    • One-component systems
    • Slide 66
    • Slide 67
    • Slide 68
    • Slide 69
    • Slide 70
    • Two component system containing liquid phase
    • Slide 72
    • The Critical Solution Temperature CST
    • Systems Showing a Decrease in Miscibility with Rise in Temperat
    • Systems Showing Upper and Lower CSTs
    • Two component system containing solid and liquid phase (Eutecti
    • Slide 77
    • Eutectic mixture Pharmaceutical Application
    • Three component system
    • Slide 80
    • Topics that we have covered

      Objectives of the lecture

      After completion of this chapter the students should be able toDescribe the solid state crystallinity solvates and polymorphismUnderstand phase equilibria and phase transitions between the three

      main states of matterUnderstand the phase rule and its application to different systems

      containing multiple components

      Gases are compressible fluids Their molecules are widely separated Liquids are relatively incompressible fluids Their molecules are more tightly packed Solids are nearly incompressible and rigid Their molecules or ions are in close contact

      and do not move

      Comparison of Gases Liquids and Solids

      In order for molecules to exist in aggregates in gases liquids and solids Intermolecular forces must exist

      As two atoms or molecules are brought closer together the opposite charges and binding forces in the two molecules are closer together than the similar charges and forces causing the molecules to attract one another

      The negatively charged electron clouds of molecules largely govern the balance (equilibrium) forces between the two molecules

      Repulsive and Attractive Forces

      Ideal Gas Equation

      Boylersquos law P a (at constant n and T)1V

      Charlesrsquo law V a T (at constant n and P)

      Avogadrorsquos law V a n (at constant P and T)

      P1V1

      T1

      =P2V2

      T2

      PV = nRTR is the gas constant

      The conditions 0 0C and 1 atm are called standard temperature and pressure (STP)

      Experiments show that at STP 1 mole of an ideal gas occupies 22414 L

      PV = nRT

      Gaseous state

      R = PVnT

      =(1 atm)(22414L)(1 mol)(27315 K)

      R = 0082057 L bull atm (mol bull K)

      9

      What is the volume (in liters) occupied by 498 g of HCl at STP

      PV = nRT

      V = nRTP

      T = 0 0C = 27315 K

      P = 1 atm

      n = 498 g x 1 mol HCl

      3645 g HCl= 137 mol

      V =1 atm

      137 mol x 00821 x 27315 KLbullatmmolbullK

      V = 307 L

      Gaseous state

      1 atm asymp 760001 mm-Hg

      P1V1

      T1

      =

      P2V2

      T2

      Gaseous state

      The critical temperature (Tc) is the temperature above which the gas cannot be made to liquefy OR is the temperature above which the liquid cannot longer exist

      The critical pressure (Pc) is the minimum pressure required to liquefy a gas at its critical temperature

      critical temperature (Tc) of water is 374degC or 647 K and its critical pressure is 218 atm

      Liquefaction of Gases

      SOLIDS amp CRYSTALLINE STATEPharmaceutical Drugs more than 80 are solid formulations

      A crystalline solid possesses rigid and long-range order

      In a crystalline solid atoms molecules or ions occupy specific (predictable) positions

      An amorphous solid does not possess a well-defined arrangement and long-range molecular order

      Solids and the crystalline state

      Classification of Solids

      Crystalline Amorphous

      Amorphous

      A unit cell is the basic repeating structural unit of a crystalline solid

      latticepoint

      Unit Cell Unit cells in 3 dimensions

      At lattice points

      bull Atoms

      bull Molecules

      bull Ions

      The crystal lattice of sodium chloride NaCl

      Na Cl

      The various crystal forms are divide to basic 7 unit according to its symmetry

      NaCl urea

      iodine

      sucrose Boric acid

      Crystal forms

      iodoform

      Be3Al2(SiO3)6

      CsCl ZnS CaF2

      Ionic Crystalsbull Lattice points occupied by cations and anionsbull Held together by electrostatic attractionbull Hard brittle high melting pointbull Poor conductor of heat and electricity

      Types of Crystals

      diamondgraphite

      carbonatoms

      Covalent Crystalsbull Lattice points occupied by atomsbull Held together by covalent bondsbull Hard high melting pointbull Poor conductor of heat and electricity

      Cross Section of a Metallic Crystal

      nucleus ampinner shell e-

      mobile ldquoseardquoof e-

      Metallic Crystalsbull Lattice points occupied by metal atomsbull Held together by metallic bondsbull Soft to hard low to high melting pointbull Good conductors of heat and electricity

      Some elemental substance such as C and S may exist in more than one crystalline form and are said to be allotropic which is a special case of polymorphism

      Polymorphism is the ability of a substance to exist in more than one crystal structure

      Polymorphism

      Polymorphism is the ability of a substance to exist in more than one crystal structure

      Polymorphs when two crystals have the same chemical composition but different internal structure (molecular packing ndashmolecular conformation or and inter or intra molecular interactions)modifications or polymorphs or forms

      Pseudo polymorphs different crystal forms have molecules of the same given substances and also contain molecules of solvent incorporated into a unique structure (solvates or hydrates (water))

      diamond graphite

      carbonatoms

      High T and p

      Diamond is metastable and converts very slowly to graphite

      The most common example of polymorphism

      Solid State Polymorphs

      Mono-component systems Polymorphs

      Multi-component systems

      Cocrystal

      The simplest definition of a cocrystal is a crystalline structure made up of two or more components in a definite stoichiometric ratio where each component is defined as either an atom ion or molecule

      Principle of polymorphism

      When the change from one form to another is reversible it is said to be enantiotropic

      When the transition takes place in one direction onlymdashfor example from a metastable to a stable formmdashthe change is said to be monotropic

      Solvates

      Pharmaceutical synthesis include purification and crystallization residual solvent can be trapped in the lattice

      This result in the formation of cocrystal or solvate

      The presence of residual solvent may affect dramatically the crystalline structure of the solid depending on the type of inter molecular forces that the solvent may have with crystalline solid

      Melting pointVapor pressureHardnessOptical electrical magnetic

      propertiesColorIR spectraNMR spectra

      Photochemical reactivityThermal stabilityFiltration and drying characteristicsDissolution rateBioavailabilityPhysical and chemical stability

      Solubility and melting point are very important in pharmaceutical processes including dissolution and

      formulation

      Polymorphism

      AMORPHOUS SOLIDS Solids that donrsquot have a definite geometrical shape are known as Amorphous Solids1 In these solids particles are randomly arranged in three dimension2 They donrsquot have sharp melting points3 Amorphous solids are formed due to sudden cooling of liquid4 Amorphous solids melt over a wide range of temperature

      Amorphous Solid

      An amorphous solid does not possess a well-defined arrangement and long-range molecular order

      Amorphous substances as well as cubic crystal are isotropic that is they exhibit similar properties in all direction

      The crystalline from of the antibiotic novobiocin acid is poorly absorbed and has no activity where the amorphous form is readily absorbed and therapeutically active due to different dissolution rate

      Amorphous or crystalline amp therapeutic activity

      General crystallization conditions 1048698Solvents ndashdifferent polarities 1048698Concentration of the solutions (super saturated saturated diluted) 1048698Cooling speed (quenching slow) 1048698Temperature (room or lower than room temperature)

      Crystallization

      Final Form

      Granulation

      Drying

      Compaction

      Tableting

      Drug Product

      API

      Crystallization

      Filtration

      Drying

      Milling

      Bulk API

      Stability

      Polymorphism and Industry Pharmaceutical

      Polymorphism and Industry Pharmaceutical

      Fluoxetine HCl the active ingredient in the antidepressant drug Prozac

      co crystal which will have increased solubility compared to the crystalline form

      Celecoxib

      CELECOXIB is a nonsteroidal anti-inflammatory drug

      However it was found that the higher bioavailability was shown by the amorphous state

      The downfall of the amorphous state was its stability

      This was due to the structural relaxation

      This was enhanced by mixing it with polymers like PVP which helped in stabilizing the amorphous system (Piyush Gupta et al 2004 Piyush Gupta et al 2005)

      A new solid state form was developed by Pharmacia

      FurosemideTwo forms with significantly differing aqueous solubility and dissolution rateOral bioavailability compromised

      Giron lists gt20 excipients that display polymorphism includingndash Lactose (anhydrous also monohydrate)ndash Aspartame (anhydrous hydrate forms)ndash Magnesium stearate (can affect lubrication of tablets)

      Bioavailability

      The rate and extent to which the active ingredient or active moiety is absorbed from a drug product and becomes available at the site of action

      Bioequivalence

      The absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study

      Carbamazepine

      CHLORPROPAMIDEat least six polymorphic white or almost white crystalline powder It exhibits polymorphism Practically insoluble in water soluble in alcohol freely soluble in acetone and in dichlo-romethane dissolves in dilute solutions of alkali hydroxides Protect from light

      blood-glucose-lowering drug

      AIDS drug ritonavir

      Theobroma oil (cacao butter ) is a polymorphic natural fat

      Theobroma oil can exist in 4 different polymorphic forms of which only one is Stabile

      1 Unstable gamma form melting at 18degC2 Alpha form melting at 22degC3 Beta prime form melting at 28degC4 Stable beta form melting at 345degC

      This is important in the preparation of theobroma suppositories

      If the oil is heated to a point where it is completely liquified (about 35 C) the crystals of the stable polymorph are destroyed amp the mass does not crystallize until it is cooled to 15 C

      The crystals that form are unstable amp the suppositories melt at 24 C

      Theobroma suppositories must be prepared below 33 C

      Polymorphism and Industry Pharmaceutical

      Polymorphism and Industry Pharmaceutical

      Anhydrates together with salts form the majority of all drug formulationsAbout a half of all APIs used today are saltsSalts are stable and well soluble in polar solvents (first of all in water) because they contain ionic bondThere is one more essential advantage of salts ndash their solubility is a function of pH Since pH in the gastrointestinal tract (GIT) vary between 1-75

      atorvastatin calcium trihydrateEach tablet contains Atorvastatin Calcium Trihydrate equivalent to Atorvastatin 20 mg

      Phase Equilibria amp The Phase Rule

      Phase diagram ndash Water

      Phase Equilibrium A stable phase structure with lowest free-energy (internal energy) of a system and also randomness or disorder of the atoms or molecules (entropy)

      Any change in Temperature Composition and Pressure causes an increase in free energy and away from Equilibrium thus forcing a move to another lsquostatersquo

      Phase Equilibria amp The Phase Rule Definitions

      A phase is defined as any homogeneous and physically distinct part of a system which is separated from other parts of the system by interfaces

      A part of a system is homogeneous if it has identical physical properties and chemical composition throughout the part

      A phase may be gas liquid or solid A gas or a gaseous mixture is a single phase Totally miscible liquids constitute a single phase In an immiscible liquid system each layer is counted as a separate phase Every solid constitutes a single phase except when a solid solution is formed A solid solution is considered as a single phase Each polymorphic form constitutes a separate phase

      Phase Definition

      1 Liquid water pieces of ice and water vapour are present together The number of phases is 3 as each form is a separate phase Ice in the system is a single phase even if it is present as a number of pieces

      2 Calcium carbonate undergoes thermal decomposition The chemical reaction is CaCO3(s) CaO(s) + CO2 (g) Number of phases = 3 This system consists of 2 solid phases CaCO3 and CaO and one gaseous phase that of CO2

      3 Ammonium chloride undergoes thermal decomposition The chemical reaction is NH4Cl(s) NH3 (g) + HCl (g) Number of phases = 2 This system has two phases one solid NH4Cl and one gaseous a mixture of NH3 and HCl

      4 A solution of NaCl in water Number of phases = 1

      bull Examples

      The number of components of a system at equilibrium is the smallest number of independently varying chemical constituents using which the composition of each and every phase in the system can be expressed

      Components

      Counting the number of components 1 The sulphur system is a one component system All the phases

      monoclinic rhombic liquid and vapour ndash can be expressed in terms of the single constituent ndash sulphur

      2 A mixture of ethanol and water is an example of a two component system We need both ethanol and water to express its composition

      bull Examples

      An example of a system in which a reaction occurs and an equilibrium is established is the thermal decomposition of solid CaCO3

      In this system there are three distinct phasesSolid CaCO3

      Solid CaOGaseous CO2

      Though there are 3 species present the number of components is only two because of the equilibrium CaCO3 (s) CaO(s) + CO2(g)

      Any two of the three constituents may be chosen as the components

      If CaO and CO2 are chosen then the composition of the phase CaCO3 is expressed as one mole of component CO2 plus one mole of component CaO

      If on the other hand CaCO3 and CO2 were chosen then the composition of the phase CaO would be described as one mole of CaCO3 minus one mole of CO2

      The degrees of freedom or variance of a system is defined as the minimum number of variables such as

      temperaturepressureconcentrationwhich must be fixed in order to define the system completely

      Degrees of freedom (or variance)

      F = C P + 2

      1 A gaseous mixture of CO2 and N2 Three variables pressure temperature and composition are required to define this system This is hence a trivariant system

      2 A system having only liquid water has two degrees of freedom or is bivariant Both temperature and pressure need to be mentioned in order to define the system

      3 If to the system containing liquid water pieces of ice are added and this system with 2 phases is allowed to come to equilibrium then it is an univariant system

      Only one variable either temperature or pressure need to be specified in order to define the systemIf the pressure on the system is maintained at 1 atm then the temperature of the system gets automatically fixed at 0oC the normal melting point of ice

      bull Examples

      Phase Equilibria amp The Phase Rule

      A phase diagram (Equilibrium Phase Diagram) summarizes the conditions at which a substance exists as a solid liquid or gas

      OR It is a ldquomaprdquo of the information about the control of phase structure of a particular material system

      The relationships between temperature and the compositions and the quantities of phases present at equilibrium are represented

      F = C P + 2The phase rule

      The phase rule JW Gibbs formulated the phase rule which is a general relation

      between the variance F the number of component C and the number of phases P at equilibrium for a system of any composition

      For a system in equilibrium

      F degree of freedom the least number of intensive variable that must be fixed (known) to describe the system completely

      Phase Rule relation to determine the least number of intensive variable that can be changed without changing the equilibrium state of the system or alternately

      The least number required to define the state of the system which is called degree of freedom F

      Intensive variable independent variable that do not depend on the volume or the size egTemp pressure

      Independent chemical species which comprise the system These could be Elements Ions Compounds

      Eg Au-Cu system Components rarr Au Cu Ice-water system Component rarr H2O

      Al2O3 ndash Cr2O3 system Components rarr Al2O3 Cr2O3

      Component the smallest number of constituent by which the composition of each phase in the system at equilibrium can be expressed in form of chemical formula or equation

      Phase Equilibria amp The Phase RuleComponents of a system

      The number of phases in a system is denoted P

      (a)A gas or a gaseous mixture is a single phase P=1

      (b) For a solid system an alloy of two metals is a two-phase system (P=2) if the metals are immiscible but a single-phase system (P=1) if they are miscible---a homogeneous mixture of the two substances---is uniform on a molecular scale

      (c) For a liquid system according to the solubility to decide whether a system consists of one phase or of two For example a solution of sodium chloride in water is a single phase A pair of liquids that are partially miscible or immiscible is a two-phase system(P=2)

      Oil in water

      Degrees of Freedom = What you can control What the system controls

      F = C + 2 P

      Can control the no of components added and P amp T

      System decided how many phases to produce given the

      conditions

      A way of understanding the Gibbs Phase RuleThe degrees of freedom can be thought of as the difference between what you (can) control and

      what the system controls

      F degree of freedom the least number of intensive variable that must be fixed (known) to describe the system completely

      Degree of freedom (or variance) F is the number of variables (T p andor composition) that can be changed independently without changing the phases of the system

      a) At the triple pointP = 3 (solid liquid and gas)

      C= 1 (water)P + F = C + 2

      F = 0 (no degree of freedom)

      b) liquid-solid curveP = 2

      2+F = 1 + 2F= 1

      One variable (T or P) can be changed

      c) LiquidP =1

      So F =2Two variables (T and P) can be varied independently

      and the system will remains a single phase

      One-component systemsPhase diagram of water

      P (

      atm

      )

      Critical point

      374

      1

      =100=0O--Triple point

      0006

      218

      Curve O -CSublimation

      Deposition

      Curve O-AVaporizationCondensation

      Curve O -BMelting

      Freezing

      F = C P + 2

      F = C P + 2

      Phase Diagram of Carbon Dioxide

      Condensed system System in which the vapor phase is ignored and only the solid andor liquid phases are considered

      Two component system For two component system F can be 3 (3D model is needed) eg T p

      and concentration usually we fix p = 1atm the vapor phase is neglected and F is reduced to 2

      For three component system the pressure and temperature are fixed

      Phenol water phase diagram

      eg for point d (24)

      Two component system containing liquid phase

      Tie Line bc line The line at which the system at equilibrium will separate into phases of constant composition termed lsquoconjugate phasesrsquo

      Lever Rule a way to calculate the proportions of each phase present on a phase diagram in a two phase field (at a given temperature and composition)

      eg for point d (24)

      For every 10 g of liquid system in equilibrium in point d

      75 g phase A25 g phase B

      ExampleMixed 24g phenol +76g water T 50degC

      equilibrium75 g phase A 25 g phase B

      11 phenol 63 phenol

      011 times75 g=825 g phenol

      063 times25 g=1575 g phenol

      water rich phasecontains water+ phenol(11)

      Phenol rich phasecontains Phenol (63)+ water

      The Critical Solution Temperature CST

      Is the maximum temperature at which the 2-phase region exists (or upper consolute temperature)

      In the case of the phenol-water system this is 668oC (point h)

      All combinations of phenol and water gt CST are completely miscible and yield 1-phase liquid systems

      Systems Showing a Decrease in Miscibility with Rise in Temperature

      A few mixtures exhibit a lower critical solution temperature (low CST) eg triethylamine plus water The miscibility with in temperature

      Systems Showing Upper and Lower CSTs

      The miscibility with temp

      a certain temperature miscibility starts to again with further in temperature

      Closed-phase diagram ie nicotine-water system

      A salol B thymol

      53

      Two component system containing solid and liquid phase (Eutectic Mixtures)

      A salol B thymol

      EMLAreg (lidocaine 25 and prilocaine 25) Cream

      EMLA Cream (lidocaine 25 and prilocaine 25) is an emulsion in which the oil phase is a eutectic mixture of lidocaine and prilocaine in a ratio of 11 by weight This eutectic mixture has a melting point below room temperature and therefore both local anesthetics exist as a liquid oil rather than as crystals

      Eutectic mixture Pharmaceutical Application

      Triangular Diagrams for three ndash component systems

      Three component system

      Birzeit University Physical Pharmacy PHAR 323 Dr Hani Shtaya

      1 Binding Forces Between Molecules2 Repulsive and Attractive Forces3 The Gaseous State The Ideal Gas Law Liquefaction of Gases Aerosols4 Solids and the Crystalline State Crystalline Solids Polymorphism Solvates Amorphous Solids5 Phase Equilibria and the Phase Rule Phase Rule Systems Containing One Component Condensed System Two-Component Systems Containing Liquid Phases Two-Component Systems Containing Solid and Liquid Phases Eutectic Mixtures Rules Relating to Triangular Diagrams

      Topics that we have covered

      • States of Matter
      • States of Matter (2)
      • Objectives of the lecture
      • Comparison of Gases Liquids and Solids
      • Slide 5
      • Repulsive and Attractive Forces
      • Ideal Gas Equation
      • Gaseous state
      • Slide 9
      • Gaseous state (2)
      • Liquefaction of Gases
      • Slide 12
      • SOLIDS amp CRYSTALLINE STATE Pharmaceutical Drugs more than 80
      • Solids and the crystalline state
      • Classification of Solids
      • Slide 16
      • Slide 17
      • Crystal forms
      • Types of Crystals
      • Slide 20
      • Slide 21
      • Polymorphism
      • Slide 23
      • Slide 24
      • Slide 25
      • Slide 26
      • Cocrystal
      • Principle of polymorphism
      • Solvates
      • Polymorphism (2)
      • Amorphous Solid
      • Amorphous or crystalline amp therapeutic activity
      • Slide 33
      • Slide 34
      • Polymorphism and Industry Pharmaceutical
      • Celecoxib
      • Furosemide
      • Bioavailability
      • Slide 39
      • Slide 40
      • Bioequivalence
      • Slide 42
      • Carbamazepine
      • Slide 44
      • AIDS drug ritonavir
      • Slide 46
      • Slide 47
      • Phase Equilibria amp The Phase Rule
      • Phase diagram ndash Water
      • Phase Equilibria amp The Phase Rule Definitions
      • Phase Definition
      • Examples
      • Components
      • Examples
      • Slide 55
      • Degrees of freedom (or variance)
      • Examples (2)
      • Phase Equilibria amp The Phase Rule
      • The phase rule
      • Slide 60
      • Phase Equilibria amp The Phase Rule (2)
      • The number of phases in a system is denoted P
      • Slide 63
      • Slide 64
      • One-component systems
      • Slide 66
      • Slide 67
      • Slide 68
      • Slide 69
      • Slide 70
      • Two component system containing liquid phase
      • Slide 72
      • The Critical Solution Temperature CST
      • Systems Showing a Decrease in Miscibility with Rise in Temperat
      • Systems Showing Upper and Lower CSTs
      • Two component system containing solid and liquid phase (Eutecti
      • Slide 77
      • Eutectic mixture Pharmaceutical Application
      • Three component system
      • Slide 80
      • Topics that we have covered

        Gases are compressible fluids Their molecules are widely separated Liquids are relatively incompressible fluids Their molecules are more tightly packed Solids are nearly incompressible and rigid Their molecules or ions are in close contact

        and do not move

        Comparison of Gases Liquids and Solids

        In order for molecules to exist in aggregates in gases liquids and solids Intermolecular forces must exist

        As two atoms or molecules are brought closer together the opposite charges and binding forces in the two molecules are closer together than the similar charges and forces causing the molecules to attract one another

        The negatively charged electron clouds of molecules largely govern the balance (equilibrium) forces between the two molecules

        Repulsive and Attractive Forces

        Ideal Gas Equation

        Boylersquos law P a (at constant n and T)1V

        Charlesrsquo law V a T (at constant n and P)

        Avogadrorsquos law V a n (at constant P and T)

        P1V1

        T1

        =P2V2

        T2

        PV = nRTR is the gas constant

        The conditions 0 0C and 1 atm are called standard temperature and pressure (STP)

        Experiments show that at STP 1 mole of an ideal gas occupies 22414 L

        PV = nRT

        Gaseous state

        R = PVnT

        =(1 atm)(22414L)(1 mol)(27315 K)

        R = 0082057 L bull atm (mol bull K)

        9

        What is the volume (in liters) occupied by 498 g of HCl at STP

        PV = nRT

        V = nRTP

        T = 0 0C = 27315 K

        P = 1 atm

        n = 498 g x 1 mol HCl

        3645 g HCl= 137 mol

        V =1 atm

        137 mol x 00821 x 27315 KLbullatmmolbullK

        V = 307 L

        Gaseous state

        1 atm asymp 760001 mm-Hg

        P1V1

        T1

        =

        P2V2

        T2

        Gaseous state

        The critical temperature (Tc) is the temperature above which the gas cannot be made to liquefy OR is the temperature above which the liquid cannot longer exist

        The critical pressure (Pc) is the minimum pressure required to liquefy a gas at its critical temperature

        critical temperature (Tc) of water is 374degC or 647 K and its critical pressure is 218 atm

        Liquefaction of Gases

        SOLIDS amp CRYSTALLINE STATEPharmaceutical Drugs more than 80 are solid formulations

        A crystalline solid possesses rigid and long-range order

        In a crystalline solid atoms molecules or ions occupy specific (predictable) positions

        An amorphous solid does not possess a well-defined arrangement and long-range molecular order

        Solids and the crystalline state

        Classification of Solids

        Crystalline Amorphous

        Amorphous

        A unit cell is the basic repeating structural unit of a crystalline solid

        latticepoint

        Unit Cell Unit cells in 3 dimensions

        At lattice points

        bull Atoms

        bull Molecules

        bull Ions

        The crystal lattice of sodium chloride NaCl

        Na Cl

        The various crystal forms are divide to basic 7 unit according to its symmetry

        NaCl urea

        iodine

        sucrose Boric acid

        Crystal forms

        iodoform

        Be3Al2(SiO3)6

        CsCl ZnS CaF2

        Ionic Crystalsbull Lattice points occupied by cations and anionsbull Held together by electrostatic attractionbull Hard brittle high melting pointbull Poor conductor of heat and electricity

        Types of Crystals

        diamondgraphite

        carbonatoms

        Covalent Crystalsbull Lattice points occupied by atomsbull Held together by covalent bondsbull Hard high melting pointbull Poor conductor of heat and electricity

        Cross Section of a Metallic Crystal

        nucleus ampinner shell e-

        mobile ldquoseardquoof e-

        Metallic Crystalsbull Lattice points occupied by metal atomsbull Held together by metallic bondsbull Soft to hard low to high melting pointbull Good conductors of heat and electricity

        Some elemental substance such as C and S may exist in more than one crystalline form and are said to be allotropic which is a special case of polymorphism

        Polymorphism is the ability of a substance to exist in more than one crystal structure

        Polymorphism

        Polymorphism is the ability of a substance to exist in more than one crystal structure

        Polymorphs when two crystals have the same chemical composition but different internal structure (molecular packing ndashmolecular conformation or and inter or intra molecular interactions)modifications or polymorphs or forms

        Pseudo polymorphs different crystal forms have molecules of the same given substances and also contain molecules of solvent incorporated into a unique structure (solvates or hydrates (water))

        diamond graphite

        carbonatoms

        High T and p

        Diamond is metastable and converts very slowly to graphite

        The most common example of polymorphism

        Solid State Polymorphs

        Mono-component systems Polymorphs

        Multi-component systems

        Cocrystal

        The simplest definition of a cocrystal is a crystalline structure made up of two or more components in a definite stoichiometric ratio where each component is defined as either an atom ion or molecule

        Principle of polymorphism

        When the change from one form to another is reversible it is said to be enantiotropic

        When the transition takes place in one direction onlymdashfor example from a metastable to a stable formmdashthe change is said to be monotropic

        Solvates

        Pharmaceutical synthesis include purification and crystallization residual solvent can be trapped in the lattice

        This result in the formation of cocrystal or solvate

        The presence of residual solvent may affect dramatically the crystalline structure of the solid depending on the type of inter molecular forces that the solvent may have with crystalline solid

        Melting pointVapor pressureHardnessOptical electrical magnetic

        propertiesColorIR spectraNMR spectra

        Photochemical reactivityThermal stabilityFiltration and drying characteristicsDissolution rateBioavailabilityPhysical and chemical stability

        Solubility and melting point are very important in pharmaceutical processes including dissolution and

        formulation

        Polymorphism

        AMORPHOUS SOLIDS Solids that donrsquot have a definite geometrical shape are known as Amorphous Solids1 In these solids particles are randomly arranged in three dimension2 They donrsquot have sharp melting points3 Amorphous solids are formed due to sudden cooling of liquid4 Amorphous solids melt over a wide range of temperature

        Amorphous Solid

        An amorphous solid does not possess a well-defined arrangement and long-range molecular order

        Amorphous substances as well as cubic crystal are isotropic that is they exhibit similar properties in all direction

        The crystalline from of the antibiotic novobiocin acid is poorly absorbed and has no activity where the amorphous form is readily absorbed and therapeutically active due to different dissolution rate

        Amorphous or crystalline amp therapeutic activity

        General crystallization conditions 1048698Solvents ndashdifferent polarities 1048698Concentration of the solutions (super saturated saturated diluted) 1048698Cooling speed (quenching slow) 1048698Temperature (room or lower than room temperature)

        Crystallization

        Final Form

        Granulation

        Drying

        Compaction

        Tableting

        Drug Product

        API

        Crystallization

        Filtration

        Drying

        Milling

        Bulk API

        Stability

        Polymorphism and Industry Pharmaceutical

        Polymorphism and Industry Pharmaceutical

        Fluoxetine HCl the active ingredient in the antidepressant drug Prozac

        co crystal which will have increased solubility compared to the crystalline form

        Celecoxib

        CELECOXIB is a nonsteroidal anti-inflammatory drug

        However it was found that the higher bioavailability was shown by the amorphous state

        The downfall of the amorphous state was its stability

        This was due to the structural relaxation

        This was enhanced by mixing it with polymers like PVP which helped in stabilizing the amorphous system (Piyush Gupta et al 2004 Piyush Gupta et al 2005)

        A new solid state form was developed by Pharmacia

        FurosemideTwo forms with significantly differing aqueous solubility and dissolution rateOral bioavailability compromised

        Giron lists gt20 excipients that display polymorphism includingndash Lactose (anhydrous also monohydrate)ndash Aspartame (anhydrous hydrate forms)ndash Magnesium stearate (can affect lubrication of tablets)

        Bioavailability

        The rate and extent to which the active ingredient or active moiety is absorbed from a drug product and becomes available at the site of action

        Bioequivalence

        The absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study

        Carbamazepine

        CHLORPROPAMIDEat least six polymorphic white or almost white crystalline powder It exhibits polymorphism Practically insoluble in water soluble in alcohol freely soluble in acetone and in dichlo-romethane dissolves in dilute solutions of alkali hydroxides Protect from light

        blood-glucose-lowering drug

        AIDS drug ritonavir

        Theobroma oil (cacao butter ) is a polymorphic natural fat

        Theobroma oil can exist in 4 different polymorphic forms of which only one is Stabile

        1 Unstable gamma form melting at 18degC2 Alpha form melting at 22degC3 Beta prime form melting at 28degC4 Stable beta form melting at 345degC

        This is important in the preparation of theobroma suppositories

        If the oil is heated to a point where it is completely liquified (about 35 C) the crystals of the stable polymorph are destroyed amp the mass does not crystallize until it is cooled to 15 C

        The crystals that form are unstable amp the suppositories melt at 24 C

        Theobroma suppositories must be prepared below 33 C

        Polymorphism and Industry Pharmaceutical

        Polymorphism and Industry Pharmaceutical

        Anhydrates together with salts form the majority of all drug formulationsAbout a half of all APIs used today are saltsSalts are stable and well soluble in polar solvents (first of all in water) because they contain ionic bondThere is one more essential advantage of salts ndash their solubility is a function of pH Since pH in the gastrointestinal tract (GIT) vary between 1-75

        atorvastatin calcium trihydrateEach tablet contains Atorvastatin Calcium Trihydrate equivalent to Atorvastatin 20 mg

        Phase Equilibria amp The Phase Rule

        Phase diagram ndash Water

        Phase Equilibrium A stable phase structure with lowest free-energy (internal energy) of a system and also randomness or disorder of the atoms or molecules (entropy)

        Any change in Temperature Composition and Pressure causes an increase in free energy and away from Equilibrium thus forcing a move to another lsquostatersquo

        Phase Equilibria amp The Phase Rule Definitions

        A phase is defined as any homogeneous and physically distinct part of a system which is separated from other parts of the system by interfaces

        A part of a system is homogeneous if it has identical physical properties and chemical composition throughout the part

        A phase may be gas liquid or solid A gas or a gaseous mixture is a single phase Totally miscible liquids constitute a single phase In an immiscible liquid system each layer is counted as a separate phase Every solid constitutes a single phase except when a solid solution is formed A solid solution is considered as a single phase Each polymorphic form constitutes a separate phase

        Phase Definition

        1 Liquid water pieces of ice and water vapour are present together The number of phases is 3 as each form is a separate phase Ice in the system is a single phase even if it is present as a number of pieces

        2 Calcium carbonate undergoes thermal decomposition The chemical reaction is CaCO3(s) CaO(s) + CO2 (g) Number of phases = 3 This system consists of 2 solid phases CaCO3 and CaO and one gaseous phase that of CO2

        3 Ammonium chloride undergoes thermal decomposition The chemical reaction is NH4Cl(s) NH3 (g) + HCl (g) Number of phases = 2 This system has two phases one solid NH4Cl and one gaseous a mixture of NH3 and HCl

        4 A solution of NaCl in water Number of phases = 1

        bull Examples

        The number of components of a system at equilibrium is the smallest number of independently varying chemical constituents using which the composition of each and every phase in the system can be expressed

        Components

        Counting the number of components 1 The sulphur system is a one component system All the phases

        monoclinic rhombic liquid and vapour ndash can be expressed in terms of the single constituent ndash sulphur

        2 A mixture of ethanol and water is an example of a two component system We need both ethanol and water to express its composition

        bull Examples

        An example of a system in which a reaction occurs and an equilibrium is established is the thermal decomposition of solid CaCO3

        In this system there are three distinct phasesSolid CaCO3

        Solid CaOGaseous CO2

        Though there are 3 species present the number of components is only two because of the equilibrium CaCO3 (s) CaO(s) + CO2(g)

        Any two of the three constituents may be chosen as the components

        If CaO and CO2 are chosen then the composition of the phase CaCO3 is expressed as one mole of component CO2 plus one mole of component CaO

        If on the other hand CaCO3 and CO2 were chosen then the composition of the phase CaO would be described as one mole of CaCO3 minus one mole of CO2

        The degrees of freedom or variance of a system is defined as the minimum number of variables such as

        temperaturepressureconcentrationwhich must be fixed in order to define the system completely

        Degrees of freedom (or variance)

        F = C P + 2

        1 A gaseous mixture of CO2 and N2 Three variables pressure temperature and composition are required to define this system This is hence a trivariant system

        2 A system having only liquid water has two degrees of freedom or is bivariant Both temperature and pressure need to be mentioned in order to define the system

        3 If to the system containing liquid water pieces of ice are added and this system with 2 phases is allowed to come to equilibrium then it is an univariant system

        Only one variable either temperature or pressure need to be specified in order to define the systemIf the pressure on the system is maintained at 1 atm then the temperature of the system gets automatically fixed at 0oC the normal melting point of ice

        bull Examples

        Phase Equilibria amp The Phase Rule

        A phase diagram (Equilibrium Phase Diagram) summarizes the conditions at which a substance exists as a solid liquid or gas

        OR It is a ldquomaprdquo of the information about the control of phase structure of a particular material system

        The relationships between temperature and the compositions and the quantities of phases present at equilibrium are represented

        F = C P + 2The phase rule

        The phase rule JW Gibbs formulated the phase rule which is a general relation

        between the variance F the number of component C and the number of phases P at equilibrium for a system of any composition

        For a system in equilibrium

        F degree of freedom the least number of intensive variable that must be fixed (known) to describe the system completely

        Phase Rule relation to determine the least number of intensive variable that can be changed without changing the equilibrium state of the system or alternately

        The least number required to define the state of the system which is called degree of freedom F

        Intensive variable independent variable that do not depend on the volume or the size egTemp pressure

        Independent chemical species which comprise the system These could be Elements Ions Compounds

        Eg Au-Cu system Components rarr Au Cu Ice-water system Component rarr H2O

        Al2O3 ndash Cr2O3 system Components rarr Al2O3 Cr2O3

        Component the smallest number of constituent by which the composition of each phase in the system at equilibrium can be expressed in form of chemical formula or equation

        Phase Equilibria amp The Phase RuleComponents of a system

        The number of phases in a system is denoted P

        (a)A gas or a gaseous mixture is a single phase P=1

        (b) For a solid system an alloy of two metals is a two-phase system (P=2) if the metals are immiscible but a single-phase system (P=1) if they are miscible---a homogeneous mixture of the two substances---is uniform on a molecular scale

        (c) For a liquid system according to the solubility to decide whether a system consists of one phase or of two For example a solution of sodium chloride in water is a single phase A pair of liquids that are partially miscible or immiscible is a two-phase system(P=2)

        Oil in water

        Degrees of Freedom = What you can control What the system controls

        F = C + 2 P

        Can control the no of components added and P amp T

        System decided how many phases to produce given the

        conditions

        A way of understanding the Gibbs Phase RuleThe degrees of freedom can be thought of as the difference between what you (can) control and

        what the system controls

        F degree of freedom the least number of intensive variable that must be fixed (known) to describe the system completely

        Degree of freedom (or variance) F is the number of variables (T p andor composition) that can be changed independently without changing the phases of the system

        a) At the triple pointP = 3 (solid liquid and gas)

        C= 1 (water)P + F = C + 2

        F = 0 (no degree of freedom)

        b) liquid-solid curveP = 2

        2+F = 1 + 2F= 1

        One variable (T or P) can be changed

        c) LiquidP =1

        So F =2Two variables (T and P) can be varied independently

        and the system will remains a single phase

        One-component systemsPhase diagram of water

        P (

        atm

        )

        Critical point

        374

        1

        =100=0O--Triple point

        0006

        218

        Curve O -CSublimation

        Deposition

        Curve O-AVaporizationCondensation

        Curve O -BMelting

        Freezing

        F = C P + 2

        F = C P + 2

        Phase Diagram of Carbon Dioxide

        Condensed system System in which the vapor phase is ignored and only the solid andor liquid phases are considered

        Two component system For two component system F can be 3 (3D model is needed) eg T p

        and concentration usually we fix p = 1atm the vapor phase is neglected and F is reduced to 2

        For three component system the pressure and temperature are fixed

        Phenol water phase diagram

        eg for point d (24)

        Two component system containing liquid phase

        Tie Line bc line The line at which the system at equilibrium will separate into phases of constant composition termed lsquoconjugate phasesrsquo

        Lever Rule a way to calculate the proportions of each phase present on a phase diagram in a two phase field (at a given temperature and composition)

        eg for point d (24)

        For every 10 g of liquid system in equilibrium in point d

        75 g phase A25 g phase B

        ExampleMixed 24g phenol +76g water T 50degC

        equilibrium75 g phase A 25 g phase B

        11 phenol 63 phenol

        011 times75 g=825 g phenol

        063 times25 g=1575 g phenol

        water rich phasecontains water+ phenol(11)

        Phenol rich phasecontains Phenol (63)+ water

        The Critical Solution Temperature CST

        Is the maximum temperature at which the 2-phase region exists (or upper consolute temperature)

        In the case of the phenol-water system this is 668oC (point h)

        All combinations of phenol and water gt CST are completely miscible and yield 1-phase liquid systems

        Systems Showing a Decrease in Miscibility with Rise in Temperature

        A few mixtures exhibit a lower critical solution temperature (low CST) eg triethylamine plus water The miscibility with in temperature

        Systems Showing Upper and Lower CSTs

        The miscibility with temp

        a certain temperature miscibility starts to again with further in temperature

        Closed-phase diagram ie nicotine-water system

        A salol B thymol

        53

        Two component system containing solid and liquid phase (Eutectic Mixtures)

        A salol B thymol

        EMLAreg (lidocaine 25 and prilocaine 25) Cream

        EMLA Cream (lidocaine 25 and prilocaine 25) is an emulsion in which the oil phase is a eutectic mixture of lidocaine and prilocaine in a ratio of 11 by weight This eutectic mixture has a melting point below room temperature and therefore both local anesthetics exist as a liquid oil rather than as crystals

        Eutectic mixture Pharmaceutical Application

        Triangular Diagrams for three ndash component systems

        Three component system

        Birzeit University Physical Pharmacy PHAR 323 Dr Hani Shtaya

        1 Binding Forces Between Molecules2 Repulsive and Attractive Forces3 The Gaseous State The Ideal Gas Law Liquefaction of Gases Aerosols4 Solids and the Crystalline State Crystalline Solids Polymorphism Solvates Amorphous Solids5 Phase Equilibria and the Phase Rule Phase Rule Systems Containing One Component Condensed System Two-Component Systems Containing Liquid Phases Two-Component Systems Containing Solid and Liquid Phases Eutectic Mixtures Rules Relating to Triangular Diagrams

        Topics that we have covered

        • States of Matter
        • States of Matter (2)
        • Objectives of the lecture
        • Comparison of Gases Liquids and Solids
        • Slide 5
        • Repulsive and Attractive Forces
        • Ideal Gas Equation
        • Gaseous state
        • Slide 9
        • Gaseous state (2)
        • Liquefaction of Gases
        • Slide 12
        • SOLIDS amp CRYSTALLINE STATE Pharmaceutical Drugs more than 80
        • Solids and the crystalline state
        • Classification of Solids
        • Slide 16
        • Slide 17
        • Crystal forms
        • Types of Crystals
        • Slide 20
        • Slide 21
        • Polymorphism
        • Slide 23
        • Slide 24
        • Slide 25
        • Slide 26
        • Cocrystal
        • Principle of polymorphism
        • Solvates
        • Polymorphism (2)
        • Amorphous Solid
        • Amorphous or crystalline amp therapeutic activity
        • Slide 33
        • Slide 34
        • Polymorphism and Industry Pharmaceutical
        • Celecoxib
        • Furosemide
        • Bioavailability
        • Slide 39
        • Slide 40
        • Bioequivalence
        • Slide 42
        • Carbamazepine
        • Slide 44
        • AIDS drug ritonavir
        • Slide 46
        • Slide 47
        • Phase Equilibria amp The Phase Rule
        • Phase diagram ndash Water
        • Phase Equilibria amp The Phase Rule Definitions
        • Phase Definition
        • Examples
        • Components
        • Examples
        • Slide 55
        • Degrees of freedom (or variance)
        • Examples (2)
        • Phase Equilibria amp The Phase Rule
        • The phase rule
        • Slide 60
        • Phase Equilibria amp The Phase Rule (2)
        • The number of phases in a system is denoted P
        • Slide 63
        • Slide 64
        • One-component systems
        • Slide 66
        • Slide 67
        • Slide 68
        • Slide 69
        • Slide 70
        • Two component system containing liquid phase
        • Slide 72
        • The Critical Solution Temperature CST
        • Systems Showing a Decrease in Miscibility with Rise in Temperat
        • Systems Showing Upper and Lower CSTs
        • Two component system containing solid and liquid phase (Eutecti
        • Slide 77
        • Eutectic mixture Pharmaceutical Application
        • Three component system
        • Slide 80
        • Topics that we have covered

          As two atoms or molecules are brought closer together the opposite charges and binding forces in the two molecules are closer together than the similar charges and forces causing the molecules to attract one another

          The negatively charged electron clouds of molecules largely govern the balance (equilibrium) forces between the two molecules

          Repulsive and Attractive Forces

          Ideal Gas Equation

          Boylersquos law P a (at constant n and T)1V

          Charlesrsquo law V a T (at constant n and P)

          Avogadrorsquos law V a n (at constant P and T)

          P1V1

          T1

          =P2V2

          T2

          PV = nRTR is the gas constant

          The conditions 0 0C and 1 atm are called standard temperature and pressure (STP)

          Experiments show that at STP 1 mole of an ideal gas occupies 22414 L

          PV = nRT

          Gaseous state

          R = PVnT

          =(1 atm)(22414L)(1 mol)(27315 K)

          R = 0082057 L bull atm (mol bull K)

          9

          What is the volume (in liters) occupied by 498 g of HCl at STP

          PV = nRT

          V = nRTP

          T = 0 0C = 27315 K

          P = 1 atm

          n = 498 g x 1 mol HCl

          3645 g HCl= 137 mol

          V =1 atm

          137 mol x 00821 x 27315 KLbullatmmolbullK

          V = 307 L

          Gaseous state

          1 atm asymp 760001 mm-Hg

          P1V1

          T1

          =

          P2V2

          T2

          Gaseous state

          The critical temperature (Tc) is the temperature above which the gas cannot be made to liquefy OR is the temperature above which the liquid cannot longer exist

          The critical pressure (Pc) is the minimum pressure required to liquefy a gas at its critical temperature

          critical temperature (Tc) of water is 374degC or 647 K and its critical pressure is 218 atm

          Liquefaction of Gases

          SOLIDS amp CRYSTALLINE STATEPharmaceutical Drugs more than 80 are solid formulations

          A crystalline solid possesses rigid and long-range order

          In a crystalline solid atoms molecules or ions occupy specific (predictable) positions

          An amorphous solid does not possess a well-defined arrangement and long-range molecular order

          Solids and the crystalline state

          Classification of Solids

          Crystalline Amorphous

          Amorphous

          A unit cell is the basic repeating structural unit of a crystalline solid

          latticepoint

          Unit Cell Unit cells in 3 dimensions

          At lattice points

          bull Atoms

          bull Molecules

          bull Ions

          The crystal lattice of sodium chloride NaCl

          Na Cl

          The various crystal forms are divide to basic 7 unit according to its symmetry

          NaCl urea

          iodine

          sucrose Boric acid

          Crystal forms

          iodoform

          Be3Al2(SiO3)6

          CsCl ZnS CaF2

          Ionic Crystalsbull Lattice points occupied by cations and anionsbull Held together by electrostatic attractionbull Hard brittle high melting pointbull Poor conductor of heat and electricity

          Types of Crystals

          diamondgraphite

          carbonatoms

          Covalent Crystalsbull Lattice points occupied by atomsbull Held together by covalent bondsbull Hard high melting pointbull Poor conductor of heat and electricity

          Cross Section of a Metallic Crystal

          nucleus ampinner shell e-

          mobile ldquoseardquoof e-

          Metallic Crystalsbull Lattice points occupied by metal atomsbull Held together by metallic bondsbull Soft to hard low to high melting pointbull Good conductors of heat and electricity

          Some elemental substance such as C and S may exist in more than one crystalline form and are said to be allotropic which is a special case of polymorphism

          Polymorphism is the ability of a substance to exist in more than one crystal structure

          Polymorphism

          Polymorphism is the ability of a substance to exist in more than one crystal structure

          Polymorphs when two crystals have the same chemical composition but different internal structure (molecular packing ndashmolecular conformation or and inter or intra molecular interactions)modifications or polymorphs or forms

          Pseudo polymorphs different crystal forms have molecules of the same given substances and also contain molecules of solvent incorporated into a unique structure (solvates or hydrates (water))

          diamond graphite

          carbonatoms

          High T and p

          Diamond is metastable and converts very slowly to graphite

          The most common example of polymorphism

          Solid State Polymorphs

          Mono-component systems Polymorphs

          Multi-component systems

          Cocrystal

          The simplest definition of a cocrystal is a crystalline structure made up of two or more components in a definite stoichiometric ratio where each component is defined as either an atom ion or molecule

          Principle of polymorphism

          When the change from one form to another is reversible it is said to be enantiotropic

          When the transition takes place in one direction onlymdashfor example from a metastable to a stable formmdashthe change is said to be monotropic

          Solvates

          Pharmaceutical synthesis include purification and crystallization residual solvent can be trapped in the lattice

          This result in the formation of cocrystal or solvate

          The presence of residual solvent may affect dramatically the crystalline structure of the solid depending on the type of inter molecular forces that the solvent may have with crystalline solid

          Melting pointVapor pressureHardnessOptical electrical magnetic

          propertiesColorIR spectraNMR spectra

          Photochemical reactivityThermal stabilityFiltration and drying characteristicsDissolution rateBioavailabilityPhysical and chemical stability

          Solubility and melting point are very important in pharmaceutical processes including dissolution and

          formulation

          Polymorphism

          AMORPHOUS SOLIDS Solids that donrsquot have a definite geometrical shape are known as Amorphous Solids1 In these solids particles are randomly arranged in three dimension2 They donrsquot have sharp melting points3 Amorphous solids are formed due to sudden cooling of liquid4 Amorphous solids melt over a wide range of temperature

          Amorphous Solid

          An amorphous solid does not possess a well-defined arrangement and long-range molecular order

          Amorphous substances as well as cubic crystal are isotropic that is they exhibit similar properties in all direction

          The crystalline from of the antibiotic novobiocin acid is poorly absorbed and has no activity where the amorphous form is readily absorbed and therapeutically active due to different dissolution rate

          Amorphous or crystalline amp therapeutic activity

          General crystallization conditions 1048698Solvents ndashdifferent polarities 1048698Concentration of the solutions (super saturated saturated diluted) 1048698Cooling speed (quenching slow) 1048698Temperature (room or lower than room temperature)

          Crystallization

          Final Form

          Granulation

          Drying

          Compaction

          Tableting

          Drug Product

          API

          Crystallization

          Filtration

          Drying

          Milling

          Bulk API

          Stability

          Polymorphism and Industry Pharmaceutical

          Polymorphism and Industry Pharmaceutical

          Fluoxetine HCl the active ingredient in the antidepressant drug Prozac

          co crystal which will have increased solubility compared to the crystalline form

          Celecoxib

          CELECOXIB is a nonsteroidal anti-inflammatory drug

          However it was found that the higher bioavailability was shown by the amorphous state

          The downfall of the amorphous state was its stability

          This was due to the structural relaxation

          This was enhanced by mixing it with polymers like PVP which helped in stabilizing the amorphous system (Piyush Gupta et al 2004 Piyush Gupta et al 2005)

          A new solid state form was developed by Pharmacia

          FurosemideTwo forms with significantly differing aqueous solubility and dissolution rateOral bioavailability compromised

          Giron lists gt20 excipients that display polymorphism includingndash Lactose (anhydrous also monohydrate)ndash Aspartame (anhydrous hydrate forms)ndash Magnesium stearate (can affect lubrication of tablets)

          Bioavailability

          The rate and extent to which the active ingredient or active moiety is absorbed from a drug product and becomes available at the site of action

          Bioequivalence

          The absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study

          Carbamazepine

          CHLORPROPAMIDEat least six polymorphic white or almost white crystalline powder It exhibits polymorphism Practically insoluble in water soluble in alcohol freely soluble in acetone and in dichlo-romethane dissolves in dilute solutions of alkali hydroxides Protect from light

          blood-glucose-lowering drug

          AIDS drug ritonavir

          Theobroma oil (cacao butter ) is a polymorphic natural fat

          Theobroma oil can exist in 4 different polymorphic forms of which only one is Stabile

          1 Unstable gamma form melting at 18degC2 Alpha form melting at 22degC3 Beta prime form melting at 28degC4 Stable beta form melting at 345degC

          This is important in the preparation of theobroma suppositories

          If the oil is heated to a point where it is completely liquified (about 35 C) the crystals of the stable polymorph are destroyed amp the mass does not crystallize until it is cooled to 15 C

          The crystals that form are unstable amp the suppositories melt at 24 C

          Theobroma suppositories must be prepared below 33 C

          Polymorphism and Industry Pharmaceutical

          Polymorphism and Industry Pharmaceutical

          Anhydrates together with salts form the majority of all drug formulationsAbout a half of all APIs used today are saltsSalts are stable and well soluble in polar solvents (first of all in water) because they contain ionic bondThere is one more essential advantage of salts ndash their solubility is a function of pH Since pH in the gastrointestinal tract (GIT) vary between 1-75

          atorvastatin calcium trihydrateEach tablet contains Atorvastatin Calcium Trihydrate equivalent to Atorvastatin 20 mg

          Phase Equilibria amp The Phase Rule

          Phase diagram ndash Water

          Phase Equilibrium A stable phase structure with lowest free-energy (internal energy) of a system and also randomness or disorder of the atoms or molecules (entropy)

          Any change in Temperature Composition and Pressure causes an increase in free energy and away from Equilibrium thus forcing a move to another lsquostatersquo

          Phase Equilibria amp The Phase Rule Definitions

          A phase is defined as any homogeneous and physically distinct part of a system which is separated from other parts of the system by interfaces

          A part of a system is homogeneous if it has identical physical properties and chemical composition throughout the part

          A phase may be gas liquid or solid A gas or a gaseous mixture is a single phase Totally miscible liquids constitute a single phase In an immiscible liquid system each layer is counted as a separate phase Every solid constitutes a single phase except when a solid solution is formed A solid solution is considered as a single phase Each polymorphic form constitutes a separate phase

          Phase Definition

          1 Liquid water pieces of ice and water vapour are present together The number of phases is 3 as each form is a separate phase Ice in the system is a single phase even if it is present as a number of pieces

          2 Calcium carbonate undergoes thermal decomposition The chemical reaction is CaCO3(s) CaO(s) + CO2 (g) Number of phases = 3 This system consists of 2 solid phases CaCO3 and CaO and one gaseous phase that of CO2

          3 Ammonium chloride undergoes thermal decomposition The chemical reaction is NH4Cl(s) NH3 (g) + HCl (g) Number of phases = 2 This system has two phases one solid NH4Cl and one gaseous a mixture of NH3 and HCl

          4 A solution of NaCl in water Number of phases = 1

          bull Examples

          The number of components of a system at equilibrium is the smallest number of independently varying chemical constituents using which the composition of each and every phase in the system can be expressed

          Components

          Counting the number of components 1 The sulphur system is a one component system All the phases

          monoclinic rhombic liquid and vapour ndash can be expressed in terms of the single constituent ndash sulphur

          2 A mixture of ethanol and water is an example of a two component system We need both ethanol and water to express its composition

          bull Examples

          An example of a system in which a reaction occurs and an equilibrium is established is the thermal decomposition of solid CaCO3

          In this system there are three distinct phasesSolid CaCO3

          Solid CaOGaseous CO2

          Though there are 3 species present the number of components is only two because of the equilibrium CaCO3 (s) CaO(s) + CO2(g)

          Any two of the three constituents may be chosen as the components

          If CaO and CO2 are chosen then the composition of the phase CaCO3 is expressed as one mole of component CO2 plus one mole of component CaO

          If on the other hand CaCO3 and CO2 were chosen then the composition of the phase CaO would be described as one mole of CaCO3 minus one mole of CO2

          The degrees of freedom or variance of a system is defined as the minimum number of variables such as

          temperaturepressureconcentrationwhich must be fixed in order to define the system completely

          Degrees of freedom (or variance)

          F = C P + 2

          1 A gaseous mixture of CO2 and N2 Three variables pressure temperature and composition are required to define this system This is hence a trivariant system

          2 A system having only liquid water has two degrees of freedom or is bivariant Both temperature and pressure need to be mentioned in order to define the system

          3 If to the system containing liquid water pieces of ice are added and this system with 2 phases is allowed to come to equilibrium then it is an univariant system

          Only one variable either temperature or pressure need to be specified in order to define the systemIf the pressure on the system is maintained at 1 atm then the temperature of the system gets automatically fixed at 0oC the normal melting point of ice

          bull Examples

          Phase Equilibria amp The Phase Rule

          A phase diagram (Equilibrium Phase Diagram) summarizes the conditions at which a substance exists as a solid liquid or gas

          OR It is a ldquomaprdquo of the information about the control of phase structure of a particular material system

          The relationships between temperature and the compositions and the quantities of phases present at equilibrium are represented

          F = C P + 2The phase rule

          The phase rule JW Gibbs formulated the phase rule which is a general relation

          between the variance F the number of component C and the number of phases P at equilibrium for a system of any composition

          For a system in equilibrium

          F degree of freedom the least number of intensive variable that must be fixed (known) to describe the system completely

          Phase Rule relation to determine the least number of intensive variable that can be changed without changing the equilibrium state of the system or alternately

          The least number required to define the state of the system which is called degree of freedom F

          Intensive variable independent variable that do not depend on the volume or the size egTemp pressure

          Independent chemical species which comprise the system These could be Elements Ions Compounds

          Eg Au-Cu system Components rarr Au Cu Ice-water system Component rarr H2O

          Al2O3 ndash Cr2O3 system Components rarr Al2O3 Cr2O3

          Component the smallest number of constituent by which the composition of each phase in the system at equilibrium can be expressed in form of chemical formula or equation

          Phase Equilibria amp The Phase RuleComponents of a system

          The number of phases in a system is denoted P

          (a)A gas or a gaseous mixture is a single phase P=1

          (b) For a solid system an alloy of two metals is a two-phase system (P=2) if the metals are immiscible but a single-phase system (P=1) if they are miscible---a homogeneous mixture of the two substances---is uniform on a molecular scale

          (c) For a liquid system according to the solubility to decide whether a system consists of one phase or of two For example a solution of sodium chloride in water is a single phase A pair of liquids that are partially miscible or immiscible is a two-phase system(P=2)

          Oil in water

          Degrees of Freedom = What you can control What the system controls

          F = C + 2 P

          Can control the no of components added and P amp T

          System decided how many phases to produce given the

          conditions

          A way of understanding the Gibbs Phase RuleThe degrees of freedom can be thought of as the difference between what you (can) control and

          what the system controls

          F degree of freedom the least number of intensive variable that must be fixed (known) to describe the system completely

          Degree of freedom (or variance) F is the number of variables (T p andor composition) that can be changed independently without changing the phases of the system

          a) At the triple pointP = 3 (solid liquid and gas)

          C= 1 (water)P + F = C + 2

          F = 0 (no degree of freedom)

          b) liquid-solid curveP = 2

          2+F = 1 + 2F= 1

          One variable (T or P) can be changed

          c) LiquidP =1

          So F =2Two variables (T and P) can be varied independently

          and the system will remains a single phase

          One-component systemsPhase diagram of water

          P (

          atm

          )

          Critical point

          374

          1

          =100=0O--Triple point

          0006

          218

          Curve O -CSublimation

          Deposition

          Curve O-AVaporizationCondensation

          Curve O -BMelting

          Freezing

          F = C P + 2

          F = C P + 2

          Phase Diagram of Carbon Dioxide

          Condensed system System in which the vapor phase is ignored and only the solid andor liquid phases are considered

          Two component system For two component system F can be 3 (3D model is needed) eg T p

          and concentration usually we fix p = 1atm the vapor phase is neglected and F is reduced to 2

          For three component system the pressure and temperature are fixed

          Phenol water phase diagram

          eg for point d (24)

          Two component system containing liquid phase

          Tie Line bc line The line at which the system at equilibrium will separate into phases of constant composition termed lsquoconjugate phasesrsquo

          Lever Rule a way to calculate the proportions of each phase present on a phase diagram in a two phase field (at a given temperature and composition)

          eg for point d (24)

          For every 10 g of liquid system in equilibrium in point d

          75 g phase A25 g phase B

          ExampleMixed 24g phenol +76g water T 50degC

          equilibrium75 g phase A 25 g phase B

          11 phenol 63 phenol

          011 times75 g=825 g phenol

          063 times25 g=1575 g phenol

          water rich phasecontains water+ phenol(11)

          Phenol rich phasecontains Phenol (63)+ water

          The Critical Solution Temperature CST

          Is the maximum temperature at which the 2-phase region exists (or upper consolute temperature)

          In the case of the phenol-water system this is 668oC (point h)

          All combinations of phenol and water gt CST are completely miscible and yield 1-phase liquid systems

          Systems Showing a Decrease in Miscibility with Rise in Temperature

          A few mixtures exhibit a lower critical solution temperature (low CST) eg triethylamine plus water The miscibility with in temperature

          Systems Showing Upper and Lower CSTs

          The miscibility with temp

          a certain temperature miscibility starts to again with further in temperature

          Closed-phase diagram ie nicotine-water system

          A salol B thymol

          53

          Two component system containing solid and liquid phase (Eutectic Mixtures)

          A salol B thymol

          EMLAreg (lidocaine 25 and prilocaine 25) Cream

          EMLA Cream (lidocaine 25 and prilocaine 25) is an emulsion in which the oil phase is a eutectic mixture of lidocaine and prilocaine in a ratio of 11 by weight This eutectic mixture has a melting point below room temperature and therefore both local anesthetics exist as a liquid oil rather than as crystals

          Eutectic mixture Pharmaceutical Application

          Triangular Diagrams for three ndash component systems

          Three component system

          Birzeit University Physical Pharmacy PHAR 323 Dr Hani Shtaya

          1 Binding Forces Between Molecules2 Repulsive and Attractive Forces3 The Gaseous State The Ideal Gas Law Liquefaction of Gases Aerosols4 Solids and the Crystalline State Crystalline Solids Polymorphism Solvates Amorphous Solids5 Phase Equilibria and the Phase Rule Phase Rule Systems Containing One Component Condensed System Two-Component Systems Containing Liquid Phases Two-Component Systems Containing Solid and Liquid Phases Eutectic Mixtures Rules Relating to Triangular Diagrams

          Topics that we have covered

          • States of Matter
          • States of Matter (2)
          • Objectives of the lecture
          • Comparison of Gases Liquids and Solids
          • Slide 5
          • Repulsive and Attractive Forces
          • Ideal Gas Equation
          • Gaseous state
          • Slide 9
          • Gaseous state (2)
          • Liquefaction of Gases
          • Slide 12
          • SOLIDS amp CRYSTALLINE STATE Pharmaceutical Drugs more than 80
          • Solids and the crystalline state
          • Classification of Solids
          • Slide 16
          • Slide 17
          • Crystal forms
          • Types of Crystals
          • Slide 20
          • Slide 21
          • Polymorphism
          • Slide 23
          • Slide 24
          • Slide 25
          • Slide 26
          • Cocrystal
          • Principle of polymorphism
          • Solvates
          • Polymorphism (2)
          • Amorphous Solid
          • Amorphous or crystalline amp therapeutic activity
          • Slide 33
          • Slide 34
          • Polymorphism and Industry Pharmaceutical
          • Celecoxib
          • Furosemide
          • Bioavailability
          • Slide 39
          • Slide 40
          • Bioequivalence
          • Slide 42
          • Carbamazepine
          • Slide 44
          • AIDS drug ritonavir
          • Slide 46
          • Slide 47
          • Phase Equilibria amp The Phase Rule
          • Phase diagram ndash Water
          • Phase Equilibria amp The Phase Rule Definitions
          • Phase Definition
          • Examples
          • Components
          • Examples
          • Slide 55
          • Degrees of freedom (or variance)
          • Examples (2)
          • Phase Equilibria amp The Phase Rule
          • The phase rule
          • Slide 60
          • Phase Equilibria amp The Phase Rule (2)
          • The number of phases in a system is denoted P
          • Slide 63
          • Slide 64
          • One-component systems
          • Slide 66
          • Slide 67
          • Slide 68
          • Slide 69
          • Slide 70
          • Two component system containing liquid phase
          • Slide 72
          • The Critical Solution Temperature CST
          • Systems Showing a Decrease in Miscibility with Rise in Temperat
          • Systems Showing Upper and Lower CSTs
          • Two component system containing solid and liquid phase (Eutecti
          • Slide 77
          • Eutectic mixture Pharmaceutical Application
          • Three component system
          • Slide 80
          • Topics that we have covered

            Ideal Gas Equation

            Boylersquos law P a (at constant n and T)1V

            Charlesrsquo law V a T (at constant n and P)

            Avogadrorsquos law V a n (at constant P and T)

            P1V1

            T1

            =P2V2

            T2

            PV = nRTR is the gas constant

            The conditions 0 0C and 1 atm are called standard temperature and pressure (STP)

            Experiments show that at STP 1 mole of an ideal gas occupies 22414 L

            PV = nRT

            Gaseous state

            R = PVnT

            =(1 atm)(22414L)(1 mol)(27315 K)

            R = 0082057 L bull atm (mol bull K)

            9

            What is the volume (in liters) occupied by 498 g of HCl at STP

            PV = nRT

            V = nRTP

            T = 0 0C = 27315 K

            P = 1 atm

            n = 498 g x 1 mol HCl

            3645 g HCl= 137 mol

            V =1 atm

            137 mol x 00821 x 27315 KLbullatmmolbullK

            V = 307 L

            Gaseous state

            1 atm asymp 760001 mm-Hg

            P1V1

            T1

            =

            P2V2

            T2

            Gaseous state

            The critical temperature (Tc) is the temperature above which the gas cannot be made to liquefy OR is the temperature above which the liquid cannot longer exist

            The critical pressure (Pc) is the minimum pressure required to liquefy a gas at its critical temperature

            critical temperature (Tc) of water is 374degC or 647 K and its critical pressure is 218 atm

            Liquefaction of Gases

            SOLIDS amp CRYSTALLINE STATEPharmaceutical Drugs more than 80 are solid formulations

            A crystalline solid possesses rigid and long-range order

            In a crystalline solid atoms molecules or ions occupy specific (predictable) positions

            An amorphous solid does not possess a well-defined arrangement and long-range molecular order

            Solids and the crystalline state

            Classification of Solids

            Crystalline Amorphous

            Amorphous

            A unit cell is the basic repeating structural unit of a crystalline solid

            latticepoint

            Unit Cell Unit cells in 3 dimensions

            At lattice points

            bull Atoms

            bull Molecules

            bull Ions

            The crystal lattice of sodium chloride NaCl

            Na Cl

            The various crystal forms are divide to basic 7 unit according to its symmetry

            NaCl urea

            iodine

            sucrose Boric acid

            Crystal forms

            iodoform

            Be3Al2(SiO3)6

            CsCl ZnS CaF2

            Ionic Crystalsbull Lattice points occupied by cations and anionsbull Held together by electrostatic attractionbull Hard brittle high melting pointbull Poor conductor of heat and electricity

            Types of Crystals

            diamondgraphite

            carbonatoms

            Covalent Crystalsbull Lattice points occupied by atomsbull Held together by covalent bondsbull Hard high melting pointbull Poor conductor of heat and electricity

            Cross Section of a Metallic Crystal

            nucleus ampinner shell e-

            mobile ldquoseardquoof e-

            Metallic Crystalsbull Lattice points occupied by metal atomsbull Held together by metallic bondsbull Soft to hard low to high melting pointbull Good conductors of heat and electricity

            Some elemental substance such as C and S may exist in more than one crystalline form and are said to be allotropic which is a special case of polymorphism

            Polymorphism is the ability of a substance to exist in more than one crystal structure

            Polymorphism

            Polymorphism is the ability of a substance to exist in more than one crystal structure

            Polymorphs when two crystals have the same chemical composition but different internal structure (molecular packing ndashmolecular conformation or and inter or intra molecular interactions)modifications or polymorphs or forms

            Pseudo polymorphs different crystal forms have molecules of the same given substances and also contain molecules of solvent incorporated into a unique structure (solvates or hydrates (water))

            diamond graphite

            carbonatoms

            High T and p

            Diamond is metastable and converts very slowly to graphite

            The most common example of polymorphism

            Solid State Polymorphs

            Mono-component systems Polymorphs

            Multi-component systems

            Cocrystal

            The simplest definition of a cocrystal is a crystalline structure made up of two or more components in a definite stoichiometric ratio where each component is defined as either an atom ion or molecule

            Principle of polymorphism

            When the change from one form to another is reversible it is said to be enantiotropic

            When the transition takes place in one direction onlymdashfor example from a metastable to a stable formmdashthe change is said to be monotropic

            Solvates

            Pharmaceutical synthesis include purification and crystallization residual solvent can be trapped in the lattice

            This result in the formation of cocrystal or solvate

            The presence of residual solvent may affect dramatically the crystalline structure of the solid depending on the type of inter molecular forces that the solvent may have with crystalline solid

            Melting pointVapor pressureHardnessOptical electrical magnetic

            propertiesColorIR spectraNMR spectra

            Photochemical reactivityThermal stabilityFiltration and drying characteristicsDissolution rateBioavailabilityPhysical and chemical stability

            Solubility and melting point are very important in pharmaceutical processes including dissolution and

            formulation

            Polymorphism

            AMORPHOUS SOLIDS Solids that donrsquot have a definite geometrical shape are known as Amorphous Solids1 In these solids particles are randomly arranged in three dimension2 They donrsquot have sharp melting points3 Amorphous solids are formed due to sudden cooling of liquid4 Amorphous solids melt over a wide range of temperature

            Amorphous Solid

            An amorphous solid does not possess a well-defined arrangement and long-range molecular order

            Amorphous substances as well as cubic crystal are isotropic that is they exhibit similar properties in all direction

            The crystalline from of the antibiotic novobiocin acid is poorly absorbed and has no activity where the amorphous form is readily absorbed and therapeutically active due to different dissolution rate

            Amorphous or crystalline amp therapeutic activity

            General crystallization conditions 1048698Solvents ndashdifferent polarities 1048698Concentration of the solutions (super saturated saturated diluted) 1048698Cooling speed (quenching slow) 1048698Temperature (room or lower than room temperature)

            Crystallization

            Final Form

            Granulation

            Drying

            Compaction

            Tableting

            Drug Product

            API

            Crystallization

            Filtration

            Drying

            Milling

            Bulk API

            Stability

            Polymorphism and Industry Pharmaceutical

            Polymorphism and Industry Pharmaceutical

            Fluoxetine HCl the active ingredient in the antidepressant drug Prozac

            co crystal which will have increased solubility compared to the crystalline form

            Celecoxib

            CELECOXIB is a nonsteroidal anti-inflammatory drug

            However it was found that the higher bioavailability was shown by the amorphous state

            The downfall of the amorphous state was its stability

            This was due to the structural relaxation

            This was enhanced by mixing it with polymers like PVP which helped in stabilizing the amorphous system (Piyush Gupta et al 2004 Piyush Gupta et al 2005)

            A new solid state form was developed by Pharmacia

            FurosemideTwo forms with significantly differing aqueous solubility and dissolution rateOral bioavailability compromised

            Giron lists gt20 excipients that display polymorphism includingndash Lactose (anhydrous also monohydrate)ndash Aspartame (anhydrous hydrate forms)ndash Magnesium stearate (can affect lubrication of tablets)

            Bioavailability

            The rate and extent to which the active ingredient or active moiety is absorbed from a drug product and becomes available at the site of action

            Bioequivalence

            The absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study

            Carbamazepine

            CHLORPROPAMIDEat least six polymorphic white or almost white crystalline powder It exhibits polymorphism Practically insoluble in water soluble in alcohol freely soluble in acetone and in dichlo-romethane dissolves in dilute solutions of alkali hydroxides Protect from light

            blood-glucose-lowering drug

            AIDS drug ritonavir

            Theobroma oil (cacao butter ) is a polymorphic natural fat

            Theobroma oil can exist in 4 different polymorphic forms of which only one is Stabile

            1 Unstable gamma form melting at 18degC2 Alpha form melting at 22degC3 Beta prime form melting at 28degC4 Stable beta form melting at 345degC

            This is important in the preparation of theobroma suppositories

            If the oil is heated to a point where it is completely liquified (about 35 C) the crystals of the stable polymorph are destroyed amp the mass does not crystallize until it is cooled to 15 C

            The crystals that form are unstable amp the suppositories melt at 24 C

            Theobroma suppositories must be prepared below 33 C

            Polymorphism and Industry Pharmaceutical

            Polymorphism and Industry Pharmaceutical

            Anhydrates together with salts form the majority of all drug formulationsAbout a half of all APIs used today are saltsSalts are stable and well soluble in polar solvents (first of all in water) because they contain ionic bondThere is one more essential advantage of salts ndash their solubility is a function of pH Since pH in the gastrointestinal tract (GIT) vary between 1-75

            atorvastatin calcium trihydrateEach tablet contains Atorvastatin Calcium Trihydrate equivalent to Atorvastatin 20 mg

            Phase Equilibria amp The Phase Rule

            Phase diagram ndash Water

            Phase Equilibrium A stable phase structure with lowest free-energy (internal energy) of a system and also randomness or disorder of the atoms or molecules (entropy)

            Any change in Temperature Composition and Pressure causes an increase in free energy and away from Equilibrium thus forcing a move to another lsquostatersquo

            Phase Equilibria amp The Phase Rule Definitions

            A phase is defined as any homogeneous and physically distinct part of a system which is separated from other parts of the system by interfaces

            A part of a system is homogeneous if it has identical physical properties and chemical composition throughout the part

            A phase may be gas liquid or solid A gas or a gaseous mixture is a single phase Totally miscible liquids constitute a single phase In an immiscible liquid system each layer is counted as a separate phase Every solid constitutes a single phase except when a solid solution is formed A solid solution is considered as a single phase Each polymorphic form constitutes a separate phase

            Phase Definition

            1 Liquid water pieces of ice and water vapour are present together The number of phases is 3 as each form is a separate phase Ice in the system is a single phase even if it is present as a number of pieces

            2 Calcium carbonate undergoes thermal decomposition The chemical reaction is CaCO3(s) CaO(s) + CO2 (g) Number of phases = 3 This system consists of 2 solid phases CaCO3 and CaO and one gaseous phase that of CO2

            3 Ammonium chloride undergoes thermal decomposition The chemical reaction is NH4Cl(s) NH3 (g) + HCl (g) Number of phases = 2 This system has two phases one solid NH4Cl and one gaseous a mixture of NH3 and HCl

            4 A solution of NaCl in water Number of phases = 1

            bull Examples

            The number of components of a system at equilibrium is the smallest number of independently varying chemical constituents using which the composition of each and every phase in the system can be expressed

            Components

            Counting the number of components 1 The sulphur system is a one component system All the phases

            monoclinic rhombic liquid and vapour ndash can be expressed in terms of the single constituent ndash sulphur

            2 A mixture of ethanol and water is an example of a two component system We need both ethanol and water to express its composition

            bull Examples

            An example of a system in which a reaction occurs and an equilibrium is established is the thermal decomposition of solid CaCO3

            In this system there are three distinct phasesSolid CaCO3

            Solid CaOGaseous CO2

            Though there are 3 species present the number of components is only two because of the equilibrium CaCO3 (s) CaO(s) + CO2(g)

            Any two of the three constituents may be chosen as the components

            If CaO and CO2 are chosen then the composition of the phase CaCO3 is expressed as one mole of component CO2 plus one mole of component CaO

            If on the other hand CaCO3 and CO2 were chosen then the composition of the phase CaO would be described as one mole of CaCO3 minus one mole of CO2

            The degrees of freedom or variance of a system is defined as the minimum number of variables such as

            temperaturepressureconcentrationwhich must be fixed in order to define the system completely

            Degrees of freedom (or variance)

            F = C P + 2

            1 A gaseous mixture of CO2 and N2 Three variables pressure temperature and composition are required to define this system This is hence a trivariant system

            2 A system having only liquid water has two degrees of freedom or is bivariant Both temperature and pressure need to be mentioned in order to define the system

            3 If to the system containing liquid water pieces of ice are added and this system with 2 phases is allowed to come to equilibrium then it is an univariant system

            Only one variable either temperature or pressure need to be specified in order to define the systemIf the pressure on the system is maintained at 1 atm then the temperature of the system gets automatically fixed at 0oC the normal melting point of ice

            bull Examples

            Phase Equilibria amp The Phase Rule

            A phase diagram (Equilibrium Phase Diagram) summarizes the conditions at which a substance exists as a solid liquid or gas

            OR It is a ldquomaprdquo of the information about the control of phase structure of a particular material system

            The relationships between temperature and the compositions and the quantities of phases present at equilibrium are represented

            F = C P + 2The phase rule

            The phase rule JW Gibbs formulated the phase rule which is a general relation

            between the variance F the number of component C and the number of phases P at equilibrium for a system of any composition

            For a system in equilibrium

            F degree of freedom the least number of intensive variable that must be fixed (known) to describe the system completely

            Phase Rule relation to determine the least number of intensive variable that can be changed without changing the equilibrium state of the system or alternately

            The least number required to define the state of the system which is called degree of freedom F

            Intensive variable independent variable that do not depend on the volume or the size egTemp pressure

            Independent chemical species which comprise the system These could be Elements Ions Compounds

            Eg Au-Cu system Components rarr Au Cu Ice-water system Component rarr H2O

            Al2O3 ndash Cr2O3 system Components rarr Al2O3 Cr2O3

            Component the smallest number of constituent by which the composition of each phase in the system at equilibrium can be expressed in form of chemical formula or equation

            Phase Equilibria amp The Phase RuleComponents of a system

            The number of phases in a system is denoted P

            (a)A gas or a gaseous mixture is a single phase P=1

            (b) For a solid system an alloy of two metals is a two-phase system (P=2) if the metals are immiscible but a single-phase system (P=1) if they are miscible---a homogeneous mixture of the two substances---is uniform on a molecular scale

            (c) For a liquid system according to the solubility to decide whether a system consists of one phase or of two For example a solution of sodium chloride in water is a single phase A pair of liquids that are partially miscible or immiscible is a two-phase system(P=2)

            Oil in water

            Degrees of Freedom = What you can control What the system controls

            F = C + 2 P

            Can control the no of components added and P amp T

            System decided how many phases to produce given the

            conditions

            A way of understanding the Gibbs Phase RuleThe degrees of freedom can be thought of as the difference between what you (can) control and

            what the system controls

            F degree of freedom the least number of intensive variable that must be fixed (known) to describe the system completely

            Degree of freedom (or variance) F is the number of variables (T p andor composition) that can be changed independently without changing the phases of the system

            a) At the triple pointP = 3 (solid liquid and gas)

            C= 1 (water)P + F = C + 2

            F = 0 (no degree of freedom)

            b) liquid-solid curveP = 2

            2+F = 1 + 2F= 1

            One variable (T or P) can be changed

            c) LiquidP =1

            So F =2Two variables (T and P) can be varied independently

            and the system will remains a single phase

            One-component systemsPhase diagram of water

            P (

            atm

            )

            Critical point

            374

            1

            =100=0O--Triple point

            0006

            218

            Curve O -CSublimation

            Deposition

            Curve O-AVaporizationCondensation

            Curve O -BMelting

            Freezing

            F = C P + 2

            F = C P + 2

            Phase Diagram of Carbon Dioxide

            Condensed system System in which the vapor phase is ignored and only the solid andor liquid phases are considered

            Two component system For two component system F can be 3 (3D model is needed) eg T p

            and concentration usually we fix p = 1atm the vapor phase is neglected and F is reduced to 2

            For three component system the pressure and temperature are fixed

            Phenol water phase diagram

            eg for point d (24)

            Two component system containing liquid phase

            Tie Line bc line The line at which the system at equilibrium will separate into phases of constant composition termed lsquoconjugate phasesrsquo

            Lever Rule a way to calculate the proportions of each phase present on a phase diagram in a two phase field (at a given temperature and composition)

            eg for point d (24)

            For every 10 g of liquid system in equilibrium in point d

            75 g phase A25 g phase B

            ExampleMixed 24g phenol +76g water T 50degC

            equilibrium75 g phase A 25 g phase B

            11 phenol 63 phenol

            011 times75 g=825 g phenol

            063 times25 g=1575 g phenol

            water rich phasecontains water+ phenol(11)

            Phenol rich phasecontains Phenol (63)+ water

            The Critical Solution Temperature CST

            Is the maximum temperature at which the 2-phase region exists (or upper consolute temperature)

            In the case of the phenol-water system this is 668oC (point h)

            All combinations of phenol and water gt CST are completely miscible and yield 1-phase liquid systems

            Systems Showing a Decrease in Miscibility with Rise in Temperature

            A few mixtures exhibit a lower critical solution temperature (low CST) eg triethylamine plus water The miscibility with in temperature

            Systems Showing Upper and Lower CSTs

            The miscibility with temp

            a certain temperature miscibility starts to again with further in temperature

            Closed-phase diagram ie nicotine-water system

            A salol B thymol

            53

            Two component system containing solid and liquid phase (Eutectic Mixtures)

            A salol B thymol

            EMLAreg (lidocaine 25 and prilocaine 25) Cream

            EMLA Cream (lidocaine 25 and prilocaine 25) is an emulsion in which the oil phase is a eutectic mixture of lidocaine and prilocaine in a ratio of 11 by weight This eutectic mixture has a melting point below room temperature and therefore both local anesthetics exist as a liquid oil rather than as crystals

            Eutectic mixture Pharmaceutical Application

            Triangular Diagrams for three ndash component systems

            Three component system

            Birzeit University Physical Pharmacy PHAR 323 Dr Hani Shtaya

            1 Binding Forces Between Molecules2 Repulsive and Attractive Forces3 The Gaseous State The Ideal Gas Law Liquefaction of Gases Aerosols4 Solids and the Crystalline State Crystalline Solids Polymorphism Solvates Amorphous Solids5 Phase Equilibria and the Phase Rule Phase Rule Systems Containing One Component Condensed System Two-Component Systems Containing Liquid Phases Two-Component Systems Containing Solid and Liquid Phases Eutectic Mixtures Rules Relating to Triangular Diagrams

            Topics that we have covered

            • States of Matter
            • States of Matter (2)
            • Objectives of the lecture
            • Comparison of Gases Liquids and Solids
            • Slide 5
            • Repulsive and Attractive Forces
            • Ideal Gas Equation
            • Gaseous state
            • Slide 9
            • Gaseous state (2)
            • Liquefaction of Gases
            • Slide 12
            • SOLIDS amp CRYSTALLINE STATE Pharmaceutical Drugs more than 80
            • Solids and the crystalline state
            • Classification of Solids
            • Slide 16
            • Slide 17
            • Crystal forms
            • Types of Crystals
            • Slide 20
            • Slide 21
            • Polymorphism
            • Slide 23
            • Slide 24
            • Slide 25
            • Slide 26
            • Cocrystal
            • Principle of polymorphism
            • Solvates
            • Polymorphism (2)
            • Amorphous Solid
            • Amorphous or crystalline amp therapeutic activity
            • Slide 33
            • Slide 34
            • Polymorphism and Industry Pharmaceutical
            • Celecoxib
            • Furosemide
            • Bioavailability
            • Slide 39
            • Slide 40
            • Bioequivalence
            • Slide 42
            • Carbamazepine
            • Slide 44
            • AIDS drug ritonavir
            • Slide 46
            • Slide 47
            • Phase Equilibria amp The Phase Rule
            • Phase diagram ndash Water
            • Phase Equilibria amp The Phase Rule Definitions
            • Phase Definition
            • Examples
            • Components
            • Examples
            • Slide 55
            • Degrees of freedom (or variance)
            • Examples (2)
            • Phase Equilibria amp The Phase Rule
            • The phase rule
            • Slide 60
            • Phase Equilibria amp The Phase Rule (2)
            • The number of phases in a system is denoted P
            • Slide 63
            • Slide 64
            • One-component systems
            • Slide 66
            • Slide 67
            • Slide 68
            • Slide 69
            • Slide 70
            • Two component system containing liquid phase
            • Slide 72
            • The Critical Solution Temperature CST
            • Systems Showing a Decrease in Miscibility with Rise in Temperat
            • Systems Showing Upper and Lower CSTs
            • Two component system containing solid and liquid phase (Eutecti
            • Slide 77
            • Eutectic mixture Pharmaceutical Application
            • Three component system
            • Slide 80
            • Topics that we have covered

              The conditions 0 0C and 1 atm are called standard temperature and pressure (STP)

              Experiments show that at STP 1 mole of an ideal gas occupies 22414 L

              PV = nRT

              Gaseous state

              R = PVnT

              =(1 atm)(22414L)(1 mol)(27315 K)

              R = 0082057 L bull atm (mol bull K)

              9

              What is the volume (in liters) occupied by 498 g of HCl at STP

              PV = nRT

              V = nRTP

              T = 0 0C = 27315 K

              P = 1 atm

              n = 498 g x 1 mol HCl

              3645 g HCl= 137 mol

              V =1 atm

              137 mol x 00821 x 27315 KLbullatmmolbullK

              V = 307 L

              Gaseous state

              1 atm asymp 760001 mm-Hg

              P1V1

              T1

              =

              P2V2

              T2

              Gaseous state

              The critical temperature (Tc) is the temperature above which the gas cannot be made to liquefy OR is the temperature above which the liquid cannot longer exist

              The critical pressure (Pc) is the minimum pressure required to liquefy a gas at its critical temperature

              critical temperature (Tc) of water is 374degC or 647 K and its critical pressure is 218 atm

              Liquefaction of Gases

              SOLIDS amp CRYSTALLINE STATEPharmaceutical Drugs more than 80 are solid formulations

              A crystalline solid possesses rigid and long-range order

              In a crystalline solid atoms molecules or ions occupy specific (predictable) positions

              An amorphous solid does not possess a well-defined arrangement and long-range molecular order

              Solids and the crystalline state

              Classification of Solids

              Crystalline Amorphous

              Amorphous

              A unit cell is the basic repeating structural unit of a crystalline solid

              latticepoint

              Unit Cell Unit cells in 3 dimensions

              At lattice points

              bull Atoms

              bull Molecules

              bull Ions

              The crystal lattice of sodium chloride NaCl

              Na Cl

              The various crystal forms are divide to basic 7 unit according to its symmetry

              NaCl urea

              iodine

              sucrose Boric acid

              Crystal forms

              iodoform

              Be3Al2(SiO3)6

              CsCl ZnS CaF2

              Ionic Crystalsbull Lattice points occupied by cations and anionsbull Held together by electrostatic attractionbull Hard brittle high melting pointbull Poor conductor of heat and electricity

              Types of Crystals

              diamondgraphite

              carbonatoms

              Covalent Crystalsbull Lattice points occupied by atomsbull Held together by covalent bondsbull Hard high melting pointbull Poor conductor of heat and electricity

              Cross Section of a Metallic Crystal

              nucleus ampinner shell e-

              mobile ldquoseardquoof e-

              Metallic Crystalsbull Lattice points occupied by metal atomsbull Held together by metallic bondsbull Soft to hard low to high melting pointbull Good conductors of heat and electricity

              Some elemental substance such as C and S may exist in more than one crystalline form and are said to be allotropic which is a special case of polymorphism

              Polymorphism is the ability of a substance to exist in more than one crystal structure

              Polymorphism

              Polymorphism is the ability of a substance to exist in more than one crystal structure

              Polymorphs when two crystals have the same chemical composition but different internal structure (molecular packing ndashmolecular conformation or and inter or intra molecular interactions)modifications or polymorphs or forms

              Pseudo polymorphs different crystal forms have molecules of the same given substances and also contain molecules of solvent incorporated into a unique structure (solvates or hydrates (water))

              diamond graphite

              carbonatoms

              High T and p

              Diamond is metastable and converts very slowly to graphite

              The most common example of polymorphism

              Solid State Polymorphs

              Mono-component systems Polymorphs

              Multi-component systems

              Cocrystal

              The simplest definition of a cocrystal is a crystalline structure made up of two or more components in a definite stoichiometric ratio where each component is defined as either an atom ion or molecule

              Principle of polymorphism

              When the change from one form to another is reversible it is said to be enantiotropic

              When the transition takes place in one direction onlymdashfor example from a metastable to a stable formmdashthe change is said to be monotropic

              Solvates

              Pharmaceutical synthesis include purification and crystallization residual solvent can be trapped in the lattice

              This result in the formation of cocrystal or solvate

              The presence of residual solvent may affect dramatically the crystalline structure of the solid depending on the type of inter molecular forces that the solvent may have with crystalline solid

              Melting pointVapor pressureHardnessOptical electrical magnetic

              propertiesColorIR spectraNMR spectra

              Photochemical reactivityThermal stabilityFiltration and drying characteristicsDissolution rateBioavailabilityPhysical and chemical stability

              Solubility and melting point are very important in pharmaceutical processes including dissolution and

              formulation

              Polymorphism

              AMORPHOUS SOLIDS Solids that donrsquot have a definite geometrical shape are known as Amorphous Solids1 In these solids particles are randomly arranged in three dimension2 They donrsquot have sharp melting points3 Amorphous solids are formed due to sudden cooling of liquid4 Amorphous solids melt over a wide range of temperature

              Amorphous Solid

              An amorphous solid does not possess a well-defined arrangement and long-range molecular order

              Amorphous substances as well as cubic crystal are isotropic that is they exhibit similar properties in all direction

              The crystalline from of the antibiotic novobiocin acid is poorly absorbed and has no activity where the amorphous form is readily absorbed and therapeutically active due to different dissolution rate

              Amorphous or crystalline amp therapeutic activity

              General crystallization conditions 1048698Solvents ndashdifferent polarities 1048698Concentration of the solutions (super saturated saturated diluted) 1048698Cooling speed (quenching slow) 1048698Temperature (room or lower than room temperature)

              Crystallization

              Final Form

              Granulation

              Drying

              Compaction

              Tableting

              Drug Product

              API

              Crystallization

              Filtration

              Drying

              Milling

              Bulk API

              Stability

              Polymorphism and Industry Pharmaceutical

              Polymorphism and Industry Pharmaceutical

              Fluoxetine HCl the active ingredient in the antidepressant drug Prozac

              co crystal which will have increased solubility compared to the crystalline form

              Celecoxib

              CELECOXIB is a nonsteroidal anti-inflammatory drug

              However it was found that the higher bioavailability was shown by the amorphous state

              The downfall of the amorphous state was its stability

              This was due to the structural relaxation

              This was enhanced by mixing it with polymers like PVP which helped in stabilizing the amorphous system (Piyush Gupta et al 2004 Piyush Gupta et al 2005)

              A new solid state form was developed by Pharmacia

              FurosemideTwo forms with significantly differing aqueous solubility and dissolution rateOral bioavailability compromised

              Giron lists gt20 excipients that display polymorphism includingndash Lactose (anhydrous also monohydrate)ndash Aspartame (anhydrous hydrate forms)ndash Magnesium stearate (can affect lubrication of tablets)

              Bioavailability

              The rate and extent to which the active ingredient or active moiety is absorbed from a drug product and becomes available at the site of action

              Bioequivalence

              The absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study

              Carbamazepine

              CHLORPROPAMIDEat least six polymorphic white or almost white crystalline powder It exhibits polymorphism Practically insoluble in water soluble in alcohol freely soluble in acetone and in dichlo-romethane dissolves in dilute solutions of alkali hydroxides Protect from light

              blood-glucose-lowering drug

              AIDS drug ritonavir

              Theobroma oil (cacao butter ) is a polymorphic natural fat

              Theobroma oil can exist in 4 different polymorphic forms of which only one is Stabile

              1 Unstable gamma form melting at 18degC2 Alpha form melting at 22degC3 Beta prime form melting at 28degC4 Stable beta form melting at 345degC

              This is important in the preparation of theobroma suppositories

              If the oil is heated to a point where it is completely liquified (about 35 C) the crystals of the stable polymorph are destroyed amp the mass does not crystallize until it is cooled to 15 C

              The crystals that form are unstable amp the suppositories melt at 24 C

              Theobroma suppositories must be prepared below 33 C

              Polymorphism and Industry Pharmaceutical

              Polymorphism and Industry Pharmaceutical

              Anhydrates together with salts form the majority of all drug formulationsAbout a half of all APIs used today are saltsSalts are stable and well soluble in polar solvents (first of all in water) because they contain ionic bondThere is one more essential advantage of salts ndash their solubility is a function of pH Since pH in the gastrointestinal tract (GIT) vary between 1-75

              atorvastatin calcium trihydrateEach tablet contains Atorvastatin Calcium Trihydrate equivalent to Atorvastatin 20 mg

              Phase Equilibria amp The Phase Rule

              Phase diagram ndash Water

              Phase Equilibrium A stable phase structure with lowest free-energy (internal energy) of a system and also randomness or disorder of the atoms or molecules (entropy)

              Any change in Temperature Composition and Pressure causes an increase in free energy and away from Equilibrium thus forcing a move to another lsquostatersquo

              Phase Equilibria amp The Phase Rule Definitions

              A phase is defined as any homogeneous and physically distinct part of a system which is separated from other parts of the system by interfaces

              A part of a system is homogeneous if it has identical physical properties and chemical composition throughout the part

              A phase may be gas liquid or solid A gas or a gaseous mixture is a single phase Totally miscible liquids constitute a single phase In an immiscible liquid system each layer is counted as a separate phase Every solid constitutes a single phase except when a solid solution is formed A solid solution is considered as a single phase Each polymorphic form constitutes a separate phase

              Phase Definition

              1 Liquid water pieces of ice and water vapour are present together The number of phases is 3 as each form is a separate phase Ice in the system is a single phase even if it is present as a number of pieces

              2 Calcium carbonate undergoes thermal decomposition The chemical reaction is CaCO3(s) CaO(s) + CO2 (g) Number of phases = 3 This system consists of 2 solid phases CaCO3 and CaO and one gaseous phase that of CO2

              3 Ammonium chloride undergoes thermal decomposition The chemical reaction is NH4Cl(s) NH3 (g) + HCl (g) Number of phases = 2 This system has two phases one solid NH4Cl and one gaseous a mixture of NH3 and HCl

              4 A solution of NaCl in water Number of phases = 1

              bull Examples

              The number of components of a system at equilibrium is the smallest number of independently varying chemical constituents using which the composition of each and every phase in the system can be expressed

              Components

              Counting the number of components 1 The sulphur system is a one component system All the phases

              monoclinic rhombic liquid and vapour ndash can be expressed in terms of the single constituent ndash sulphur

              2 A mixture of ethanol and water is an example of a two component system We need both ethanol and water to express its composition

              bull Examples

              An example of a system in which a reaction occurs and an equilibrium is established is the thermal decomposition of solid CaCO3

              In this system there are three distinct phasesSolid CaCO3

              Solid CaOGaseous CO2

              Though there are 3 species present the number of components is only two because of the equilibrium CaCO3 (s) CaO(s) + CO2(g)

              Any two of the three constituents may be chosen as the components

              If CaO and CO2 are chosen then the composition of the phase CaCO3 is expressed as one mole of component CO2 plus one mole of component CaO

              If on the other hand CaCO3 and CO2 were chosen then the composition of the phase CaO would be described as one mole of CaCO3 minus one mole of CO2

              The degrees of freedom or variance of a system is defined as the minimum number of variables such as

              temperaturepressureconcentrationwhich must be fixed in order to define the system completely

              Degrees of freedom (or variance)

              F = C P + 2

              1 A gaseous mixture of CO2 and N2 Three variables pressure temperature and composition are required to define this system This is hence a trivariant system

              2 A system having only liquid water has two degrees of freedom or is bivariant Both temperature and pressure need to be mentioned in order to define the system

              3 If to the system containing liquid water pieces of ice are added and this system with 2 phases is allowed to come to equilibrium then it is an univariant system

              Only one variable either temperature or pressure need to be specified in order to define the systemIf the pressure on the system is maintained at 1 atm then the temperature of the system gets automatically fixed at 0oC the normal melting point of ice

              bull Examples

              Phase Equilibria amp The Phase Rule

              A phase diagram (Equilibrium Phase Diagram) summarizes the conditions at which a substance exists as a solid liquid or gas

              OR It is a ldquomaprdquo of the information about the control of phase structure of a particular material system

              The relationships between temperature and the compositions and the quantities of phases present at equilibrium are represented

              F = C P + 2The phase rule

              The phase rule JW Gibbs formulated the phase rule which is a general relation

              between the variance F the number of component C and the number of phases P at equilibrium for a system of any composition

              For a system in equilibrium

              F degree of freedom the least number of intensive variable that must be fixed (known) to describe the system completely

              Phase Rule relation to determine the least number of intensive variable that can be changed without changing the equilibrium state of the system or alternately

              The least number required to define the state of the system which is called degree of freedom F

              Intensive variable independent variable that do not depend on the volume or the size egTemp pressure

              Independent chemical species which comprise the system These could be Elements Ions Compounds

              Eg Au-Cu system Components rarr Au Cu Ice-water system Component rarr H2O

              Al2O3 ndash Cr2O3 system Components rarr Al2O3 Cr2O3

              Component the smallest number of constituent by which the composition of each phase in the system at equilibrium can be expressed in form of chemical formula or equation

              Phase Equilibria amp The Phase RuleComponents of a system

              The number of phases in a system is denoted P

              (a)A gas or a gaseous mixture is a single phase P=1

              (b) For a solid system an alloy of two metals is a two-phase system (P=2) if the metals are immiscible but a single-phase system (P=1) if they are miscible---a homogeneous mixture of the two substances---is uniform on a molecular scale

              (c) For a liquid system according to the solubility to decide whether a system consists of one phase or of two For example a solution of sodium chloride in water is a single phase A pair of liquids that are partially miscible or immiscible is a two-phase system(P=2)

              Oil in water

              Degrees of Freedom = What you can control What the system controls

              F = C + 2 P

              Can control the no of components added and P amp T

              System decided how many phases to produce given the

              conditions

              A way of understanding the Gibbs Phase RuleThe degrees of freedom can be thought of as the difference between what you (can) control and

              what the system controls

              F degree of freedom the least number of intensive variable that must be fixed (known) to describe the system completely

              Degree of freedom (or variance) F is the number of variables (T p andor composition) that can be changed independently without changing the phases of the system

              a) At the triple pointP = 3 (solid liquid and gas)

              C= 1 (water)P + F = C + 2

              F = 0 (no degree of freedom)

              b) liquid-solid curveP = 2

              2+F = 1 + 2F= 1

              One variable (T or P) can be changed

              c) LiquidP =1

              So F =2Two variables (T and P) can be varied independently

              and the system will remains a single phase

              One-component systemsPhase diagram of water

              P (

              atm

              )

              Critical point

              374

              1

              =100=0O--Triple point

              0006

              218

              Curve O -CSublimation

              Deposition

              Curve O-AVaporizationCondensation

              Curve O -BMelting

              Freezing

              F = C P + 2

              F = C P + 2

              Phase Diagram of Carbon Dioxide

              Condensed system System in which the vapor phase is ignored and only the solid andor liquid phases are considered

              Two component system For two component system F can be 3 (3D model is needed) eg T p

              and concentration usually we fix p = 1atm the vapor phase is neglected and F is reduced to 2

              For three component system the pressure and temperature are fixed

              Phenol water phase diagram

              eg for point d (24)

              Two component system containing liquid phase

              Tie Line bc line The line at which the system at equilibrium will separate into phases of constant composition termed lsquoconjugate phasesrsquo

              Lever Rule a way to calculate the proportions of each phase present on a phase diagram in a two phase field (at a given temperature and composition)

              eg for point d (24)

              For every 10 g of liquid system in equilibrium in point d

              75 g phase A25 g phase B

              ExampleMixed 24g phenol +76g water T 50degC

              equilibrium75 g phase A 25 g phase B

              11 phenol 63 phenol

              011 times75 g=825 g phenol

              063 times25 g=1575 g phenol

              water rich phasecontains water+ phenol(11)

              Phenol rich phasecontains Phenol (63)+ water

              The Critical Solution Temperature CST

              Is the maximum temperature at which the 2-phase region exists (or upper consolute temperature)

              In the case of the phenol-water system this is 668oC (point h)

              All combinations of phenol and water gt CST are completely miscible and yield 1-phase liquid systems

              Systems Showing a Decrease in Miscibility with Rise in Temperature

              A few mixtures exhibit a lower critical solution temperature (low CST) eg triethylamine plus water The miscibility with in temperature

              Systems Showing Upper and Lower CSTs

              The miscibility with temp

              a certain temperature miscibility starts to again with further in temperature

              Closed-phase diagram ie nicotine-water system

              A salol B thymol

              53

              Two component system containing solid and liquid phase (Eutectic Mixtures)

              A salol B thymol

              EMLAreg (lidocaine 25 and prilocaine 25) Cream

              EMLA Cream (lidocaine 25 and prilocaine 25) is an emulsion in which the oil phase is a eutectic mixture of lidocaine and prilocaine in a ratio of 11 by weight This eutectic mixture has a melting point below room temperature and therefore both local anesthetics exist as a liquid oil rather than as crystals

              Eutectic mixture Pharmaceutical Application

              Triangular Diagrams for three ndash component systems

              Three component system

              Birzeit University Physical Pharmacy PHAR 323 Dr Hani Shtaya

              1 Binding Forces Between Molecules2 Repulsive and Attractive Forces3 The Gaseous State The Ideal Gas Law Liquefaction of Gases Aerosols4 Solids and the Crystalline State Crystalline Solids Polymorphism Solvates Amorphous Solids5 Phase Equilibria and the Phase Rule Phase Rule Systems Containing One Component Condensed System Two-Component Systems Containing Liquid Phases Two-Component Systems Containing Solid and Liquid Phases Eutectic Mixtures Rules Relating to Triangular Diagrams

              Topics that we have covered

              • States of Matter
              • States of Matter (2)
              • Objectives of the lecture
              • Comparison of Gases Liquids and Solids
              • Slide 5
              • Repulsive and Attractive Forces
              • Ideal Gas Equation
              • Gaseous state
              • Slide 9
              • Gaseous state (2)
              • Liquefaction of Gases
              • Slide 12
              • SOLIDS amp CRYSTALLINE STATE Pharmaceutical Drugs more than 80
              • Solids and the crystalline state
              • Classification of Solids
              • Slide 16
              • Slide 17
              • Crystal forms
              • Types of Crystals
              • Slide 20
              • Slide 21
              • Polymorphism
              • Slide 23
              • Slide 24
              • Slide 25
              • Slide 26
              • Cocrystal
              • Principle of polymorphism
              • Solvates
              • Polymorphism (2)
              • Amorphous Solid
              • Amorphous or crystalline amp therapeutic activity
              • Slide 33
              • Slide 34
              • Polymorphism and Industry Pharmaceutical
              • Celecoxib
              • Furosemide
              • Bioavailability
              • Slide 39
              • Slide 40
              • Bioequivalence
              • Slide 42
              • Carbamazepine
              • Slide 44
              • AIDS drug ritonavir
              • Slide 46
              • Slide 47
              • Phase Equilibria amp The Phase Rule
              • Phase diagram ndash Water
              • Phase Equilibria amp The Phase Rule Definitions
              • Phase Definition
              • Examples
              • Components
              • Examples
              • Slide 55
              • Degrees of freedom (or variance)
              • Examples (2)
              • Phase Equilibria amp The Phase Rule
              • The phase rule
              • Slide 60
              • Phase Equilibria amp The Phase Rule (2)
              • The number of phases in a system is denoted P
              • Slide 63
              • Slide 64
              • One-component systems
              • Slide 66
              • Slide 67
              • Slide 68
              • Slide 69
              • Slide 70
              • Two component system containing liquid phase
              • Slide 72
              • The Critical Solution Temperature CST
              • Systems Showing a Decrease in Miscibility with Rise in Temperat
              • Systems Showing Upper and Lower CSTs
              • Two component system containing solid and liquid phase (Eutecti
              • Slide 77
              • Eutectic mixture Pharmaceutical Application
              • Three component system
              • Slide 80
              • Topics that we have covered

                9

                What is the volume (in liters) occupied by 498 g of HCl at STP

                PV = nRT

                V = nRTP

                T = 0 0C = 27315 K

                P = 1 atm

                n = 498 g x 1 mol HCl

                3645 g HCl= 137 mol

                V =1 atm

                137 mol x 00821 x 27315 KLbullatmmolbullK

                V = 307 L

                Gaseous state

                1 atm asymp 760001 mm-Hg

                P1V1

                T1

                =

                P2V2

                T2

                Gaseous state

                The critical temperature (Tc) is the temperature above which the gas cannot be made to liquefy OR is the temperature above which the liquid cannot longer exist

                The critical pressure (Pc) is the minimum pressure required to liquefy a gas at its critical temperature

                critical temperature (Tc) of water is 374degC or 647 K and its critical pressure is 218 atm

                Liquefaction of Gases

                SOLIDS amp CRYSTALLINE STATEPharmaceutical Drugs more than 80 are solid formulations

                A crystalline solid possesses rigid and long-range order

                In a crystalline solid atoms molecules or ions occupy specific (predictable) positions

                An amorphous solid does not possess a well-defined arrangement and long-range molecular order

                Solids and the crystalline state

                Classification of Solids

                Crystalline Amorphous

                Amorphous

                A unit cell is the basic repeating structural unit of a crystalline solid

                latticepoint

                Unit Cell Unit cells in 3 dimensions

                At lattice points

                bull Atoms

                bull Molecules

                bull Ions

                The crystal lattice of sodium chloride NaCl

                Na Cl

                The various crystal forms are divide to basic 7 unit according to its symmetry

                NaCl urea

                iodine

                sucrose Boric acid

                Crystal forms

                iodoform

                Be3Al2(SiO3)6

                CsCl ZnS CaF2

                Ionic Crystalsbull Lattice points occupied by cations and anionsbull Held together by electrostatic attractionbull Hard brittle high melting pointbull Poor conductor of heat and electricity

                Types of Crystals

                diamondgraphite

                carbonatoms

                Covalent Crystalsbull Lattice points occupied by atomsbull Held together by covalent bondsbull Hard high melting pointbull Poor conductor of heat and electricity

                Cross Section of a Metallic Crystal

                nucleus ampinner shell e-

                mobile ldquoseardquoof e-

                Metallic Crystalsbull Lattice points occupied by metal atomsbull Held together by metallic bondsbull Soft to hard low to high melting pointbull Good conductors of heat and electricity

                Some elemental substance such as C and S may exist in more than one crystalline form and are said to be allotropic which is a special case of polymorphism

                Polymorphism is the ability of a substance to exist in more than one crystal structure

                Polymorphism

                Polymorphism is the ability of a substance to exist in more than one crystal structure

                Polymorphs when two crystals have the same chemical composition but different internal structure (molecular packing ndashmolecular conformation or and inter or intra molecular interactions)modifications or polymorphs or forms

                Pseudo polymorphs different crystal forms have molecules of the same given substances and also contain molecules of solvent incorporated into a unique structure (solvates or hydrates (water))

                diamond graphite

                carbonatoms

                High T and p

                Diamond is metastable and converts very slowly to graphite

                The most common example of polymorphism

                Solid State Polymorphs

                Mono-component systems Polymorphs

                Multi-component systems

                Cocrystal

                The simplest definition of a cocrystal is a crystalline structure made up of two or more components in a definite stoichiometric ratio where each component is defined as either an atom ion or molecule

                Principle of polymorphism

                When the change from one form to another is reversible it is said to be enantiotropic

                When the transition takes place in one direction onlymdashfor example from a metastable to a stable formmdashthe change is said to be monotropic

                Solvates

                Pharmaceutical synthesis include purification and crystallization residual solvent can be trapped in the lattice

                This result in the formation of cocrystal or solvate

                The presence of residual solvent may affect dramatically the crystalline structure of the solid depending on the type of inter molecular forces that the solvent may have with crystalline solid

                Melting pointVapor pressureHardnessOptical electrical magnetic

                propertiesColorIR spectraNMR spectra

                Photochemical reactivityThermal stabilityFiltration and drying characteristicsDissolution rateBioavailabilityPhysical and chemical stability

                Solubility and melting point are very important in pharmaceutical processes including dissolution and

                formulation

                Polymorphism

                AMORPHOUS SOLIDS Solids that donrsquot have a definite geometrical shape are known as Amorphous Solids1 In these solids particles are randomly arranged in three dimension2 They donrsquot have sharp melting points3 Amorphous solids are formed due to sudden cooling of liquid4 Amorphous solids melt over a wide range of temperature

                Amorphous Solid

                An amorphous solid does not possess a well-defined arrangement and long-range molecular order

                Amorphous substances as well as cubic crystal are isotropic that is they exhibit similar properties in all direction

                The crystalline from of the antibiotic novobiocin acid is poorly absorbed and has no activity where the amorphous form is readily absorbed and therapeutically active due to different dissolution rate

                Amorphous or crystalline amp therapeutic activity

                General crystallization conditions 1048698Solvents ndashdifferent polarities 1048698Concentration of the solutions (super saturated saturated diluted) 1048698Cooling speed (quenching slow) 1048698Temperature (room or lower than room temperature)

                Crystallization

                Final Form

                Granulation

                Drying

                Compaction

                Tableting

                Drug Product

                API

                Crystallization

                Filtration

                Drying

                Milling

                Bulk API

                Stability

                Polymorphism and Industry Pharmaceutical

                Polymorphism and Industry Pharmaceutical

                Fluoxetine HCl the active ingredient in the antidepressant drug Prozac

                co crystal which will have increased solubility compared to the crystalline form

                Celecoxib

                CELECOXIB is a nonsteroidal anti-inflammatory drug

                However it was found that the higher bioavailability was shown by the amorphous state

                The downfall of the amorphous state was its stability

                This was due to the structural relaxation

                This was enhanced by mixing it with polymers like PVP which helped in stabilizing the amorphous system (Piyush Gupta et al 2004 Piyush Gupta et al 2005)

                A new solid state form was developed by Pharmacia

                FurosemideTwo forms with significantly differing aqueous solubility and dissolution rateOral bioavailability compromised

                Giron lists gt20 excipients that display polymorphism includingndash Lactose (anhydrous also monohydrate)ndash Aspartame (anhydrous hydrate forms)ndash Magnesium stearate (can affect lubrication of tablets)

                Bioavailability

                The rate and extent to which the active ingredient or active moiety is absorbed from a drug product and becomes available at the site of action

                Bioequivalence

                The absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study

                Carbamazepine

                CHLORPROPAMIDEat least six polymorphic white or almost white crystalline powder It exhibits polymorphism Practically insoluble in water soluble in alcohol freely soluble in acetone and in dichlo-romethane dissolves in dilute solutions of alkali hydroxides Protect from light

                blood-glucose-lowering drug

                AIDS drug ritonavir

                Theobroma oil (cacao butter ) is a polymorphic natural fat

                Theobroma oil can exist in 4 different polymorphic forms of which only one is Stabile

                1 Unstable gamma form melting at 18degC2 Alpha form melting at 22degC3 Beta prime form melting at 28degC4 Stable beta form melting at 345degC

                This is important in the preparation of theobroma suppositories

                If the oil is heated to a point where it is completely liquified (about 35 C) the crystals of the stable polymorph are destroyed amp the mass does not crystallize until it is cooled to 15 C

                The crystals that form are unstable amp the suppositories melt at 24 C

                Theobroma suppositories must be prepared below 33 C

                Polymorphism and Industry Pharmaceutical

                Polymorphism and Industry Pharmaceutical

                Anhydrates together with salts form the majority of all drug formulationsAbout a half of all APIs used today are saltsSalts are stable and well soluble in polar solvents (first of all in water) because they contain ionic bondThere is one more essential advantage of salts ndash their solubility is a function of pH Since pH in the gastrointestinal tract (GIT) vary between 1-75

                atorvastatin calcium trihydrateEach tablet contains Atorvastatin Calcium Trihydrate equivalent to Atorvastatin 20 mg

                Phase Equilibria amp The Phase Rule

                Phase diagram ndash Water

                Phase Equilibrium A stable phase structure with lowest free-energy (internal energy) of a system and also randomness or disorder of the atoms or molecules (entropy)

                Any change in Temperature Composition and Pressure causes an increase in free energy and away from Equilibrium thus forcing a move to another lsquostatersquo

                Phase Equilibria amp The Phase Rule Definitions

                A phase is defined as any homogeneous and physically distinct part of a system which is separated from other parts of the system by interfaces

                A part of a system is homogeneous if it has identical physical properties and chemical composition throughout the part

                A phase may be gas liquid or solid A gas or a gaseous mixture is a single phase Totally miscible liquids constitute a single phase In an immiscible liquid system each layer is counted as a separate phase Every solid constitutes a single phase except when a solid solution is formed A solid solution is considered as a single phase Each polymorphic form constitutes a separate phase

                Phase Definition

                1 Liquid water pieces of ice and water vapour are present together The number of phases is 3 as each form is a separate phase Ice in the system is a single phase even if it is present as a number of pieces

                2 Calcium carbonate undergoes thermal decomposition The chemical reaction is CaCO3(s) CaO(s) + CO2 (g) Number of phases = 3 This system consists of 2 solid phases CaCO3 and CaO and one gaseous phase that of CO2

                3 Ammonium chloride undergoes thermal decomposition The chemical reaction is NH4Cl(s) NH3 (g) + HCl (g) Number of phases = 2 This system has two phases one solid NH4Cl and one gaseous a mixture of NH3 and HCl

                4 A solution of NaCl in water Number of phases = 1

                bull Examples

                The number of components of a system at equilibrium is the smallest number of independently varying chemical constituents using which the composition of each and every phase in the system can be expressed

                Components

                Counting the number of components 1 The sulphur system is a one component system All the phases

                monoclinic rhombic liquid and vapour ndash can be expressed in terms of the single constituent ndash sulphur

                2 A mixture of ethanol and water is an example of a two component system We need both ethanol and water to express its composition

                bull Examples

                An example of a system in which a reaction occurs and an equilibrium is established is the thermal decomposition of solid CaCO3

                In this system there are three distinct phasesSolid CaCO3

                Solid CaOGaseous CO2

                Though there are 3 species present the number of components is only two because of the equilibrium CaCO3 (s) CaO(s) + CO2(g)

                Any two of the three constituents may be chosen as the components

                If CaO and CO2 are chosen then the composition of the phase CaCO3 is expressed as one mole of component CO2 plus one mole of component CaO

                If on the other hand CaCO3 and CO2 were chosen then the composition of the phase CaO would be described as one mole of CaCO3 minus one mole of CO2

                The degrees of freedom or variance of a system is defined as the minimum number of variables such as

                temperaturepressureconcentrationwhich must be fixed in order to define the system completely

                Degrees of freedom (or variance)

                F = C P + 2

                1 A gaseous mixture of CO2 and N2 Three variables pressure temperature and composition are required to define this system This is hence a trivariant system

                2 A system having only liquid water has two degrees of freedom or is bivariant Both temperature and pressure need to be mentioned in order to define the system

                3 If to the system containing liquid water pieces of ice are added and this system with 2 phases is allowed to come to equilibrium then it is an univariant system

                Only one variable either temperature or pressure need to be specified in order to define the systemIf the pressure on the system is maintained at 1 atm then the temperature of the system gets automatically fixed at 0oC the normal melting point of ice

                bull Examples

                Phase Equilibria amp The Phase Rule

                A phase diagram (Equilibrium Phase Diagram) summarizes the conditions at which a substance exists as a solid liquid or gas

                OR It is a ldquomaprdquo of the information about the control of phase structure of a particular material system

                The relationships between temperature and the compositions and the quantities of phases present at equilibrium are represented

                F = C P + 2The phase rule

                The phase rule JW Gibbs formulated the phase rule which is a general relation

                between the variance F the number of component C and the number of phases P at equilibrium for a system of any composition

                For a system in equilibrium

                F degree of freedom the least number of intensive variable that must be fixed (known) to describe the system completely

                Phase Rule relation to determine the least number of intensive variable that can be changed without changing the equilibrium state of the system or alternately

                The least number required to define the state of the system which is called degree of freedom F

                Intensive variable independent variable that do not depend on the volume or the size egTemp pressure

                Independent chemical species which comprise the system These could be Elements Ions Compounds

                Eg Au-Cu system Components rarr Au Cu Ice-water system Component rarr H2O

                Al2O3 ndash Cr2O3 system Components rarr Al2O3 Cr2O3

                Component the smallest number of constituent by which the composition of each phase in the system at equilibrium can be expressed in form of chemical formula or equation

                Phase Equilibria amp The Phase RuleComponents of a system

                The number of phases in a system is denoted P

                (a)A gas or a gaseous mixture is a single phase P=1

                (b) For a solid system an alloy of two metals is a two-phase system (P=2) if the metals are immiscible but a single-phase system (P=1) if they are miscible---a homogeneous mixture of the two substances---is uniform on a molecular scale

                (c) For a liquid system according to the solubility to decide whether a system consists of one phase or of two For example a solution of sodium chloride in water is a single phase A pair of liquids that are partially miscible or immiscible is a two-phase system(P=2)

                Oil in water

                Degrees of Freedom = What you can control What the system controls

                F = C + 2 P

                Can control the no of components added and P amp T

                System decided how many phases to produce given the

                conditions

                A way of understanding the Gibbs Phase RuleThe degrees of freedom can be thought of as the difference between what you (can) control and

                what the system controls

                F degree of freedom the least number of intensive variable that must be fixed (known) to describe the system completely

                Degree of freedom (or variance) F is the number of variables (T p andor composition) that can be changed independently without changing the phases of the system

                a) At the triple pointP = 3 (solid liquid and gas)

                C= 1 (water)P + F = C + 2

                F = 0 (no degree of freedom)

                b) liquid-solid curveP = 2

                2+F = 1 + 2F= 1

                One variable (T or P) can be changed

                c) LiquidP =1

                So F =2Two variables (T and P) can be varied independently

                and the system will remains a single phase

                One-component systemsPhase diagram of water

                P (

                atm

                )

                Critical point

                374

                1

                =100=0O--Triple point

                0006

                218

                Curve O -CSublimation

                Deposition

                Curve O-AVaporizationCondensation

                Curve O -BMelting

                Freezing

                F = C P + 2

                F = C P + 2

                Phase Diagram of Carbon Dioxide

                Condensed system System in which the vapor phase is ignored and only the solid andor liquid phases are considered

                Two component system For two component system F can be 3 (3D model is needed) eg T p

                and concentration usually we fix p = 1atm the vapor phase is neglected and F is reduced to 2

                For three component system the pressure and temperature are fixed

                Phenol water phase diagram

                eg for point d (24)

                Two component system containing liquid phase

                Tie Line bc line The line at which the system at equilibrium will separate into phases of constant composition termed lsquoconjugate phasesrsquo

                Lever Rule a way to calculate the proportions of each phase present on a phase diagram in a two phase field (at a given temperature and composition)

                eg for point d (24)

                For every 10 g of liquid system in equilibrium in point d

                75 g phase A25 g phase B

                ExampleMixed 24g phenol +76g water T 50degC

                equilibrium75 g phase A 25 g phase B

                11 phenol 63 phenol

                011 times75 g=825 g phenol

                063 times25 g=1575 g phenol

                water rich phasecontains water+ phenol(11)

                Phenol rich phasecontains Phenol (63)+ water

                The Critical Solution Temperature CST

                Is the maximum temperature at which the 2-phase region exists (or upper consolute temperature)

                In the case of the phenol-water system this is 668oC (point h)

                All combinations of phenol and water gt CST are completely miscible and yield 1-phase liquid systems

                Systems Showing a Decrease in Miscibility with Rise in Temperature

                A few mixtures exhibit a lower critical solution temperature (low CST) eg triethylamine plus water The miscibility with in temperature

                Systems Showing Upper and Lower CSTs

                The miscibility with temp

                a certain temperature miscibility starts to again with further in temperature

                Closed-phase diagram ie nicotine-water system

                A salol B thymol

                53

                Two component system containing solid and liquid phase (Eutectic Mixtures)

                A salol B thymol

                EMLAreg (lidocaine 25 and prilocaine 25) Cream

                EMLA Cream (lidocaine 25 and prilocaine 25) is an emulsion in which the oil phase is a eutectic mixture of lidocaine and prilocaine in a ratio of 11 by weight This eutectic mixture has a melting point below room temperature and therefore both local anesthetics exist as a liquid oil rather than as crystals

                Eutectic mixture Pharmaceutical Application

                Triangular Diagrams for three ndash component systems

                Three component system

                Birzeit University Physical Pharmacy PHAR 323 Dr Hani Shtaya

                1 Binding Forces Between Molecules2 Repulsive and Attractive Forces3 The Gaseous State The Ideal Gas Law Liquefaction of Gases Aerosols4 Solids and the Crystalline State Crystalline Solids Polymorphism Solvates Amorphous Solids5 Phase Equilibria and the Phase Rule Phase Rule Systems Containing One Component Condensed System Two-Component Systems Containing Liquid Phases Two-Component Systems Containing Solid and Liquid Phases Eutectic Mixtures Rules Relating to Triangular Diagrams

                Topics that we have covered

                • States of Matter
                • States of Matter (2)
                • Objectives of the lecture
                • Comparison of Gases Liquids and Solids
                • Slide 5
                • Repulsive and Attractive Forces
                • Ideal Gas Equation
                • Gaseous state
                • Slide 9
                • Gaseous state (2)
                • Liquefaction of Gases
                • Slide 12
                • SOLIDS amp CRYSTALLINE STATE Pharmaceutical Drugs more than 80
                • Solids and the crystalline state
                • Classification of Solids
                • Slide 16
                • Slide 17
                • Crystal forms
                • Types of Crystals
                • Slide 20
                • Slide 21
                • Polymorphism
                • Slide 23
                • Slide 24
                • Slide 25
                • Slide 26
                • Cocrystal
                • Principle of polymorphism
                • Solvates
                • Polymorphism (2)
                • Amorphous Solid
                • Amorphous or crystalline amp therapeutic activity
                • Slide 33
                • Slide 34
                • Polymorphism and Industry Pharmaceutical
                • Celecoxib
                • Furosemide
                • Bioavailability
                • Slide 39
                • Slide 40
                • Bioequivalence
                • Slide 42
                • Carbamazepine
                • Slide 44
                • AIDS drug ritonavir
                • Slide 46
                • Slide 47
                • Phase Equilibria amp The Phase Rule
                • Phase diagram ndash Water
                • Phase Equilibria amp The Phase Rule Definitions
                • Phase Definition
                • Examples
                • Components
                • Examples
                • Slide 55
                • Degrees of freedom (or variance)
                • Examples (2)
                • Phase Equilibria amp The Phase Rule
                • The phase rule
                • Slide 60
                • Phase Equilibria amp The Phase Rule (2)
                • The number of phases in a system is denoted P
                • Slide 63
                • Slide 64
                • One-component systems
                • Slide 66
                • Slide 67
                • Slide 68
                • Slide 69
                • Slide 70
                • Two component system containing liquid phase
                • Slide 72
                • The Critical Solution Temperature CST
                • Systems Showing a Decrease in Miscibility with Rise in Temperat
                • Systems Showing Upper and Lower CSTs
                • Two component system containing solid and liquid phase (Eutecti
                • Slide 77
                • Eutectic mixture Pharmaceutical Application
                • Three component system
                • Slide 80
                • Topics that we have covered

                  P1V1

                  T1

                  =

                  P2V2

                  T2

                  Gaseous state

                  The critical temperature (Tc) is the temperature above which the gas cannot be made to liquefy OR is the temperature above which the liquid cannot longer exist

                  The critical pressure (Pc) is the minimum pressure required to liquefy a gas at its critical temperature

                  critical temperature (Tc) of water is 374degC or 647 K and its critical pressure is 218 atm

                  Liquefaction of Gases

                  SOLIDS amp CRYSTALLINE STATEPharmaceutical Drugs more than 80 are solid formulations

                  A crystalline solid possesses rigid and long-range order

                  In a crystalline solid atoms molecules or ions occupy specific (predictable) positions

                  An amorphous solid does not possess a well-defined arrangement and long-range molecular order

                  Solids and the crystalline state

                  Classification of Solids

                  Crystalline Amorphous

                  Amorphous

                  A unit cell is the basic repeating structural unit of a crystalline solid

                  latticepoint

                  Unit Cell Unit cells in 3 dimensions

                  At lattice points

                  bull Atoms

                  bull Molecules

                  bull Ions

                  The crystal lattice of sodium chloride NaCl

                  Na Cl

                  The various crystal forms are divide to basic 7 unit according to its symmetry

                  NaCl urea

                  iodine

                  sucrose Boric acid

                  Crystal forms

                  iodoform

                  Be3Al2(SiO3)6

                  CsCl ZnS CaF2

                  Ionic Crystalsbull Lattice points occupied by cations and anionsbull Held together by electrostatic attractionbull Hard brittle high melting pointbull Poor conductor of heat and electricity

                  Types of Crystals

                  diamondgraphite

                  carbonatoms

                  Covalent Crystalsbull Lattice points occupied by atomsbull Held together by covalent bondsbull Hard high melting pointbull Poor conductor of heat and electricity

                  Cross Section of a Metallic Crystal

                  nucleus ampinner shell e-

                  mobile ldquoseardquoof e-

                  Metallic Crystalsbull Lattice points occupied by metal atomsbull Held together by metallic bondsbull Soft to hard low to high melting pointbull Good conductors of heat and electricity

                  Some elemental substance such as C and S may exist in more than one crystalline form and are said to be allotropic which is a special case of polymorphism

                  Polymorphism is the ability of a substance to exist in more than one crystal structure

                  Polymorphism

                  Polymorphism is the ability of a substance to exist in more than one crystal structure

                  Polymorphs when two crystals have the same chemical composition but different internal structure (molecular packing ndashmolecular conformation or and inter or intra molecular interactions)modifications or polymorphs or forms

                  Pseudo polymorphs different crystal forms have molecules of the same given substances and also contain molecules of solvent incorporated into a unique structure (solvates or hydrates (water))

                  diamond graphite

                  carbonatoms

                  High T and p

                  Diamond is metastable and converts very slowly to graphite

                  The most common example of polymorphism

                  Solid State Polymorphs

                  Mono-component systems Polymorphs

                  Multi-component systems

                  Cocrystal

                  The simplest definition of a cocrystal is a crystalline structure made up of two or more components in a definite stoichiometric ratio where each component is defined as either an atom ion or molecule

                  Principle of polymorphism

                  When the change from one form to another is reversible it is said to be enantiotropic

                  When the transition takes place in one direction onlymdashfor example from a metastable to a stable formmdashthe change is said to be monotropic

                  Solvates

                  Pharmaceutical synthesis include purification and crystallization residual solvent can be trapped in the lattice

                  This result in the formation of cocrystal or solvate

                  The presence of residual solvent may affect dramatically the crystalline structure of the solid depending on the type of inter molecular forces that the solvent may have with crystalline solid

                  Melting pointVapor pressureHardnessOptical electrical magnetic

                  propertiesColorIR spectraNMR spectra

                  Photochemical reactivityThermal stabilityFiltration and drying characteristicsDissolution rateBioavailabilityPhysical and chemical stability

                  Solubility and melting point are very important in pharmaceutical processes including dissolution and

                  formulation

                  Polymorphism

                  AMORPHOUS SOLIDS Solids that donrsquot have a definite geometrical shape are known as Amorphous Solids1 In these solids particles are randomly arranged in three dimension2 They donrsquot have sharp melting points3 Amorphous solids are formed due to sudden cooling of liquid4 Amorphous solids melt over a wide range of temperature

                  Amorphous Solid

                  An amorphous solid does not possess a well-defined arrangement and long-range molecular order

                  Amorphous substances as well as cubic crystal are isotropic that is they exhibit similar properties in all direction

                  The crystalline from of the antibiotic novobiocin acid is poorly absorbed and has no activity where the amorphous form is readily absorbed and therapeutically active due to different dissolution rate

                  Amorphous or crystalline amp therapeutic activity

                  General crystallization conditions 1048698Solvents ndashdifferent polarities 1048698Concentration of the solutions (super saturated saturated diluted) 1048698Cooling speed (quenching slow) 1048698Temperature (room or lower than room temperature)

                  Crystallization

                  Final Form

                  Granulation

                  Drying

                  Compaction

                  Tableting

                  Drug Product

                  API

                  Crystallization

                  Filtration

                  Drying

                  Milling

                  Bulk API

                  Stability

                  Polymorphism and Industry Pharmaceutical

                  Polymorphism and Industry Pharmaceutical

                  Fluoxetine HCl the active ingredient in the antidepressant drug Prozac

                  co crystal which will have increased solubility compared to the crystalline form

                  Celecoxib

                  CELECOXIB is a nonsteroidal anti-inflammatory drug

                  However it was found that the higher bioavailability was shown by the amorphous state

                  The downfall of the amorphous state was its stability

                  This was due to the structural relaxation

                  This was enhanced by mixing it with polymers like PVP which helped in stabilizing the amorphous system (Piyush Gupta et al 2004 Piyush Gupta et al 2005)

                  A new solid state form was developed by Pharmacia

                  FurosemideTwo forms with significantly differing aqueous solubility and dissolution rateOral bioavailability compromised

                  Giron lists gt20 excipients that display polymorphism includingndash Lactose (anhydrous also monohydrate)ndash Aspartame (anhydrous hydrate forms)ndash Magnesium stearate (can affect lubrication of tablets)

                  Bioavailability

                  The rate and extent to which the active ingredient or active moiety is absorbed from a drug product and becomes available at the site of action

                  Bioequivalence

                  The absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study

                  Carbamazepine

                  CHLORPROPAMIDEat least six polymorphic white or almost white crystalline powder It exhibits polymorphism Practically insoluble in water soluble in alcohol freely soluble in acetone and in dichlo-romethane dissolves in dilute solutions of alkali hydroxides Protect from light

                  blood-glucose-lowering drug

                  AIDS drug ritonavir

                  Theobroma oil (cacao butter ) is a polymorphic natural fat

                  Theobroma oil can exist in 4 different polymorphic forms of which only one is Stabile

                  1 Unstable gamma form melting at 18degC2 Alpha form melting at 22degC3 Beta prime form melting at 28degC4 Stable beta form melting at 345degC

                  This is important in the preparation of theobroma suppositories

                  If the oil is heated to a point where it is completely liquified (about 35 C) the crystals of the stable polymorph are destroyed amp the mass does not crystallize until it is cooled to 15 C

                  The crystals that form are unstable amp the suppositories melt at 24 C

                  Theobroma suppositories must be prepared below 33 C

                  Polymorphism and Industry Pharmaceutical

                  Polymorphism and Industry Pharmaceutical

                  Anhydrates together with salts form the majority of all drug formulationsAbout a half of all APIs used today are saltsSalts are stable and well soluble in polar solvents (first of all in water) because they contain ionic bondThere is one more essential advantage of salts ndash their solubility is a function of pH Since pH in the gastrointestinal tract (GIT) vary between 1-75

                  atorvastatin calcium trihydrateEach tablet contains Atorvastatin Calcium Trihydrate equivalent to Atorvastatin 20 mg

                  Phase Equilibria amp The Phase Rule

                  Phase diagram ndash Water

                  Phase Equilibrium A stable phase structure with lowest free-energy (internal energy) of a system and also randomness or disorder of the atoms or molecules (entropy)

                  Any change in Temperature Composition and Pressure causes an increase in free energy and away from Equilibrium thus forcing a move to another lsquostatersquo

                  Phase Equilibria amp The Phase Rule Definitions

                  A phase is defined as any homogeneous and physically distinct part of a system which is separated from other parts of the system by interfaces

                  A part of a system is homogeneous if it has identical physical properties and chemical composition throughout the part

                  A phase may be gas liquid or solid A gas or a gaseous mixture is a single phase Totally miscible liquids constitute a single phase In an immiscible liquid system each layer is counted as a separate phase Every solid constitutes a single phase except when a solid solution is formed A solid solution is considered as a single phase Each polymorphic form constitutes a separate phase

                  Phase Definition

                  1 Liquid water pieces of ice and water vapour are present together The number of phases is 3 as each form is a separate phase Ice in the system is a single phase even if it is present as a number of pieces

                  2 Calcium carbonate undergoes thermal decomposition The chemical reaction is CaCO3(s) CaO(s) + CO2 (g) Number of phases = 3 This system consists of 2 solid phases CaCO3 and CaO and one gaseous phase that of CO2

                  3 Ammonium chloride undergoes thermal decomposition The chemical reaction is NH4Cl(s) NH3 (g) + HCl (g) Number of phases = 2 This system has two phases one solid NH4Cl and one gaseous a mixture of NH3 and HCl

                  4 A solution of NaCl in water Number of phases = 1

                  bull Examples

                  The number of components of a system at equilibrium is the smallest number of independently varying chemical constituents using which the composition of each and every phase in the system can be expressed

                  Components

                  Counting the number of components 1 The sulphur system is a one component system All the phases

                  monoclinic rhombic liquid and vapour ndash can be expressed in terms of the single constituent ndash sulphur

                  2 A mixture of ethanol and water is an example of a two component system We need both ethanol and water to express its composition

                  bull Examples

                  An example of a system in which a reaction occurs and an equilibrium is established is the thermal decomposition of solid CaCO3

                  In this system there are three distinct phasesSolid CaCO3

                  Solid CaOGaseous CO2

                  Though there are 3 species present the number of components is only two because of the equilibrium CaCO3 (s) CaO(s) + CO2(g)

                  Any two of the three constituents may be chosen as the components

                  If CaO and CO2 are chosen then the composition of the phase CaCO3 is expressed as one mole of component CO2 plus one mole of component CaO

                  If on the other hand CaCO3 and CO2 were chosen then the composition of the phase CaO would be described as one mole of CaCO3 minus one mole of CO2

                  The degrees of freedom or variance of a system is defined as the minimum number of variables such as

                  temperaturepressureconcentrationwhich must be fixed in order to define the system completely

                  Degrees of freedom (or variance)

                  F = C P + 2

                  1 A gaseous mixture of CO2 and N2 Three variables pressure temperature and composition are required to define this system This is hence a trivariant system

                  2 A system having only liquid water has two degrees of freedom or is bivariant Both temperature and pressure need to be mentioned in order to define the system

                  3 If to the system containing liquid water pieces of ice are added and this system with 2 phases is allowed to come to equilibrium then it is an univariant system

                  Only one variable either temperature or pressure need to be specified in order to define the systemIf the pressure on the system is maintained at 1 atm then the temperature of the system gets automatically fixed at 0oC the normal melting point of ice

                  bull Examples

                  Phase Equilibria amp The Phase Rule

                  A phase diagram (Equilibrium Phase Diagram) summarizes the conditions at which a substance exists as a solid liquid or gas

                  OR It is a ldquomaprdquo of the information about the control of phase structure of a particular material system

                  The relationships between temperature and the compositions and the quantities of phases present at equilibrium are represented

                  F = C P + 2The phase rule

                  The phase rule JW Gibbs formulated the phase rule which is a general relation

                  between the variance F the number of component C and the number of phases P at equilibrium for a system of any composition

                  For a system in equilibrium

                  F degree of freedom the least number of intensive variable that must be fixed (known) to describe the system completely

                  Phase Rule relation to determine the least number of intensive variable that can be changed without changing the equilibrium state of the system or alternately

                  The least number required to define the state of the system which is called degree of freedom F

                  Intensive variable independent variable that do not depend on the volume or the size egTemp pressure

                  Independent chemical species which comprise the system These could be Elements Ions Compounds

                  Eg Au-Cu system Components rarr Au Cu Ice-water system Component rarr H2O

                  Al2O3 ndash Cr2O3 system Components rarr Al2O3 Cr2O3

                  Component the smallest number of constituent by which the composition of each phase in the system at equilibrium can be expressed in form of chemical formula or equation

                  Phase Equilibria amp The Phase RuleComponents of a system

                  The number of phases in a system is denoted P

                  (a)A gas or a gaseous mixture is a single phase P=1

                  (b) For a solid system an alloy of two metals is a two-phase system (P=2) if the metals are immiscible but a single-phase system (P=1) if they are miscible---a homogeneous mixture of the two substances---is uniform on a molecular scale

                  (c) For a liquid system according to the solubility to decide whether a system consists of one phase or of two For example a solution of sodium chloride in water is a single phase A pair of liquids that are partially miscible or immiscible is a two-phase system(P=2)

                  Oil in water

                  Degrees of Freedom = What you can control What the system controls

                  F = C + 2 P

                  Can control the no of components added and P amp T

                  System decided how many phases to produce given the

                  conditions

                  A way of understanding the Gibbs Phase RuleThe degrees of freedom can be thought of as the difference between what you (can) control and

                  what the system controls

                  F degree of freedom the least number of intensive variable that must be fixed (known) to describe the system completely

                  Degree of freedom (or variance) F is the number of variables (T p andor composition) that can be changed independently without changing the phases of the system

                  a) At the triple pointP = 3 (solid liquid and gas)

                  C= 1 (water)P + F = C + 2

                  F = 0 (no degree of freedom)

                  b) liquid-solid curveP = 2

                  2+F = 1 + 2F= 1

                  One variable (T or P) can be changed

                  c) LiquidP =1

                  So F =2Two variables (T and P) can be varied independently

                  and the system will remains a single phase

                  One-component systemsPhase diagram of water

                  P (

                  atm

                  )

                  Critical point

                  374

                  1

                  =100=0O--Triple point

                  0006

                  218

                  Curve O -CSublimation

                  Deposition

                  Curve O-AVaporizationCondensation

                  Curve O -BMelting

                  Freezing

                  F = C P + 2

                  F = C P + 2

                  Phase Diagram of Carbon Dioxide

                  Condensed system System in which the vapor phase is ignored and only the solid andor liquid phases are considered

                  Two component system For two component system F can be 3 (3D model is needed) eg T p

                  and concentration usually we fix p = 1atm the vapor phase is neglected and F is reduced to 2

                  For three component system the pressure and temperature are fixed

                  Phenol water phase diagram

                  eg for point d (24)

                  Two component system containing liquid phase

                  Tie Line bc line The line at which the system at equilibrium will separate into phases of constant composition termed lsquoconjugate phasesrsquo

                  Lever Rule a way to calculate the proportions of each phase present on a phase diagram in a two phase field (at a given temperature and composition)

                  eg for point d (24)

                  For every 10 g of liquid system in equilibrium in point d

                  75 g phase A25 g phase B

                  ExampleMixed 24g phenol +76g water T 50degC

                  equilibrium75 g phase A 25 g phase B

                  11 phenol 63 phenol

                  011 times75 g=825 g phenol

                  063 times25 g=1575 g phenol

                  water rich phasecontains water+ phenol(11)

                  Phenol rich phasecontains Phenol (63)+ water

                  The Critical Solution Temperature CST

                  Is the maximum temperature at which the 2-phase region exists (or upper consolute temperature)

                  In the case of the phenol-water system this is 668oC (point h)

                  All combinations of phenol and water gt CST are completely miscible and yield 1-phase liquid systems

                  Systems Showing a Decrease in Miscibility with Rise in Temperature

                  A few mixtures exhibit a lower critical solution temperature (low CST) eg triethylamine plus water The miscibility with in temperature

                  Systems Showing Upper and Lower CSTs

                  The miscibility with temp

                  a certain temperature miscibility starts to again with further in temperature

                  Closed-phase diagram ie nicotine-water system

                  A salol B thymol

                  53

                  Two component system containing solid and liquid phase (Eutectic Mixtures)

                  A salol B thymol

                  EMLAreg (lidocaine 25 and prilocaine 25) Cream

                  EMLA Cream (lidocaine 25 and prilocaine 25) is an emulsion in which the oil phase is a eutectic mixture of lidocaine and prilocaine in a ratio of 11 by weight This eutectic mixture has a melting point below room temperature and therefore both local anesthetics exist as a liquid oil rather than as crystals

                  Eutectic mixture Pharmaceutical Application

                  Triangular Diagrams for three ndash component systems

                  Three component system

                  Birzeit University Physical Pharmacy PHAR 323 Dr Hani Shtaya

                  1 Binding Forces Between Molecules2 Repulsive and Attractive Forces3 The Gaseous State The Ideal Gas Law Liquefaction of Gases Aerosols4 Solids and the Crystalline State Crystalline Solids Polymorphism Solvates Amorphous Solids5 Phase Equilibria and the Phase Rule Phase Rule Systems Containing One Component Condensed System Two-Component Systems Containing Liquid Phases Two-Component Systems Containing Solid and Liquid Phases Eutectic Mixtures Rules Relating to Triangular Diagrams

                  Topics that we have covered

                  • States of Matter
                  • States of Matter (2)
                  • Objectives of the lecture
                  • Comparison of Gases Liquids and Solids
                  • Slide 5
                  • Repulsive and Attractive Forces
                  • Ideal Gas Equation
                  • Gaseous state
                  • Slide 9
                  • Gaseous state (2)
                  • Liquefaction of Gases
                  • Slide 12
                  • SOLIDS amp CRYSTALLINE STATE Pharmaceutical Drugs more than 80
                  • Solids and the crystalline state
                  • Classification of Solids
                  • Slide 16
                  • Slide 17
                  • Crystal forms
                  • Types of Crystals
                  • Slide 20
                  • Slide 21
                  • Polymorphism
                  • Slide 23
                  • Slide 24
                  • Slide 25
                  • Slide 26
                  • Cocrystal
                  • Principle of polymorphism
                  • Solvates
                  • Polymorphism (2)
                  • Amorphous Solid
                  • Amorphous or crystalline amp therapeutic activity
                  • Slide 33
                  • Slide 34
                  • Polymorphism and Industry Pharmaceutical
                  • Celecoxib
                  • Furosemide
                  • Bioavailability
                  • Slide 39
                  • Slide 40
                  • Bioequivalence
                  • Slide 42
                  • Carbamazepine
                  • Slide 44
                  • AIDS drug ritonavir
                  • Slide 46
                  • Slide 47
                  • Phase Equilibria amp The Phase Rule
                  • Phase diagram ndash Water
                  • Phase Equilibria amp The Phase Rule Definitions
                  • Phase Definition
                  • Examples
                  • Components
                  • Examples
                  • Slide 55
                  • Degrees of freedom (or variance)
                  • Examples (2)
                  • Phase Equilibria amp The Phase Rule
                  • The phase rule
                  • Slide 60
                  • Phase Equilibria amp The Phase Rule (2)
                  • The number of phases in a system is denoted P
                  • Slide 63
                  • Slide 64
                  • One-component systems
                  • Slide 66
                  • Slide 67
                  • Slide 68
                  • Slide 69
                  • Slide 70
                  • Two component system containing liquid phase
                  • Slide 72
                  • The Critical Solution Temperature CST
                  • Systems Showing a Decrease in Miscibility with Rise in Temperat
                  • Systems Showing Upper and Lower CSTs
                  • Two component system containing solid and liquid phase (Eutecti
                  • Slide 77
                  • Eutectic mixture Pharmaceutical Application
                  • Three component system
                  • Slide 80
                  • Topics that we have covered

                    The critical temperature (Tc) is the temperature above which the gas cannot be made to liquefy OR is the temperature above which the liquid cannot longer exist

                    The critical pressure (Pc) is the minimum pressure required to liquefy a gas at its critical temperature

                    critical temperature (Tc) of water is 374degC or 647 K and its critical pressure is 218 atm

                    Liquefaction of Gases

                    SOLIDS amp CRYSTALLINE STATEPharmaceutical Drugs more than 80 are solid formulations

                    A crystalline solid possesses rigid and long-range order

                    In a crystalline solid atoms molecules or ions occupy specific (predictable) positions

                    An amorphous solid does not possess a well-defined arrangement and long-range molecular order

                    Solids and the crystalline state

                    Classification of Solids

                    Crystalline Amorphous

                    Amorphous

                    A unit cell is the basic repeating structural unit of a crystalline solid

                    latticepoint

                    Unit Cell Unit cells in 3 dimensions

                    At lattice points

                    bull Atoms

                    bull Molecules

                    bull Ions

                    The crystal lattice of sodium chloride NaCl

                    Na Cl

                    The various crystal forms are divide to basic 7 unit according to its symmetry

                    NaCl urea

                    iodine

                    sucrose Boric acid

                    Crystal forms

                    iodoform

                    Be3Al2(SiO3)6

                    CsCl ZnS CaF2

                    Ionic Crystalsbull Lattice points occupied by cations and anionsbull Held together by electrostatic attractionbull Hard brittle high melting pointbull Poor conductor of heat and electricity

                    Types of Crystals

                    diamondgraphite

                    carbonatoms

                    Covalent Crystalsbull Lattice points occupied by atomsbull Held together by covalent bondsbull Hard high melting pointbull Poor conductor of heat and electricity

                    Cross Section of a Metallic Crystal

                    nucleus ampinner shell e-

                    mobile ldquoseardquoof e-

                    Metallic Crystalsbull Lattice points occupied by metal atomsbull Held together by metallic bondsbull Soft to hard low to high melting pointbull Good conductors of heat and electricity

                    Some elemental substance such as C and S may exist in more than one crystalline form and are said to be allotropic which is a special case of polymorphism

                    Polymorphism is the ability of a substance to exist in more than one crystal structure

                    Polymorphism

                    Polymorphism is the ability of a substance to exist in more than one crystal structure

                    Polymorphs when two crystals have the same chemical composition but different internal structure (molecular packing ndashmolecular conformation or and inter or intra molecular interactions)modifications or polymorphs or forms

                    Pseudo polymorphs different crystal forms have molecules of the same given substances and also contain molecules of solvent incorporated into a unique structure (solvates or hydrates (water))

                    diamond graphite

                    carbonatoms

                    High T and p

                    Diamond is metastable and converts very slowly to graphite

                    The most common example of polymorphism

                    Solid State Polymorphs

                    Mono-component systems Polymorphs

                    Multi-component systems

                    Cocrystal

                    The simplest definition of a cocrystal is a crystalline structure made up of two or more components in a definite stoichiometric ratio where each component is defined as either an atom ion or molecule

                    Principle of polymorphism

                    When the change from one form to another is reversible it is said to be enantiotropic

                    When the transition takes place in one direction onlymdashfor example from a metastable to a stable formmdashthe change is said to be monotropic

                    Solvates

                    Pharmaceutical synthesis include purification and crystallization residual solvent can be trapped in the lattice

                    This result in the formation of cocrystal or solvate

                    The presence of residual solvent may affect dramatically the crystalline structure of the solid depending on the type of inter molecular forces that the solvent may have with crystalline solid

                    Melting pointVapor pressureHardnessOptical electrical magnetic

                    propertiesColorIR spectraNMR spectra

                    Photochemical reactivityThermal stabilityFiltration and drying characteristicsDissolution rateBioavailabilityPhysical and chemical stability

                    Solubility and melting point are very important in pharmaceutical processes including dissolution and

                    formulation

                    Polymorphism

                    AMORPHOUS SOLIDS Solids that donrsquot have a definite geometrical shape are known as Amorphous Solids1 In these solids particles are randomly arranged in three dimension2 They donrsquot have sharp melting points3 Amorphous solids are formed due to sudden cooling of liquid4 Amorphous solids melt over a wide range of temperature

                    Amorphous Solid

                    An amorphous solid does not possess a well-defined arrangement and long-range molecular order

                    Amorphous substances as well as cubic crystal are isotropic that is they exhibit similar properties in all direction

                    The crystalline from of the antibiotic novobiocin acid is poorly absorbed and has no activity where the amorphous form is readily absorbed and therapeutically active due to different dissolution rate

                    Amorphous or crystalline amp therapeutic activity

                    General crystallization conditions 1048698Solvents ndashdifferent polarities 1048698Concentration of the solutions (super saturated saturated diluted) 1048698Cooling speed (quenching slow) 1048698Temperature (room or lower than room temperature)

                    Crystallization

                    Final Form

                    Granulation

                    Drying

                    Compaction

                    Tableting

                    Drug Product

                    API

                    Crystallization

                    Filtration

                    Drying

                    Milling

                    Bulk API

                    Stability

                    Polymorphism and Industry Pharmaceutical

                    Polymorphism and Industry Pharmaceutical

                    Fluoxetine HCl the active ingredient in the antidepressant drug Prozac

                    co crystal which will have increased solubility compared to the crystalline form

                    Celecoxib

                    CELECOXIB is a nonsteroidal anti-inflammatory drug

                    However it was found that the higher bioavailability was shown by the amorphous state

                    The downfall of the amorphous state was its stability

                    This was due to the structural relaxation

                    This was enhanced by mixing it with polymers like PVP which helped in stabilizing the amorphous system (Piyush Gupta et al 2004 Piyush Gupta et al 2005)

                    A new solid state form was developed by Pharmacia

                    FurosemideTwo forms with significantly differing aqueous solubility and dissolution rateOral bioavailability compromised

                    Giron lists gt20 excipients that display polymorphism includingndash Lactose (anhydrous also monohydrate)ndash Aspartame (anhydrous hydrate forms)ndash Magnesium stearate (can affect lubrication of tablets)

                    Bioavailability

                    The rate and extent to which the active ingredient or active moiety is absorbed from a drug product and becomes available at the site of action

                    Bioequivalence

                    The absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study

                    Carbamazepine

                    CHLORPROPAMIDEat least six polymorphic white or almost white crystalline powder It exhibits polymorphism Practically insoluble in water soluble in alcohol freely soluble in acetone and in dichlo-romethane dissolves in dilute solutions of alkali hydroxides Protect from light

                    blood-glucose-lowering drug

                    AIDS drug ritonavir

                    Theobroma oil (cacao butter ) is a polymorphic natural fat

                    Theobroma oil can exist in 4 different polymorphic forms of which only one is Stabile

                    1 Unstable gamma form melting at 18degC2 Alpha form melting at 22degC3 Beta prime form melting at 28degC4 Stable beta form melting at 345degC

                    This is important in the preparation of theobroma suppositories

                    If the oil is heated to a point where it is completely liquified (about 35 C) the crystals of the stable polymorph are destroyed amp the mass does not crystallize until it is cooled to 15 C

                    The crystals that form are unstable amp the suppositories melt at 24 C

                    Theobroma suppositories must be prepared below 33 C

                    Polymorphism and Industry Pharmaceutical

                    Polymorphism and Industry Pharmaceutical

                    Anhydrates together with salts form the majority of all drug formulationsAbout a half of all APIs used today are saltsSalts are stable and well soluble in polar solvents (first of all in water) because they contain ionic bondThere is one more essential advantage of salts ndash their solubility is a function of pH Since pH in the gastrointestinal tract (GIT) vary between 1-75

                    atorvastatin calcium trihydrateEach tablet contains Atorvastatin Calcium Trihydrate equivalent to Atorvastatin 20 mg

                    Phase Equilibria amp The Phase Rule

                    Phase diagram ndash Water

                    Phase Equilibrium A stable phase structure with lowest free-energy (internal energy) of a system and also randomness or disorder of the atoms or molecules (entropy)

                    Any change in Temperature Composition and Pressure causes an increase in free energy and away from Equilibrium thus forcing a move to another lsquostatersquo

                    Phase Equilibria amp The Phase Rule Definitions

                    A phase is defined as any homogeneous and physically distinct part of a system which is separated from other parts of the system by interfaces

                    A part of a system is homogeneous if it has identical physical properties and chemical composition throughout the part

                    A phase may be gas liquid or solid A gas or a gaseous mixture is a single phase Totally miscible liquids constitute a single phase In an immiscible liquid system each layer is counted as a separate phase Every solid constitutes a single phase except when a solid solution is formed A solid solution is considered as a single phase Each polymorphic form constitutes a separate phase

                    Phase Definition

                    1 Liquid water pieces of ice and water vapour are present together The number of phases is 3 as each form is a separate phase Ice in the system is a single phase even if it is present as a number of pieces

                    2 Calcium carbonate undergoes thermal decomposition The chemical reaction is CaCO3(s) CaO(s) + CO2 (g) Number of phases = 3 This system consists of 2 solid phases CaCO3 and CaO and one gaseous phase that of CO2

                    3 Ammonium chloride undergoes thermal decomposition The chemical reaction is NH4Cl(s) NH3 (g) + HCl (g) Number of phases = 2 This system has two phases one solid NH4Cl and one gaseous a mixture of NH3 and HCl

                    4 A solution of NaCl in water Number of phases = 1

                    bull Examples

                    The number of components of a system at equilibrium is the smallest number of independently varying chemical constituents using which the composition of each and every phase in the system can be expressed

                    Components

                    Counting the number of components 1 The sulphur system is a one component system All the phases

                    monoclinic rhombic liquid and vapour ndash can be expressed in terms of the single constituent ndash sulphur

                    2 A mixture of ethanol and water is an example of a two component system We need both ethanol and water to express its composition

                    bull Examples

                    An example of a system in which a reaction occurs and an equilibrium is established is the thermal decomposition of solid CaCO3

                    In this system there are three distinct phasesSolid CaCO3

                    Solid CaOGaseous CO2

                    Though there are 3 species present the number of components is only two because of the equilibrium CaCO3 (s) CaO(s) + CO2(g)

                    Any two of the three constituents may be chosen as the components

                    If CaO and CO2 are chosen then the composition of the phase CaCO3 is expressed as one mole of component CO2 plus one mole of component CaO

                    If on the other hand CaCO3 and CO2 were chosen then the composition of the phase CaO would be described as one mole of CaCO3 minus one mole of CO2

                    The degrees of freedom or variance of a system is defined as the minimum number of variables such as

                    temperaturepressureconcentrationwhich must be fixed in order to define the system completely

                    Degrees of freedom (or variance)

                    F = C P + 2

                    1 A gaseous mixture of CO2 and N2 Three variables pressure temperature and composition are required to define this system This is hence a trivariant system

                    2 A system having only liquid water has two degrees of freedom or is bivariant Both temperature and pressure need to be mentioned in order to define the system

                    3 If to the system containing liquid water pieces of ice are added and this system with 2 phases is allowed to come to equilibrium then it is an univariant system

                    Only one variable either temperature or pressure need to be specified in order to define the systemIf the pressure on the system is maintained at 1 atm then the temperature of the system gets automatically fixed at 0oC the normal melting point of ice

                    bull Examples

                    Phase Equilibria amp The Phase Rule

                    A phase diagram (Equilibrium Phase Diagram) summarizes the conditions at which a substance exists as a solid liquid or gas

                    OR It is a ldquomaprdquo of the information about the control of phase structure of a particular material system

                    The relationships between temperature and the compositions and the quantities of phases present at equilibrium are represented

                    F = C P + 2The phase rule

                    The phase rule JW Gibbs formulated the phase rule which is a general relation

                    between the variance F the number of component C and the number of phases P at equilibrium for a system of any composition

                    For a system in equilibrium

                    F degree of freedom the least number of intensive variable that must be fixed (known) to describe the system completely

                    Phase Rule relation to determine the least number of intensive variable that can be changed without changing the equilibrium state of the system or alternately

                    The least number required to define the state of the system which is called degree of freedom F

                    Intensive variable independent variable that do not depend on the volume or the size egTemp pressure

                    Independent chemical species which comprise the system These could be Elements Ions Compounds

                    Eg Au-Cu system Components rarr Au Cu Ice-water system Component rarr H2O

                    Al2O3 ndash Cr2O3 system Components rarr Al2O3 Cr2O3

                    Component the smallest number of constituent by which the composition of each phase in the system at equilibrium can be expressed in form of chemical formula or equation

                    Phase Equilibria amp The Phase RuleComponents of a system

                    The number of phases in a system is denoted P

                    (a)A gas or a gaseous mixture is a single phase P=1

                    (b) For a solid system an alloy of two metals is a two-phase system (P=2) if the metals are immiscible but a single-phase system (P=1) if they are miscible---a homogeneous mixture of the two substances---is uniform on a molecular scale

                    (c) For a liquid system according to the solubility to decide whether a system consists of one phase or of two For example a solution of sodium chloride in water is a single phase A pair of liquids that are partially miscible or immiscible is a two-phase system(P=2)

                    Oil in water

                    Degrees of Freedom = What you can control What the system controls

                    F = C + 2 P

                    Can control the no of components added and P amp T

                    System decided how many phases to produce given the

                    conditions

                    A way of understanding the Gibbs Phase RuleThe degrees of freedom can be thought of as the difference between what you (can) control and

                    what the system controls

                    F degree of freedom the least number of intensive variable that must be fixed (known) to describe the system completely

                    Degree of freedom (or variance) F is the number of variables (T p andor composition) that can be changed independently without changing the phases of the system

                    a) At the triple pointP = 3 (solid liquid and gas)

                    C= 1 (water)P + F = C + 2

                    F = 0 (no degree of freedom)

                    b) liquid-solid curveP = 2

                    2+F = 1 + 2F= 1

                    One variable (T or P) can be changed

                    c) LiquidP =1

                    So F =2Two variables (T and P) can be varied independently

                    and the system will remains a single phase

                    One-component systemsPhase diagram of water

                    P (

                    atm

                    )

                    Critical point

                    374

                    1

                    =100=0O--Triple point

                    0006

                    218

                    Curve O -CSublimation

                    Deposition

                    Curve O-AVaporizationCondensation

                    Curve O -BMelting

                    Freezing

                    F = C P + 2

                    F = C P + 2

                    Phase Diagram of Carbon Dioxide

                    Condensed system System in which the vapor phase is ignored and only the solid andor liquid phases are considered

                    Two component system For two component system F can be 3 (3D model is needed) eg T p

                    and concentration usually we fix p = 1atm the vapor phase is neglected and F is reduced to 2

                    For three component system the pressure and temperature are fixed

                    Phenol water phase diagram

                    eg for point d (24)

                    Two component system containing liquid phase

                    Tie Line bc line The line at which the system at equilibrium will separate into phases of constant composition termed lsquoconjugate phasesrsquo

                    Lever Rule a way to calculate the proportions of each phase present on a phase diagram in a two phase field (at a given temperature and composition)

                    eg for point d (24)

                    For every 10 g of liquid system in equilibrium in point d

                    75 g phase A25 g phase B

                    ExampleMixed 24g phenol +76g water T 50degC

                    equilibrium75 g phase A 25 g phase B

                    11 phenol 63 phenol

                    011 times75 g=825 g phenol

                    063 times25 g=1575 g phenol

                    water rich phasecontains water+ phenol(11)

                    Phenol rich phasecontains Phenol (63)+ water

                    The Critical Solution Temperature CST

                    Is the maximum temperature at which the 2-phase region exists (or upper consolute temperature)

                    In the case of the phenol-water system this is 668oC (point h)

                    All combinations of phenol and water gt CST are completely miscible and yield 1-phase liquid systems

                    Systems Showing a Decrease in Miscibility with Rise in Temperature

                    A few mixtures exhibit a lower critical solution temperature (low CST) eg triethylamine plus water The miscibility with in temperature

                    Systems Showing Upper and Lower CSTs

                    The miscibility with temp

                    a certain temperature miscibility starts to again with further in temperature

                    Closed-phase diagram ie nicotine-water system

                    A salol B thymol

                    53

                    Two component system containing solid and liquid phase (Eutectic Mixtures)

                    A salol B thymol

                    EMLAreg (lidocaine 25 and prilocaine 25) Cream

                    EMLA Cream (lidocaine 25 and prilocaine 25) is an emulsion in which the oil phase is a eutectic mixture of lidocaine and prilocaine in a ratio of 11 by weight This eutectic mixture has a melting point below room temperature and therefore both local anesthetics exist as a liquid oil rather than as crystals

                    Eutectic mixture Pharmaceutical Application

                    Triangular Diagrams for three ndash component systems

                    Three component system

                    Birzeit University Physical Pharmacy PHAR 323 Dr Hani Shtaya

                    1 Binding Forces Between Molecules2 Repulsive and Attractive Forces3 The Gaseous State The Ideal Gas Law Liquefaction of Gases Aerosols4 Solids and the Crystalline State Crystalline Solids Polymorphism Solvates Amorphous Solids5 Phase Equilibria and the Phase Rule Phase Rule Systems Containing One Component Condensed System Two-Component Systems Containing Liquid Phases Two-Component Systems Containing Solid and Liquid Phases Eutectic Mixtures Rules Relating to Triangular Diagrams

                    Topics that we have covered

                    • States of Matter
                    • States of Matter (2)
                    • Objectives of the lecture
                    • Comparison of Gases Liquids and Solids
                    • Slide 5
                    • Repulsive and Attractive Forces
                    • Ideal Gas Equation
                    • Gaseous state
                    • Slide 9
                    • Gaseous state (2)
                    • Liquefaction of Gases
                    • Slide 12
                    • SOLIDS amp CRYSTALLINE STATE Pharmaceutical Drugs more than 80
                    • Solids and the crystalline state
                    • Classification of Solids
                    • Slide 16
                    • Slide 17
                    • Crystal forms
                    • Types of Crystals
                    • Slide 20
                    • Slide 21
                    • Polymorphism
                    • Slide 23
                    • Slide 24
                    • Slide 25
                    • Slide 26
                    • Cocrystal
                    • Principle of polymorphism
                    • Solvates
                    • Polymorphism (2)
                    • Amorphous Solid
                    • Amorphous or crystalline amp therapeutic activity
                    • Slide 33
                    • Slide 34
                    • Polymorphism and Industry Pharmaceutical
                    • Celecoxib
                    • Furosemide
                    • Bioavailability
                    • Slide 39
                    • Slide 40
                    • Bioequivalence
                    • Slide 42
                    • Carbamazepine
                    • Slide 44
                    • AIDS drug ritonavir
                    • Slide 46
                    • Slide 47
                    • Phase Equilibria amp The Phase Rule
                    • Phase diagram ndash Water
                    • Phase Equilibria amp The Phase Rule Definitions
                    • Phase Definition
                    • Examples
                    • Components
                    • Examples
                    • Slide 55
                    • Degrees of freedom (or variance)
                    • Examples (2)
                    • Phase Equilibria amp The Phase Rule
                    • The phase rule
                    • Slide 60
                    • Phase Equilibria amp The Phase Rule (2)
                    • The number of phases in a system is denoted P
                    • Slide 63
                    • Slide 64
                    • One-component systems
                    • Slide 66
                    • Slide 67
                    • Slide 68
                    • Slide 69
                    • Slide 70
                    • Two component system containing liquid phase
                    • Slide 72
                    • The Critical Solution Temperature CST
                    • Systems Showing a Decrease in Miscibility with Rise in Temperat
                    • Systems Showing Upper and Lower CSTs
                    • Two component system containing solid and liquid phase (Eutecti
                    • Slide 77
                    • Eutectic mixture Pharmaceutical Application
                    • Three component system
                    • Slide 80
                    • Topics that we have covered

                      SOLIDS amp CRYSTALLINE STATEPharmaceutical Drugs more than 80 are solid formulations

                      A crystalline solid possesses rigid and long-range order

                      In a crystalline solid atoms molecules or ions occupy specific (predictable) positions

                      An amorphous solid does not possess a well-defined arrangement and long-range molecular order

                      Solids and the crystalline state

                      Classification of Solids

                      Crystalline Amorphous

                      Amorphous

                      A unit cell is the basic repeating structural unit of a crystalline solid

                      latticepoint

                      Unit Cell Unit cells in 3 dimensions

                      At lattice points

                      bull Atoms

                      bull Molecules

                      bull Ions

                      The crystal lattice of sodium chloride NaCl

                      Na Cl

                      The various crystal forms are divide to basic 7 unit according to its symmetry

                      NaCl urea

                      iodine

                      sucrose Boric acid

                      Crystal forms

                      iodoform

                      Be3Al2(SiO3)6

                      CsCl ZnS CaF2

                      Ionic Crystalsbull Lattice points occupied by cations and anionsbull Held together by electrostatic attractionbull Hard brittle high melting pointbull Poor conductor of heat and electricity

                      Types of Crystals

                      diamondgraphite

                      carbonatoms

                      Covalent Crystalsbull Lattice points occupied by atomsbull Held together by covalent bondsbull Hard high melting pointbull Poor conductor of heat and electricity

                      Cross Section of a Metallic Crystal

                      nucleus ampinner shell e-

                      mobile ldquoseardquoof e-

                      Metallic Crystalsbull Lattice points occupied by metal atomsbull Held together by metallic bondsbull Soft to hard low to high melting pointbull Good conductors of heat and electricity

                      Some elemental substance such as C and S may exist in more than one crystalline form and are said to be allotropic which is a special case of polymorphism

                      Polymorphism is the ability of a substance to exist in more than one crystal structure

                      Polymorphism

                      Polymorphism is the ability of a substance to exist in more than one crystal structure

                      Polymorphs when two crystals have the same chemical composition but different internal structure (molecular packing ndashmolecular conformation or and inter or intra molecular interactions)modifications or polymorphs or forms

                      Pseudo polymorphs different crystal forms have molecules of the same given substances and also contain molecules of solvent incorporated into a unique structure (solvates or hydrates (water))

                      diamond graphite

                      carbonatoms

                      High T and p

                      Diamond is metastable and converts very slowly to graphite

                      The most common example of polymorphism

                      Solid State Polymorphs

                      Mono-component systems Polymorphs

                      Multi-component systems

                      Cocrystal

                      The simplest definition of a cocrystal is a crystalline structure made up of two or more components in a definite stoichiometric ratio where each component is defined as either an atom ion or molecule

                      Principle of polymorphism

                      When the change from one form to another is reversible it is said to be enantiotropic

                      When the transition takes place in one direction onlymdashfor example from a metastable to a stable formmdashthe change is said to be monotropic

                      Solvates

                      Pharmaceutical synthesis include purification and crystallization residual solvent can be trapped in the lattice

                      This result in the formation of cocrystal or solvate

                      The presence of residual solvent may affect dramatically the crystalline structure of the solid depending on the type of inter molecular forces that the solvent may have with crystalline solid

                      Melting pointVapor pressureHardnessOptical electrical magnetic

                      propertiesColorIR spectraNMR spectra

                      Photochemical reactivityThermal stabilityFiltration and drying characteristicsDissolution rateBioavailabilityPhysical and chemical stability

                      Solubility and melting point are very important in pharmaceutical processes including dissolution and

                      formulation

                      Polymorphism

                      AMORPHOUS SOLIDS Solids that donrsquot have a definite geometrical shape are known as Amorphous Solids1 In these solids particles are randomly arranged in three dimension2 They donrsquot have sharp melting points3 Amorphous solids are formed due to sudden cooling of liquid4 Amorphous solids melt over a wide range of temperature

                      Amorphous Solid

                      An amorphous solid does not possess a well-defined arrangement and long-range molecular order

                      Amorphous substances as well as cubic crystal are isotropic that is they exhibit similar properties in all direction

                      The crystalline from of the antibiotic novobiocin acid is poorly absorbed and has no activity where the amorphous form is readily absorbed and therapeutically active due to different dissolution rate

                      Amorphous or crystalline amp therapeutic activity

                      General crystallization conditions 1048698Solvents ndashdifferent polarities 1048698Concentration of the solutions (super saturated saturated diluted) 1048698Cooling speed (quenching slow) 1048698Temperature (room or lower than room temperature)

                      Crystallization

                      Final Form

                      Granulation

                      Drying

                      Compaction

                      Tableting

                      Drug Product

                      API

                      Crystallization

                      Filtration

                      Drying

                      Milling

                      Bulk API

                      Stability

                      Polymorphism and Industry Pharmaceutical

                      Polymorphism and Industry Pharmaceutical

                      Fluoxetine HCl the active ingredient in the antidepressant drug Prozac

                      co crystal which will have increased solubility compared to the crystalline form

                      Celecoxib

                      CELECOXIB is a nonsteroidal anti-inflammatory drug

                      However it was found that the higher bioavailability was shown by the amorphous state

                      The downfall of the amorphous state was its stability

                      This was due to the structural relaxation

                      This was enhanced by mixing it with polymers like PVP which helped in stabilizing the amorphous system (Piyush Gupta et al 2004 Piyush Gupta et al 2005)

                      A new solid state form was developed by Pharmacia

                      FurosemideTwo forms with significantly differing aqueous solubility and dissolution rateOral bioavailability compromised

                      Giron lists gt20 excipients that display polymorphism includingndash Lactose (anhydrous also monohydrate)ndash Aspartame (anhydrous hydrate forms)ndash Magnesium stearate (can affect lubrication of tablets)

                      Bioavailability

                      The rate and extent to which the active ingredient or active moiety is absorbed from a drug product and becomes available at the site of action

                      Bioequivalence

                      The absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study

                      Carbamazepine

                      CHLORPROPAMIDEat least six polymorphic white or almost white crystalline powder It exhibits polymorphism Practically insoluble in water soluble in alcohol freely soluble in acetone and in dichlo-romethane dissolves in dilute solutions of alkali hydroxides Protect from light

                      blood-glucose-lowering drug

                      AIDS drug ritonavir

                      Theobroma oil (cacao butter ) is a polymorphic natural fat

                      Theobroma oil can exist in 4 different polymorphic forms of which only one is Stabile

                      1 Unstable gamma form melting at 18degC2 Alpha form melting at 22degC3 Beta prime form melting at 28degC4 Stable beta form melting at 345degC

                      This is important in the preparation of theobroma suppositories

                      If the oil is heated to a point where it is completely liquified (about 35 C) the crystals of the stable polymorph are destroyed amp the mass does not crystallize until it is cooled to 15 C

                      The crystals that form are unstable amp the suppositories melt at 24 C

                      Theobroma suppositories must be prepared below 33 C

                      Polymorphism and Industry Pharmaceutical

                      Polymorphism and Industry Pharmaceutical

                      Anhydrates together with salts form the majority of all drug formulationsAbout a half of all APIs used today are saltsSalts are stable and well soluble in polar solvents (first of all in water) because they contain ionic bondThere is one more essential advantage of salts ndash their solubility is a function of pH Since pH in the gastrointestinal tract (GIT) vary between 1-75

                      atorvastatin calcium trihydrateEach tablet contains Atorvastatin Calcium Trihydrate equivalent to Atorvastatin 20 mg

                      Phase Equilibria amp The Phase Rule

                      Phase diagram ndash Water

                      Phase Equilibrium A stable phase structure with lowest free-energy (internal energy) of a system and also randomness or disorder of the atoms or molecules (entropy)

                      Any change in Temperature Composition and Pressure causes an increase in free energy and away from Equilibrium thus forcing a move to another lsquostatersquo

                      Phase Equilibria amp The Phase Rule Definitions

                      A phase is defined as any homogeneous and physically distinct part of a system which is separated from other parts of the system by interfaces

                      A part of a system is homogeneous if it has identical physical properties and chemical composition throughout the part

                      A phase may be gas liquid or solid A gas or a gaseous mixture is a single phase Totally miscible liquids constitute a single phase In an immiscible liquid system each layer is counted as a separate phase Every solid constitutes a single phase except when a solid solution is formed A solid solution is considered as a single phase Each polymorphic form constitutes a separate phase

                      Phase Definition

                      1 Liquid water pieces of ice and water vapour are present together The number of phases is 3 as each form is a separate phase Ice in the system is a single phase even if it is present as a number of pieces

                      2 Calcium carbonate undergoes thermal decomposition The chemical reaction is CaCO3(s) CaO(s) + CO2 (g) Number of phases = 3 This system consists of 2 solid phases CaCO3 and CaO and one gaseous phase that of CO2

                      3 Ammonium chloride undergoes thermal decomposition The chemical reaction is NH4Cl(s) NH3 (g) + HCl (g) Number of phases = 2 This system has two phases one solid NH4Cl and one gaseous a mixture of NH3 and HCl

                      4 A solution of NaCl in water Number of phases = 1

                      bull Examples

                      The number of components of a system at equilibrium is the smallest number of independently varying chemical constituents using which the composition of each and every phase in the system can be expressed

                      Components

                      Counting the number of components 1 The sulphur system is a one component system All the phases

                      monoclinic rhombic liquid and vapour ndash can be expressed in terms of the single constituent ndash sulphur

                      2 A mixture of ethanol and water is an example of a two component system We need both ethanol and water to express its composition

                      bull Examples

                      An example of a system in which a reaction occurs and an equilibrium is established is the thermal decomposition of solid CaCO3

                      In this system there are three distinct phasesSolid CaCO3

                      Solid CaOGaseous CO2

                      Though there are 3 species present the number of components is only two because of the equilibrium CaCO3 (s) CaO(s) + CO2(g)

                      Any two of the three constituents may be chosen as the components

                      If CaO and CO2 are chosen then the composition of the phase CaCO3 is expressed as one mole of component CO2 plus one mole of component CaO

                      If on the other hand CaCO3 and CO2 were chosen then the composition of the phase CaO would be described as one mole of CaCO3 minus one mole of CO2

                      The degrees of freedom or variance of a system is defined as the minimum number of variables such as

                      temperaturepressureconcentrationwhich must be fixed in order to define the system completely

                      Degrees of freedom (or variance)

                      F = C P + 2

                      1 A gaseous mixture of CO2 and N2 Three variables pressure temperature and composition are required to define this system This is hence a trivariant system

                      2 A system having only liquid water has two degrees of freedom or is bivariant Both temperature and pressure need to be mentioned in order to define the system

                      3 If to the system containing liquid water pieces of ice are added and this system with 2 phases is allowed to come to equilibrium then it is an univariant system

                      Only one variable either temperature or pressure need to be specified in order to define the systemIf the pressure on the system is maintained at 1 atm then the temperature of the system gets automatically fixed at 0oC the normal melting point of ice

                      bull Examples

                      Phase Equilibria amp The Phase Rule

                      A phase diagram (Equilibrium Phase Diagram) summarizes the conditions at which a substance exists as a solid liquid or gas

                      OR It is a ldquomaprdquo of the information about the control of phase structure of a particular material system

                      The relationships between temperature and the compositions and the quantities of phases present at equilibrium are represented

                      F = C P + 2The phase rule

                      The phase rule JW Gibbs formulated the phase rule which is a general relation

                      between the variance F the number of component C and the number of phases P at equilibrium for a system of any composition

                      For a system in equilibrium

                      F degree of freedom the least number of intensive variable that must be fixed (known) to describe the system completely

                      Phase Rule relation to determine the least number of intensive variable that can be changed without changing the equilibrium state of the system or alternately

                      The least number required to define the state of the system which is called degree of freedom F

                      Intensive variable independent variable that do not depend on the volume or the size egTemp pressure

                      Independent chemical species which comprise the system These could be Elements Ions Compounds

                      Eg Au-Cu system Components rarr Au Cu Ice-water system Component rarr H2O

                      Al2O3 ndash Cr2O3 system Components rarr Al2O3 Cr2O3

                      Component the smallest number of constituent by which the composition of each phase in the system at equilibrium can be expressed in form of chemical formula or equation

                      Phase Equilibria amp The Phase RuleComponents of a system

                      The number of phases in a system is denoted P

                      (a)A gas or a gaseous mixture is a single phase P=1

                      (b) For a solid system an alloy of two metals is a two-phase system (P=2) if the metals are immiscible but a single-phase system (P=1) if they are miscible---a homogeneous mixture of the two substances---is uniform on a molecular scale

                      (c) For a liquid system according to the solubility to decide whether a system consists of one phase or of two For example a solution of sodium chloride in water is a single phase A pair of liquids that are partially miscible or immiscible is a two-phase system(P=2)

                      Oil in water

                      Degrees of Freedom = What you can control What the system controls

                      F = C + 2 P

                      Can control the no of components added and P amp T

                      System decided how many phases to produce given the

                      conditions

                      A way of understanding the Gibbs Phase RuleThe degrees of freedom can be thought of as the difference between what you (can) control and

                      what the system controls

                      F degree of freedom the least number of intensive variable that must be fixed (known) to describe the system completely

                      Degree of freedom (or variance) F is the number of variables (T p andor composition) that can be changed independently without changing the phases of the system

                      a) At the triple pointP = 3 (solid liquid and gas)

                      C= 1 (water)P + F = C + 2

                      F = 0 (no degree of freedom)

                      b) liquid-solid curveP = 2

                      2+F = 1 + 2F= 1

                      One variable (T or P) can be changed

                      c) LiquidP =1

                      So F =2Two variables (T and P) can be varied independently

                      and the system will remains a single phase

                      One-component systemsPhase diagram of water

                      P (

                      atm

                      )

                      Critical point

                      374

                      1

                      =100=0O--Triple point

                      0006

                      218

                      Curve O -CSublimation

                      Deposition

                      Curve O-AVaporizationCondensation

                      Curve O -BMelting

                      Freezing

                      F = C P + 2

                      F = C P + 2

                      Phase Diagram of Carbon Dioxide

                      Condensed system System in which the vapor phase is ignored and only the solid andor liquid phases are considered

                      Two component system For two component system F can be 3 (3D model is needed) eg T p

                      and concentration usually we fix p = 1atm the vapor phase is neglected and F is reduced to 2

                      For three component system the pressure and temperature are fixed

                      Phenol water phase diagram

                      eg for point d (24)

                      Two component system containing liquid phase

                      Tie Line bc line The line at which the system at equilibrium will separate into phases of constant composition termed lsquoconjugate phasesrsquo

                      Lever Rule a way to calculate the proportions of each phase present on a phase diagram in a two phase field (at a given temperature and composition)

                      eg for point d (24)

                      For every 10 g of liquid system in equilibrium in point d

                      75 g phase A25 g phase B

                      ExampleMixed 24g phenol +76g water T 50degC

                      equilibrium75 g phase A 25 g phase B

                      11 phenol 63 phenol

                      011 times75 g=825 g phenol

                      063 times25 g=1575 g phenol

                      water rich phasecontains water+ phenol(11)

                      Phenol rich phasecontains Phenol (63)+ water

                      The Critical Solution Temperature CST

                      Is the maximum temperature at which the 2-phase region exists (or upper consolute temperature)

                      In the case of the phenol-water system this is 668oC (point h)

                      All combinations of phenol and water gt CST are completely miscible and yield 1-phase liquid systems

                      Systems Showing a Decrease in Miscibility with Rise in Temperature

                      A few mixtures exhibit a lower critical solution temperature (low CST) eg triethylamine plus water The miscibility with in temperature

                      Systems Showing Upper and Lower CSTs

                      The miscibility with temp

                      a certain temperature miscibility starts to again with further in temperature

                      Closed-phase diagram ie nicotine-water system

                      A salol B thymol

                      53

                      Two component system containing solid and liquid phase (Eutectic Mixtures)

                      A salol B thymol

                      EMLAreg (lidocaine 25 and prilocaine 25) Cream

                      EMLA Cream (lidocaine 25 and prilocaine 25) is an emulsion in which the oil phase is a eutectic mixture of lidocaine and prilocaine in a ratio of 11 by weight This eutectic mixture has a melting point below room temperature and therefore both local anesthetics exist as a liquid oil rather than as crystals

                      Eutectic mixture Pharmaceutical Application

                      Triangular Diagrams for three ndash component systems

                      Three component system

                      Birzeit University Physical Pharmacy PHAR 323 Dr Hani Shtaya

                      1 Binding Forces Between Molecules2 Repulsive and Attractive Forces3 The Gaseous State The Ideal Gas Law Liquefaction of Gases Aerosols4 Solids and the Crystalline State Crystalline Solids Polymorphism Solvates Amorphous Solids5 Phase Equilibria and the Phase Rule Phase Rule Systems Containing One Component Condensed System Two-Component Systems Containing Liquid Phases Two-Component Systems Containing Solid and Liquid Phases Eutectic Mixtures Rules Relating to Triangular Diagrams

                      Topics that we have covered

                      • States of Matter
                      • States of Matter (2)
                      • Objectives of the lecture
                      • Comparison of Gases Liquids and Solids
                      • Slide 5
                      • Repulsive and Attractive Forces
                      • Ideal Gas Equation
                      • Gaseous state
                      • Slide 9
                      • Gaseous state (2)
                      • Liquefaction of Gases
                      • Slide 12
                      • SOLIDS amp CRYSTALLINE STATE Pharmaceutical Drugs more than 80
                      • Solids and the crystalline state
                      • Classification of Solids
                      • Slide 16
                      • Slide 17
                      • Crystal forms
                      • Types of Crystals
                      • Slide 20
                      • Slide 21
                      • Polymorphism
                      • Slide 23
                      • Slide 24
                      • Slide 25
                      • Slide 26
                      • Cocrystal
                      • Principle of polymorphism
                      • Solvates
                      • Polymorphism (2)
                      • Amorphous Solid
                      • Amorphous or crystalline amp therapeutic activity
                      • Slide 33
                      • Slide 34
                      • Polymorphism and Industry Pharmaceutical
                      • Celecoxib
                      • Furosemide
                      • Bioavailability
                      • Slide 39
                      • Slide 40
                      • Bioequivalence
                      • Slide 42
                      • Carbamazepine
                      • Slide 44
                      • AIDS drug ritonavir
                      • Slide 46
                      • Slide 47
                      • Phase Equilibria amp The Phase Rule
                      • Phase diagram ndash Water
                      • Phase Equilibria amp The Phase Rule Definitions
                      • Phase Definition
                      • Examples
                      • Components
                      • Examples
                      • Slide 55
                      • Degrees of freedom (or variance)
                      • Examples (2)
                      • Phase Equilibria amp The Phase Rule
                      • The phase rule
                      • Slide 60
                      • Phase Equilibria amp The Phase Rule (2)
                      • The number of phases in a system is denoted P
                      • Slide 63
                      • Slide 64
                      • One-component systems
                      • Slide 66
                      • Slide 67
                      • Slide 68
                      • Slide 69
                      • Slide 70
                      • Two component system containing liquid phase
                      • Slide 72
                      • The Critical Solution Temperature CST
                      • Systems Showing a Decrease in Miscibility with Rise in Temperat
                      • Systems Showing Upper and Lower CSTs
                      • Two component system containing solid and liquid phase (Eutecti
                      • Slide 77
                      • Eutectic mixture Pharmaceutical Application
                      • Three component system
                      • Slide 80
                      • Topics that we have covered

                        A crystalline solid possesses rigid and long-range order

                        In a crystalline solid atoms molecules or ions occupy specific (predictable) positions

                        An amorphous solid does not possess a well-defined arrangement and long-range molecular order

                        Solids and the crystalline state

                        Classification of Solids

                        Crystalline Amorphous

                        Amorphous

                        A unit cell is the basic repeating structural unit of a crystalline solid

                        latticepoint

                        Unit Cell Unit cells in 3 dimensions

                        At lattice points

                        bull Atoms

                        bull Molecules

                        bull Ions

                        The crystal lattice of sodium chloride NaCl

                        Na Cl

                        The various crystal forms are divide to basic 7 unit according to its symmetry

                        NaCl urea

                        iodine

                        sucrose Boric acid

                        Crystal forms

                        iodoform

                        Be3Al2(SiO3)6

                        CsCl ZnS CaF2

                        Ionic Crystalsbull Lattice points occupied by cations and anionsbull Held together by electrostatic attractionbull Hard brittle high melting pointbull Poor conductor of heat and electricity

                        Types of Crystals

                        diamondgraphite

                        carbonatoms

                        Covalent Crystalsbull Lattice points occupied by atomsbull Held together by covalent bondsbull Hard high melting pointbull Poor conductor of heat and electricity

                        Cross Section of a Metallic Crystal

                        nucleus ampinner shell e-

                        mobile ldquoseardquoof e-

                        Metallic Crystalsbull Lattice points occupied by metal atomsbull Held together by metallic bondsbull Soft to hard low to high melting pointbull Good conductors of heat and electricity

                        Some elemental substance such as C and S may exist in more than one crystalline form and are said to be allotropic which is a special case of polymorphism

                        Polymorphism is the ability of a substance to exist in more than one crystal structure

                        Polymorphism

                        Polymorphism is the ability of a substance to exist in more than one crystal structure

                        Polymorphs when two crystals have the same chemical composition but different internal structure (molecular packing ndashmolecular conformation or and inter or intra molecular interactions)modifications or polymorphs or forms

                        Pseudo polymorphs different crystal forms have molecules of the same given substances and also contain molecules of solvent incorporated into a unique structure (solvates or hydrates (water))

                        diamond graphite

                        carbonatoms

                        High T and p

                        Diamond is metastable and converts very slowly to graphite

                        The most common example of polymorphism

                        Solid State Polymorphs

                        Mono-component systems Polymorphs

                        Multi-component systems

                        Cocrystal

                        The simplest definition of a cocrystal is a crystalline structure made up of two or more components in a definite stoichiometric ratio where each component is defined as either an atom ion or molecule

                        Principle of polymorphism

                        When the change from one form to another is reversible it is said to be enantiotropic

                        When the transition takes place in one direction onlymdashfor example from a metastable to a stable formmdashthe change is said to be monotropic

                        Solvates

                        Pharmaceutical synthesis include purification and crystallization residual solvent can be trapped in the lattice

                        This result in the formation of cocrystal or solvate

                        The presence of residual solvent may affect dramatically the crystalline structure of the solid depending on the type of inter molecular forces that the solvent may have with crystalline solid

                        Melting pointVapor pressureHardnessOptical electrical magnetic

                        propertiesColorIR spectraNMR spectra

                        Photochemical reactivityThermal stabilityFiltration and drying characteristicsDissolution rateBioavailabilityPhysical and chemical stability

                        Solubility and melting point are very important in pharmaceutical processes including dissolution and

                        formulation

                        Polymorphism

                        AMORPHOUS SOLIDS Solids that donrsquot have a definite geometrical shape are known as Amorphous Solids1 In these solids particles are randomly arranged in three dimension2 They donrsquot have sharp melting points3 Amorphous solids are formed due to sudden cooling of liquid4 Amorphous solids melt over a wide range of temperature

                        Amorphous Solid

                        An amorphous solid does not possess a well-defined arrangement and long-range molecular order

                        Amorphous substances as well as cubic crystal are isotropic that is they exhibit similar properties in all direction

                        The crystalline from of the antibiotic novobiocin acid is poorly absorbed and has no activity where the amorphous form is readily absorbed and therapeutically active due to different dissolution rate

                        Amorphous or crystalline amp therapeutic activity

                        General crystallization conditions 1048698Solvents ndashdifferent polarities 1048698Concentration of the solutions (super saturated saturated diluted) 1048698Cooling speed (quenching slow) 1048698Temperature (room or lower than room temperature)

                        Crystallization

                        Final Form

                        Granulation

                        Drying

                        Compaction

                        Tableting

                        Drug Product

                        API

                        Crystallization

                        Filtration

                        Drying

                        Milling

                        Bulk API

                        Stability

                        Polymorphism and Industry Pharmaceutical

                        Polymorphism and Industry Pharmaceutical

                        Fluoxetine HCl the active ingredient in the antidepressant drug Prozac

                        co crystal which will have increased solubility compared to the crystalline form

                        Celecoxib

                        CELECOXIB is a nonsteroidal anti-inflammatory drug

                        However it was found that the higher bioavailability was shown by the amorphous state

                        The downfall of the amorphous state was its stability

                        This was due to the structural relaxation

                        This was enhanced by mixing it with polymers like PVP which helped in stabilizing the amorphous system (Piyush Gupta et al 2004 Piyush Gupta et al 2005)

                        A new solid state form was developed by Pharmacia

                        FurosemideTwo forms with significantly differing aqueous solubility and dissolution rateOral bioavailability compromised

                        Giron lists gt20 excipients that display polymorphism includingndash Lactose (anhydrous also monohydrate)ndash Aspartame (anhydrous hydrate forms)ndash Magnesium stearate (can affect lubrication of tablets)

                        Bioavailability

                        The rate and extent to which the active ingredient or active moiety is absorbed from a drug product and becomes available at the site of action

                        Bioequivalence

                        The absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study

                        Carbamazepine

                        CHLORPROPAMIDEat least six polymorphic white or almost white crystalline powder It exhibits polymorphism Practically insoluble in water soluble in alcohol freely soluble in acetone and in dichlo-romethane dissolves in dilute solutions of alkali hydroxides Protect from light

                        blood-glucose-lowering drug

                        AIDS drug ritonavir

                        Theobroma oil (cacao butter ) is a polymorphic natural fat

                        Theobroma oil can exist in 4 different polymorphic forms of which only one is Stabile

                        1 Unstable gamma form melting at 18degC2 Alpha form melting at 22degC3 Beta prime form melting at 28degC4 Stable beta form melting at 345degC

                        This is important in the preparation of theobroma suppositories

                        If the oil is heated to a point where it is completely liquified (about 35 C) the crystals of the stable polymorph are destroyed amp the mass does not crystallize until it is cooled to 15 C

                        The crystals that form are unstable amp the suppositories melt at 24 C

                        Theobroma suppositories must be prepared below 33 C

                        Polymorphism and Industry Pharmaceutical

                        Polymorphism and Industry Pharmaceutical

                        Anhydrates together with salts form the majority of all drug formulationsAbout a half of all APIs used today are saltsSalts are stable and well soluble in polar solvents (first of all in water) because they contain ionic bondThere is one more essential advantage of salts ndash their solubility is a function of pH Since pH in the gastrointestinal tract (GIT) vary between 1-75

                        atorvastatin calcium trihydrateEach tablet contains Atorvastatin Calcium Trihydrate equivalent to Atorvastatin 20 mg

                        Phase Equilibria amp The Phase Rule

                        Phase diagram ndash Water

                        Phase Equilibrium A stable phase structure with lowest free-energy (internal energy) of a system and also randomness or disorder of the atoms or molecules (entropy)

                        Any change in Temperature Composition and Pressure causes an increase in free energy and away from Equilibrium thus forcing a move to another lsquostatersquo

                        Phase Equilibria amp The Phase Rule Definitions

                        A phase is defined as any homogeneous and physically distinct part of a system which is separated from other parts of the system by interfaces

                        A part of a system is homogeneous if it has identical physical properties and chemical composition throughout the part

                        A phase may be gas liquid or solid A gas or a gaseous mixture is a single phase Totally miscible liquids constitute a single phase In an immiscible liquid system each layer is counted as a separate phase Every solid constitutes a single phase except when a solid solution is formed A solid solution is considered as a single phase Each polymorphic form constitutes a separate phase

                        Phase Definition

                        1 Liquid water pieces of ice and water vapour are present together The number of phases is 3 as each form is a separate phase Ice in the system is a single phase even if it is present as a number of pieces

                        2 Calcium carbonate undergoes thermal decomposition The chemical reaction is CaCO3(s) CaO(s) + CO2 (g) Number of phases = 3 This system consists of 2 solid phases CaCO3 and CaO and one gaseous phase that of CO2

                        3 Ammonium chloride undergoes thermal decomposition The chemical reaction is NH4Cl(s) NH3 (g) + HCl (g) Number of phases = 2 This system has two phases one solid NH4Cl and one gaseous a mixture of NH3 and HCl

                        4 A solution of NaCl in water Number of phases = 1

                        bull Examples

                        The number of components of a system at equilibrium is the smallest number of independently varying chemical constituents using which the composition of each and every phase in the system can be expressed

                        Components

                        Counting the number of components 1 The sulphur system is a one component system All the phases

                        monoclinic rhombic liquid and vapour ndash can be expressed in terms of the single constituent ndash sulphur

                        2 A mixture of ethanol and water is an example of a two component system We need both ethanol and water to express its composition

                        bull Examples

                        An example of a system in which a reaction occurs and an equilibrium is established is the thermal decomposition of solid CaCO3

                        In this system there are three distinct phasesSolid CaCO3

                        Solid CaOGaseous CO2

                        Though there are 3 species present the number of components is only two because of the equilibrium CaCO3 (s) CaO(s) + CO2(g)

                        Any two of the three constituents may be chosen as the components

                        If CaO and CO2 are chosen then the composition of the phase CaCO3 is expressed as one mole of component CO2 plus one mole of component CaO

                        If on the other hand CaCO3 and CO2 were chosen then the composition of the phase CaO would be described as one mole of CaCO3 minus one mole of CO2

                        The degrees of freedom or variance of a system is defined as the minimum number of variables such as

                        temperaturepressureconcentrationwhich must be fixed in order to define the system completely

                        Degrees of freedom (or variance)

                        F = C P + 2

                        1 A gaseous mixture of CO2 and N2 Three variables pressure temperature and composition are required to define this system This is hence a trivariant system

                        2 A system having only liquid water has two degrees of freedom or is bivariant Both temperature and pressure need to be mentioned in order to define the system

                        3 If to the system containing liquid water pieces of ice are added and this system with 2 phases is allowed to come to equilibrium then it is an univariant system

                        Only one variable either temperature or pressure need to be specified in order to define the systemIf the pressure on the system is maintained at 1 atm then the temperature of the system gets automatically fixed at 0oC the normal melting point of ice

                        bull Examples

                        Phase Equilibria amp The Phase Rule

                        A phase diagram (Equilibrium Phase Diagram) summarizes the conditions at which a substance exists as a solid liquid or gas

                        OR It is a ldquomaprdquo of the information about the control of phase structure of a particular material system

                        The relationships between temperature and the compositions and the quantities of phases present at equilibrium are represented

                        F = C P + 2The phase rule

                        The phase rule JW Gibbs formulated the phase rule which is a general relation

                        between the variance F the number of component C and the number of phases P at equilibrium for a system of any composition

                        For a system in equilibrium

                        F degree of freedom the least number of intensive variable that must be fixed (known) to describe the system completely

                        Phase Rule relation to determine the least number of intensive variable that can be changed without changing the equilibrium state of the system or alternately

                        The least number required to define the state of the system which is called degree of freedom F

                        Intensive variable independent variable that do not depend on the volume or the size egTemp pressure

                        Independent chemical species which comprise the system These could be Elements Ions Compounds

                        Eg Au-Cu system Components rarr Au Cu Ice-water system Component rarr H2O

                        Al2O3 ndash Cr2O3 system Components rarr Al2O3 Cr2O3

                        Component the smallest number of constituent by which the composition of each phase in the system at equilibrium can be expressed in form of chemical formula or equation

                        Phase Equilibria amp The Phase RuleComponents of a system

                        The number of phases in a system is denoted P

                        (a)A gas or a gaseous mixture is a single phase P=1

                        (b) For a solid system an alloy of two metals is a two-phase system (P=2) if the metals are immiscible but a single-phase system (P=1) if they are miscible---a homogeneous mixture of the two substances---is uniform on a molecular scale

                        (c) For a liquid system according to the solubility to decide whether a system consists of one phase or of two For example a solution of sodium chloride in water is a single phase A pair of liquids that are partially miscible or immiscible is a two-phase system(P=2)

                        Oil in water

                        Degrees of Freedom = What you can control What the system controls

                        F = C + 2 P

                        Can control the no of components added and P amp T

                        System decided how many phases to produce given the

                        conditions

                        A way of understanding the Gibbs Phase RuleThe degrees of freedom can be thought of as the difference between what you (can) control and

                        what the system controls

                        F degree of freedom the least number of intensive variable that must be fixed (known) to describe the system completely

                        Degree of freedom (or variance) F is the number of variables (T p andor composition) that can be changed independently without changing the phases of the system

                        a) At the triple pointP = 3 (solid liquid and gas)

                        C= 1 (water)P + F = C + 2

                        F = 0 (no degree of freedom)

                        b) liquid-solid curveP = 2

                        2+F = 1 + 2F= 1

                        One variable (T or P) can be changed

                        c) LiquidP =1

                        So F =2Two variables (T and P) can be varied independently

                        and the system will remains a single phase

                        One-component systemsPhase diagram of water

                        P (

                        atm

                        )

                        Critical point

                        374

                        1

                        =100=0O--Triple point

                        0006

                        218

                        Curve O -CSublimation

                        Deposition

                        Curve O-AVaporizationCondensation

                        Curve O -BMelting

                        Freezing

                        F = C P + 2

                        F = C P + 2

                        Phase Diagram of Carbon Dioxide

                        Condensed system System in which the vapor phase is ignored and only the solid andor liquid phases are considered

                        Two component system For two component system F can be 3 (3D model is needed) eg T p

                        and concentration usually we fix p = 1atm the vapor phase is neglected and F is reduced to 2

                        For three component system the pressure and temperature are fixed

                        Phenol water phase diagram

                        eg for point d (24)

                        Two component system containing liquid phase

                        Tie Line bc line The line at which the system at equilibrium will separate into phases of constant composition termed lsquoconjugate phasesrsquo

                        Lever Rule a way to calculate the proportions of each phase present on a phase diagram in a two phase field (at a given temperature and composition)

                        eg for point d (24)

                        For every 10 g of liquid system in equilibrium in point d

                        75 g phase A25 g phase B

                        ExampleMixed 24g phenol +76g water T 50degC

                        equilibrium75 g phase A 25 g phase B

                        11 phenol 63 phenol

                        011 times75 g=825 g phenol

                        063 times25 g=1575 g phenol

                        water rich phasecontains water+ phenol(11)

                        Phenol rich phasecontains Phenol (63)+ water

                        The Critical Solution Temperature CST

                        Is the maximum temperature at which the 2-phase region exists (or upper consolute temperature)

                        In the case of the phenol-water system this is 668oC (point h)

                        All combinations of phenol and water gt CST are completely miscible and yield 1-phase liquid systems

                        Systems Showing a Decrease in Miscibility with Rise in Temperature

                        A few mixtures exhibit a lower critical solution temperature (low CST) eg triethylamine plus water The miscibility with in temperature

                        Systems Showing Upper and Lower CSTs

                        The miscibility with temp

                        a certain temperature miscibility starts to again with further in temperature

                        Closed-phase diagram ie nicotine-water system

                        A salol B thymol

                        53

                        Two component system containing solid and liquid phase (Eutectic Mixtures)

                        A salol B thymol

                        EMLAreg (lidocaine 25 and prilocaine 25) Cream

                        EMLA Cream (lidocaine 25 and prilocaine 25) is an emulsion in which the oil phase is a eutectic mixture of lidocaine and prilocaine in a ratio of 11 by weight This eutectic mixture has a melting point below room temperature and therefore both local anesthetics exist as a liquid oil rather than as crystals

                        Eutectic mixture Pharmaceutical Application

                        Triangular Diagrams for three ndash component systems

                        Three component system

                        Birzeit University Physical Pharmacy PHAR 323 Dr Hani Shtaya

                        1 Binding Forces Between Molecules2 Repulsive and Attractive Forces3 The Gaseous State The Ideal Gas Law Liquefaction of Gases Aerosols4 Solids and the Crystalline State Crystalline Solids Polymorphism Solvates Amorphous Solids5 Phase Equilibria and the Phase Rule Phase Rule Systems Containing One Component Condensed System Two-Component Systems Containing Liquid Phases Two-Component Systems Containing Solid and Liquid Phases Eutectic Mixtures Rules Relating to Triangular Diagrams

                        Topics that we have covered

                        • States of Matter
                        • States of Matter (2)
                        • Objectives of the lecture
                        • Comparison of Gases Liquids and Solids
                        • Slide 5
                        • Repulsive and Attractive Forces
                        • Ideal Gas Equation
                        • Gaseous state
                        • Slide 9
                        • Gaseous state (2)
                        • Liquefaction of Gases
                        • Slide 12
                        • SOLIDS amp CRYSTALLINE STATE Pharmaceutical Drugs more than 80
                        • Solids and the crystalline state
                        • Classification of Solids
                        • Slide 16
                        • Slide 17
                        • Crystal forms
                        • Types of Crystals
                        • Slide 20
                        • Slide 21
                        • Polymorphism
                        • Slide 23
                        • Slide 24
                        • Slide 25
                        • Slide 26
                        • Cocrystal
                        • Principle of polymorphism
                        • Solvates
                        • Polymorphism (2)
                        • Amorphous Solid
                        • Amorphous or crystalline amp therapeutic activity
                        • Slide 33
                        • Slide 34
                        • Polymorphism and Industry Pharmaceutical
                        • Celecoxib
                        • Furosemide
                        • Bioavailability
                        • Slide 39
                        • Slide 40
                        • Bioequivalence
                        • Slide 42
                        • Carbamazepine
                        • Slide 44
                        • AIDS drug ritonavir
                        • Slide 46
                        • Slide 47
                        • Phase Equilibria amp The Phase Rule
                        • Phase diagram ndash Water
                        • Phase Equilibria amp The Phase Rule Definitions
                        • Phase Definition
                        • Examples
                        • Components
                        • Examples
                        • Slide 55
                        • Degrees of freedom (or variance)
                        • Examples (2)
                        • Phase Equilibria amp The Phase Rule
                        • The phase rule
                        • Slide 60
                        • Phase Equilibria amp The Phase Rule (2)
                        • The number of phases in a system is denoted P
                        • Slide 63
                        • Slide 64
                        • One-component systems
                        • Slide 66
                        • Slide 67
                        • Slide 68
                        • Slide 69
                        • Slide 70
                        • Two component system containing liquid phase
                        • Slide 72
                        • The Critical Solution Temperature CST
                        • Systems Showing a Decrease in Miscibility with Rise in Temperat
                        • Systems Showing Upper and Lower CSTs
                        • Two component system containing solid and liquid phase (Eutecti
                        • Slide 77
                        • Eutectic mixture Pharmaceutical Application
                        • Three component system
                        • Slide 80
                        • Topics that we have covered

                          Classification of Solids

                          Crystalline Amorphous

                          Amorphous

                          A unit cell is the basic repeating structural unit of a crystalline solid

                          latticepoint

                          Unit Cell Unit cells in 3 dimensions

                          At lattice points

                          bull Atoms

                          bull Molecules

                          bull Ions

                          The crystal lattice of sodium chloride NaCl

                          Na Cl

                          The various crystal forms are divide to basic 7 unit according to its symmetry

                          NaCl urea

                          iodine

                          sucrose Boric acid

                          Crystal forms

                          iodoform

                          Be3Al2(SiO3)6

                          CsCl ZnS CaF2

                          Ionic Crystalsbull Lattice points occupied by cations and anionsbull Held together by electrostatic attractionbull Hard brittle high melting pointbull Poor conductor of heat and electricity

                          Types of Crystals

                          diamondgraphite

                          carbonatoms

                          Covalent Crystalsbull Lattice points occupied by atomsbull Held together by covalent bondsbull Hard high melting pointbull Poor conductor of heat and electricity

                          Cross Section of a Metallic Crystal

                          nucleus ampinner shell e-

                          mobile ldquoseardquoof e-

                          Metallic Crystalsbull Lattice points occupied by metal atomsbull Held together by metallic bondsbull Soft to hard low to high melting pointbull Good conductors of heat and electricity

                          Some elemental substance such as C and S may exist in more than one crystalline form and are said to be allotropic which is a special case of polymorphism

                          Polymorphism is the ability of a substance to exist in more than one crystal structure

                          Polymorphism

                          Polymorphism is the ability of a substance to exist in more than one crystal structure

                          Polymorphs when two crystals have the same chemical composition but different internal structure (molecular packing ndashmolecular conformation or and inter or intra molecular interactions)modifications or polymorphs or forms

                          Pseudo polymorphs different crystal forms have molecules of the same given substances and also contain molecules of solvent incorporated into a unique structure (solvates or hydrates (water))

                          diamond graphite

                          carbonatoms

                          High T and p

                          Diamond is metastable and converts very slowly to graphite

                          The most common example of polymorphism

                          Solid State Polymorphs

                          Mono-component systems Polymorphs

                          Multi-component systems

                          Cocrystal

                          The simplest definition of a cocrystal is a crystalline structure made up of two or more components in a definite stoichiometric ratio where each component is defined as either an atom ion or molecule

                          Principle of polymorphism

                          When the change from one form to another is reversible it is said to be enantiotropic

                          When the transition takes place in one direction onlymdashfor example from a metastable to a stable formmdashthe change is said to be monotropic

                          Solvates

                          Pharmaceutical synthesis include purification and crystallization residual solvent can be trapped in the lattice

                          This result in the formation of cocrystal or solvate

                          The presence of residual solvent may affect dramatically the crystalline structure of the solid depending on the type of inter molecular forces that the solvent may have with crystalline solid

                          Melting pointVapor pressureHardnessOptical electrical magnetic

                          propertiesColorIR spectraNMR spectra

                          Photochemical reactivityThermal stabilityFiltration and drying characteristicsDissolution rateBioavailabilityPhysical and chemical stability

                          Solubility and melting point are very important in pharmaceutical processes including dissolution and

                          formulation

                          Polymorphism

                          AMORPHOUS SOLIDS Solids that donrsquot have a definite geometrical shape are known as Amorphous Solids1 In these solids particles are randomly arranged in three dimension2 They donrsquot have sharp melting points3 Amorphous solids are formed due to sudden cooling of liquid4 Amorphous solids melt over a wide range of temperature

                          Amorphous Solid

                          An amorphous solid does not possess a well-defined arrangement and long-range molecular order

                          Amorphous substances as well as cubic crystal are isotropic that is they exhibit similar properties in all direction

                          The crystalline from of the antibiotic novobiocin acid is poorly absorbed and has no activity where the amorphous form is readily absorbed and therapeutically active due to different dissolution rate

                          Amorphous or crystalline amp therapeutic activity

                          General crystallization conditions 1048698Solvents ndashdifferent polarities 1048698Concentration of the solutions (super saturated saturated diluted) 1048698Cooling speed (quenching slow) 1048698Temperature (room or lower than room temperature)

                          Crystallization

                          Final Form

                          Granulation

                          Drying

                          Compaction

                          Tableting

                          Drug Product

                          API

                          Crystallization

                          Filtration

                          Drying

                          Milling

                          Bulk API

                          Stability

                          Polymorphism and Industry Pharmaceutical

                          Polymorphism and Industry Pharmaceutical

                          Fluoxetine HCl the active ingredient in the antidepressant drug Prozac

                          co crystal which will have increased solubility compared to the crystalline form

                          Celecoxib

                          CELECOXIB is a nonsteroidal anti-inflammatory drug

                          However it was found that the higher bioavailability was shown by the amorphous state

                          The downfall of the amorphous state was its stability

                          This was due to the structural relaxation

                          This was enhanced by mixing it with polymers like PVP which helped in stabilizing the amorphous system (Piyush Gupta et al 2004 Piyush Gupta et al 2005)

                          A new solid state form was developed by Pharmacia

                          FurosemideTwo forms with significantly differing aqueous solubility and dissolution rateOral bioavailability compromised

                          Giron lists gt20 excipients that display polymorphism includingndash Lactose (anhydrous also monohydrate)ndash Aspartame (anhydrous hydrate forms)ndash Magnesium stearate (can affect lubrication of tablets)

                          Bioavailability

                          The rate and extent to which the active ingredient or active moiety is absorbed from a drug product and becomes available at the site of action

                          Bioequivalence

                          The absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study

                          Carbamazepine

                          CHLORPROPAMIDEat least six polymorphic white or almost white crystalline powder It exhibits polymorphism Practically insoluble in water soluble in alcohol freely soluble in acetone and in dichlo-romethane dissolves in dilute solutions of alkali hydroxides Protect from light

                          blood-glucose-lowering drug

                          AIDS drug ritonavir

                          Theobroma oil (cacao butter ) is a polymorphic natural fat

                          Theobroma oil can exist in 4 different polymorphic forms of which only one is Stabile

                          1 Unstable gamma form melting at 18degC2 Alpha form melting at 22degC3 Beta prime form melting at 28degC4 Stable beta form melting at 345degC

                          This is important in the preparation of theobroma suppositories

                          If the oil is heated to a point where it is completely liquified (about 35 C) the crystals of the stable polymorph are destroyed amp the mass does not crystallize until it is cooled to 15 C

                          The crystals that form are unstable amp the suppositories melt at 24 C

                          Theobroma suppositories must be prepared below 33 C

                          Polymorphism and Industry Pharmaceutical

                          Polymorphism and Industry Pharmaceutical

                          Anhydrates together with salts form the majority of all drug formulationsAbout a half of all APIs used today are saltsSalts are stable and well soluble in polar solvents (first of all in water) because they contain ionic bondThere is one more essential advantage of salts ndash their solubility is a function of pH Since pH in the gastrointestinal tract (GIT) vary between 1-75

                          atorvastatin calcium trihydrateEach tablet contains Atorvastatin Calcium Trihydrate equivalent to Atorvastatin 20 mg

                          Phase Equilibria amp The Phase Rule

                          Phase diagram ndash Water

                          Phase Equilibrium A stable phase structure with lowest free-energy (internal energy) of a system and also randomness or disorder of the atoms or molecules (entropy)

                          Any change in Temperature Composition and Pressure causes an increase in free energy and away from Equilibrium thus forcing a move to another lsquostatersquo

                          Phase Equilibria amp The Phase Rule Definitions

                          A phase is defined as any homogeneous and physically distinct part of a system which is separated from other parts of the system by interfaces

                          A part of a system is homogeneous if it has identical physical properties and chemical composition throughout the part

                          A phase may be gas liquid or solid A gas or a gaseous mixture is a single phase Totally miscible liquids constitute a single phase In an immiscible liquid system each layer is counted as a separate phase Every solid constitutes a single phase except when a solid solution is formed A solid solution is considered as a single phase Each polymorphic form constitutes a separate phase

                          Phase Definition

                          1 Liquid water pieces of ice and water vapour are present together The number of phases is 3 as each form is a separate phase Ice in the system is a single phase even if it is present as a number of pieces

                          2 Calcium carbonate undergoes thermal decomposition The chemical reaction is CaCO3(s) CaO(s) + CO2 (g) Number of phases = 3 This system consists of 2 solid phases CaCO3 and CaO and one gaseous phase that of CO2

                          3 Ammonium chloride undergoes thermal decomposition The chemical reaction is NH4Cl(s) NH3 (g) + HCl (g) Number of phases = 2 This system has two phases one solid NH4Cl and one gaseous a mixture of NH3 and HCl

                          4 A solution of NaCl in water Number of phases = 1

                          bull Examples

                          The number of components of a system at equilibrium is the smallest number of independently varying chemical constituents using which the composition of each and every phase in the system can be expressed

                          Components

                          Counting the number of components 1 The sulphur system is a one component system All the phases

                          monoclinic rhombic liquid and vapour ndash can be expressed in terms of the single constituent ndash sulphur

                          2 A mixture of ethanol and water is an example of a two component system We need both ethanol and water to express its composition

                          bull Examples

                          An example of a system in which a reaction occurs and an equilibrium is established is the thermal decomposition of solid CaCO3

                          In this system there are three distinct phasesSolid CaCO3

                          Solid CaOGaseous CO2

                          Though there are 3 species present the number of components is only two because of the equilibrium CaCO3 (s) CaO(s) + CO2(g)

                          Any two of the three constituents may be chosen as the components

                          If CaO and CO2 are chosen then the composition of the phase CaCO3 is expressed as one mole of component CO2 plus one mole of component CaO

                          If on the other hand CaCO3 and CO2 were chosen then the composition of the phase CaO would be described as one mole of CaCO3 minus one mole of CO2

                          The degrees of freedom or variance of a system is defined as the minimum number of variables such as

                          temperaturepressureconcentrationwhich must be fixed in order to define the system completely

                          Degrees of freedom (or variance)

                          F = C P + 2

                          1 A gaseous mixture of CO2 and N2 Three variables pressure temperature and composition are required to define this system This is hence a trivariant system

                          2 A system having only liquid water has two degrees of freedom or is bivariant Both temperature and pressure need to be mentioned in order to define the system

                          3 If to the system containing liquid water pieces of ice are added and this system with 2 phases is allowed to come to equilibrium then it is an univariant system

                          Only one variable either temperature or pressure need to be specified in order to define the systemIf the pressure on the system is maintained at 1 atm then the temperature of the system gets automatically fixed at 0oC the normal melting point of ice

                          bull Examples

                          Phase Equilibria amp The Phase Rule

                          A phase diagram (Equilibrium Phase Diagram) summarizes the conditions at which a substance exists as a solid liquid or gas

                          OR It is a ldquomaprdquo of the information about the control of phase structure of a particular material system

                          The relationships between temperature and the compositions and the quantities of phases present at equilibrium are represented

                          F = C P + 2The phase rule

                          The phase rule JW Gibbs formulated the phase rule which is a general relation

                          between the variance F the number of component C and the number of phases P at equilibrium for a system of any composition

                          For a system in equilibrium

                          F degree of freedom the least number of intensive variable that must be fixed (known) to describe the system completely

                          Phase Rule relation to determine the least number of intensive variable that can be changed without changing the equilibrium state of the system or alternately

                          The least number required to define the state of the system which is called degree of freedom F

                          Intensive variable independent variable that do not depend on the volume or the size egTemp pressure

                          Independent chemical species which comprise the system These could be Elements Ions Compounds

                          Eg Au-Cu system Components rarr Au Cu Ice-water system Component rarr H2O

                          Al2O3 ndash Cr2O3 system Components rarr Al2O3 Cr2O3

                          Component the smallest number of constituent by which the composition of each phase in the system at equilibrium can be expressed in form of chemical formula or equation

                          Phase Equilibria amp The Phase RuleComponents of a system

                          The number of phases in a system is denoted P

                          (a)A gas or a gaseous mixture is a single phase P=1

                          (b) For a solid system an alloy of two metals is a two-phase system (P=2) if the metals are immiscible but a single-phase system (P=1) if they are miscible---a homogeneous mixture of the two substances---is uniform on a molecular scale

                          (c) For a liquid system according to the solubility to decide whether a system consists of one phase or of two For example a solution of sodium chloride in water is a single phase A pair of liquids that are partially miscible or immiscible is a two-phase system(P=2)

                          Oil in water

                          Degrees of Freedom = What you can control What the system controls

                          F = C + 2 P

                          Can control the no of components added and P amp T

                          System decided how many phases to produce given the

                          conditions

                          A way of understanding the Gibbs Phase RuleThe degrees of freedom can be thought of as the difference between what you (can) control and

                          what the system controls

                          F degree of freedom the least number of intensive variable that must be fixed (known) to describe the system completely

                          Degree of freedom (or variance) F is the number of variables (T p andor composition) that can be changed independently without changing the phases of the system

                          a) At the triple pointP = 3 (solid liquid and gas)

                          C= 1 (water)P + F = C + 2

                          F = 0 (no degree of freedom)

                          b) liquid-solid curveP = 2

                          2+F = 1 + 2F= 1

                          One variable (T or P) can be changed

                          c) LiquidP =1

                          So F =2Two variables (T and P) can be varied independently

                          and the system will remains a single phase

                          One-component systemsPhase diagram of water

                          P (

                          atm

                          )

                          Critical point

                          374

                          1

                          =100=0O--Triple point

                          0006

                          218

                          Curve O -CSublimation

                          Deposition

                          Curve O-AVaporizationCondensation

                          Curve O -BMelting

                          Freezing

                          F = C P + 2

                          F = C P + 2

                          Phase Diagram of Carbon Dioxide

                          Condensed system System in which the vapor phase is ignored and only the solid andor liquid phases are considered

                          Two component system For two component system F can be 3 (3D model is needed) eg T p

                          and concentration usually we fix p = 1atm the vapor phase is neglected and F is reduced to 2

                          For three component system the pressure and temperature are fixed

                          Phenol water phase diagram

                          eg for point d (24)

                          Two component system containing liquid phase

                          Tie Line bc line The line at which the system at equilibrium will separate into phases of constant composition termed lsquoconjugate phasesrsquo

                          Lever Rule a way to calculate the proportions of each phase present on a phase diagram in a two phase field (at a given temperature and composition)

                          eg for point d (24)

                          For every 10 g of liquid system in equilibrium in point d

                          75 g phase A25 g phase B

                          ExampleMixed 24g phenol +76g water T 50degC

                          equilibrium75 g phase A 25 g phase B

                          11 phenol 63 phenol

                          011 times75 g=825 g phenol

                          063 times25 g=1575 g phenol

                          water rich phasecontains water+ phenol(11)

                          Phenol rich phasecontains Phenol (63)+ water

                          The Critical Solution Temperature CST

                          Is the maximum temperature at which the 2-phase region exists (or upper consolute temperature)

                          In the case of the phenol-water system this is 668oC (point h)

                          All combinations of phenol and water gt CST are completely miscible and yield 1-phase liquid systems

                          Systems Showing a Decrease in Miscibility with Rise in Temperature

                          A few mixtures exhibit a lower critical solution temperature (low CST) eg triethylamine plus water The miscibility with in temperature

                          Systems Showing Upper and Lower CSTs

                          The miscibility with temp

                          a certain temperature miscibility starts to again with further in temperature

                          Closed-phase diagram ie nicotine-water system

                          A salol B thymol

                          53

                          Two component system containing solid and liquid phase (Eutectic Mixtures)

                          A salol B thymol

                          EMLAreg (lidocaine 25 and prilocaine 25) Cream

                          EMLA Cream (lidocaine 25 and prilocaine 25) is an emulsion in which the oil phase is a eutectic mixture of lidocaine and prilocaine in a ratio of 11 by weight This eutectic mixture has a melting point below room temperature and therefore both local anesthetics exist as a liquid oil rather than as crystals

                          Eutectic mixture Pharmaceutical Application

                          Triangular Diagrams for three ndash component systems

                          Three component system

                          Birzeit University Physical Pharmacy PHAR 323 Dr Hani Shtaya

                          1 Binding Forces Between Molecules2 Repulsive and Attractive Forces3 The Gaseous State The Ideal Gas Law Liquefaction of Gases Aerosols4 Solids and the Crystalline State Crystalline Solids Polymorphism Solvates Amorphous Solids5 Phase Equilibria and the Phase Rule Phase Rule Systems Containing One Component Condensed System Two-Component Systems Containing Liquid Phases Two-Component Systems Containing Solid and Liquid Phases Eutectic Mixtures Rules Relating to Triangular Diagrams

                          Topics that we have covered

                          • States of Matter
                          • States of Matter (2)
                          • Objectives of the lecture
                          • Comparison of Gases Liquids and Solids
                          • Slide 5
                          • Repulsive and Attractive Forces
                          • Ideal Gas Equation
                          • Gaseous state
                          • Slide 9
                          • Gaseous state (2)
                          • Liquefaction of Gases
                          • Slide 12
                          • SOLIDS amp CRYSTALLINE STATE Pharmaceutical Drugs more than 80
                          • Solids and the crystalline state
                          • Classification of Solids
                          • Slide 16
                          • Slide 17
                          • Crystal forms
                          • Types of Crystals
                          • Slide 20
                          • Slide 21
                          • Polymorphism
                          • Slide 23
                          • Slide 24
                          • Slide 25
                          • Slide 26
                          • Cocrystal
                          • Principle of polymorphism
                          • Solvates
                          • Polymorphism (2)
                          • Amorphous Solid
                          • Amorphous or crystalline amp therapeutic activity
                          • Slide 33
                          • Slide 34
                          • Polymorphism and Industry Pharmaceutical
                          • Celecoxib
                          • Furosemide
                          • Bioavailability
                          • Slide 39
                          • Slide 40
                          • Bioequivalence
                          • Slide 42
                          • Carbamazepine
                          • Slide 44
                          • AIDS drug ritonavir
                          • Slide 46
                          • Slide 47
                          • Phase Equilibria amp The Phase Rule
                          • Phase diagram ndash Water
                          • Phase Equilibria amp The Phase Rule Definitions
                          • Phase Definition
                          • Examples
                          • Components
                          • Examples
                          • Slide 55
                          • Degrees of freedom (or variance)
                          • Examples (2)
                          • Phase Equilibria amp The Phase Rule
                          • The phase rule
                          • Slide 60
                          • Phase Equilibria amp The Phase Rule (2)
                          • The number of phases in a system is denoted P
                          • Slide 63
                          • Slide 64
                          • One-component systems
                          • Slide 66
                          • Slide 67
                          • Slide 68
                          • Slide 69
                          • Slide 70
                          • Two component system containing liquid phase
                          • Slide 72
                          • The Critical Solution Temperature CST
                          • Systems Showing a Decrease in Miscibility with Rise in Temperat
                          • Systems Showing Upper and Lower CSTs
                          • Two component system containing solid and liquid phase (Eutecti
                          • Slide 77
                          • Eutectic mixture Pharmaceutical Application
                          • Three component system
                          • Slide 80
                          • Topics that we have covered

                            A unit cell is the basic repeating structural unit of a crystalline solid

                            latticepoint

                            Unit Cell Unit cells in 3 dimensions

                            At lattice points

                            bull Atoms

                            bull Molecules

                            bull Ions

                            The crystal lattice of sodium chloride NaCl

                            Na Cl

                            The various crystal forms are divide to basic 7 unit according to its symmetry

                            NaCl urea

                            iodine

                            sucrose Boric acid

                            Crystal forms

                            iodoform

                            Be3Al2(SiO3)6

                            CsCl ZnS CaF2

                            Ionic Crystalsbull Lattice points occupied by cations and anionsbull Held together by electrostatic attractionbull Hard brittle high melting pointbull Poor conductor of heat and electricity

                            Types of Crystals

                            diamondgraphite

                            carbonatoms

                            Covalent Crystalsbull Lattice points occupied by atomsbull Held together by covalent bondsbull Hard high melting pointbull Poor conductor of heat and electricity

                            Cross Section of a Metallic Crystal

                            nucleus ampinner shell e-

                            mobile ldquoseardquoof e-

                            Metallic Crystalsbull Lattice points occupied by metal atomsbull Held together by metallic bondsbull Soft to hard low to high melting pointbull Good conductors of heat and electricity

                            Some elemental substance such as C and S may exist in more than one crystalline form and are said to be allotropic which is a special case of polymorphism

                            Polymorphism is the ability of a substance to exist in more than one crystal structure

                            Polymorphism

                            Polymorphism is the ability of a substance to exist in more than one crystal structure

                            Polymorphs when two crystals have the same chemical composition but different internal structure (molecular packing ndashmolecular conformation or and inter or intra molecular interactions)modifications or polymorphs or forms

                            Pseudo polymorphs different crystal forms have molecules of the same given substances and also contain molecules of solvent incorporated into a unique structure (solvates or hydrates (water))

                            diamond graphite

                            carbonatoms

                            High T and p

                            Diamond is metastable and converts very slowly to graphite

                            The most common example of polymorphism

                            Solid State Polymorphs

                            Mono-component systems Polymorphs

                            Multi-component systems

                            Cocrystal

                            The simplest definition of a cocrystal is a crystalline structure made up of two or more components in a definite stoichiometric ratio where each component is defined as either an atom ion or molecule

                            Principle of polymorphism

                            When the change from one form to another is reversible it is said to be enantiotropic

                            When the transition takes place in one direction onlymdashfor example from a metastable to a stable formmdashthe change is said to be monotropic

                            Solvates

                            Pharmaceutical synthesis include purification and crystallization residual solvent can be trapped in the lattice

                            This result in the formation of cocrystal or solvate

                            The presence of residual solvent may affect dramatically the crystalline structure of the solid depending on the type of inter molecular forces that the solvent may have with crystalline solid

                            Melting pointVapor pressureHardnessOptical electrical magnetic

                            propertiesColorIR spectraNMR spectra

                            Photochemical reactivityThermal stabilityFiltration and drying characteristicsDissolution rateBioavailabilityPhysical and chemical stability

                            Solubility and melting point are very important in pharmaceutical processes including dissolution and

                            formulation

                            Polymorphism

                            AMORPHOUS SOLIDS Solids that donrsquot have a definite geometrical shape are known as Amorphous Solids1 In these solids particles are randomly arranged in three dimension2 They donrsquot have sharp melting points3 Amorphous solids are formed due to sudden cooling of liquid4 Amorphous solids melt over a wide range of temperature

                            Amorphous Solid

                            An amorphous solid does not possess a well-defined arrangement and long-range molecular order

                            Amorphous substances as well as cubic crystal are isotropic that is they exhibit similar properties in all direction

                            The crystalline from of the antibiotic novobiocin acid is poorly absorbed and has no activity where the amorphous form is readily absorbed and therapeutically active due to different dissolution rate

                            Amorphous or crystalline amp therapeutic activity

                            General crystallization conditions 1048698Solvents ndashdifferent polarities 1048698Concentration of the solutions (super saturated saturated diluted) 1048698Cooling speed (quenching slow) 1048698Temperature (room or lower than room temperature)

                            Crystallization

                            Final Form

                            Granulation

                            Drying

                            Compaction

                            Tableting

                            Drug Product

                            API

                            Crystallization

                            Filtration

                            Drying

                            Milling

                            Bulk API

                            Stability

                            Polymorphism and Industry Pharmaceutical

                            Polymorphism and Industry Pharmaceutical

                            Fluoxetine HCl the active ingredient in the antidepressant drug Prozac

                            co crystal which will have increased solubility compared to the crystalline form

                            Celecoxib

                            CELECOXIB is a nonsteroidal anti-inflammatory drug

                            However it was found that the higher bioavailability was shown by the amorphous state

                            The downfall of the amorphous state was its stability

                            This was due to the structural relaxation

                            This was enhanced by mixing it with polymers like PVP which helped in stabilizing the amorphous system (Piyush Gupta et al 2004 Piyush Gupta et al 2005)

                            A new solid state form was developed by Pharmacia

                            FurosemideTwo forms with significantly differing aqueous solubility and dissolution rateOral bioavailability compromised

                            Giron lists gt20 excipients that display polymorphism includingndash Lactose (anhydrous also monohydrate)ndash Aspartame (anhydrous hydrate forms)ndash Magnesium stearate (can affect lubrication of tablets)

                            Bioavailability

                            The rate and extent to which the active ingredient or active moiety is absorbed from a drug product and becomes available at the site of action

                            Bioequivalence

                            The absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study

                            Carbamazepine

                            CHLORPROPAMIDEat least six polymorphic white or almost white crystalline powder It exhibits polymorphism Practically insoluble in water soluble in alcohol freely soluble in acetone and in dichlo-romethane dissolves in dilute solutions of alkali hydroxides Protect from light

                            blood-glucose-lowering drug

                            AIDS drug ritonavir

                            Theobroma oil (cacao butter ) is a polymorphic natural fat

                            Theobroma oil can exist in 4 different polymorphic forms of which only one is Stabile

                            1 Unstable gamma form melting at 18degC2 Alpha form melting at 22degC3 Beta prime form melting at 28degC4 Stable beta form melting at 345degC

                            This is important in the preparation of theobroma suppositories

                            If the oil is heated to a point where it is completely liquified (about 35 C) the crystals of the stable polymorph are destroyed amp the mass does not crystallize until it is cooled to 15 C

                            The crystals that form are unstable amp the suppositories melt at 24 C

                            Theobroma suppositories must be prepared below 33 C

                            Polymorphism and Industry Pharmaceutical

                            Polymorphism and Industry Pharmaceutical

                            Anhydrates together with salts form the majority of all drug formulationsAbout a half of all APIs used today are saltsSalts are stable and well soluble in polar solvents (first of all in water) because they contain ionic bondThere is one more essential advantage of salts ndash their solubility is a function of pH Since pH in the gastrointestinal tract (GIT) vary between 1-75

                            atorvastatin calcium trihydrateEach tablet contains Atorvastatin Calcium Trihydrate equivalent to Atorvastatin 20 mg

                            Phase Equilibria amp The Phase Rule

                            Phase diagram ndash Water

                            Phase Equilibrium A stable phase structure with lowest free-energy (internal energy) of a system and also randomness or disorder of the atoms or molecules (entropy)

                            Any change in Temperature Composition and Pressure causes an increase in free energy and away from Equilibrium thus forcing a move to another lsquostatersquo

                            Phase Equilibria amp The Phase Rule Definitions

                            A phase is defined as any homogeneous and physically distinct part of a system which is separated from other parts of the system by interfaces

                            A part of a system is homogeneous if it has identical physical properties and chemical composition throughout the part

                            A phase may be gas liquid or solid A gas or a gaseous mixture is a single phase Totally miscible liquids constitute a single phase In an immiscible liquid system each layer is counted as a separate phase Every solid constitutes a single phase except when a solid solution is formed A solid solution is considered as a single phase Each polymorphic form constitutes a separate phase

                            Phase Definition

                            1 Liquid water pieces of ice and water vapour are present together The number of phases is 3 as each form is a separate phase Ice in the system is a single phase even if it is present as a number of pieces

                            2 Calcium carbonate undergoes thermal decomposition The chemical reaction is CaCO3(s) CaO(s) + CO2 (g) Number of phases = 3 This system consists of 2 solid phases CaCO3 and CaO and one gaseous phase that of CO2

                            3 Ammonium chloride undergoes thermal decomposition The chemical reaction is NH4Cl(s) NH3 (g) + HCl (g) Number of phases = 2 This system has two phases one solid NH4Cl and one gaseous a mixture of NH3 and HCl

                            4 A solution of NaCl in water Number of phases = 1

                            bull Examples

                            The number of components of a system at equilibrium is the smallest number of independently varying chemical constituents using which the composition of each and every phase in the system can be expressed

                            Components

                            Counting the number of components 1 The sulphur system is a one component system All the phases

                            monoclinic rhombic liquid and vapour ndash can be expressed in terms of the single constituent ndash sulphur

                            2 A mixture of ethanol and water is an example of a two component system We need both ethanol and water to express its composition

                            bull Examples

                            An example of a system in which a reaction occurs and an equilibrium is established is the thermal decomposition of solid CaCO3

                            In this system there are three distinct phasesSolid CaCO3

                            Solid CaOGaseous CO2

                            Though there are 3 species present the number of components is only two because of the equilibrium CaCO3 (s) CaO(s) + CO2(g)

                            Any two of the three constituents may be chosen as the components

                            If CaO and CO2 are chosen then the composition of the phase CaCO3 is expressed as one mole of component CO2 plus one mole of component CaO

                            If on the other hand CaCO3 and CO2 were chosen then the composition of the phase CaO would be described as one mole of CaCO3 minus one mole of CO2

                            The degrees of freedom or variance of a system is defined as the minimum number of variables such as

                            temperaturepressureconcentrationwhich must be fixed in order to define the system completely

                            Degrees of freedom (or variance)

                            F = C P + 2

                            1 A gaseous mixture of CO2 and N2 Three variables pressure temperature and composition are required to define this system This is hence a trivariant system

                            2 A system having only liquid water has two degrees of freedom or is bivariant Both temperature and pressure need to be mentioned in order to define the system

                            3 If to the system containing liquid water pieces of ice are added and this system with 2 phases is allowed to come to equilibrium then it is an univariant system

                            Only one variable either temperature or pressure need to be specified in order to define the systemIf the pressure on the system is maintained at 1 atm then the temperature of the system gets automatically fixed at 0oC the normal melting point of ice

                            bull Examples

                            Phase Equilibria amp The Phase Rule

                            A phase diagram (Equilibrium Phase Diagram) summarizes the conditions at which a substance exists as a solid liquid or gas

                            OR It is a ldquomaprdquo of the information about the control of phase structure of a particular material system

                            The relationships between temperature and the compositions and the quantities of phases present at equilibrium are represented

                            F = C P + 2The phase rule

                            The phase rule JW Gibbs formulated the phase rule which is a general relation

                            between the variance F the number of component C and the number of phases P at equilibrium for a system of any composition

                            For a system in equilibrium

                            F degree of freedom the least number of intensive variable that must be fixed (known) to describe the system completely

                            Phase Rule relation to determine the least number of intensive variable that can be changed without changing the equilibrium state of the system or alternately

                            The least number required to define the state of the system which is called degree of freedom F

                            Intensive variable independent variable that do not depend on the volume or the size egTemp pressure

                            Independent chemical species which comprise the system These could be Elements Ions Compounds

                            Eg Au-Cu system Components rarr Au Cu Ice-water system Component rarr H2O

                            Al2O3 ndash Cr2O3 system Components rarr Al2O3 Cr2O3

                            Component the smallest number of constituent by which the composition of each phase in the system at equilibrium can be expressed in form of chemical formula or equation

                            Phase Equilibria amp The Phase RuleComponents of a system

                            The number of phases in a system is denoted P

                            (a)A gas or a gaseous mixture is a single phase P=1

                            (b) For a solid system an alloy of two metals is a two-phase system (P=2) if the metals are immiscible but a single-phase system (P=1) if they are miscible---a homogeneous mixture of the two substances---is uniform on a molecular scale

                            (c) For a liquid system according to the solubility to decide whether a system consists of one phase or of two For example a solution of sodium chloride in water is a single phase A pair of liquids that are partially miscible or immiscible is a two-phase system(P=2)

                            Oil in water

                            Degrees of Freedom = What you can control What the system controls

                            F = C + 2 P

                            Can control the no of components added and P amp T

                            System decided how many phases to produce given the

                            conditions

                            A way of understanding the Gibbs Phase RuleThe degrees of freedom can be thought of as the difference between what you (can) control and

                            what the system controls

                            F degree of freedom the least number of intensive variable that must be fixed (known) to describe the system completely

                            Degree of freedom (or variance) F is the number of variables (T p andor composition) that can be changed independently without changing the phases of the system

                            a) At the triple pointP = 3 (solid liquid and gas)

                            C= 1 (water)P + F = C + 2

                            F = 0 (no degree of freedom)

                            b) liquid-solid curveP = 2

                            2+F = 1 + 2F= 1

                            One variable (T or P) can be changed

                            c) LiquidP =1

                            So F =2Two variables (T and P) can be varied independently

                            and the system will remains a single phase

                            One-component systemsPhase diagram of water

                            P (

                            atm

                            )

                            Critical point

                            374

                            1

                            =100=0O--Triple point

                            0006

                            218

                            Curve O -CSublimation

                            Deposition

                            Curve O-AVaporizationCondensation

                            Curve O -BMelting

                            Freezing

                            F = C P + 2

                            F = C P + 2

                            Phase Diagram of Carbon Dioxide

                            Condensed system System in which the vapor phase is ignored and only the solid andor liquid phases are considered

                            Two component system For two component system F can be 3 (3D model is needed) eg T p

                            and concentration usually we fix p = 1atm the vapor phase is neglected and F is reduced to 2

                            For three component system the pressure and temperature are fixed

                            Phenol water phase diagram

                            eg for point d (24)

                            Two component system containing liquid phase

                            Tie Line bc line The line at which the system at equilibrium will separate into phases of constant composition termed lsquoconjugate phasesrsquo

                            Lever Rule a way to calculate the proportions of each phase present on a phase diagram in a two phase field (at a given temperature and composition)

                            eg for point d (24)

                            For every 10 g of liquid system in equilibrium in point d

                            75 g phase A25 g phase B

                            ExampleMixed 24g phenol +76g water T 50degC

                            equilibrium75 g phase A 25 g phase B

                            11 phenol 63 phenol

                            011 times75 g=825 g phenol

                            063 times25 g=1575 g phenol

                            water rich phasecontains water+ phenol(11)

                            Phenol rich phasecontains Phenol (63)+ water

                            The Critical Solution Temperature CST

                            Is the maximum temperature at which the 2-phase region exists (or upper consolute temperature)

                            In the case of the phenol-water system this is 668oC (point h)

                            All combinations of phenol and water gt CST are completely miscible and yield 1-phase liquid systems

                            Systems Showing a Decrease in Miscibility with Rise in Temperature

                            A few mixtures exhibit a lower critical solution temperature (low CST) eg triethylamine plus water The miscibility with in temperature

                            Systems Showing Upper and Lower CSTs

                            The miscibility with temp

                            a certain temperature miscibility starts to again with further in temperature

                            Closed-phase diagram ie nicotine-water system

                            A salol B thymol

                            53

                            Two component system containing solid and liquid phase (Eutectic Mixtures)

                            A salol B thymol

                            EMLAreg (lidocaine 25 and prilocaine 25) Cream

                            EMLA Cream (lidocaine 25 and prilocaine 25) is an emulsion in which the oil phase is a eutectic mixture of lidocaine and prilocaine in a ratio of 11 by weight This eutectic mixture has a melting point below room temperature and therefore both local anesthetics exist as a liquid oil rather than as crystals

                            Eutectic mixture Pharmaceutical Application

                            Triangular Diagrams for three ndash component systems

                            Three component system

                            Birzeit University Physical Pharmacy PHAR 323 Dr Hani Shtaya

                            1 Binding Forces Between Molecules2 Repulsive and Attractive Forces3 The Gaseous State The Ideal Gas Law Liquefaction of Gases Aerosols4 Solids and the Crystalline State Crystalline Solids Polymorphism Solvates Amorphous Solids5 Phase Equilibria and the Phase Rule Phase Rule Systems Containing One Component Condensed System Two-Component Systems Containing Liquid Phases Two-Component Systems Containing Solid and Liquid Phases Eutectic Mixtures Rules Relating to Triangular Diagrams

                            Topics that we have covered

                            • States of Matter
                            • States of Matter (2)
                            • Objectives of the lecture
                            • Comparison of Gases Liquids and Solids
                            • Slide 5
                            • Repulsive and Attractive Forces
                            • Ideal Gas Equation
                            • Gaseous state
                            • Slide 9
                            • Gaseous state (2)
                            • Liquefaction of Gases
                            • Slide 12
                            • SOLIDS amp CRYSTALLINE STATE Pharmaceutical Drugs more than 80
                            • Solids and the crystalline state
                            • Classification of Solids
                            • Slide 16
                            • Slide 17
                            • Crystal forms
                            • Types of Crystals
                            • Slide 20
                            • Slide 21
                            • Polymorphism
                            • Slide 23
                            • Slide 24
                            • Slide 25
                            • Slide 26
                            • Cocrystal
                            • Principle of polymorphism
                            • Solvates
                            • Polymorphism (2)
                            • Amorphous Solid
                            • Amorphous or crystalline amp therapeutic activity
                            • Slide 33
                            • Slide 34
                            • Polymorphism and Industry Pharmaceutical
                            • Celecoxib
                            • Furosemide
                            • Bioavailability
                            • Slide 39
                            • Slide 40
                            • Bioequivalence
                            • Slide 42
                            • Carbamazepine
                            • Slide 44
                            • AIDS drug ritonavir
                            • Slide 46
                            • Slide 47
                            • Phase Equilibria amp The Phase Rule
                            • Phase diagram ndash Water
                            • Phase Equilibria amp The Phase Rule Definitions
                            • Phase Definition
                            • Examples
                            • Components
                            • Examples
                            • Slide 55
                            • Degrees of freedom (or variance)
                            • Examples (2)
                            • Phase Equilibria amp The Phase Rule
                            • The phase rule
                            • Slide 60
                            • Phase Equilibria amp The Phase Rule (2)
                            • The number of phases in a system is denoted P
                            • Slide 63
                            • Slide 64
                            • One-component systems
                            • Slide 66
                            • Slide 67
                            • Slide 68
                            • Slide 69
                            • Slide 70
                            • Two component system containing liquid phase
                            • Slide 72
                            • The Critical Solution Temperature CST
                            • Systems Showing a Decrease in Miscibility with Rise in Temperat
                            • Systems Showing Upper and Lower CSTs
                            • Two component system containing solid and liquid phase (Eutecti
                            • Slide 77
                            • Eutectic mixture Pharmaceutical Application
                            • Three component system
                            • Slide 80
                            • Topics that we have covered

                              The crystal lattice of sodium chloride NaCl

                              Na Cl

                              The various crystal forms are divide to basic 7 unit according to its symmetry

                              NaCl urea

                              iodine

                              sucrose Boric acid

                              Crystal forms

                              iodoform

                              Be3Al2(SiO3)6

                              CsCl ZnS CaF2

                              Ionic Crystalsbull Lattice points occupied by cations and anionsbull Held together by electrostatic attractionbull Hard brittle high melting pointbull Poor conductor of heat and electricity

                              Types of Crystals

                              diamondgraphite

                              carbonatoms

                              Covalent Crystalsbull Lattice points occupied by atomsbull Held together by covalent bondsbull Hard high melting pointbull Poor conductor of heat and electricity

                              Cross Section of a Metallic Crystal

                              nucleus ampinner shell e-

                              mobile ldquoseardquoof e-

                              Metallic Crystalsbull Lattice points occupied by metal atomsbull Held together by metallic bondsbull Soft to hard low to high melting pointbull Good conductors of heat and electricity

                              Some elemental substance such as C and S may exist in more than one crystalline form and are said to be allotropic which is a special case of polymorphism

                              Polymorphism is the ability of a substance to exist in more than one crystal structure

                              Polymorphism

                              Polymorphism is the ability of a substance to exist in more than one crystal structure

                              Polymorphs when two crystals have the same chemical composition but different internal structure (molecular packing ndashmolecular conformation or and inter or intra molecular interactions)modifications or polymorphs or forms

                              Pseudo polymorphs different crystal forms have molecules of the same given substances and also contain molecules of solvent incorporated into a unique structure (solvates or hydrates (water))

                              diamond graphite

                              carbonatoms

                              High T and p

                              Diamond is metastable and converts very slowly to graphite

                              The most common example of polymorphism

                              Solid State Polymorphs

                              Mono-component systems Polymorphs

                              Multi-component systems

                              Cocrystal

                              The simplest definition of a cocrystal is a crystalline structure made up of two or more components in a definite stoichiometric ratio where each component is defined as either an atom ion or molecule

                              Principle of polymorphism

                              When the change from one form to another is reversible it is said to be enantiotropic

                              When the transition takes place in one direction onlymdashfor example from a metastable to a stable formmdashthe change is said to be monotropic

                              Solvates

                              Pharmaceutical synthesis include purification and crystallization residual solvent can be trapped in the lattice

                              This result in the formation of cocrystal or solvate

                              The presence of residual solvent may affect dramatically the crystalline structure of the solid depending on the type of inter molecular forces that the solvent may have with crystalline solid

                              Melting pointVapor pressureHardnessOptical electrical magnetic

                              propertiesColorIR spectraNMR spectra

                              Photochemical reactivityThermal stabilityFiltration and drying characteristicsDissolution rateBioavailabilityPhysical and chemical stability

                              Solubility and melting point are very important in pharmaceutical processes including dissolution and

                              formulation

                              Polymorphism

                              AMORPHOUS SOLIDS Solids that donrsquot have a definite geometrical shape are known as Amorphous Solids1 In these solids particles are randomly arranged in three dimension2 They donrsquot have sharp melting points3 Amorphous solids are formed due to sudden cooling of liquid4 Amorphous solids melt over a wide range of temperature

                              Amorphous Solid

                              An amorphous solid does not possess a well-defined arrangement and long-range molecular order

                              Amorphous substances as well as cubic crystal are isotropic that is they exhibit similar properties in all direction

                              The crystalline from of the antibiotic novobiocin acid is poorly absorbed and has no activity where the amorphous form is readily absorbed and therapeutically active due to different dissolution rate

                              Amorphous or crystalline amp therapeutic activity

                              General crystallization conditions 1048698Solvents ndashdifferent polarities 1048698Concentration of the solutions (super saturated saturated diluted) 1048698Cooling speed (quenching slow) 1048698Temperature (room or lower than room temperature)

                              Crystallization

                              Final Form

                              Granulation

                              Drying

                              Compaction

                              Tableting

                              Drug Product

                              API

                              Crystallization

                              Filtration

                              Drying

                              Milling

                              Bulk API

                              Stability

                              Polymorphism and Industry Pharmaceutical

                              Polymorphism and Industry Pharmaceutical

                              Fluoxetine HCl the active ingredient in the antidepressant drug Prozac

                              co crystal which will have increased solubility compared to the crystalline form

                              Celecoxib

                              CELECOXIB is a nonsteroidal anti-inflammatory drug

                              However it was found that the higher bioavailability was shown by the amorphous state

                              The downfall of the amorphous state was its stability

                              This was due to the structural relaxation

                              This was enhanced by mixing it with polymers like PVP which helped in stabilizing the amorphous system (Piyush Gupta et al 2004 Piyush Gupta et al 2005)

                              A new solid state form was developed by Pharmacia

                              FurosemideTwo forms with significantly differing aqueous solubility and dissolution rateOral bioavailability compromised

                              Giron lists gt20 excipients that display polymorphism includingndash Lactose (anhydrous also monohydrate)ndash Aspartame (anhydrous hydrate forms)ndash Magnesium stearate (can affect lubrication of tablets)

                              Bioavailability

                              The rate and extent to which the active ingredient or active moiety is absorbed from a drug product and becomes available at the site of action

                              Bioequivalence

                              The absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study

                              Carbamazepine

                              CHLORPROPAMIDEat least six polymorphic white or almost white crystalline powder It exhibits polymorphism Practically insoluble in water soluble in alcohol freely soluble in acetone and in dichlo-romethane dissolves in dilute solutions of alkali hydroxides Protect from light

                              blood-glucose-lowering drug

                              AIDS drug ritonavir

                              Theobroma oil (cacao butter ) is a polymorphic natural fat

                              Theobroma oil can exist in 4 different polymorphic forms of which only one is Stabile

                              1 Unstable gamma form melting at 18degC2 Alpha form melting at 22degC3 Beta prime form melting at 28degC4 Stable beta form melting at 345degC

                              This is important in the preparation of theobroma suppositories

                              If the oil is heated to a point where it is completely liquified (about 35 C) the crystals of the stable polymorph are destroyed amp the mass does not crystallize until it is cooled to 15 C

                              The crystals that form are unstable amp the suppositories melt at 24 C

                              Theobroma suppositories must be prepared below 33 C

                              Polymorphism and Industry Pharmaceutical

                              Polymorphism and Industry Pharmaceutical

                              Anhydrates together with salts form the majority of all drug formulationsAbout a half of all APIs used today are saltsSalts are stable and well soluble in polar solvents (first of all in water) because they contain ionic bondThere is one more essential advantage of salts ndash their solubility is a function of pH Since pH in the gastrointestinal tract (GIT) vary between 1-75

                              atorvastatin calcium trihydrateEach tablet contains Atorvastatin Calcium Trihydrate equivalent to Atorvastatin 20 mg

                              Phase Equilibria amp The Phase Rule

                              Phase diagram ndash Water

                              Phase Equilibrium A stable phase structure with lowest free-energy (internal energy) of a system and also randomness or disorder of the atoms or molecules (entropy)

                              Any change in Temperature Composition and Pressure causes an increase in free energy and away from Equilibrium thus forcing a move to another lsquostatersquo

                              Phase Equilibria amp The Phase Rule Definitions

                              A phase is defined as any homogeneous and physically distinct part of a system which is separated from other parts of the system by interfaces

                              A part of a system is homogeneous if it has identical physical properties and chemical composition throughout the part

                              A phase may be gas liquid or solid A gas or a gaseous mixture is a single phase Totally miscible liquids constitute a single phase In an immiscible liquid system each layer is counted as a separate phase Every solid constitutes a single phase except when a solid solution is formed A solid solution is considered as a single phase Each polymorphic form constitutes a separate phase

                              Phase Definition

                              1 Liquid water pieces of ice and water vapour are present together The number of phases is 3 as each form is a separate phase Ice in the system is a single phase even if it is present as a number of pieces

                              2 Calcium carbonate undergoes thermal decomposition The chemical reaction is CaCO3(s) CaO(s) + CO2 (g) Number of phases = 3 This system consists of 2 solid phases CaCO3 and CaO and one gaseous phase that of CO2

                              3 Ammonium chloride undergoes thermal decomposition The chemical reaction is NH4Cl(s) NH3 (g) + HCl (g) Number of phases = 2 This system has two phases one solid NH4Cl and one gaseous a mixture of NH3 and HCl

                              4 A solution of NaCl in water Number of phases = 1

                              bull Examples

                              The number of components of a system at equilibrium is the smallest number of independently varying chemical constituents using which the composition of each and every phase in the system can be expressed

                              Components

                              Counting the number of components 1 The sulphur system is a one component system All the phases

                              monoclinic rhombic liquid and vapour ndash can be expressed in terms of the single constituent ndash sulphur

                              2 A mixture of ethanol and water is an example of a two component system We need both ethanol and water to express its composition

                              bull Examples

                              An example of a system in which a reaction occurs and an equilibrium is established is the thermal decomposition of solid CaCO3

                              In this system there are three distinct phasesSolid CaCO3

                              Solid CaOGaseous CO2

                              Though there are 3 species present the number of components is only two because of the equilibrium CaCO3 (s) CaO(s) + CO2(g)

                              Any two of the three constituents may be chosen as the components

                              If CaO and CO2 are chosen then the composition of the phase CaCO3 is expressed as one mole of component CO2 plus one mole of component CaO

                              If on the other hand CaCO3 and CO2 were chosen then the composition of the phase CaO would be described as one mole of CaCO3 minus one mole of CO2

                              The degrees of freedom or variance of a system is defined as the minimum number of variables such as

                              temperaturepressureconcentrationwhich must be fixed in order to define the system completely

                              Degrees of freedom (or variance)

                              F = C P + 2

                              1 A gaseous mixture of CO2 and N2 Three variables pressure temperature and composition are required to define this system This is hence a trivariant system

                              2 A system having only liquid water has two degrees of freedom or is bivariant Both temperature and pressure need to be mentioned in order to define the system

                              3 If to the system containing liquid water pieces of ice are added and this system with 2 phases is allowed to come to equilibrium then it is an univariant system

                              Only one variable either temperature or pressure need to be specified in order to define the systemIf the pressure on the system is maintained at 1 atm then the temperature of the system gets automatically fixed at 0oC the normal melting point of ice

                              bull Examples

                              Phase Equilibria amp The Phase Rule

                              A phase diagram (Equilibrium Phase Diagram) summarizes the conditions at which a substance exists as a solid liquid or gas

                              OR It is a ldquomaprdquo of the information about the control of phase structure of a particular material system

                              The relationships between temperature and the compositions and the quantities of phases present at equilibrium are represented

                              F = C P + 2The phase rule

                              The phase rule JW Gibbs formulated the phase rule which is a general relation

                              between the variance F the number of component C and the number of phases P at equilibrium for a system of any composition

                              For a system in equilibrium

                              F degree of freedom the least number of intensive variable that must be fixed (known) to describe the system completely

                              Phase Rule relation to determine the least number of intensive variable that can be changed without changing the equilibrium state of the system or alternately

                              The least number required to define the state of the system which is called degree of freedom F

                              Intensive variable independent variable that do not depend on the volume or the size egTemp pressure

                              Independent chemical species which comprise the system These could be Elements Ions Compounds

                              Eg Au-Cu system Components rarr Au Cu Ice-water system Component rarr H2O

                              Al2O3 ndash Cr2O3 system Components rarr Al2O3 Cr2O3

                              Component the smallest number of constituent by which the composition of each phase in the system at equilibrium can be expressed in form of chemical formula or equation

                              Phase Equilibria amp The Phase RuleComponents of a system

                              The number of phases in a system is denoted P

                              (a)A gas or a gaseous mixture is a single phase P=1

                              (b) For a solid system an alloy of two metals is a two-phase system (P=2) if the metals are immiscible but a single-phase system (P=1) if they are miscible---a homogeneous mixture of the two substances---is uniform on a molecular scale

                              (c) For a liquid system according to the solubility to decide whether a system consists of one phase or of two For example a solution of sodium chloride in water is a single phase A pair of liquids that are partially miscible or immiscible is a two-phase system(P=2)

                              Oil in water

                              Degrees of Freedom = What you can control What the system controls

                              F = C + 2 P

                              Can control the no of components added and P amp T

                              System decided how many phases to produce given the

                              conditions

                              A way of understanding the Gibbs Phase RuleThe degrees of freedom can be thought of as the difference between what you (can) control and

                              what the system controls

                              F degree of freedom the least number of intensive variable that must be fixed (known) to describe the system completely

                              Degree of freedom (or variance) F is the number of variables (T p andor composition) that can be changed independently without changing the phases of the system

                              a) At the triple pointP = 3 (solid liquid and gas)

                              C= 1 (water)P + F = C + 2

                              F = 0 (no degree of freedom)

                              b) liquid-solid curveP = 2

                              2+F = 1 + 2F= 1

                              One variable (T or P) can be changed

                              c) LiquidP =1

                              So F =2Two variables (T and P) can be varied independently

                              and the system will remains a single phase

                              One-component systemsPhase diagram of water

                              P (

                              atm

                              )

                              Critical point

                              374

                              1

                              =100=0O--Triple point

                              0006

                              218

                              Curve O -CSublimation

                              Deposition

                              Curve O-AVaporizationCondensation

                              Curve O -BMelting

                              Freezing

                              F = C P + 2

                              F = C P + 2

                              Phase Diagram of Carbon Dioxide

                              Condensed system System in which the vapor phase is ignored and only the solid andor liquid phases are considered

                              Two component system For two component system F can be 3 (3D model is needed) eg T p

                              and concentration usually we fix p = 1atm the vapor phase is neglected and F is reduced to 2

                              For three component system the pressure and temperature are fixed

                              Phenol water phase diagram

                              eg for point d (24)

                              Two component system containing liquid phase

                              Tie Line bc line The line at which the system at equilibrium will separate into phases of constant composition termed lsquoconjugate phasesrsquo

                              Lever Rule a way to calculate the proportions of each phase present on a phase diagram in a two phase field (at a given temperature and composition)

                              eg for point d (24)

                              For every 10 g of liquid system in equilibrium in point d

                              75 g phase A25 g phase B

                              ExampleMixed 24g phenol +76g water T 50degC

                              equilibrium75 g phase A 25 g phase B

                              11 phenol 63 phenol

                              011 times75 g=825 g phenol

                              063 times25 g=1575 g phenol

                              water rich phasecontains water+ phenol(11)

                              Phenol rich phasecontains Phenol (63)+ water

                              The Critical Solution Temperature CST

                              Is the maximum temperature at which the 2-phase region exists (or upper consolute temperature)

                              In the case of the phenol-water system this is 668oC (point h)

                              All combinations of phenol and water gt CST are completely miscible and yield 1-phase liquid systems

                              Systems Showing a Decrease in Miscibility with Rise in Temperature

                              A few mixtures exhibit a lower critical solution temperature (low CST) eg triethylamine plus water The miscibility with in temperature

                              Systems Showing Upper and Lower CSTs

                              The miscibility with temp

                              a certain temperature miscibility starts to again with further in temperature

                              Closed-phase diagram ie nicotine-water system

                              A salol B thymol

                              53

                              Two component system containing solid and liquid phase (Eutectic Mixtures)

                              A salol B thymol

                              EMLAreg (lidocaine 25 and prilocaine 25) Cream

                              EMLA Cream (lidocaine 25 and prilocaine 25) is an emulsion in which the oil phase is a eutectic mixture of lidocaine and prilocaine in a ratio of 11 by weight This eutectic mixture has a melting point below room temperature and therefore both local anesthetics exist as a liquid oil rather than as crystals

                              Eutectic mixture Pharmaceutical Application

                              Triangular Diagrams for three ndash component systems

                              Three component system

                              Birzeit University Physical Pharmacy PHAR 323 Dr Hani Shtaya

                              1 Binding Forces Between Molecules2 Repulsive and Attractive Forces3 The Gaseous State The Ideal Gas Law Liquefaction of Gases Aerosols4 Solids and the Crystalline State Crystalline Solids Polymorphism Solvates Amorphous Solids5 Phase Equilibria and the Phase Rule Phase Rule Systems Containing One Component Condensed System Two-Component Systems Containing Liquid Phases Two-Component Systems Containing Solid and Liquid Phases Eutectic Mixtures Rules Relating to Triangular Diagrams

                              Topics that we have covered

                              • States of Matter
                              • States of Matter (2)
                              • Objectives of the lecture
                              • Comparison of Gases Liquids and Solids
                              • Slide 5
                              • Repulsive and Attractive Forces
                              • Ideal Gas Equation
                              • Gaseous state
                              • Slide 9
                              • Gaseous state (2)
                              • Liquefaction of Gases
                              • Slide 12
                              • SOLIDS amp CRYSTALLINE STATE Pharmaceutical Drugs more than 80
                              • Solids and the crystalline state
                              • Classification of Solids
                              • Slide 16
                              • Slide 17
                              • Crystal forms
                              • Types of Crystals
                              • Slide 20
                              • Slide 21
                              • Polymorphism
                              • Slide 23
                              • Slide 24
                              • Slide 25
                              • Slide 26
                              • Cocrystal
                              • Principle of polymorphism
                              • Solvates
                              • Polymorphism (2)
                              • Amorphous Solid
                              • Amorphous or crystalline amp therapeutic activity
                              • Slide 33
                              • Slide 34
                              • Polymorphism and Industry Pharmaceutical
                              • Celecoxib
                              • Furosemide
                              • Bioavailability
                              • Slide 39
                              • Slide 40
                              • Bioequivalence
                              • Slide 42
                              • Carbamazepine
                              • Slide 44
                              • AIDS drug ritonavir
                              • Slide 46
                              • Slide 47
                              • Phase Equilibria amp The Phase Rule
                              • Phase diagram ndash Water
                              • Phase Equilibria amp The Phase Rule Definitions
                              • Phase Definition
                              • Examples
                              • Components
                              • Examples
                              • Slide 55
                              • Degrees of freedom (or variance)
                              • Examples (2)
                              • Phase Equilibria amp The Phase Rule
                              • The phase rule
                              • Slide 60
                              • Phase Equilibria amp The Phase Rule (2)
                              • The number of phases in a system is denoted P
                              • Slide 63
                              • Slide 64
                              • One-component systems
                              • Slide 66
                              • Slide 67
                              • Slide 68
                              • Slide 69
                              • Slide 70
                              • Two component system containing liquid phase
                              • Slide 72
                              • The Critical Solution Temperature CST
                              • Systems Showing a Decrease in Miscibility with Rise in Temperat
                              • Systems Showing Upper and Lower CSTs
                              • Two component system containing solid and liquid phase (Eutecti
                              • Slide 77
                              • Eutectic mixture Pharmaceutical Application
                              • Three component system
                              • Slide 80
                              • Topics that we have covered

                                The various crystal forms are divide to basic 7 unit according to its symmetry

                                NaCl urea

                                iodine

                                sucrose Boric acid

                                Crystal forms

                                iodoform

                                Be3Al2(SiO3)6

                                CsCl ZnS CaF2

                                Ionic Crystalsbull Lattice points occupied by cations and anionsbull Held together by electrostatic attractionbull Hard brittle high melting pointbull Poor conductor of heat and electricity

                                Types of Crystals

                                diamondgraphite

                                carbonatoms

                                Covalent Crystalsbull Lattice points occupied by atomsbull Held together by covalent bondsbull Hard high melting pointbull Poor conductor of heat and electricity

                                Cross Section of a Metallic Crystal

                                nucleus ampinner shell e-

                                mobile ldquoseardquoof e-

                                Metallic Crystalsbull Lattice points occupied by metal atomsbull Held together by metallic bondsbull Soft to hard low to high melting pointbull Good conductors of heat and electricity

                                Some elemental substance such as C and S may exist in more than one crystalline form and are said to be allotropic which is a special case of polymorphism

                                Polymorphism is the ability of a substance to exist in more than one crystal structure

                                Polymorphism

                                Polymorphism is the ability of a substance to exist in more than one crystal structure

                                Polymorphs when two crystals have the same chemical composition but different internal structure (molecular packing ndashmolecular conformation or and inter or intra molecular interactions)modifications or polymorphs or forms

                                Pseudo polymorphs different crystal forms have molecules of the same given substances and also contain molecules of solvent incorporated into a unique structure (solvates or hydrates (water))

                                diamond graphite

                                carbonatoms

                                High T and p

                                Diamond is metastable and converts very slowly to graphite

                                The most common example of polymorphism

                                Solid State Polymorphs

                                Mono-component systems Polymorphs

                                Multi-component systems

                                Cocrystal

                                The simplest definition of a cocrystal is a crystalline structure made up of two or more components in a definite stoichiometric ratio where each component is defined as either an atom ion or molecule

                                Principle of polymorphism

                                When the change from one form to another is reversible it is said to be enantiotropic

                                When the transition takes place in one direction onlymdashfor example from a metastable to a stable formmdashthe change is said to be monotropic

                                Solvates

                                Pharmaceutical synthesis include purification and crystallization residual solvent can be trapped in the lattice

                                This result in the formation of cocrystal or solvate

                                The presence of residual solvent may affect dramatically the crystalline structure of the solid depending on the type of inter molecular forces that the solvent may have with crystalline solid

                                Melting pointVapor pressureHardnessOptical electrical magnetic

                                propertiesColorIR spectraNMR spectra

                                Photochemical reactivityThermal stabilityFiltration and drying characteristicsDissolution rateBioavailabilityPhysical and chemical stability

                                Solubility and melting point are very important in pharmaceutical processes including dissolution and

                                formulation

                                Polymorphism

                                AMORPHOUS SOLIDS Solids that donrsquot have a definite geometrical shape are known as Amorphous Solids1 In these solids particles are randomly arranged in three dimension2 They donrsquot have sharp melting points3 Amorphous solids are formed due to sudden cooling of liquid4 Amorphous solids melt over a wide range of temperature

                                Amorphous Solid

                                An amorphous solid does not possess a well-defined arrangement and long-range molecular order

                                Amorphous substances as well as cubic crystal are isotropic that is they exhibit similar properties in all direction

                                The crystalline from of the antibiotic novobiocin acid is poorly absorbed and has no activity where the amorphous form is readily absorbed and therapeutically active due to different dissolution rate

                                Amorphous or crystalline amp therapeutic activity

                                General crystallization conditions 1048698Solvents ndashdifferent polarities 1048698Concentration of the solutions (super saturated saturated diluted) 1048698Cooling speed (quenching slow) 1048698Temperature (room or lower than room temperature)

                                Crystallization

                                Final Form

                                Granulation

                                Drying

                                Compaction

                                Tableting

                                Drug Product

                                API

                                Crystallization

                                Filtration

                                Drying

                                Milling

                                Bulk API

                                Stability

                                Polymorphism and Industry Pharmaceutical

                                Polymorphism and Industry Pharmaceutical

                                Fluoxetine HCl the active ingredient in the antidepressant drug Prozac

                                co crystal which will have increased solubility compared to the crystalline form

                                Celecoxib

                                CELECOXIB is a nonsteroidal anti-inflammatory drug

                                However it was found that the higher bioavailability was shown by the amorphous state

                                The downfall of the amorphous state was its stability

                                This was due to the structural relaxation

                                This was enhanced by mixing it with polymers like PVP which helped in stabilizing the amorphous system (Piyush Gupta et al 2004 Piyush Gupta et al 2005)

                                A new solid state form was developed by Pharmacia

                                FurosemideTwo forms with significantly differing aqueous solubility and dissolution rateOral bioavailability compromised

                                Giron lists gt20 excipients that display polymorphism includingndash Lactose (anhydrous also monohydrate)ndash Aspartame (anhydrous hydrate forms)ndash Magnesium stearate (can affect lubrication of tablets)

                                Bioavailability

                                The rate and extent to which the active ingredient or active moiety is absorbed from a drug product and becomes available at the site of action

                                Bioequivalence

                                The absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study

                                Carbamazepine

                                CHLORPROPAMIDEat least six polymorphic white or almost white crystalline powder It exhibits polymorphism Practically insoluble in water soluble in alcohol freely soluble in acetone and in dichlo-romethane dissolves in dilute solutions of alkali hydroxides Protect from light

                                blood-glucose-lowering drug

                                AIDS drug ritonavir

                                Theobroma oil (cacao butter ) is a polymorphic natural fat

                                Theobroma oil can exist in 4 different polymorphic forms of which only one is Stabile

                                1 Unstable gamma form melting at 18degC2 Alpha form melting at 22degC3 Beta prime form melting at 28degC4 Stable beta form melting at 345degC

                                This is important in the preparation of theobroma suppositories

                                If the oil is heated to a point where it is completely liquified (about 35 C) the crystals of the stable polymorph are destroyed amp the mass does not crystallize until it is cooled to 15 C

                                The crystals that form are unstable amp the suppositories melt at 24 C

                                Theobroma suppositories must be prepared below 33 C

                                Polymorphism and Industry Pharmaceutical

                                Polymorphism and Industry Pharmaceutical

                                Anhydrates together with salts form the majority of all drug formulationsAbout a half of all APIs used today are saltsSalts are stable and well soluble in polar solvents (first of all in water) because they contain ionic bondThere is one more essential advantage of salts ndash their solubility is a function of pH Since pH in the gastrointestinal tract (GIT) vary between 1-75

                                atorvastatin calcium trihydrateEach tablet contains Atorvastatin Calcium Trihydrate equivalent to Atorvastatin 20 mg

                                Phase Equilibria amp The Phase Rule

                                Phase diagram ndash Water

                                Phase Equilibrium A stable phase structure with lowest free-energy (internal energy) of a system and also randomness or disorder of the atoms or molecules (entropy)

                                Any change in Temperature Composition and Pressure causes an increase in free energy and away from Equilibrium thus forcing a move to another lsquostatersquo

                                Phase Equilibria amp The Phase Rule Definitions

                                A phase is defined as any homogeneous and physically distinct part of a system which is separated from other parts of the system by interfaces

                                A part of a system is homogeneous if it has identical physical properties and chemical composition throughout the part

                                A phase may be gas liquid or solid A gas or a gaseous mixture is a single phase Totally miscible liquids constitute a single phase In an immiscible liquid system each layer is counted as a separate phase Every solid constitutes a single phase except when a solid solution is formed A solid solution is considered as a single phase Each polymorphic form constitutes a separate phase

                                Phase Definition

                                1 Liquid water pieces of ice and water vapour are present together The number of phases is 3 as each form is a separate phase Ice in the system is a single phase even if it is present as a number of pieces

                                2 Calcium carbonate undergoes thermal decomposition The chemical reaction is CaCO3(s) CaO(s) + CO2 (g) Number of phases = 3 This system consists of 2 solid phases CaCO3 and CaO and one gaseous phase that of CO2

                                3 Ammonium chloride undergoes thermal decomposition The chemical reaction is NH4Cl(s) NH3 (g) + HCl (g) Number of phases = 2 This system has two phases one solid NH4Cl and one gaseous a mixture of NH3 and HCl

                                4 A solution of NaCl in water Number of phases = 1

                                bull Examples

                                The number of components of a system at equilibrium is the smallest number of independently varying chemical constituents using which the composition of each and every phase in the system can be expressed

                                Components

                                Counting the number of components 1 The sulphur system is a one component system All the phases

                                monoclinic rhombic liquid and vapour ndash can be expressed in terms of the single constituent ndash sulphur

                                2 A mixture of ethanol and water is an example of a two component system We need both ethanol and water to express its composition

                                bull Examples

                                An example of a system in which a reaction occurs and an equilibrium is established is the thermal decomposition of solid CaCO3

                                In this system there are three distinct phasesSolid CaCO3

                                Solid CaOGaseous CO2

                                Though there are 3 species present the number of components is only two because of the equilibrium CaCO3 (s) CaO(s) + CO2(g)

                                Any two of the three constituents may be chosen as the components

                                If CaO and CO2 are chosen then the composition of the phase CaCO3 is expressed as one mole of component CO2 plus one mole of component CaO

                                If on the other hand CaCO3 and CO2 were chosen then the composition of the phase CaO would be described as one mole of CaCO3 minus one mole of CO2

                                The degrees of freedom or variance of a system is defined as the minimum number of variables such as

                                temperaturepressureconcentrationwhich must be fixed in order to define the system completely

                                Degrees of freedom (or variance)

                                F = C P + 2

                                1 A gaseous mixture of CO2 and N2 Three variables pressure temperature and composition are required to define this system This is hence a trivariant system

                                2 A system having only liquid water has two degrees of freedom or is bivariant Both temperature and pressure need to be mentioned in order to define the system

                                3 If to the system containing liquid water pieces of ice are added and this system with 2 phases is allowed to come to equilibrium then it is an univariant system

                                Only one variable either temperature or pressure need to be specified in order to define the systemIf the pressure on the system is maintained at 1 atm then the temperature of the system gets automatically fixed at 0oC the normal melting point of ice

                                bull Examples

                                Phase Equilibria amp The Phase Rule

                                A phase diagram (Equilibrium Phase Diagram) summarizes the conditions at which a substance exists as a solid liquid or gas

                                OR It is a ldquomaprdquo of the information about the control of phase structure of a particular material system

                                The relationships between temperature and the compositions and the quantities of phases present at equilibrium are represented

                                F = C P + 2The phase rule

                                The phase rule JW Gibbs formulated the phase rule which is a general relation

                                between the variance F the number of component C and the number of phases P at equilibrium for a system of any composition

                                For a system in equilibrium

                                F degree of freedom the least number of intensive variable that must be fixed (known) to describe the system completely

                                Phase Rule relation to determine the least number of intensive variable that can be changed without changing the equilibrium state of the system or alternately

                                The least number required to define the state of the system which is called degree of freedom F

                                Intensive variable independent variable that do not depend on the volume or the size egTemp pressure

                                Independent chemical species which comprise the system These could be Elements Ions Compounds

                                Eg Au-Cu system Components rarr Au Cu Ice-water system Component rarr H2O

                                Al2O3 ndash Cr2O3 system Components rarr Al2O3 Cr2O3

                                Component the smallest number of constituent by which the composition of each phase in the system at equilibrium can be expressed in form of chemical formula or equation

                                Phase Equilibria amp The Phase RuleComponents of a system

                                The number of phases in a system is denoted P

                                (a)A gas or a gaseous mixture is a single phase P=1

                                (b) For a solid system an alloy of two metals is a two-phase system (P=2) if the metals are immiscible but a single-phase system (P=1) if they are miscible---a homogeneous mixture of the two substances---is uniform on a molecular scale

                                (c) For a liquid system according to the solubility to decide whether a system consists of one phase or of two For example a solution of sodium chloride in water is a single phase A pair of liquids that are partially miscible or immiscible is a two-phase system(P=2)

                                Oil in water

                                Degrees of Freedom = What you can control What the system controls

                                F = C + 2 P

                                Can control the no of components added and P amp T

                                System decided how many phases to produce given the

                                conditions

                                A way of understanding the Gibbs Phase RuleThe degrees of freedom can be thought of as the difference between what you (can) control and

                                what the system controls

                                F degree of freedom the least number of intensive variable that must be fixed (known) to describe the system completely

                                Degree of freedom (or variance) F is the number of variables (T p andor composition) that can be changed independently without changing the phases of the system

                                a) At the triple pointP = 3 (solid liquid and gas)

                                C= 1 (water)P + F = C + 2

                                F = 0 (no degree of freedom)

                                b) liquid-solid curveP = 2

                                2+F = 1 + 2F= 1

                                One variable (T or P) can be changed

                                c) LiquidP =1

                                So F =2Two variables (T and P) can be varied independently

                                and the system will remains a single phase

                                One-component systemsPhase diagram of water

                                P (

                                atm

                                )

                                Critical point

                                374

                                1

                                =100=0O--Triple point

                                0006

                                218

                                Curve O -CSublimation

                                Deposition

                                Curve O-AVaporizationCondensation

                                Curve O -BMelting

                                Freezing

                                F = C P + 2

                                F = C P + 2

                                Phase Diagram of Carbon Dioxide

                                Condensed system System in which the vapor phase is ignored and only the solid andor liquid phases are considered

                                Two component system For two component system F can be 3 (3D model is needed) eg T p

                                and concentration usually we fix p = 1atm the vapor phase is neglected and F is reduced to 2

                                For three component system the pressure and temperature are fixed

                                Phenol water phase diagram

                                eg for point d (24)

                                Two component system containing liquid phase

                                Tie Line bc line The line at which the system at equilibrium will separate into phases of constant composition termed lsquoconjugate phasesrsquo

                                Lever Rule a way to calculate the proportions of each phase present on a phase diagram in a two phase field (at a given temperature and composition)

                                eg for point d (24)

                                For every 10 g of liquid system in equilibrium in point d

                                75 g phase A25 g phase B

                                ExampleMixed 24g phenol +76g water T 50degC

                                equilibrium75 g phase A 25 g phase B

                                11 phenol 63 phenol

                                011 times75 g=825 g phenol

                                063 times25 g=1575 g phenol

                                water rich phasecontains water+ phenol(11)

                                Phenol rich phasecontains Phenol (63)+ water

                                The Critical Solution Temperature CST

                                Is the maximum temperature at which the 2-phase region exists (or upper consolute temperature)

                                In the case of the phenol-water system this is 668oC (point h)

                                All combinations of phenol and water gt CST are completely miscible and yield 1-phase liquid systems

                                Systems Showing a Decrease in Miscibility with Rise in Temperature

                                A few mixtures exhibit a lower critical solution temperature (low CST) eg triethylamine plus water The miscibility with in temperature

                                Systems Showing Upper and Lower CSTs

                                The miscibility with temp

                                a certain temperature miscibility starts to again with further in temperature

                                Closed-phase diagram ie nicotine-water system

                                A salol B thymol

                                53

                                Two component system containing solid and liquid phase (Eutectic Mixtures)

                                A salol B thymol

                                EMLAreg (lidocaine 25 and prilocaine 25) Cream

                                EMLA Cream (lidocaine 25 and prilocaine 25) is an emulsion in which the oil phase is a eutectic mixture of lidocaine and prilocaine in a ratio of 11 by weight This eutectic mixture has a melting point below room temperature and therefore both local anesthetics exist as a liquid oil rather than as crystals

                                Eutectic mixture Pharmaceutical Application

                                Triangular Diagrams for three ndash component systems

                                Three component system

                                Birzeit University Physical Pharmacy PHAR 323 Dr Hani Shtaya

                                1 Binding Forces Between Molecules2 Repulsive and Attractive Forces3 The Gaseous State The Ideal Gas Law Liquefaction of Gases Aerosols4 Solids and the Crystalline State Crystalline Solids Polymorphism Solvates Amorphous Solids5 Phase Equilibria and the Phase Rule Phase Rule Systems Containing One Component Condensed System Two-Component Systems Containing Liquid Phases Two-Component Systems Containing Solid and Liquid Phases Eutectic Mixtures Rules Relating to Triangular Diagrams

                                Topics that we have covered

                                • States of Matter
                                • States of Matter (2)
                                • Objectives of the lecture
                                • Comparison of Gases Liquids and Solids
                                • Slide 5
                                • Repulsive and Attractive Forces
                                • Ideal Gas Equation
                                • Gaseous state
                                • Slide 9
                                • Gaseous state (2)
                                • Liquefaction of Gases
                                • Slide 12
                                • SOLIDS amp CRYSTALLINE STATE Pharmaceutical Drugs more than 80
                                • Solids and the crystalline state
                                • Classification of Solids
                                • Slide 16
                                • Slide 17
                                • Crystal forms
                                • Types of Crystals
                                • Slide 20
                                • Slide 21
                                • Polymorphism
                                • Slide 23
                                • Slide 24
                                • Slide 25
                                • Slide 26
                                • Cocrystal
                                • Principle of polymorphism
                                • Solvates
                                • Polymorphism (2)
                                • Amorphous Solid
                                • Amorphous or crystalline amp therapeutic activity
                                • Slide 33
                                • Slide 34
                                • Polymorphism and Industry Pharmaceutical
                                • Celecoxib
                                • Furosemide
                                • Bioavailability
                                • Slide 39
                                • Slide 40
                                • Bioequivalence
                                • Slide 42
                                • Carbamazepine
                                • Slide 44
                                • AIDS drug ritonavir
                                • Slide 46
                                • Slide 47
                                • Phase Equilibria amp The Phase Rule
                                • Phase diagram ndash Water
                                • Phase Equilibria amp The Phase Rule Definitions
                                • Phase Definition
                                • Examples
                                • Components
                                • Examples
                                • Slide 55
                                • Degrees of freedom (or variance)
                                • Examples (2)
                                • Phase Equilibria amp The Phase Rule
                                • The phase rule
                                • Slide 60
                                • Phase Equilibria amp The Phase Rule (2)
                                • The number of phases in a system is denoted P
                                • Slide 63
                                • Slide 64
                                • One-component systems
                                • Slide 66
                                • Slide 67
                                • Slide 68
                                • Slide 69
                                • Slide 70
                                • Two component system containing liquid phase
                                • Slide 72
                                • The Critical Solution Temperature CST
                                • Systems Showing a Decrease in Miscibility with Rise in Temperat
                                • Systems Showing Upper and Lower CSTs
                                • Two component system containing solid and liquid phase (Eutecti
                                • Slide 77
                                • Eutectic mixture Pharmaceutical Application
                                • Three component system
                                • Slide 80
                                • Topics that we have covered

                                  CsCl ZnS CaF2

                                  Ionic Crystalsbull Lattice points occupied by cations and anionsbull Held together by electrostatic attractionbull Hard brittle high melting pointbull Poor conductor of heat and electricity

                                  Types of Crystals

                                  diamondgraphite

                                  carbonatoms

                                  Covalent Crystalsbull Lattice points occupied by atomsbull Held together by covalent bondsbull Hard high melting pointbull Poor conductor of heat and electricity

                                  Cross Section of a Metallic Crystal

                                  nucleus ampinner shell e-

                                  mobile ldquoseardquoof e-

                                  Metallic Crystalsbull Lattice points occupied by metal atomsbull Held together by metallic bondsbull Soft to hard low to high melting pointbull Good conductors of heat and electricity

                                  Some elemental substance such as C and S may exist in more than one crystalline form and are said to be allotropic which is a special case of polymorphism

                                  Polymorphism is the ability of a substance to exist in more than one crystal structure

                                  Polymorphism

                                  Polymorphism is the ability of a substance to exist in more than one crystal structure

                                  Polymorphs when two crystals have the same chemical composition but different internal structure (molecular packing ndashmolecular conformation or and inter or intra molecular interactions)modifications or polymorphs or forms

                                  Pseudo polymorphs different crystal forms have molecules of the same given substances and also contain molecules of solvent incorporated into a unique structure (solvates or hydrates (water))

                                  diamond graphite

                                  carbonatoms

                                  High T and p

                                  Diamond is metastable and converts very slowly to graphite

                                  The most common example of polymorphism

                                  Solid State Polymorphs

                                  Mono-component systems Polymorphs

                                  Multi-component systems

                                  Cocrystal

                                  The simplest definition of a cocrystal is a crystalline structure made up of two or more components in a definite stoichiometric ratio where each component is defined as either an atom ion or molecule

                                  Principle of polymorphism

                                  When the change from one form to another is reversible it is said to be enantiotropic

                                  When the transition takes place in one direction onlymdashfor example from a metastable to a stable formmdashthe change is said to be monotropic

                                  Solvates

                                  Pharmaceutical synthesis include purification and crystallization residual solvent can be trapped in the lattice

                                  This result in the formation of cocrystal or solvate

                                  The presence of residual solvent may affect dramatically the crystalline structure of the solid depending on the type of inter molecular forces that the solvent may have with crystalline solid

                                  Melting pointVapor pressureHardnessOptical electrical magnetic

                                  propertiesColorIR spectraNMR spectra

                                  Photochemical reactivityThermal stabilityFiltration and drying characteristicsDissolution rateBioavailabilityPhysical and chemical stability

                                  Solubility and melting point are very important in pharmaceutical processes including dissolution and

                                  formulation

                                  Polymorphism

                                  AMORPHOUS SOLIDS Solids that donrsquot have a definite geometrical shape are known as Amorphous Solids1 In these solids particles are randomly arranged in three dimension2 They donrsquot have sharp melting points3 Amorphous solids are formed due to sudden cooling of liquid4 Amorphous solids melt over a wide range of temperature

                                  Amorphous Solid

                                  An amorphous solid does not possess a well-defined arrangement and long-range molecular order

                                  Amorphous substances as well as cubic crystal are isotropic that is they exhibit similar properties in all direction

                                  The crystalline from of the antibiotic novobiocin acid is poorly absorbed and has no activity where the amorphous form is readily absorbed and therapeutically active due to different dissolution rate

                                  Amorphous or crystalline amp therapeutic activity

                                  General crystallization conditions 1048698Solvents ndashdifferent polarities 1048698Concentration of the solutions (super saturated saturated diluted) 1048698Cooling speed (quenching slow) 1048698Temperature (room or lower than room temperature)

                                  Crystallization

                                  Final Form

                                  Granulation

                                  Drying

                                  Compaction

                                  Tableting

                                  Drug Product

                                  API

                                  Crystallization

                                  Filtration

                                  Drying

                                  Milling

                                  Bulk API

                                  Stability

                                  Polymorphism and Industry Pharmaceutical

                                  Polymorphism and Industry Pharmaceutical

                                  Fluoxetine HCl the active ingredient in the antidepressant drug Prozac

                                  co crystal which will have increased solubility compared to the crystalline form

                                  Celecoxib

                                  CELECOXIB is a nonsteroidal anti-inflammatory drug

                                  However it was found that the higher bioavailability was shown by the amorphous state

                                  The downfall of the amorphous state was its stability

                                  This was due to the structural relaxation

                                  This was enhanced by mixing it with polymers like PVP which helped in stabilizing the amorphous system (Piyush Gupta et al 2004 Piyush Gupta et al 2005)

                                  A new solid state form was developed by Pharmacia

                                  FurosemideTwo forms with significantly differing aqueous solubility and dissolution rateOral bioavailability compromised

                                  Giron lists gt20 excipients that display polymorphism includingndash Lactose (anhydrous also monohydrate)ndash Aspartame (anhydrous hydrate forms)ndash Magnesium stearate (can affect lubrication of tablets)

                                  Bioavailability

                                  The rate and extent to which the active ingredient or active moiety is absorbed from a drug product and becomes available at the site of action

                                  Bioequivalence

                                  The absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study

                                  Carbamazepine

                                  CHLORPROPAMIDEat least six polymorphic white or almost white crystalline powder It exhibits polymorphism Practically insoluble in water soluble in alcohol freely soluble in acetone and in dichlo-romethane dissolves in dilute solutions of alkali hydroxides Protect from light

                                  blood-glucose-lowering drug

                                  AIDS drug ritonavir

                                  Theobroma oil (cacao butter ) is a polymorphic natural fat

                                  Theobroma oil can exist in 4 different polymorphic forms of which only one is Stabile

                                  1 Unstable gamma form melting at 18degC2 Alpha form melting at 22degC3 Beta prime form melting at 28degC4 Stable beta form melting at 345degC

                                  This is important in the preparation of theobroma suppositories

                                  If the oil is heated to a point where it is completely liquified (about 35 C) the crystals of the stable polymorph are destroyed amp the mass does not crystallize until it is cooled to 15 C

                                  The crystals that form are unstable amp the suppositories melt at 24 C

                                  Theobroma suppositories must be prepared below 33 C

                                  Polymorphism and Industry Pharmaceutical

                                  Polymorphism and Industry Pharmaceutical

                                  Anhydrates together with salts form the majority of all drug formulationsAbout a half of all APIs used today are saltsSalts are stable and well soluble in polar solvents (first of all in water) because they contain ionic bondThere is one more essential advantage of salts ndash their solubility is a function of pH Since pH in the gastrointestinal tract (GIT) vary between 1-75

                                  atorvastatin calcium trihydrateEach tablet contains Atorvastatin Calcium Trihydrate equivalent to Atorvastatin 20 mg

                                  Phase Equilibria amp The Phase Rule

                                  Phase diagram ndash Water

                                  Phase Equilibrium A stable phase structure with lowest free-energy (internal energy) of a system and also randomness or disorder of the atoms or molecules (entropy)

                                  Any change in Temperature Composition and Pressure causes an increase in free energy and away from Equilibrium thus forcing a move to another lsquostatersquo

                                  Phase Equilibria amp The Phase Rule Definitions

                                  A phase is defined as any homogeneous and physically distinct part of a system which is separated from other parts of the system by interfaces

                                  A part of a system is homogeneous if it has identical physical properties and chemical composition throughout the part

                                  A phase may be gas liquid or solid A gas or a gaseous mixture is a single phase Totally miscible liquids constitute a single phase In an immiscible liquid system each layer is counted as a separate phase Every solid constitutes a single phase except when a solid solution is formed A solid solution is considered as a single phase Each polymorphic form constitutes a separate phase

                                  Phase Definition

                                  1 Liquid water pieces of ice and water vapour are present together The number of phases is 3 as each form is a separate phase Ice in the system is a single phase even if it is present as a number of pieces

                                  2 Calcium carbonate undergoes thermal decomposition The chemical reaction is CaCO3(s) CaO(s) + CO2 (g) Number of phases = 3 This system consists of 2 solid phases CaCO3 and CaO and one gaseous phase that of CO2

                                  3 Ammonium chloride undergoes thermal decomposition The chemical reaction is NH4Cl(s) NH3 (g) + HCl (g) Number of phases = 2 This system has two phases one solid NH4Cl and one gaseous a mixture of NH3 and HCl

                                  4 A solution of NaCl in water Number of phases = 1

                                  bull Examples

                                  The number of components of a system at equilibrium is the smallest number of independently varying chemical constituents using which the composition of each and every phase in the system can be expressed

                                  Components

                                  Counting the number of components 1 The sulphur system is a one component system All the phases

                                  monoclinic rhombic liquid and vapour ndash can be expressed in terms of the single constituent ndash sulphur

                                  2 A mixture of ethanol and water is an example of a two component system We need both ethanol and water to express its composition

                                  bull Examples

                                  An example of a system in which a reaction occurs and an equilibrium is established is the thermal decomposition of solid CaCO3

                                  In this system there are three distinct phasesSolid CaCO3

                                  Solid CaOGaseous CO2

                                  Though there are 3 species present the number of components is only two because of the equilibrium CaCO3 (s) CaO(s) + CO2(g)

                                  Any two of the three constituents may be chosen as the components

                                  If CaO and CO2 are chosen then the composition of the phase CaCO3 is expressed as one mole of component CO2 plus one mole of component CaO

                                  If on the other hand CaCO3 and CO2 were chosen then the composition of the phase CaO would be described as one mole of CaCO3 minus one mole of CO2

                                  The degrees of freedom or variance of a system is defined as the minimum number of variables such as

                                  temperaturepressureconcentrationwhich must be fixed in order to define the system completely

                                  Degrees of freedom (or variance)

                                  F = C P + 2

                                  1 A gaseous mixture of CO2 and N2 Three variables pressure temperature and composition are required to define this system This is hence a trivariant system

                                  2 A system having only liquid water has two degrees of freedom or is bivariant Both temperature and pressure need to be mentioned in order to define the system

                                  3 If to the system containing liquid water pieces of ice are added and this system with 2 phases is allowed to come to equilibrium then it is an univariant system

                                  Only one variable either temperature or pressure need to be specified in order to define the systemIf the pressure on the system is maintained at 1 atm then the temperature of the system gets automatically fixed at 0oC the normal melting point of ice

                                  bull Examples

                                  Phase Equilibria amp The Phase Rule

                                  A phase diagram (Equilibrium Phase Diagram) summarizes the conditions at which a substance exists as a solid liquid or gas

                                  OR It is a ldquomaprdquo of the information about the control of phase structure of a particular material system

                                  The relationships between temperature and the compositions and the quantities of phases present at equilibrium are represented

                                  F = C P + 2The phase rule

                                  The phase rule JW Gibbs formulated the phase rule which is a general relation

                                  between the variance F the number of component C and the number of phases P at equilibrium for a system of any composition

                                  For a system in equilibrium

                                  F degree of freedom the least number of intensive variable that must be fixed (known) to describe the system completely

                                  Phase Rule relation to determine the least number of intensive variable that can be changed without changing the equilibrium state of the system or alternately

                                  The least number required to define the state of the system which is called degree of freedom F

                                  Intensive variable independent variable that do not depend on the volume or the size egTemp pressure

                                  Independent chemical species which comprise the system These could be Elements Ions Compounds

                                  Eg Au-Cu system Components rarr Au Cu Ice-water system Component rarr H2O

                                  Al2O3 ndash Cr2O3 system Components rarr Al2O3 Cr2O3

                                  Component the smallest number of constituent by which the composition of each phase in the system at equilibrium can be expressed in form of chemical formula or equation

                                  Phase Equilibria amp The Phase RuleComponents of a system

                                  The number of phases in a system is denoted P

                                  (a)A gas or a gaseous mixture is a single phase P=1

                                  (b) For a solid system an alloy of two metals is a two-phase system (P=2) if the metals are immiscible but a single-phase system (P=1) if they are miscible---a homogeneous mixture of the two substances---is uniform on a molecular scale

                                  (c) For a liquid system according to the solubility to decide whether a system consists of one phase or of two For example a solution of sodium chloride in water is a single phase A pair of liquids that are partially miscible or immiscible is a two-phase system(P=2)

                                  Oil in water

                                  Degrees of Freedom = What you can control What the system controls

                                  F = C + 2 P

                                  Can control the no of components added and P amp T

                                  System decided how many phases to produce given the

                                  conditions

                                  A way of understanding the Gibbs Phase RuleThe degrees of freedom can be thought of as the difference between what you (can) control and

                                  what the system controls

                                  F degree of freedom the least number of intensive variable that must be fixed (known) to describe the system completely

                                  Degree of freedom (or variance) F is the number of variables (T p andor composition) that can be changed independently without changing the phases of the system

                                  a) At the triple pointP = 3 (solid liquid and gas)

                                  C= 1 (water)P + F = C + 2

                                  F = 0 (no degree of freedom)

                                  b) liquid-solid curveP = 2

                                  2+F = 1 + 2F= 1

                                  One variable (T or P) can be changed

                                  c) LiquidP =1

                                  So F =2Two variables (T and P) can be varied independently

                                  and the system will remains a single phase

                                  One-component systemsPhase diagram of water

                                  P (

                                  atm

                                  )

                                  Critical point

                                  374

                                  1

                                  =100=0O--Triple point

                                  0006

                                  218

                                  Curve O -CSublimation

                                  Deposition

                                  Curve O-AVaporizationCondensation

                                  Curve O -BMelting

                                  Freezing

                                  F = C P + 2

                                  F = C P + 2

                                  Phase Diagram of Carbon Dioxide

                                  Condensed system System in which the vapor phase is ignored and only the solid andor liquid phases are considered

                                  Two component system For two component system F can be 3 (3D model is needed) eg T p

                                  and concentration usually we fix p = 1atm the vapor phase is neglected and F is reduced to 2

                                  For three component system the pressure and temperature are fixed

                                  Phenol water phase diagram

                                  eg for point d (24)

                                  Two component system containing liquid phase

                                  Tie Line bc line The line at which the system at equilibrium will separate into phases of constant composition termed lsquoconjugate phasesrsquo

                                  Lever Rule a way to calculate the proportions of each phase present on a phase diagram in a two phase field (at a given temperature and composition)

                                  eg for point d (24)

                                  For every 10 g of liquid system in equilibrium in point d

                                  75 g phase A25 g phase B

                                  ExampleMixed 24g phenol +76g water T 50degC

                                  equilibrium75 g phase A 25 g phase B

                                  11 phenol 63 phenol

                                  011 times75 g=825 g phenol

                                  063 times25 g=1575 g phenol

                                  water rich phasecontains water+ phenol(11)

                                  Phenol rich phasecontains Phenol (63)+ water

                                  The Critical Solution Temperature CST

                                  Is the maximum temperature at which the 2-phase region exists (or upper consolute temperature)

                                  In the case of the phenol-water system this is 668oC (point h)

                                  All combinations of phenol and water gt CST are completely miscible and yield 1-phase liquid systems

                                  Systems Showing a Decrease in Miscibility with Rise in Temperature

                                  A few mixtures exhibit a lower critical solution temperature (low CST) eg triethylamine plus water The miscibility with in temperature

                                  Systems Showing Upper and Lower CSTs

                                  The miscibility with temp

                                  a certain temperature miscibility starts to again with further in temperature

                                  Closed-phase diagram ie nicotine-water system

                                  A salol B thymol

                                  53

                                  Two component system containing solid and liquid phase (Eutectic Mixtures)

                                  A salol B thymol

                                  EMLAreg (lidocaine 25 and prilocaine 25) Cream

                                  EMLA Cream (lidocaine 25 and prilocaine 25) is an emulsion in which the oil phase is a eutectic mixture of lidocaine and prilocaine in a ratio of 11 by weight This eutectic mixture has a melting point below room temperature and therefore both local anesthetics exist as a liquid oil rather than as crystals

                                  Eutectic mixture Pharmaceutical Application

                                  Triangular Diagrams for three ndash component systems

                                  Three component system

                                  Birzeit University Physical Pharmacy PHAR 323 Dr Hani Shtaya

                                  1 Binding Forces Between Molecules2 Repulsive and Attractive Forces3 The Gaseous State The Ideal Gas Law Liquefaction of Gases Aerosols4 Solids and the Crystalline State Crystalline Solids Polymorphism Solvates Amorphous Solids5 Phase Equilibria and the Phase Rule Phase Rule Systems Containing One Component Condensed System Two-Component Systems Containing Liquid Phases Two-Component Systems Containing Solid and Liquid Phases Eutectic Mixtures Rules Relating to Triangular Diagrams

                                  Topics that we have covered

                                  • States of Matter
                                  • States of Matter (2)
                                  • Objectives of the lecture
                                  • Comparison of Gases Liquids and Solids
                                  • Slide 5
                                  • Repulsive and Attractive Forces
                                  • Ideal Gas Equation
                                  • Gaseous state
                                  • Slide 9
                                  • Gaseous state (2)
                                  • Liquefaction of Gases
                                  • Slide 12
                                  • SOLIDS amp CRYSTALLINE STATE Pharmaceutical Drugs more than 80
                                  • Solids and the crystalline state
                                  • Classification of Solids
                                  • Slide 16
                                  • Slide 17
                                  • Crystal forms
                                  • Types of Crystals
                                  • Slide 20
                                  • Slide 21
                                  • Polymorphism
                                  • Slide 23
                                  • Slide 24
                                  • Slide 25
                                  • Slide 26
                                  • Cocrystal
                                  • Principle of polymorphism
                                  • Solvates
                                  • Polymorphism (2)
                                  • Amorphous Solid
                                  • Amorphous or crystalline amp therapeutic activity
                                  • Slide 33
                                  • Slide 34
                                  • Polymorphism and Industry Pharmaceutical
                                  • Celecoxib
                                  • Furosemide
                                  • Bioavailability
                                  • Slide 39
                                  • Slide 40
                                  • Bioequivalence
                                  • Slide 42
                                  • Carbamazepine
                                  • Slide 44
                                  • AIDS drug ritonavir
                                  • Slide 46
                                  • Slide 47
                                  • Phase Equilibria amp The Phase Rule
                                  • Phase diagram ndash Water
                                  • Phase Equilibria amp The Phase Rule Definitions
                                  • Phase Definition
                                  • Examples
                                  • Components
                                  • Examples
                                  • Slide 55
                                  • Degrees of freedom (or variance)
                                  • Examples (2)
                                  • Phase Equilibria amp The Phase Rule
                                  • The phase rule
                                  • Slide 60
                                  • Phase Equilibria amp The Phase Rule (2)
                                  • The number of phases in a system is denoted P
                                  • Slide 63
                                  • Slide 64
                                  • One-component systems
                                  • Slide 66
                                  • Slide 67
                                  • Slide 68
                                  • Slide 69
                                  • Slide 70
                                  • Two component system containing liquid phase
                                  • Slide 72
                                  • The Critical Solution Temperature CST
                                  • Systems Showing a Decrease in Miscibility with Rise in Temperat
                                  • Systems Showing Upper and Lower CSTs
                                  • Two component system containing solid and liquid phase (Eutecti
                                  • Slide 77
                                  • Eutectic mixture Pharmaceutical Application
                                  • Three component system
                                  • Slide 80
                                  • Topics that we have covered

                                    diamondgraphite

                                    carbonatoms

                                    Covalent Crystalsbull Lattice points occupied by atomsbull Held together by covalent bondsbull Hard high melting pointbull Poor conductor of heat and electricity

                                    Cross Section of a Metallic Crystal

                                    nucleus ampinner shell e-

                                    mobile ldquoseardquoof e-

                                    Metallic Crystalsbull Lattice points occupied by metal atomsbull Held together by metallic bondsbull Soft to hard low to high melting pointbull Good conductors of heat and electricity

                                    Some elemental substance such as C and S may exist in more than one crystalline form and are said to be allotropic which is a special case of polymorphism

                                    Polymorphism is the ability of a substance to exist in more than one crystal structure

                                    Polymorphism

                                    Polymorphism is the ability of a substance to exist in more than one crystal structure

                                    Polymorphs when two crystals have the same chemical composition but different internal structure (molecular packing ndashmolecular conformation or and inter or intra molecular interactions)modifications or polymorphs or forms

                                    Pseudo polymorphs different crystal forms have molecules of the same given substances and also contain molecules of solvent incorporated into a unique structure (solvates or hydrates (water))

                                    diamond graphite

                                    carbonatoms

                                    High T and p

                                    Diamond is metastable and converts very slowly to graphite

                                    The most common example of polymorphism

                                    Solid State Polymorphs

                                    Mono-component systems Polymorphs

                                    Multi-component systems

                                    Cocrystal

                                    The simplest definition of a cocrystal is a crystalline structure made up of two or more components in a definite stoichiometric ratio where each component is defined as either an atom ion or molecule

                                    Principle of polymorphism

                                    When the change from one form to another is reversible it is said to be enantiotropic

                                    When the transition takes place in one direction onlymdashfor example from a metastable to a stable formmdashthe change is said to be monotropic

                                    Solvates

                                    Pharmaceutical synthesis include purification and crystallization residual solvent can be trapped in the lattice

                                    This result in the formation of cocrystal or solvate

                                    The presence of residual solvent may affect dramatically the crystalline structure of the solid depending on the type of inter molecular forces that the solvent may have with crystalline solid

                                    Melting pointVapor pressureHardnessOptical electrical magnetic

                                    propertiesColorIR spectraNMR spectra

                                    Photochemical reactivityThermal stabilityFiltration and drying characteristicsDissolution rateBioavailabilityPhysical and chemical stability

                                    Solubility and melting point are very important in pharmaceutical processes including dissolution and

                                    formulation

                                    Polymorphism

                                    AMORPHOUS SOLIDS Solids that donrsquot have a definite geometrical shape are known as Amorphous Solids1 In these solids particles are randomly arranged in three dimension2 They donrsquot have sharp melting points3 Amorphous solids are formed due to sudden cooling of liquid4 Amorphous solids melt over a wide range of temperature

                                    Amorphous Solid

                                    An amorphous solid does not possess a well-defined arrangement and long-range molecular order

                                    Amorphous substances as well as cubic crystal are isotropic that is they exhibit similar properties in all direction

                                    The crystalline from of the antibiotic novobiocin acid is poorly absorbed and has no activity where the amorphous form is readily absorbed and therapeutically active due to different dissolution rate

                                    Amorphous or crystalline amp therapeutic activity

                                    General crystallization conditions 1048698Solvents ndashdifferent polarities 1048698Concentration of the solutions (super saturated saturated diluted) 1048698Cooling speed (quenching slow) 1048698Temperature (room or lower than room temperature)

                                    Crystallization

                                    Final Form

                                    Granulation

                                    Drying

                                    Compaction

                                    Tableting

                                    Drug Product

                                    API

                                    Crystallization

                                    Filtration

                                    Drying

                                    Milling

                                    Bulk API

                                    Stability

                                    Polymorphism and Industry Pharmaceutical

                                    Polymorphism and Industry Pharmaceutical

                                    Fluoxetine HCl the active ingredient in the antidepressant drug Prozac

                                    co crystal which will have increased solubility compared to the crystalline form

                                    Celecoxib

                                    CELECOXIB is a nonsteroidal anti-inflammatory drug

                                    However it was found that the higher bioavailability was shown by the amorphous state

                                    The downfall of the amorphous state was its stability

                                    This was due to the structural relaxation

                                    This was enhanced by mixing it with polymers like PVP which helped in stabilizing the amorphous system (Piyush Gupta et al 2004 Piyush Gupta et al 2005)

                                    A new solid state form was developed by Pharmacia

                                    FurosemideTwo forms with significantly differing aqueous solubility and dissolution rateOral bioavailability compromised

                                    Giron lists gt20 excipients that display polymorphism includingndash Lactose (anhydrous also monohydrate)ndash Aspartame (anhydrous hydrate forms)ndash Magnesium stearate (can affect lubrication of tablets)

                                    Bioavailability

                                    The rate and extent to which the active ingredient or active moiety is absorbed from a drug product and becomes available at the site of action

                                    Bioequivalence

                                    The absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study

                                    Carbamazepine

                                    CHLORPROPAMIDEat least six polymorphic white or almost white crystalline powder It exhibits polymorphism Practically insoluble in water soluble in alcohol freely soluble in acetone and in dichlo-romethane dissolves in dilute solutions of alkali hydroxides Protect from light

                                    blood-glucose-lowering drug

                                    AIDS drug ritonavir

                                    Theobroma oil (cacao butter ) is a polymorphic natural fat

                                    Theobroma oil can exist in 4 different polymorphic forms of which only one is Stabile

                                    1 Unstable gamma form melting at 18degC2 Alpha form melting at 22degC3 Beta prime form melting at 28degC4 Stable beta form melting at 345degC

                                    This is important in the preparation of theobroma suppositories

                                    If the oil is heated to a point where it is completely liquified (about 35 C) the crystals of the stable polymorph are destroyed amp the mass does not crystallize until it is cooled to 15 C

                                    The crystals that form are unstable amp the suppositories melt at 24 C

                                    Theobroma suppositories must be prepared below 33 C

                                    Polymorphism and Industry Pharmaceutical

                                    Polymorphism and Industry Pharmaceutical

                                    Anhydrates together with salts form the majority of all drug formulationsAbout a half of all APIs used today are saltsSalts are stable and well soluble in polar solvents (first of all in water) because they contain ionic bondThere is one more essential advantage of salts ndash their solubility is a function of pH Since pH in the gastrointestinal tract (GIT) vary between 1-75

                                    atorvastatin calcium trihydrateEach tablet contains Atorvastatin Calcium Trihydrate equivalent to Atorvastatin 20 mg

                                    Phase Equilibria amp The Phase Rule

                                    Phase diagram ndash Water

                                    Phase Equilibrium A stable phase structure with lowest free-energy (internal energy) of a system and also randomness or disorder of the atoms or molecules (entropy)

                                    Any change in Temperature Composition and Pressure causes an increase in free energy and away from Equilibrium thus forcing a move to another lsquostatersquo

                                    Phase Equilibria amp The Phase Rule Definitions

                                    A phase is defined as any homogeneous and physically distinct part of a system which is separated from other parts of the system by interfaces

                                    A part of a system is homogeneous if it has identical physical properties and chemical composition throughout the part

                                    A phase may be gas liquid or solid A gas or a gaseous mixture is a single phase Totally miscible liquids constitute a single phase In an immiscible liquid system each layer is counted as a separate phase Every solid constitutes a single phase except when a solid solution is formed A solid solution is considered as a single phase Each polymorphic form constitutes a separate phase

                                    Phase Definition

                                    1 Liquid water pieces of ice and water vapour are present together The number of phases is 3 as each form is a separate phase Ice in the system is a single phase even if it is present as a number of pieces

                                    2 Calcium carbonate undergoes thermal decomposition The chemical reaction is CaCO3(s) CaO(s) + CO2 (g) Number of phases = 3 This system consists of 2 solid phases CaCO3 and CaO and one gaseous phase that of CO2

                                    3 Ammonium chloride undergoes thermal decomposition The chemical reaction is NH4Cl(s) NH3 (g) + HCl (g) Number of phases = 2 This system has two phases one solid NH4Cl and one gaseous a mixture of NH3 and HCl

                                    4 A solution of NaCl in water Number of phases = 1

                                    bull Examples

                                    The number of components of a system at equilibrium is the smallest number of independently varying chemical constituents using which the composition of each and every phase in the system can be expressed

                                    Components

                                    Counting the number of components 1 The sulphur system is a one component system All the phases

                                    monoclinic rhombic liquid and vapour ndash can be expressed in terms of the single constituent ndash sulphur

                                    2 A mixture of ethanol and water is an example of a two component system We need both ethanol and water to express its composition

                                    bull Examples

                                    An example of a system in which a reaction occurs and an equilibrium is established is the thermal decomposition of solid CaCO3

                                    In this system there are three distinct phasesSolid CaCO3

                                    Solid CaOGaseous CO2

                                    Though there are 3 species present the number of components is only two because of the equilibrium CaCO3 (s) CaO(s) + CO2(g)

                                    Any two of the three constituents may be chosen as the components

                                    If CaO and CO2 are chosen then the composition of the phase CaCO3 is expressed as one mole of component CO2 plus one mole of component CaO

                                    If on the other hand CaCO3 and CO2 were chosen then the composition of the phase CaO would be described as one mole of CaCO3 minus one mole of CO2

                                    The degrees of freedom or variance of a system is defined as the minimum number of variables such as

                                    temperaturepressureconcentrationwhich must be fixed in order to define the system completely

                                    Degrees of freedom (or variance)

                                    F = C P + 2

                                    1 A gaseous mixture of CO2 and N2 Three variables pressure temperature and composition are required to define this system This is hence a trivariant system

                                    2 A system having only liquid water has two degrees of freedom or is bivariant Both temperature and pressure need to be mentioned in order to define the system

                                    3 If to the system containing liquid water pieces of ice are added and this system with 2 phases is allowed to come to equilibrium then it is an univariant system

                                    Only one variable either temperature or pressure need to be specified in order to define the systemIf the pressure on the system is maintained at 1 atm then the temperature of the system gets automatically fixed at 0oC the normal melting point of ice

                                    bull Examples

                                    Phase Equilibria amp The Phase Rule

                                    A phase diagram (Equilibrium Phase Diagram) summarizes the conditions at which a substance exists as a solid liquid or gas

                                    OR It is a ldquomaprdquo of the information about the control of phase structure of a particular material system

                                    The relationships between temperature and the compositions and the quantities of phases present at equilibrium are represented

                                    F = C P + 2The phase rule

                                    The phase rule JW Gibbs formulated the phase rule which is a general relation

                                    between the variance F the number of component C and the number of phases P at equilibrium for a system of any composition

                                    For a system in equilibrium

                                    F degree of freedom the least number of intensive variable that must be fixed (known) to describe the system completely

                                    Phase Rule relation to determine the least number of intensive variable that can be changed without changing the equilibrium state of the system or alternately

                                    The least number required to define the state of the system which is called degree of freedom F

                                    Intensive variable independent variable that do not depend on the volume or the size egTemp pressure

                                    Independent chemical species which comprise the system These could be Elements Ions Compounds

                                    Eg Au-Cu system Components rarr Au Cu Ice-water system Component rarr H2O

                                    Al2O3 ndash Cr2O3 system Components rarr Al2O3 Cr2O3

                                    Component the smallest number of constituent by which the composition of each phase in the system at equilibrium can be expressed in form of chemical formula or equation

                                    Phase Equilibria amp The Phase RuleComponents of a system

                                    The number of phases in a system is denoted P

                                    (a)A gas or a gaseous mixture is a single phase P=1

                                    (b) For a solid system an alloy of two metals is a two-phase system (P=2) if the metals are immiscible but a single-phase system (P=1) if they are miscible---a homogeneous mixture of the two substances---is uniform on a molecular scale

                                    (c) For a liquid system according to the solubility to decide whether a system consists of one phase or of two For example a solution of sodium chloride in water is a single phase A pair of liquids that are partially miscible or immiscible is a two-phase system(P=2)

                                    Oil in water

                                    Degrees of Freedom = What you can control What the system controls

                                    F = C + 2 P

                                    Can control the no of components added and P amp T

                                    System decided how many phases to produce given the

                                    conditions

                                    A way of understanding the Gibbs Phase RuleThe degrees of freedom can be thought of as the difference between what you (can) control and

                                    what the system controls

                                    F degree of freedom the least number of intensive variable that must be fixed (known) to describe the system completely

                                    Degree of freedom (or variance) F is the number of variables (T p andor composition) that can be changed independently without changing the phases of the system

                                    a) At the triple pointP = 3 (solid liquid and gas)

                                    C= 1 (water)P + F = C + 2

                                    F = 0 (no degree of freedom)

                                    b) liquid-solid curveP = 2

                                    2+F = 1 + 2F= 1

                                    One variable (T or P) can be changed

                                    c) LiquidP =1

                                    So F =2Two variables (T and P) can be varied independently

                                    and the system will remains a single phase

                                    One-component systemsPhase diagram of water

                                    P (

                                    atm

                                    )

                                    Critical point

                                    374

                                    1

                                    =100=0O--Triple point

                                    0006

                                    218

                                    Curve O -CSublimation

                                    Deposition

                                    Curve O-AVaporizationCondensation

                                    Curve O -BMelting

                                    Freezing

                                    F = C P + 2

                                    F = C P + 2

                                    Phase Diagram of Carbon Dioxide

                                    Condensed system System in which the vapor phase is ignored and only the solid andor liquid phases are considered

                                    Two component system For two component system F can be 3 (3D model is needed) eg T p

                                    and concentration usually we fix p = 1atm the vapor phase is neglected and F is reduced to 2

                                    For three component system the pressure and temperature are fixed

                                    Phenol water phase diagram

                                    eg for point d (24)

                                    Two component system containing liquid phase

                                    Tie Line bc line The line at which the system at equilibrium will separate into phases of constant composition termed lsquoconjugate phasesrsquo

                                    Lever Rule a way to calculate the proportions of each phase present on a phase diagram in a two phase field (at a given temperature and composition)

                                    eg for point d (24)

                                    For every 10 g of liquid system in equilibrium in point d

                                    75 g phase A25 g phase B

                                    ExampleMixed 24g phenol +76g water T 50degC

                                    equilibrium75 g phase A 25 g phase B

                                    11 phenol 63 phenol

                                    011 times75 g=825 g phenol

                                    063 times25 g=1575 g phenol

                                    water rich phasecontains water+ phenol(11)

                                    Phenol rich phasecontains Phenol (63)+ water

                                    The Critical Solution Temperature CST

                                    Is the maximum temperature at which the 2-phase region exists (or upper consolute temperature)

                                    In the case of the phenol-water system this is 668oC (point h)

                                    All combinations of phenol and water gt CST are completely miscible and yield 1-phase liquid systems

                                    Systems Showing a Decrease in Miscibility with Rise in Temperature

                                    A few mixtures exhibit a lower critical solution temperature (low CST) eg triethylamine plus water The miscibility with in temperature

                                    Systems Showing Upper and Lower CSTs

                                    The miscibility with temp

                                    a certain temperature miscibility starts to again with further in temperature

                                    Closed-phase diagram ie nicotine-water system

                                    A salol B thymol

                                    53

                                    Two component system containing solid and liquid phase (Eutectic Mixtures)

                                    A salol B thymol

                                    EMLAreg (lidocaine 25 and prilocaine 25) Cream

                                    EMLA Cream (lidocaine 25 and prilocaine 25) is an emulsion in which the oil phase is a eutectic mixture of lidocaine and prilocaine in a ratio of 11 by weight This eutectic mixture has a melting point below room temperature and therefore both local anesthetics exist as a liquid oil rather than as crystals

                                    Eutectic mixture Pharmaceutical Application

                                    Triangular Diagrams for three ndash component systems

                                    Three component system

                                    Birzeit University Physical Pharmacy PHAR 323 Dr Hani Shtaya

                                    1 Binding Forces Between Molecules2 Repulsive and Attractive Forces3 The Gaseous State The Ideal Gas Law Liquefaction of Gases Aerosols4 Solids and the Crystalline State Crystalline Solids Polymorphism Solvates Amorphous Solids5 Phase Equilibria and the Phase Rule Phase Rule Systems Containing One Component Condensed System Two-Component Systems Containing Liquid Phases Two-Component Systems Containing Solid and Liquid Phases Eutectic Mixtures Rules Relating to Triangular Diagrams

                                    Topics that we have covered

                                    • States of Matter
                                    • States of Matter (2)
                                    • Objectives of the lecture
                                    • Comparison of Gases Liquids and Solids
                                    • Slide 5
                                    • Repulsive and Attractive Forces
                                    • Ideal Gas Equation
                                    • Gaseous state
                                    • Slide 9
                                    • Gaseous state (2)
                                    • Liquefaction of Gases
                                    • Slide 12
                                    • SOLIDS amp CRYSTALLINE STATE Pharmaceutical Drugs more than 80
                                    • Solids and the crystalline state
                                    • Classification of Solids
                                    • Slide 16
                                    • Slide 17
                                    • Crystal forms
                                    • Types of Crystals
                                    • Slide 20
                                    • Slide 21
                                    • Polymorphism
                                    • Slide 23
                                    • Slide 24
                                    • Slide 25
                                    • Slide 26
                                    • Cocrystal
                                    • Principle of polymorphism
                                    • Solvates
                                    • Polymorphism (2)
                                    • Amorphous Solid
                                    • Amorphous or crystalline amp therapeutic activity
                                    • Slide 33
                                    • Slide 34
                                    • Polymorphism and Industry Pharmaceutical
                                    • Celecoxib
                                    • Furosemide
                                    • Bioavailability
                                    • Slide 39
                                    • Slide 40
                                    • Bioequivalence
                                    • Slide 42
                                    • Carbamazepine
                                    • Slide 44
                                    • AIDS drug ritonavir
                                    • Slide 46
                                    • Slide 47
                                    • Phase Equilibria amp The Phase Rule
                                    • Phase diagram ndash Water
                                    • Phase Equilibria amp The Phase Rule Definitions
                                    • Phase Definition
                                    • Examples
                                    • Components
                                    • Examples
                                    • Slide 55
                                    • Degrees of freedom (or variance)
                                    • Examples (2)
                                    • Phase Equilibria amp The Phase Rule
                                    • The phase rule
                                    • Slide 60
                                    • Phase Equilibria amp The Phase Rule (2)
                                    • The number of phases in a system is denoted P
                                    • Slide 63
                                    • Slide 64
                                    • One-component systems
                                    • Slide 66
                                    • Slide 67
                                    • Slide 68
                                    • Slide 69
                                    • Slide 70
                                    • Two component system containing liquid phase
                                    • Slide 72
                                    • The Critical Solution Temperature CST
                                    • Systems Showing a Decrease in Miscibility with Rise in Temperat
                                    • Systems Showing Upper and Lower CSTs
                                    • Two component system containing solid and liquid phase (Eutecti
                                    • Slide 77
                                    • Eutectic mixture Pharmaceutical Application
                                    • Three component system
                                    • Slide 80
                                    • Topics that we have covered

                                      Cross Section of a Metallic Crystal

                                      nucleus ampinner shell e-

                                      mobile ldquoseardquoof e-

                                      Metallic Crystalsbull Lattice points occupied by metal atomsbull Held together by metallic bondsbull Soft to hard low to high melting pointbull Good conductors of heat and electricity

                                      Some elemental substance such as C and S may exist in more than one crystalline form and are said to be allotropic which is a special case of polymorphism

                                      Polymorphism is the ability of a substance to exist in more than one crystal structure

                                      Polymorphism

                                      Polymorphism is the ability of a substance to exist in more than one crystal structure

                                      Polymorphs when two crystals have the same chemical composition but different internal structure (molecular packing ndashmolecular conformation or and inter or intra molecular interactions)modifications or polymorphs or forms

                                      Pseudo polymorphs different crystal forms have molecules of the same given substances and also contain molecules of solvent incorporated into a unique structure (solvates or hydrates (water))

                                      diamond graphite

                                      carbonatoms

                                      High T and p

                                      Diamond is metastable and converts very slowly to graphite

                                      The most common example of polymorphism

                                      Solid State Polymorphs

                                      Mono-component systems Polymorphs

                                      Multi-component systems

                                      Cocrystal

                                      The simplest definition of a cocrystal is a crystalline structure made up of two or more components in a definite stoichiometric ratio where each component is defined as either an atom ion or molecule

                                      Principle of polymorphism

                                      When the change from one form to another is reversible it is said to be enantiotropic

                                      When the transition takes place in one direction onlymdashfor example from a metastable to a stable formmdashthe change is said to be monotropic

                                      Solvates

                                      Pharmaceutical synthesis include purification and crystallization residual solvent can be trapped in the lattice

                                      This result in the formation of cocrystal or solvate

                                      The presence of residual solvent may affect dramatically the crystalline structure of the solid depending on the type of inter molecular forces that the solvent may have with crystalline solid

                                      Melting pointVapor pressureHardnessOptical electrical magnetic

                                      propertiesColorIR spectraNMR spectra

                                      Photochemical reactivityThermal stabilityFiltration and drying characteristicsDissolution rateBioavailabilityPhysical and chemical stability

                                      Solubility and melting point are very important in pharmaceutical processes including dissolution and

                                      formulation

                                      Polymorphism

                                      AMORPHOUS SOLIDS Solids that donrsquot have a definite geometrical shape are known as Amorphous Solids1 In these solids particles are randomly arranged in three dimension2 They donrsquot have sharp melting points3 Amorphous solids are formed due to sudden cooling of liquid4 Amorphous solids melt over a wide range of temperature

                                      Amorphous Solid

                                      An amorphous solid does not possess a well-defined arrangement and long-range molecular order

                                      Amorphous substances as well as cubic crystal are isotropic that is they exhibit similar properties in all direction

                                      The crystalline from of the antibiotic novobiocin acid is poorly absorbed and has no activity where the amorphous form is readily absorbed and therapeutically active due to different dissolution rate

                                      Amorphous or crystalline amp therapeutic activity

                                      General crystallization conditions 1048698Solvents ndashdifferent polarities 1048698Concentration of the solutions (super saturated saturated diluted) 1048698Cooling speed (quenching slow) 1048698Temperature (room or lower than room temperature)

                                      Crystallization

                                      Final Form

                                      Granulation

                                      Drying

                                      Compaction

                                      Tableting

                                      Drug Product

                                      API

                                      Crystallization

                                      Filtration

                                      Drying

                                      Milling

                                      Bulk API

                                      Stability

                                      Polymorphism and Industry Pharmaceutical

                                      Polymorphism and Industry Pharmaceutical

                                      Fluoxetine HCl the active ingredient in the antidepressant drug Prozac

                                      co crystal which will have increased solubility compared to the crystalline form

                                      Celecoxib

                                      CELECOXIB is a nonsteroidal anti-inflammatory drug

                                      However it was found that the higher bioavailability was shown by the amorphous state

                                      The downfall of the amorphous state was its stability

                                      This was due to the structural relaxation

                                      This was enhanced by mixing it with polymers like PVP which helped in stabilizing the amorphous system (Piyush Gupta et al 2004 Piyush Gupta et al 2005)

                                      A new solid state form was developed by Pharmacia

                                      FurosemideTwo forms with significantly differing aqueous solubility and dissolution rateOral bioavailability compromised

                                      Giron lists gt20 excipients that display polymorphism includingndash Lactose (anhydrous also monohydrate)ndash Aspartame (anhydrous hydrate forms)ndash Magnesium stearate (can affect lubrication of tablets)

                                      Bioavailability

                                      The rate and extent to which the active ingredient or active moiety is absorbed from a drug product and becomes available at the site of action

                                      Bioequivalence

                                      The absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study

                                      Carbamazepine

                                      CHLORPROPAMIDEat least six polymorphic white or almost white crystalline powder It exhibits polymorphism Practically insoluble in water soluble in alcohol freely soluble in acetone and in dichlo-romethane dissolves in dilute solutions of alkali hydroxides Protect from light

                                      blood-glucose-lowering drug

                                      AIDS drug ritonavir

                                      Theobroma oil (cacao butter ) is a polymorphic natural fat

                                      Theobroma oil can exist in 4 different polymorphic forms of which only one is Stabile

                                      1 Unstable gamma form melting at 18degC2 Alpha form melting at 22degC3 Beta prime form melting at 28degC4 Stable beta form melting at 345degC

                                      This is important in the preparation of theobroma suppositories

                                      If the oil is heated to a point where it is completely liquified (about 35 C) the crystals of the stable polymorph are destroyed amp the mass does not crystallize until it is cooled to 15 C

                                      The crystals that form are unstable amp the suppositories melt at 24 C

                                      Theobroma suppositories must be prepared below 33 C

                                      Polymorphism and Industry Pharmaceutical

                                      Polymorphism and Industry Pharmaceutical

                                      Anhydrates together with salts form the majority of all drug formulationsAbout a half of all APIs used today are saltsSalts are stable and well soluble in polar solvents (first of all in water) because they contain ionic bondThere is one more essential advantage of salts ndash their solubility is a function of pH Since pH in the gastrointestinal tract (GIT) vary between 1-75

                                      atorvastatin calcium trihydrateEach tablet contains Atorvastatin Calcium Trihydrate equivalent to Atorvastatin 20 mg

                                      Phase Equilibria amp The Phase Rule

                                      Phase diagram ndash Water

                                      Phase Equilibrium A stable phase structure with lowest free-energy (internal energy) of a system and also randomness or disorder of the atoms or molecules (entropy)

                                      Any change in Temperature Composition and Pressure causes an increase in free energy and away from Equilibrium thus forcing a move to another lsquostatersquo

                                      Phase Equilibria amp The Phase Rule Definitions

                                      A phase is defined as any homogeneous and physically distinct part of a system which is separated from other parts of the system by interfaces

                                      A part of a system is homogeneous if it has identical physical properties and chemical composition throughout the part

                                      A phase may be gas liquid or solid A gas or a gaseous mixture is a single phase Totally miscible liquids constitute a single phase In an immiscible liquid system each layer is counted as a separate phase Every solid constitutes a single phase except when a solid solution is formed A solid solution is considered as a single phase Each polymorphic form constitutes a separate phase

                                      Phase Definition

                                      1 Liquid water pieces of ice and water vapour are present together The number of phases is 3 as each form is a separate phase Ice in the system is a single phase even if it is present as a number of pieces

                                      2 Calcium carbonate undergoes thermal decomposition The chemical reaction is CaCO3(s) CaO(s) + CO2 (g) Number of phases = 3 This system consists of 2 solid phases CaCO3 and CaO and one gaseous phase that of CO2

                                      3 Ammonium chloride undergoes thermal decomposition The chemical reaction is NH4Cl(s) NH3 (g) + HCl (g) Number of phases = 2 This system has two phases one solid NH4Cl and one gaseous a mixture of NH3 and HCl

                                      4 A solution of NaCl in water Number of phases = 1

                                      bull Examples

                                      The number of components of a system at equilibrium is the smallest number of independently varying chemical constituents using which the composition of each and every phase in the system can be expressed

                                      Components

                                      Counting the number of components 1 The sulphur system is a one component system All the phases

                                      monoclinic rhombic liquid and vapour ndash can be expressed in terms of the single constituent ndash sulphur

                                      2 A mixture of ethanol and water is an example of a two component system We need both ethanol and water to express its composition

                                      bull Examples

                                      An example of a system in which a reaction occurs and an equilibrium is established is the thermal decomposition of solid CaCO3

                                      In this system there are three distinct phasesSolid CaCO3

                                      Solid CaOGaseous CO2

                                      Though there are 3 species present the number of components is only two because of the equilibrium CaCO3 (s) CaO(s) + CO2(g)

                                      Any two of the three constituents may be chosen as the components

                                      If CaO and CO2 are chosen then the composition of the phase CaCO3 is expressed as one mole of component CO2 plus one mole of component CaO

                                      If on the other hand CaCO3 and CO2 were chosen then the composition of the phase CaO would be described as one mole of CaCO3 minus one mole of CO2

                                      The degrees of freedom or variance of a system is defined as the minimum number of variables such as

                                      temperaturepressureconcentrationwhich must be fixed in order to define the system completely

                                      Degrees of freedom (or variance)

                                      F = C P + 2

                                      1 A gaseous mixture of CO2 and N2 Three variables pressure temperature and composition are required to define this system This is hence a trivariant system

                                      2 A system having only liquid water has two degrees of freedom or is bivariant Both temperature and pressure need to be mentioned in order to define the system

                                      3 If to the system containing liquid water pieces of ice are added and this system with 2 phases is allowed to come to equilibrium then it is an univariant system

                                      Only one variable either temperature or pressure need to be specified in order to define the systemIf the pressure on the system is maintained at 1 atm then the temperature of the system gets automatically fixed at 0oC the normal melting point of ice

                                      bull Examples

                                      Phase Equilibria amp The Phase Rule

                                      A phase diagram (Equilibrium Phase Diagram) summarizes the conditions at which a substance exists as a solid liquid or gas

                                      OR It is a ldquomaprdquo of the information about the control of phase structure of a particular material system

                                      The relationships between temperature and the compositions and the quantities of phases present at equilibrium are represented

                                      F = C P + 2The phase rule

                                      The phase rule JW Gibbs formulated the phase rule which is a general relation

                                      between the variance F the number of component C and the number of phases P at equilibrium for a system of any composition

                                      For a system in equilibrium

                                      F degree of freedom the least number of intensive variable that must be fixed (known) to describe the system completely

                                      Phase Rule relation to determine the least number of intensive variable that can be changed without changing the equilibrium state of the system or alternately

                                      The least number required to define the state of the system which is called degree of freedom F

                                      Intensive variable independent variable that do not depend on the volume or the size egTemp pressure

                                      Independent chemical species which comprise the system These could be Elements Ions Compounds

                                      Eg Au-Cu system Components rarr Au Cu Ice-water system Component rarr H2O

                                      Al2O3 ndash Cr2O3 system Components rarr Al2O3 Cr2O3

                                      Component the smallest number of constituent by which the composition of each phase in the system at equilibrium can be expressed in form of chemical formula or equation

                                      Phase Equilibria amp The Phase RuleComponents of a system

                                      The number of phases in a system is denoted P

                                      (a)A gas or a gaseous mixture is a single phase P=1

                                      (b) For a solid system an alloy of two metals is a two-phase system (P=2) if the metals are immiscible but a single-phase system (P=1) if they are miscible---a homogeneous mixture of the two substances---is uniform on a molecular scale

                                      (c) For a liquid system according to the solubility to decide whether a system consists of one phase or of two For example a solution of sodium chloride in water is a single phase A pair of liquids that are partially miscible or immiscible is a two-phase system(P=2)

                                      Oil in water

                                      Degrees of Freedom = What you can control What the system controls

                                      F = C + 2 P

                                      Can control the no of components added and P amp T

                                      System decided how many phases to produce given the

                                      conditions

                                      A way of understanding the Gibbs Phase RuleThe degrees of freedom can be thought of as the difference between what you (can) control and

                                      what the system controls

                                      F degree of freedom the least number of intensive variable that must be fixed (known) to describe the system completely

                                      Degree of freedom (or variance) F is the number of variables (T p andor composition) that can be changed independently without changing the phases of the system

                                      a) At the triple pointP = 3 (solid liquid and gas)

                                      C= 1 (water)P + F = C + 2

                                      F = 0 (no degree of freedom)

                                      b) liquid-solid curveP = 2

                                      2+F = 1 + 2F= 1

                                      One variable (T or P) can be changed

                                      c) LiquidP =1

                                      So F =2Two variables (T and P) can be varied independently

                                      and the system will remains a single phase

                                      One-component systemsPhase diagram of water

                                      P (

                                      atm

                                      )

                                      Critical point

                                      374

                                      1

                                      =100=0O--Triple point

                                      0006

                                      218

                                      Curve O -CSublimation

                                      Deposition

                                      Curve O-AVaporizationCondensation

                                      Curve O -BMelting

                                      Freezing

                                      F = C P + 2

                                      F = C P + 2

                                      Phase Diagram of Carbon Dioxide

                                      Condensed system System in which the vapor phase is ignored and only the solid andor liquid phases are considered

                                      Two component system For two component system F can be 3 (3D model is needed) eg T p

                                      and concentration usually we fix p = 1atm the vapor phase is neglected and F is reduced to 2

                                      For three component system the pressure and temperature are fixed

                                      Phenol water phase diagram

                                      eg for point d (24)

                                      Two component system containing liquid phase

                                      Tie Line bc line The line at which the system at equilibrium will separate into phases of constant composition termed lsquoconjugate phasesrsquo

                                      Lever Rule a way to calculate the proportions of each phase present on a phase diagram in a two phase field (at a given temperature and composition)

                                      eg for point d (24)

                                      For every 10 g of liquid system in equilibrium in point d

                                      75 g phase A25 g phase B

                                      ExampleMixed 24g phenol +76g water T 50degC

                                      equilibrium75 g phase A 25 g phase B

                                      11 phenol 63 phenol

                                      011 times75 g=825 g phenol

                                      063 times25 g=1575 g phenol

                                      water rich phasecontains water+ phenol(11)

                                      Phenol rich phasecontains Phenol (63)+ water

                                      The Critical Solution Temperature CST

                                      Is the maximum temperature at which the 2-phase region exists (or upper consolute temperature)

                                      In the case of the phenol-water system this is 668oC (point h)

                                      All combinations of phenol and water gt CST are completely miscible and yield 1-phase liquid systems

                                      Systems Showing a Decrease in Miscibility with Rise in Temperature

                                      A few mixtures exhibit a lower critical solution temperature (low CST) eg triethylamine plus water The miscibility with in temperature

                                      Systems Showing Upper and Lower CSTs

                                      The miscibility with temp

                                      a certain temperature miscibility starts to again with further in temperature

                                      Closed-phase diagram ie nicotine-water system

                                      A salol B thymol

                                      53

                                      Two component system containing solid and liquid phase (Eutectic Mixtures)

                                      A salol B thymol

                                      EMLAreg (lidocaine 25 and prilocaine 25) Cream

                                      EMLA Cream (lidocaine 25 and prilocaine 25) is an emulsion in which the oil phase is a eutectic mixture of lidocaine and prilocaine in a ratio of 11 by weight This eutectic mixture has a melting point below room temperature and therefore both local anesthetics exist as a liquid oil rather than as crystals

                                      Eutectic mixture Pharmaceutical Application

                                      Triangular Diagrams for three ndash component systems

                                      Three component system

                                      Birzeit University Physical Pharmacy PHAR 323 Dr Hani Shtaya

                                      1 Binding Forces Between Molecules2 Repulsive and Attractive Forces3 The Gaseous State The Ideal Gas Law Liquefaction of Gases Aerosols4 Solids and the Crystalline State Crystalline Solids Polymorphism Solvates Amorphous Solids5 Phase Equilibria and the Phase Rule Phase Rule Systems Containing One Component Condensed System Two-Component Systems Containing Liquid Phases Two-Component Systems Containing Solid and Liquid Phases Eutectic Mixtures Rules Relating to Triangular Diagrams

                                      Topics that we have covered

                                      • States of Matter
                                      • States of Matter (2)
                                      • Objectives of the lecture
                                      • Comparison of Gases Liquids and Solids
                                      • Slide 5
                                      • Repulsive and Attractive Forces
                                      • Ideal Gas Equation
                                      • Gaseous state
                                      • Slide 9
                                      • Gaseous state (2)
                                      • Liquefaction of Gases
                                      • Slide 12
                                      • SOLIDS amp CRYSTALLINE STATE Pharmaceutical Drugs more than 80
                                      • Solids and the crystalline state
                                      • Classification of Solids
                                      • Slide 16
                                      • Slide 17
                                      • Crystal forms
                                      • Types of Crystals
                                      • Slide 20
                                      • Slide 21
                                      • Polymorphism
                                      • Slide 23
                                      • Slide 24
                                      • Slide 25
                                      • Slide 26
                                      • Cocrystal
                                      • Principle of polymorphism
                                      • Solvates
                                      • Polymorphism (2)
                                      • Amorphous Solid
                                      • Amorphous or crystalline amp therapeutic activity
                                      • Slide 33
                                      • Slide 34
                                      • Polymorphism and Industry Pharmaceutical
                                      • Celecoxib
                                      • Furosemide
                                      • Bioavailability
                                      • Slide 39
                                      • Slide 40
                                      • Bioequivalence
                                      • Slide 42
                                      • Carbamazepine
                                      • Slide 44
                                      • AIDS drug ritonavir
                                      • Slide 46
                                      • Slide 47
                                      • Phase Equilibria amp The Phase Rule
                                      • Phase diagram ndash Water
                                      • Phase Equilibria amp The Phase Rule Definitions
                                      • Phase Definition
                                      • Examples
                                      • Components
                                      • Examples
                                      • Slide 55
                                      • Degrees of freedom (or variance)
                                      • Examples (2)
                                      • Phase Equilibria amp The Phase Rule
                                      • The phase rule
                                      • Slide 60
                                      • Phase Equilibria amp The Phase Rule (2)
                                      • The number of phases in a system is denoted P
                                      • Slide 63
                                      • Slide 64
                                      • One-component systems
                                      • Slide 66
                                      • Slide 67
                                      • Slide 68
                                      • Slide 69
                                      • Slide 70
                                      • Two component system containing liquid phase
                                      • Slide 72
                                      • The Critical Solution Temperature CST
                                      • Systems Showing a Decrease in Miscibility with Rise in Temperat
                                      • Systems Showing Upper and Lower CSTs
                                      • Two component system containing solid and liquid phase (Eutecti
                                      • Slide 77
                                      • Eutectic mixture Pharmaceutical Application
                                      • Three component system
                                      • Slide 80
                                      • Topics that we have covered

                                        Some elemental substance such as C and S may exist in more than one crystalline form and are said to be allotropic which is a special case of polymorphism

                                        Polymorphism is the ability of a substance to exist in more than one crystal structure

                                        Polymorphism

                                        Polymorphism is the ability of a substance to exist in more than one crystal structure

                                        Polymorphs when two crystals have the same chemical composition but different internal structure (molecular packing ndashmolecular conformation or and inter or intra molecular interactions)modifications or polymorphs or forms

                                        Pseudo polymorphs different crystal forms have molecules of the same given substances and also contain molecules of solvent incorporated into a unique structure (solvates or hydrates (water))

                                        diamond graphite

                                        carbonatoms

                                        High T and p

                                        Diamond is metastable and converts very slowly to graphite

                                        The most common example of polymorphism

                                        Solid State Polymorphs

                                        Mono-component systems Polymorphs

                                        Multi-component systems

                                        Cocrystal

                                        The simplest definition of a cocrystal is a crystalline structure made up of two or more components in a definite stoichiometric ratio where each component is defined as either an atom ion or molecule

                                        Principle of polymorphism

                                        When the change from one form to another is reversible it is said to be enantiotropic

                                        When the transition takes place in one direction onlymdashfor example from a metastable to a stable formmdashthe change is said to be monotropic

                                        Solvates

                                        Pharmaceutical synthesis include purification and crystallization residual solvent can be trapped in the lattice

                                        This result in the formation of cocrystal or solvate

                                        The presence of residual solvent may affect dramatically the crystalline structure of the solid depending on the type of inter molecular forces that the solvent may have with crystalline solid

                                        Melting pointVapor pressureHardnessOptical electrical magnetic

                                        propertiesColorIR spectraNMR spectra

                                        Photochemical reactivityThermal stabilityFiltration and drying characteristicsDissolution rateBioavailabilityPhysical and chemical stability

                                        Solubility and melting point are very important in pharmaceutical processes including dissolution and

                                        formulation

                                        Polymorphism

                                        AMORPHOUS SOLIDS Solids that donrsquot have a definite geometrical shape are known as Amorphous Solids1 In these solids particles are randomly arranged in three dimension2 They donrsquot have sharp melting points3 Amorphous solids are formed due to sudden cooling of liquid4 Amorphous solids melt over a wide range of temperature

                                        Amorphous Solid

                                        An amorphous solid does not possess a well-defined arrangement and long-range molecular order

                                        Amorphous substances as well as cubic crystal are isotropic that is they exhibit similar properties in all direction

                                        The crystalline from of the antibiotic novobiocin acid is poorly absorbed and has no activity where the amorphous form is readily absorbed and therapeutically active due to different dissolution rate

                                        Amorphous or crystalline amp therapeutic activity

                                        General crystallization conditions 1048698Solvents ndashdifferent polarities 1048698Concentration of the solutions (super saturated saturated diluted) 1048698Cooling speed (quenching slow) 1048698Temperature (room or lower than room temperature)

                                        Crystallization

                                        Final Form

                                        Granulation

                                        Drying

                                        Compaction

                                        Tableting

                                        Drug Product

                                        API

                                        Crystallization

                                        Filtration

                                        Drying

                                        Milling

                                        Bulk API

                                        Stability

                                        Polymorphism and Industry Pharmaceutical

                                        Polymorphism and Industry Pharmaceutical

                                        Fluoxetine HCl the active ingredient in the antidepressant drug Prozac

                                        co crystal which will have increased solubility compared to the crystalline form

                                        Celecoxib

                                        CELECOXIB is a nonsteroidal anti-inflammatory drug

                                        However it was found that the higher bioavailability was shown by the amorphous state

                                        The downfall of the amorphous state was its stability

                                        This was due to the structural relaxation

                                        This was enhanced by mixing it with polymers like PVP which helped in stabilizing the amorphous system (Piyush Gupta et al 2004 Piyush Gupta et al 2005)

                                        A new solid state form was developed by Pharmacia

                                        FurosemideTwo forms with significantly differing aqueous solubility and dissolution rateOral bioavailability compromised

                                        Giron lists gt20 excipients that display polymorphism includingndash Lactose (anhydrous also monohydrate)ndash Aspartame (anhydrous hydrate forms)ndash Magnesium stearate (can affect lubrication of tablets)

                                        Bioavailability

                                        The rate and extent to which the active ingredient or active moiety is absorbed from a drug product and becomes available at the site of action

                                        Bioequivalence

                                        The absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study

                                        Carbamazepine

                                        CHLORPROPAMIDEat least six polymorphic white or almost white crystalline powder It exhibits polymorphism Practically insoluble in water soluble in alcohol freely soluble in acetone and in dichlo-romethane dissolves in dilute solutions of alkali hydroxides Protect from light

                                        blood-glucose-lowering drug

                                        AIDS drug ritonavir

                                        Theobroma oil (cacao butter ) is a polymorphic natural fat

                                        Theobroma oil can exist in 4 different polymorphic forms of which only one is Stabile

                                        1 Unstable gamma form melting at 18degC2 Alpha form melting at 22degC3 Beta prime form melting at 28degC4 Stable beta form melting at 345degC

                                        This is important in the preparation of theobroma suppositories

                                        If the oil is heated to a point where it is completely liquified (about 35 C) the crystals of the stable polymorph are destroyed amp the mass does not crystallize until it is cooled to 15 C

                                        The crystals that form are unstable amp the suppositories melt at 24 C

                                        Theobroma suppositories must be prepared below 33 C

                                        Polymorphism and Industry Pharmaceutical

                                        Polymorphism and Industry Pharmaceutical

                                        Anhydrates together with salts form the majority of all drug formulationsAbout a half of all APIs used today are saltsSalts are stable and well soluble in polar solvents (first of all in water) because they contain ionic bondThere is one more essential advantage of salts ndash their solubility is a function of pH Since pH in the gastrointestinal tract (GIT) vary between 1-75

                                        atorvastatin calcium trihydrateEach tablet contains Atorvastatin Calcium Trihydrate equivalent to Atorvastatin 20 mg

                                        Phase Equilibria amp The Phase Rule

                                        Phase diagram ndash Water

                                        Phase Equilibrium A stable phase structure with lowest free-energy (internal energy) of a system and also randomness or disorder of the atoms or molecules (entropy)

                                        Any change in Temperature Composition and Pressure causes an increase in free energy and away from Equilibrium thus forcing a move to another lsquostatersquo

                                        Phase Equilibria amp The Phase Rule Definitions

                                        A phase is defined as any homogeneous and physically distinct part of a system which is separated from other parts of the system by interfaces

                                        A part of a system is homogeneous if it has identical physical properties and chemical composition throughout the part

                                        A phase may be gas liquid or solid A gas or a gaseous mixture is a single phase Totally miscible liquids constitute a single phase In an immiscible liquid system each layer is counted as a separate phase Every solid constitutes a single phase except when a solid solution is formed A solid solution is considered as a single phase Each polymorphic form constitutes a separate phase

                                        Phase Definition

                                        1 Liquid water pieces of ice and water vapour are present together The number of phases is 3 as each form is a separate phase Ice in the system is a single phase even if it is present as a number of pieces

                                        2 Calcium carbonate undergoes thermal decomposition The chemical reaction is CaCO3(s) CaO(s) + CO2 (g) Number of phases = 3 This system consists of 2 solid phases CaCO3 and CaO and one gaseous phase that of CO2

                                        3 Ammonium chloride undergoes thermal decomposition The chemical reaction is NH4Cl(s) NH3 (g) + HCl (g) Number of phases = 2 This system has two phases one solid NH4Cl and one gaseous a mixture of NH3 and HCl

                                        4 A solution of NaCl in water Number of phases = 1

                                        bull Examples

                                        The number of components of a system at equilibrium is the smallest number of independently varying chemical constituents using which the composition of each and every phase in the system can be expressed

                                        Components

                                        Counting the number of components 1 The sulphur system is a one component system All the phases

                                        monoclinic rhombic liquid and vapour ndash can be expressed in terms of the single constituent ndash sulphur

                                        2 A mixture of ethanol and water is an example of a two component system We need both ethanol and water to express its composition

                                        bull Examples

                                        An example of a system in which a reaction occurs and an equilibrium is established is the thermal decomposition of solid CaCO3

                                        In this system there are three distinct phasesSolid CaCO3

                                        Solid CaOGaseous CO2

                                        Though there are 3 species present the number of components is only two because of the equilibrium CaCO3 (s) CaO(s) + CO2(g)

                                        Any two of the three constituents may be chosen as the components

                                        If CaO and CO2 are chosen then the composition of the phase CaCO3 is expressed as one mole of component CO2 plus one mole of component CaO

                                        If on the other hand CaCO3 and CO2 were chosen then the composition of the phase CaO would be described as one mole of CaCO3 minus one mole of CO2

                                        The degrees of freedom or variance of a system is defined as the minimum number of variables such as

                                        temperaturepressureconcentrationwhich must be fixed in order to define the system completely

                                        Degrees of freedom (or variance)

                                        F = C P + 2

                                        1 A gaseous mixture of CO2 and N2 Three variables pressure temperature and composition are required to define this system This is hence a trivariant system

                                        2 A system having only liquid water has two degrees of freedom or is bivariant Both temperature and pressure need to be mentioned in order to define the system

                                        3 If to the system containing liquid water pieces of ice are added and this system with 2 phases is allowed to come to equilibrium then it is an univariant system

                                        Only one variable either temperature or pressure need to be specified in order to define the systemIf the pressure on the system is maintained at 1 atm then the temperature of the system gets automatically fixed at 0oC the normal melting point of ice

                                        bull Examples

                                        Phase Equilibria amp The Phase Rule

                                        A phase diagram (Equilibrium Phase Diagram) summarizes the conditions at which a substance exists as a solid liquid or gas

                                        OR It is a ldquomaprdquo of the information about the control of phase structure of a particular material system

                                        The relationships between temperature and the compositions and the quantities of phases present at equilibrium are represented

                                        F = C P + 2The phase rule

                                        The phase rule JW Gibbs formulated the phase rule which is a general relation

                                        between the variance F the number of component C and the number of phases P at equilibrium for a system of any composition

                                        For a system in equilibrium

                                        F degree of freedom the least number of intensive variable that must be fixed (known) to describe the system completely

                                        Phase Rule relation to determine the least number of intensive variable that can be changed without changing the equilibrium state of the system or alternately

                                        The least number required to define the state of the system which is called degree of freedom F

                                        Intensive variable independent variable that do not depend on the volume or the size egTemp pressure

                                        Independent chemical species which comprise the system These could be Elements Ions Compounds

                                        Eg Au-Cu system Components rarr Au Cu Ice-water system Component rarr H2O

                                        Al2O3 ndash Cr2O3 system Components rarr Al2O3 Cr2O3

                                        Component the smallest number of constituent by which the composition of each phase in the system at equilibrium can be expressed in form of chemical formula or equation

                                        Phase Equilibria amp The Phase RuleComponents of a system

                                        The number of phases in a system is denoted P

                                        (a)A gas or a gaseous mixture is a single phase P=1

                                        (b) For a solid system an alloy of two metals is a two-phase system (P=2) if the metals are immiscible but a single-phase system (P=1) if they are miscible---a homogeneous mixture of the two substances---is uniform on a molecular scale

                                        (c) For a liquid system according to the solubility to decide whether a system consists of one phase or of two For example a solution of sodium chloride in water is a single phase A pair of liquids that are partially miscible or immiscible is a two-phase system(P=2)

                                        Oil in water

                                        Degrees of Freedom = What you can control What the system controls

                                        F = C + 2 P

                                        Can control the no of components added and P amp T

                                        System decided how many phases to produce given the

                                        conditions

                                        A way of understanding the Gibbs Phase RuleThe degrees of freedom can be thought of as the difference between what you (can) control and

                                        what the system controls

                                        F degree of freedom the least number of intensive variable that must be fixed (known) to describe the system completely

                                        Degree of freedom (or variance) F is the number of variables (T p andor composition) that can be changed independently without changing the phases of the system

                                        a) At the triple pointP = 3 (solid liquid and gas)

                                        C= 1 (water)P + F = C + 2

                                        F = 0 (no degree of freedom)

                                        b) liquid-solid curveP = 2

                                        2+F = 1 + 2F= 1

                                        One variable (T or P) can be changed

                                        c) LiquidP =1

                                        So F =2Two variables (T and P) can be varied independently

                                        and the system will remains a single phase

                                        One-component systemsPhase diagram of water

                                        P (

                                        atm

                                        )

                                        Critical point

                                        374

                                        1

                                        =100=0O--Triple point

                                        0006

                                        218

                                        Curve O -CSublimation

                                        Deposition

                                        Curve O-AVaporizationCondensation

                                        Curve O -BMelting

                                        Freezing

                                        F = C P + 2

                                        F = C P + 2

                                        Phase Diagram of Carbon Dioxide

                                        Condensed system System in which the vapor phase is ignored and only the solid andor liquid phases are considered

                                        Two component system For two component system F can be 3 (3D model is needed) eg T p

                                        and concentration usually we fix p = 1atm the vapor phase is neglected and F is reduced to 2

                                        For three component system the pressure and temperature are fixed

                                        Phenol water phase diagram

                                        eg for point d (24)

                                        Two component system containing liquid phase

                                        Tie Line bc line The line at which the system at equilibrium will separate into phases of constant composition termed lsquoconjugate phasesrsquo

                                        Lever Rule a way to calculate the proportions of each phase present on a phase diagram in a two phase field (at a given temperature and composition)

                                        eg for point d (24)

                                        For every 10 g of liquid system in equilibrium in point d

                                        75 g phase A25 g phase B

                                        ExampleMixed 24g phenol +76g water T 50degC

                                        equilibrium75 g phase A 25 g phase B

                                        11 phenol 63 phenol

                                        011 times75 g=825 g phenol

                                        063 times25 g=1575 g phenol

                                        water rich phasecontains water+ phenol(11)

                                        Phenol rich phasecontains Phenol (63)+ water

                                        The Critical Solution Temperature CST

                                        Is the maximum temperature at which the 2-phase region exists (or upper consolute temperature)

                                        In the case of the phenol-water system this is 668oC (point h)

                                        All combinations of phenol and water gt CST are completely miscible and yield 1-phase liquid systems

                                        Systems Showing a Decrease in Miscibility with Rise in Temperature

                                        A few mixtures exhibit a lower critical solution temperature (low CST) eg triethylamine plus water The miscibility with in temperature

                                        Systems Showing Upper and Lower CSTs

                                        The miscibility with temp

                                        a certain temperature miscibility starts to again with further in temperature

                                        Closed-phase diagram ie nicotine-water system

                                        A salol B thymol

                                        53

                                        Two component system containing solid and liquid phase (Eutectic Mixtures)

                                        A salol B thymol

                                        EMLAreg (lidocaine 25 and prilocaine 25) Cream

                                        EMLA Cream (lidocaine 25 and prilocaine 25) is an emulsion in which the oil phase is a eutectic mixture of lidocaine and prilocaine in a ratio of 11 by weight This eutectic mixture has a melting point below room temperature and therefore both local anesthetics exist as a liquid oil rather than as crystals

                                        Eutectic mixture Pharmaceutical Application

                                        Triangular Diagrams for three ndash component systems

                                        Three component system

                                        Birzeit University Physical Pharmacy PHAR 323 Dr Hani Shtaya

                                        1 Binding Forces Between Molecules2 Repulsive and Attractive Forces3 The Gaseous State The Ideal Gas Law Liquefaction of Gases Aerosols4 Solids and the Crystalline State Crystalline Solids Polymorphism Solvates Amorphous Solids5 Phase Equilibria and the Phase Rule Phase Rule Systems Containing One Component Condensed System Two-Component Systems Containing Liquid Phases Two-Component Systems Containing Solid and Liquid Phases Eutectic Mixtures Rules Relating to Triangular Diagrams

                                        Topics that we have covered

                                        • States of Matter
                                        • States of Matter (2)
                                        • Objectives of the lecture
                                        • Comparison of Gases Liquids and Solids
                                        • Slide 5
                                        • Repulsive and Attractive Forces
                                        • Ideal Gas Equation
                                        • Gaseous state
                                        • Slide 9
                                        • Gaseous state (2)
                                        • Liquefaction of Gases
                                        • Slide 12
                                        • SOLIDS amp CRYSTALLINE STATE Pharmaceutical Drugs more than 80
                                        • Solids and the crystalline state
                                        • Classification of Solids
                                        • Slide 16
                                        • Slide 17
                                        • Crystal forms
                                        • Types of Crystals
                                        • Slide 20
                                        • Slide 21
                                        • Polymorphism
                                        • Slide 23
                                        • Slide 24
                                        • Slide 25
                                        • Slide 26
                                        • Cocrystal
                                        • Principle of polymorphism
                                        • Solvates
                                        • Polymorphism (2)
                                        • Amorphous Solid
                                        • Amorphous or crystalline amp therapeutic activity
                                        • Slide 33
                                        • Slide 34
                                        • Polymorphism and Industry Pharmaceutical
                                        • Celecoxib
                                        • Furosemide
                                        • Bioavailability
                                        • Slide 39
                                        • Slide 40
                                        • Bioequivalence
                                        • Slide 42
                                        • Carbamazepine
                                        • Slide 44
                                        • AIDS drug ritonavir
                                        • Slide 46
                                        • Slide 47
                                        • Phase Equilibria amp The Phase Rule
                                        • Phase diagram ndash Water
                                        • Phase Equilibria amp The Phase Rule Definitions
                                        • Phase Definition
                                        • Examples
                                        • Components
                                        • Examples
                                        • Slide 55
                                        • Degrees of freedom (or variance)
                                        • Examples (2)
                                        • Phase Equilibria amp The Phase Rule
                                        • The phase rule
                                        • Slide 60
                                        • Phase Equilibria amp The Phase Rule (2)
                                        • The number of phases in a system is denoted P
                                        • Slide 63
                                        • Slide 64
                                        • One-component systems
                                        • Slide 66
                                        • Slide 67
                                        • Slide 68
                                        • Slide 69
                                        • Slide 70
                                        • Two component system containing liquid phase
                                        • Slide 72
                                        • The Critical Solution Temperature CST
                                        • Systems Showing a Decrease in Miscibility with Rise in Temperat
                                        • Systems Showing Upper and Lower CSTs
                                        • Two component system containing solid and liquid phase (Eutecti
                                        • Slide 77
                                        • Eutectic mixture Pharmaceutical Application
                                        • Three component system
                                        • Slide 80
                                        • Topics that we have covered

                                          Polymorphism is the ability of a substance to exist in more than one crystal structure

                                          Polymorphs when two crystals have the same chemical composition but different internal structure (molecular packing ndashmolecular conformation or and inter or intra molecular interactions)modifications or polymorphs or forms

                                          Pseudo polymorphs different crystal forms have molecules of the same given substances and also contain molecules of solvent incorporated into a unique structure (solvates or hydrates (water))

                                          diamond graphite

                                          carbonatoms

                                          High T and p

                                          Diamond is metastable and converts very slowly to graphite

                                          The most common example of polymorphism

                                          Solid State Polymorphs

                                          Mono-component systems Polymorphs

                                          Multi-component systems

                                          Cocrystal

                                          The simplest definition of a cocrystal is a crystalline structure made up of two or more components in a definite stoichiometric ratio where each component is defined as either an atom ion or molecule

                                          Principle of polymorphism

                                          When the change from one form to another is reversible it is said to be enantiotropic

                                          When the transition takes place in one direction onlymdashfor example from a metastable to a stable formmdashthe change is said to be monotropic

                                          Solvates

                                          Pharmaceutical synthesis include purification and crystallization residual solvent can be trapped in the lattice

                                          This result in the formation of cocrystal or solvate

                                          The presence of residual solvent may affect dramatically the crystalline structure of the solid depending on the type of inter molecular forces that the solvent may have with crystalline solid

                                          Melting pointVapor pressureHardnessOptical electrical magnetic

                                          propertiesColorIR spectraNMR spectra

                                          Photochemical reactivityThermal stabilityFiltration and drying characteristicsDissolution rateBioavailabilityPhysical and chemical stability

                                          Solubility and melting point are very important in pharmaceutical processes including dissolution and

                                          formulation

                                          Polymorphism

                                          AMORPHOUS SOLIDS Solids that donrsquot have a definite geometrical shape are known as Amorphous Solids1 In these solids particles are randomly arranged in three dimension2 They donrsquot have sharp melting points3 Amorphous solids are formed due to sudden cooling of liquid4 Amorphous solids melt over a wide range of temperature

                                          Amorphous Solid

                                          An amorphous solid does not possess a well-defined arrangement and long-range molecular order

                                          Amorphous substances as well as cubic crystal are isotropic that is they exhibit similar properties in all direction

                                          The crystalline from of the antibiotic novobiocin acid is poorly absorbed and has no activity where the amorphous form is readily absorbed and therapeutically active due to different dissolution rate

                                          Amorphous or crystalline amp therapeutic activity

                                          General crystallization conditions 1048698Solvents ndashdifferent polarities 1048698Concentration of the solutions (super saturated saturated diluted) 1048698Cooling speed (quenching slow) 1048698Temperature (room or lower than room temperature)

                                          Crystallization

                                          Final Form

                                          Granulation

                                          Drying

                                          Compaction

                                          Tableting

                                          Drug Product

                                          API

                                          Crystallization

                                          Filtration

                                          Drying

                                          Milling

                                          Bulk API

                                          Stability

                                          Polymorphism and Industry Pharmaceutical

                                          Polymorphism and Industry Pharmaceutical

                                          Fluoxetine HCl the active ingredient in the antidepressant drug Prozac

                                          co crystal which will have increased solubility compared to the crystalline form

                                          Celecoxib

                                          CELECOXIB is a nonsteroidal anti-inflammatory drug

                                          However it was found that the higher bioavailability was shown by the amorphous state

                                          The downfall of the amorphous state was its stability

                                          This was due to the structural relaxation

                                          This was enhanced by mixing it with polymers like PVP which helped in stabilizing the amorphous system (Piyush Gupta et al 2004 Piyush Gupta et al 2005)

                                          A new solid state form was developed by Pharmacia

                                          FurosemideTwo forms with significantly differing aqueous solubility and dissolution rateOral bioavailability compromised

                                          Giron lists gt20 excipients that display polymorphism includingndash Lactose (anhydrous also monohydrate)ndash Aspartame (anhydrous hydrate forms)ndash Magnesium stearate (can affect lubrication of tablets)

                                          Bioavailability

                                          The rate and extent to which the active ingredient or active moiety is absorbed from a drug product and becomes available at the site of action

                                          Bioequivalence

                                          The absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study

                                          Carbamazepine

                                          CHLORPROPAMIDEat least six polymorphic white or almost white crystalline powder It exhibits polymorphism Practically insoluble in water soluble in alcohol freely soluble in acetone and in dichlo-romethane dissolves in dilute solutions of alkali hydroxides Protect from light

                                          blood-glucose-lowering drug

                                          AIDS drug ritonavir

                                          Theobroma oil (cacao butter ) is a polymorphic natural fat

                                          Theobroma oil can exist in 4 different polymorphic forms of which only one is Stabile

                                          1 Unstable gamma form melting at 18degC2 Alpha form melting at 22degC3 Beta prime form melting at 28degC4 Stable beta form melting at 345degC

                                          This is important in the preparation of theobroma suppositories

                                          If the oil is heated to a point where it is completely liquified (about 35 C) the crystals of the stable polymorph are destroyed amp the mass does not crystallize until it is cooled to 15 C

                                          The crystals that form are unstable amp the suppositories melt at 24 C

                                          Theobroma suppositories must be prepared below 33 C

                                          Polymorphism and Industry Pharmaceutical

                                          Polymorphism and Industry Pharmaceutical

                                          Anhydrates together with salts form the majority of all drug formulationsAbout a half of all APIs used today are saltsSalts are stable and well soluble in polar solvents (first of all in water) because they contain ionic bondThere is one more essential advantage of salts ndash their solubility is a function of pH Since pH in the gastrointestinal tract (GIT) vary between 1-75

                                          atorvastatin calcium trihydrateEach tablet contains Atorvastatin Calcium Trihydrate equivalent to Atorvastatin 20 mg

                                          Phase Equilibria amp The Phase Rule

                                          Phase diagram ndash Water

                                          Phase Equilibrium A stable phase structure with lowest free-energy (internal energy) of a system and also randomness or disorder of the atoms or molecules (entropy)

                                          Any change in Temperature Composition and Pressure causes an increase in free energy and away from Equilibrium thus forcing a move to another lsquostatersquo

                                          Phase Equilibria amp The Phase Rule Definitions

                                          A phase is defined as any homogeneous and physically distinct part of a system which is separated from other parts of the system by interfaces

                                          A part of a system is homogeneous if it has identical physical properties and chemical composition throughout the part

                                          A phase may be gas liquid or solid A gas or a gaseous mixture is a single phase Totally miscible liquids constitute a single phase In an immiscible liquid system each layer is counted as a separate phase Every solid constitutes a single phase except when a solid solution is formed A solid solution is considered as a single phase Each polymorphic form constitutes a separate phase

                                          Phase Definition

                                          1 Liquid water pieces of ice and water vapour are present together The number of phases is 3 as each form is a separate phase Ice in the system is a single phase even if it is present as a number of pieces

                                          2 Calcium carbonate undergoes thermal decomposition The chemical reaction is CaCO3(s) CaO(s) + CO2 (g) Number of phases = 3 This system consists of 2 solid phases CaCO3 and CaO and one gaseous phase that of CO2

                                          3 Ammonium chloride undergoes thermal decomposition The chemical reaction is NH4Cl(s) NH3 (g) + HCl (g) Number of phases = 2 This system has two phases one solid NH4Cl and one gaseous a mixture of NH3 and HCl

                                          4 A solution of NaCl in water Number of phases = 1

                                          bull Examples

                                          The number of components of a system at equilibrium is the smallest number of independently varying chemical constituents using which the composition of each and every phase in the system can be expressed

                                          Components

                                          Counting the number of components 1 The sulphur system is a one component system All the phases

                                          monoclinic rhombic liquid and vapour ndash can be expressed in terms of the single constituent ndash sulphur

                                          2 A mixture of ethanol and water is an example of a two component system We need both ethanol and water to express its composition

                                          bull Examples

                                          An example of a system in which a reaction occurs and an equilibrium is established is the thermal decomposition of solid CaCO3

                                          In this system there are three distinct phasesSolid CaCO3

                                          Solid CaOGaseous CO2

                                          Though there are 3 species present the number of components is only two because of the equilibrium CaCO3 (s) CaO(s) + CO2(g)

                                          Any two of the three constituents may be chosen as the components

                                          If CaO and CO2 are chosen then the composition of the phase CaCO3 is expressed as one mole of component CO2 plus one mole of component CaO

                                          If on the other hand CaCO3 and CO2 were chosen then the composition of the phase CaO would be described as one mole of CaCO3 minus one mole of CO2

                                          The degrees of freedom or variance of a system is defined as the minimum number of variables such as

                                          temperaturepressureconcentrationwhich must be fixed in order to define the system completely

                                          Degrees of freedom (or variance)

                                          F = C P + 2

                                          1 A gaseous mixture of CO2 and N2 Three variables pressure temperature and composition are required to define this system This is hence a trivariant system

                                          2 A system having only liquid water has two degrees of freedom or is bivariant Both temperature and pressure need to be mentioned in order to define the system

                                          3 If to the system containing liquid water pieces of ice are added and this system with 2 phases is allowed to come to equilibrium then it is an univariant system

                                          Only one variable either temperature or pressure need to be specified in order to define the systemIf the pressure on the system is maintained at 1 atm then the temperature of the system gets automatically fixed at 0oC the normal melting point of ice

                                          bull Examples

                                          Phase Equilibria amp The Phase Rule

                                          A phase diagram (Equilibrium Phase Diagram) summarizes the conditions at which a substance exists as a solid liquid or gas

                                          OR It is a ldquomaprdquo of the information about the control of phase structure of a particular material system

                                          The relationships between temperature and the compositions and the quantities of phases present at equilibrium are represented

                                          F = C P + 2The phase rule

                                          The phase rule JW Gibbs formulated the phase rule which is a general relation

                                          between the variance F the number of component C and the number of phases P at equilibrium for a system of any composition

                                          For a system in equilibrium

                                          F degree of freedom the least number of intensive variable that must be fixed (known) to describe the system completely

                                          Phase Rule relation to determine the least number of intensive variable that can be changed without changing the equilibrium state of the system or alternately

                                          The least number required to define the state of the system which is called degree of freedom F

                                          Intensive variable independent variable that do not depend on the volume or the size egTemp pressure

                                          Independent chemical species which comprise the system These could be Elements Ions Compounds

                                          Eg Au-Cu system Components rarr Au Cu Ice-water system Component rarr H2O

                                          Al2O3 ndash Cr2O3 system Components rarr Al2O3 Cr2O3

                                          Component the smallest number of constituent by which the composition of each phase in the system at equilibrium can be expressed in form of chemical formula or equation

                                          Phase Equilibria amp The Phase RuleComponents of a system

                                          The number of phases in a system is denoted P

                                          (a)A gas or a gaseous mixture is a single phase P=1

                                          (b) For a solid system an alloy of two metals is a two-phase system (P=2) if the metals are immiscible but a single-phase system (P=1) if they are miscible---a homogeneous mixture of the two substances---is uniform on a molecular scale

                                          (c) For a liquid system according to the solubility to decide whether a system consists of one phase or of two For example a solution of sodium chloride in water is a single phase A pair of liquids that are partially miscible or immiscible is a two-phase system(P=2)

                                          Oil in water

                                          Degrees of Freedom = What you can control What the system controls

                                          F = C + 2 P

                                          Can control the no of components added and P amp T

                                          System decided how many phases to produce given the

                                          conditions

                                          A way of understanding the Gibbs Phase RuleThe degrees of freedom can be thought of as the difference between what you (can) control and

                                          what the system controls

                                          F degree of freedom the least number of intensive variable that must be fixed (known) to describe the system completely

                                          Degree of freedom (or variance) F is the number of variables (T p andor composition) that can be changed independently without changing the phases of the system

                                          a) At the triple pointP = 3 (solid liquid and gas)

                                          C= 1 (water)P + F = C + 2

                                          F = 0 (no degree of freedom)

                                          b) liquid-solid curveP = 2

                                          2+F = 1 + 2F= 1

                                          One variable (T or P) can be changed

                                          c) LiquidP =1

                                          So F =2Two variables (T and P) can be varied independently

                                          and the system will remains a single phase

                                          One-component systemsPhase diagram of water

                                          P (

                                          atm

                                          )

                                          Critical point

                                          374

                                          1

                                          =100=0O--Triple point

                                          0006

                                          218

                                          Curve O -CSublimation

                                          Deposition

                                          Curve O-AVaporizationCondensation

                                          Curve O -BMelting

                                          Freezing

                                          F = C P + 2

                                          F = C P + 2

                                          Phase Diagram of Carbon Dioxide

                                          Condensed system System in which the vapor phase is ignored and only the solid andor liquid phases are considered

                                          Two component system For two component system F can be 3 (3D model is needed) eg T p

                                          and concentration usually we fix p = 1atm the vapor phase is neglected and F is reduced to 2

                                          For three component system the pressure and temperature are fixed

                                          Phenol water phase diagram

                                          eg for point d (24)

                                          Two component system containing liquid phase

                                          Tie Line bc line The line at which the system at equilibrium will separate into phases of constant composition termed lsquoconjugate phasesrsquo

                                          Lever Rule a way to calculate the proportions of each phase present on a phase diagram in a two phase field (at a given temperature and composition)

                                          eg for point d (24)

                                          For every 10 g of liquid system in equilibrium in point d

                                          75 g phase A25 g phase B

                                          ExampleMixed 24g phenol +76g water T 50degC

                                          equilibrium75 g phase A 25 g phase B

                                          11 phenol 63 phenol

                                          011 times75 g=825 g phenol

                                          063 times25 g=1575 g phenol

                                          water rich phasecontains water+ phenol(11)

                                          Phenol rich phasecontains Phenol (63)+ water

                                          The Critical Solution Temperature CST

                                          Is the maximum temperature at which the 2-phase region exists (or upper consolute temperature)

                                          In the case of the phenol-water system this is 668oC (point h)

                                          All combinations of phenol and water gt CST are completely miscible and yield 1-phase liquid systems

                                          Systems Showing a Decrease in Miscibility with Rise in Temperature

                                          A few mixtures exhibit a lower critical solution temperature (low CST) eg triethylamine plus water The miscibility with in temperature

                                          Systems Showing Upper and Lower CSTs

                                          The miscibility with temp

                                          a certain temperature miscibility starts to again with further in temperature

                                          Closed-phase diagram ie nicotine-water system

                                          A salol B thymol

                                          53

                                          Two component system containing solid and liquid phase (Eutectic Mixtures)

                                          A salol B thymol

                                          EMLAreg (lidocaine 25 and prilocaine 25) Cream

                                          EMLA Cream (lidocaine 25 and prilocaine 25) is an emulsion in which the oil phase is a eutectic mixture of lidocaine and prilocaine in a ratio of 11 by weight This eutectic mixture has a melting point below room temperature and therefore both local anesthetics exist as a liquid oil rather than as crystals

                                          Eutectic mixture Pharmaceutical Application

                                          Triangular Diagrams for three ndash component systems

                                          Three component system

                                          Birzeit University Physical Pharmacy PHAR 323 Dr Hani Shtaya

                                          1 Binding Forces Between Molecules2 Repulsive and Attractive Forces3 The Gaseous State The Ideal Gas Law Liquefaction of Gases Aerosols4 Solids and the Crystalline State Crystalline Solids Polymorphism Solvates Amorphous Solids5 Phase Equilibria and the Phase Rule Phase Rule Systems Containing One Component Condensed System Two-Component Systems Containing Liquid Phases Two-Component Systems Containing Solid and Liquid Phases Eutectic Mixtures Rules Relating to Triangular Diagrams

                                          Topics that we have covered

                                          • States of Matter
                                          • States of Matter (2)
                                          • Objectives of the lecture
                                          • Comparison of Gases Liquids and Solids
                                          • Slide 5
                                          • Repulsive and Attractive Forces
                                          • Ideal Gas Equation
                                          • Gaseous state
                                          • Slide 9
                                          • Gaseous state (2)
                                          • Liquefaction of Gases
                                          • Slide 12
                                          • SOLIDS amp CRYSTALLINE STATE Pharmaceutical Drugs more than 80
                                          • Solids and the crystalline state
                                          • Classification of Solids
                                          • Slide 16
                                          • Slide 17
                                          • Crystal forms
                                          • Types of Crystals
                                          • Slide 20
                                          • Slide 21
                                          • Polymorphism
                                          • Slide 23
                                          • Slide 24
                                          • Slide 25
                                          • Slide 26
                                          • Cocrystal
                                          • Principle of polymorphism
                                          • Solvates
                                          • Polymorphism (2)
                                          • Amorphous Solid
                                          • Amorphous or crystalline amp therapeutic activity
                                          • Slide 33
                                          • Slide 34
                                          • Polymorphism and Industry Pharmaceutical
                                          • Celecoxib
                                          • Furosemide
                                          • Bioavailability
                                          • Slide 39
                                          • Slide 40
                                          • Bioequivalence
                                          • Slide 42
                                          • Carbamazepine
                                          • Slide 44
                                          • AIDS drug ritonavir
                                          • Slide 46
                                          • Slide 47
                                          • Phase Equilibria amp The Phase Rule
                                          • Phase diagram ndash Water
                                          • Phase Equilibria amp The Phase Rule Definitions
                                          • Phase Definition
                                          • Examples
                                          • Components
                                          • Examples
                                          • Slide 55
                                          • Degrees of freedom (or variance)
                                          • Examples (2)
                                          • Phase Equilibria amp The Phase Rule
                                          • The phase rule
                                          • Slide 60
                                          • Phase Equilibria amp The Phase Rule (2)
                                          • The number of phases in a system is denoted P
                                          • Slide 63
                                          • Slide 64
                                          • One-component systems
                                          • Slide 66
                                          • Slide 67
                                          • Slide 68
                                          • Slide 69
                                          • Slide 70
                                          • Two component system containing liquid phase
                                          • Slide 72
                                          • The Critical Solution Temperature CST
                                          • Systems Showing a Decrease in Miscibility with Rise in Temperat
                                          • Systems Showing Upper and Lower CSTs
                                          • Two component system containing solid and liquid phase (Eutecti
                                          • Slide 77
                                          • Eutectic mixture Pharmaceutical Application
                                          • Three component system
                                          • Slide 80
                                          • Topics that we have covered

                                            diamond graphite

                                            carbonatoms

                                            High T and p

                                            Diamond is metastable and converts very slowly to graphite

                                            The most common example of polymorphism

                                            Solid State Polymorphs

                                            Mono-component systems Polymorphs

                                            Multi-component systems

                                            Cocrystal

                                            The simplest definition of a cocrystal is a crystalline structure made up of two or more components in a definite stoichiometric ratio where each component is defined as either an atom ion or molecule

                                            Principle of polymorphism

                                            When the change from one form to another is reversible it is said to be enantiotropic

                                            When the transition takes place in one direction onlymdashfor example from a metastable to a stable formmdashthe change is said to be monotropic

                                            Solvates

                                            Pharmaceutical synthesis include purification and crystallization residual solvent can be trapped in the lattice

                                            This result in the formation of cocrystal or solvate

                                            The presence of residual solvent may affect dramatically the crystalline structure of the solid depending on the type of inter molecular forces that the solvent may have with crystalline solid

                                            Melting pointVapor pressureHardnessOptical electrical magnetic

                                            propertiesColorIR spectraNMR spectra

                                            Photochemical reactivityThermal stabilityFiltration and drying characteristicsDissolution rateBioavailabilityPhysical and chemical stability

                                            Solubility and melting point are very important in pharmaceutical processes including dissolution and

                                            formulation

                                            Polymorphism

                                            AMORPHOUS SOLIDS Solids that donrsquot have a definite geometrical shape are known as Amorphous Solids1 In these solids particles are randomly arranged in three dimension2 They donrsquot have sharp melting points3 Amorphous solids are formed due to sudden cooling of liquid4 Amorphous solids melt over a wide range of temperature

                                            Amorphous Solid

                                            An amorphous solid does not possess a well-defined arrangement and long-range molecular order

                                            Amorphous substances as well as cubic crystal are isotropic that is they exhibit similar properties in all direction

                                            The crystalline from of the antibiotic novobiocin acid is poorly absorbed and has no activity where the amorphous form is readily absorbed and therapeutically active due to different dissolution rate

                                            Amorphous or crystalline amp therapeutic activity

                                            General crystallization conditions 1048698Solvents ndashdifferent polarities 1048698Concentration of the solutions (super saturated saturated diluted) 1048698Cooling speed (quenching slow) 1048698Temperature (room or lower than room temperature)

                                            Crystallization

                                            Final Form

                                            Granulation

                                            Drying

                                            Compaction

                                            Tableting

                                            Drug Product

                                            API

                                            Crystallization

                                            Filtration

                                            Drying

                                            Milling

                                            Bulk API

                                            Stability

                                            Polymorphism and Industry Pharmaceutical

                                            Polymorphism and Industry Pharmaceutical

                                            Fluoxetine HCl the active ingredient in the antidepressant drug Prozac

                                            co crystal which will have increased solubility compared to the crystalline form

                                            Celecoxib

                                            CELECOXIB is a nonsteroidal anti-inflammatory drug

                                            However it was found that the higher bioavailability was shown by the amorphous state

                                            The downfall of the amorphous state was its stability

                                            This was due to the structural relaxation

                                            This was enhanced by mixing it with polymers like PVP which helped in stabilizing the amorphous system (Piyush Gupta et al 2004 Piyush Gupta et al 2005)

                                            A new solid state form was developed by Pharmacia

                                            FurosemideTwo forms with significantly differing aqueous solubility and dissolution rateOral bioavailability compromised

                                            Giron lists gt20 excipients that display polymorphism includingndash Lactose (anhydrous also monohydrate)ndash Aspartame (anhydrous hydrate forms)ndash Magnesium stearate (can affect lubrication of tablets)

                                            Bioavailability

                                            The rate and extent to which the active ingredient or active moiety is absorbed from a drug product and becomes available at the site of action

                                            Bioequivalence

                                            The absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study

                                            Carbamazepine

                                            CHLORPROPAMIDEat least six polymorphic white or almost white crystalline powder It exhibits polymorphism Practically insoluble in water soluble in alcohol freely soluble in acetone and in dichlo-romethane dissolves in dilute solutions of alkali hydroxides Protect from light

                                            blood-glucose-lowering drug

                                            AIDS drug ritonavir

                                            Theobroma oil (cacao butter ) is a polymorphic natural fat

                                            Theobroma oil can exist in 4 different polymorphic forms of which only one is Stabile

                                            1 Unstable gamma form melting at 18degC2 Alpha form melting at 22degC3 Beta prime form melting at 28degC4 Stable beta form melting at 345degC

                                            This is important in the preparation of theobroma suppositories

                                            If the oil is heated to a point where it is completely liquified (about 35 C) the crystals of the stable polymorph are destroyed amp the mass does not crystallize until it is cooled to 15 C

                                            The crystals that form are unstable amp the suppositories melt at 24 C

                                            Theobroma suppositories must be prepared below 33 C

                                            Polymorphism and Industry Pharmaceutical

                                            Polymorphism and Industry Pharmaceutical

                                            Anhydrates together with salts form the majority of all drug formulationsAbout a half of all APIs used today are saltsSalts are stable and well soluble in polar solvents (first of all in water) because they contain ionic bondThere is one more essential advantage of salts ndash their solubility is a function of pH Since pH in the gastrointestinal tract (GIT) vary between 1-75

                                            atorvastatin calcium trihydrateEach tablet contains Atorvastatin Calcium Trihydrate equivalent to Atorvastatin 20 mg

                                            Phase Equilibria amp The Phase Rule

                                            Phase diagram ndash Water

                                            Phase Equilibrium A stable phase structure with lowest free-energy (internal energy) of a system and also randomness or disorder of the atoms or molecules (entropy)

                                            Any change in Temperature Composition and Pressure causes an increase in free energy and away from Equilibrium thus forcing a move to another lsquostatersquo

                                            Phase Equilibria amp The Phase Rule Definitions

                                            A phase is defined as any homogeneous and physically distinct part of a system which is separated from other parts of the system by interfaces

                                            A part of a system is homogeneous if it has identical physical properties and chemical composition throughout the part

                                            A phase may be gas liquid or solid A gas or a gaseous mixture is a single phase Totally miscible liquids constitute a single phase In an immiscible liquid system each layer is counted as a separate phase Every solid constitutes a single phase except when a solid solution is formed A solid solution is considered as a single phase Each polymorphic form constitutes a separate phase

                                            Phase Definition

                                            1 Liquid water pieces of ice and water vapour are present together The number of phases is 3 as each form is a separate phase Ice in the system is a single phase even if it is present as a number of pieces

                                            2 Calcium carbonate undergoes thermal decomposition The chemical reaction is CaCO3(s) CaO(s) + CO2 (g) Number of phases = 3 This system consists of 2 solid phases CaCO3 and CaO and one gaseous phase that of CO2

                                            3 Ammonium chloride undergoes thermal decomposition The chemical reaction is NH4Cl(s) NH3 (g) + HCl (g) Number of phases = 2 This system has two phases one solid NH4Cl and one gaseous a mixture of NH3 and HCl

                                            4 A solution of NaCl in water Number of phases = 1

                                            bull Examples

                                            The number of components of a system at equilibrium is the smallest number of independently varying chemical constituents using which the composition of each and every phase in the system can be expressed

                                            Components

                                            Counting the number of components 1 The sulphur system is a one component system All the phases

                                            monoclinic rhombic liquid and vapour ndash can be expressed in terms of the single constituent ndash sulphur

                                            2 A mixture of ethanol and water is an example of a two component system We need both ethanol and water to express its composition

                                            bull Examples

                                            An example of a system in which a reaction occurs and an equilibrium is established is the thermal decomposition of solid CaCO3

                                            In this system there are three distinct phasesSolid CaCO3

                                            Solid CaOGaseous CO2

                                            Though there are 3 species present the number of components is only two because of the equilibrium CaCO3 (s) CaO(s) + CO2(g)

                                            Any two of the three constituents may be chosen as the components

                                            If CaO and CO2 are chosen then the composition of the phase CaCO3 is expressed as one mole of component CO2 plus one mole of component CaO

                                            If on the other hand CaCO3 and CO2 were chosen then the composition of the phase CaO would be described as one mole of CaCO3 minus one mole of CO2

                                            The degrees of freedom or variance of a system is defined as the minimum number of variables such as

                                            temperaturepressureconcentrationwhich must be fixed in order to define the system completely

                                            Degrees of freedom (or variance)

                                            F = C P + 2

                                            1 A gaseous mixture of CO2 and N2 Three variables pressure temperature and composition are required to define this system This is hence a trivariant system

                                            2 A system having only liquid water has two degrees of freedom or is bivariant Both temperature and pressure need to be mentioned in order to define the system

                                            3 If to the system containing liquid water pieces of ice are added and this system with 2 phases is allowed to come to equilibrium then it is an univariant system

                                            Only one variable either temperature or pressure need to be specified in order to define the systemIf the pressure on the system is maintained at 1 atm then the temperature of the system gets automatically fixed at 0oC the normal melting point of ice

                                            bull Examples

                                            Phase Equilibria amp The Phase Rule

                                            A phase diagram (Equilibrium Phase Diagram) summarizes the conditions at which a substance exists as a solid liquid or gas

                                            OR It is a ldquomaprdquo of the information about the control of phase structure of a particular material system

                                            The relationships between temperature and the compositions and the quantities of phases present at equilibrium are represented

                                            F = C P + 2The phase rule

                                            The phase rule JW Gibbs formulated the phase rule which is a general relation

                                            between the variance F the number of component C and the number of phases P at equilibrium for a system of any composition

                                            For a system in equilibrium

                                            F degree of freedom the least number of intensive variable that must be fixed (known) to describe the system completely

                                            Phase Rule relation to determine the least number of intensive variable that can be changed without changing the equilibrium state of the system or alternately

                                            The least number required to define the state of the system which is called degree of freedom F

                                            Intensive variable independent variable that do not depend on the volume or the size egTemp pressure

                                            Independent chemical species which comprise the system These could be Elements Ions Compounds

                                            Eg Au-Cu system Components rarr Au Cu Ice-water system Component rarr H2O

                                            Al2O3 ndash Cr2O3 system Components rarr Al2O3 Cr2O3

                                            Component the smallest number of constituent by which the composition of each phase in the system at equilibrium can be expressed in form of chemical formula or equation

                                            Phase Equilibria amp The Phase RuleComponents of a system

                                            The number of phases in a system is denoted P

                                            (a)A gas or a gaseous mixture is a single phase P=1

                                            (b) For a solid system an alloy of two metals is a two-phase system (P=2) if the metals are immiscible but a single-phase system (P=1) if they are miscible---a homogeneous mixture of the two substances---is uniform on a molecular scale

                                            (c) For a liquid system according to the solubility to decide whether a system consists of one phase or of two For example a solution of sodium chloride in water is a single phase A pair of liquids that are partially miscible or immiscible is a two-phase system(P=2)

                                            Oil in water

                                            Degrees of Freedom = What you can control What the system controls

                                            F = C + 2 P

                                            Can control the no of components added and P amp T

                                            System decided how many phases to produce given the

                                            conditions

                                            A way of understanding the Gibbs Phase RuleThe degrees of freedom can be thought of as the difference between what you (can) control and

                                            what the system controls

                                            F degree of freedom the least number of intensive variable that must be fixed (known) to describe the system completely

                                            Degree of freedom (or variance) F is the number of variables (T p andor composition) that can be changed independently without changing the phases of the system

                                            a) At the triple pointP = 3 (solid liquid and gas)

                                            C= 1 (water)P + F = C + 2

                                            F = 0 (no degree of freedom)

                                            b) liquid-solid curveP = 2

                                            2+F = 1 + 2F= 1

                                            One variable (T or P) can be changed

                                            c) LiquidP =1

                                            So F =2Two variables (T and P) can be varied independently

                                            and the system will remains a single phase

                                            One-component systemsPhase diagram of water

                                            P (

                                            atm

                                            )

                                            Critical point

                                            374

                                            1

                                            =100=0O--Triple point

                                            0006

                                            218

                                            Curve O -CSublimation

                                            Deposition

                                            Curve O-AVaporizationCondensation

                                            Curve O -BMelting

                                            Freezing

                                            F = C P + 2

                                            F = C P + 2

                                            Phase Diagram of Carbon Dioxide

                                            Condensed system System in which the vapor phase is ignored and only the solid andor liquid phases are considered

                                            Two component system For two component system F can be 3 (3D model is needed) eg T p

                                            and concentration usually we fix p = 1atm the vapor phase is neglected and F is reduced to 2

                                            For three component system the pressure and temperature are fixed

                                            Phenol water phase diagram

                                            eg for point d (24)

                                            Two component system containing liquid phase

                                            Tie Line bc line The line at which the system at equilibrium will separate into phases of constant composition termed lsquoconjugate phasesrsquo

                                            Lever Rule a way to calculate the proportions of each phase present on a phase diagram in a two phase field (at a given temperature and composition)

                                            eg for point d (24)

                                            For every 10 g of liquid system in equilibrium in point d

                                            75 g phase A25 g phase B

                                            ExampleMixed 24g phenol +76g water T 50degC

                                            equilibrium75 g phase A 25 g phase B

                                            11 phenol 63 phenol

                                            011 times75 g=825 g phenol

                                            063 times25 g=1575 g phenol

                                            water rich phasecontains water+ phenol(11)

                                            Phenol rich phasecontains Phenol (63)+ water

                                            The Critical Solution Temperature CST

                                            Is the maximum temperature at which the 2-phase region exists (or upper consolute temperature)

                                            In the case of the phenol-water system this is 668oC (point h)

                                            All combinations of phenol and water gt CST are completely miscible and yield 1-phase liquid systems

                                            Systems Showing a Decrease in Miscibility with Rise in Temperature

                                            A few mixtures exhibit a lower critical solution temperature (low CST) eg triethylamine plus water The miscibility with in temperature

                                            Systems Showing Upper and Lower CSTs

                                            The miscibility with temp

                                            a certain temperature miscibility starts to again with further in temperature

                                            Closed-phase diagram ie nicotine-water system

                                            A salol B thymol

                                            53

                                            Two component system containing solid and liquid phase (Eutectic Mixtures)

                                            A salol B thymol

                                            EMLAreg (lidocaine 25 and prilocaine 25) Cream

                                            EMLA Cream (lidocaine 25 and prilocaine 25) is an emulsion in which the oil phase is a eutectic mixture of lidocaine and prilocaine in a ratio of 11 by weight This eutectic mixture has a melting point below room temperature and therefore both local anesthetics exist as a liquid oil rather than as crystals

                                            Eutectic mixture Pharmaceutical Application

                                            Triangular Diagrams for three ndash component systems

                                            Three component system

                                            Birzeit University Physical Pharmacy PHAR 323 Dr Hani Shtaya

                                            1 Binding Forces Between Molecules2 Repulsive and Attractive Forces3 The Gaseous State The Ideal Gas Law Liquefaction of Gases Aerosols4 Solids and the Crystalline State Crystalline Solids Polymorphism Solvates Amorphous Solids5 Phase Equilibria and the Phase Rule Phase Rule Systems Containing One Component Condensed System Two-Component Systems Containing Liquid Phases Two-Component Systems Containing Solid and Liquid Phases Eutectic Mixtures Rules Relating to Triangular Diagrams

                                            Topics that we have covered

                                            • States of Matter
                                            • States of Matter (2)
                                            • Objectives of the lecture
                                            • Comparison of Gases Liquids and Solids
                                            • Slide 5
                                            • Repulsive and Attractive Forces
                                            • Ideal Gas Equation
                                            • Gaseous state
                                            • Slide 9
                                            • Gaseous state (2)
                                            • Liquefaction of Gases
                                            • Slide 12
                                            • SOLIDS amp CRYSTALLINE STATE Pharmaceutical Drugs more than 80
                                            • Solids and the crystalline state
                                            • Classification of Solids
                                            • Slide 16
                                            • Slide 17
                                            • Crystal forms
                                            • Types of Crystals
                                            • Slide 20
                                            • Slide 21
                                            • Polymorphism
                                            • Slide 23
                                            • Slide 24
                                            • Slide 25
                                            • Slide 26
                                            • Cocrystal
                                            • Principle of polymorphism
                                            • Solvates
                                            • Polymorphism (2)
                                            • Amorphous Solid
                                            • Amorphous or crystalline amp therapeutic activity
                                            • Slide 33
                                            • Slide 34
                                            • Polymorphism and Industry Pharmaceutical
                                            • Celecoxib
                                            • Furosemide
                                            • Bioavailability
                                            • Slide 39
                                            • Slide 40
                                            • Bioequivalence
                                            • Slide 42
                                            • Carbamazepine
                                            • Slide 44
                                            • AIDS drug ritonavir
                                            • Slide 46
                                            • Slide 47
                                            • Phase Equilibria amp The Phase Rule
                                            • Phase diagram ndash Water
                                            • Phase Equilibria amp The Phase Rule Definitions
                                            • Phase Definition
                                            • Examples
                                            • Components
                                            • Examples
                                            • Slide 55
                                            • Degrees of freedom (or variance)
                                            • Examples (2)
                                            • Phase Equilibria amp The Phase Rule
                                            • The phase rule
                                            • Slide 60
                                            • Phase Equilibria amp The Phase Rule (2)
                                            • The number of phases in a system is denoted P
                                            • Slide 63
                                            • Slide 64
                                            • One-component systems
                                            • Slide 66
                                            • Slide 67
                                            • Slide 68
                                            • Slide 69
                                            • Slide 70
                                            • Two component system containing liquid phase
                                            • Slide 72
                                            • The Critical Solution Temperature CST
                                            • Systems Showing a Decrease in Miscibility with Rise in Temperat
                                            • Systems Showing Upper and Lower CSTs
                                            • Two component system containing solid and liquid phase (Eutecti
                                            • Slide 77
                                            • Eutectic mixture Pharmaceutical Application
                                            • Three component system
                                            • Slide 80
                                            • Topics that we have covered

                                              Solid State Polymorphs

                                              Mono-component systems Polymorphs

                                              Multi-component systems

                                              Cocrystal

                                              The simplest definition of a cocrystal is a crystalline structure made up of two or more components in a definite stoichiometric ratio where each component is defined as either an atom ion or molecule

                                              Principle of polymorphism

                                              When the change from one form to another is reversible it is said to be enantiotropic

                                              When the transition takes place in one direction onlymdashfor example from a metastable to a stable formmdashthe change is said to be monotropic

                                              Solvates

                                              Pharmaceutical synthesis include purification and crystallization residual solvent can be trapped in the lattice

                                              This result in the formation of cocrystal or solvate

                                              The presence of residual solvent may affect dramatically the crystalline structure of the solid depending on the type of inter molecular forces that the solvent may have with crystalline solid

                                              Melting pointVapor pressureHardnessOptical electrical magnetic

                                              propertiesColorIR spectraNMR spectra

                                              Photochemical reactivityThermal stabilityFiltration and drying characteristicsDissolution rateBioavailabilityPhysical and chemical stability

                                              Solubility and melting point are very important in pharmaceutical processes including dissolution and

                                              formulation

                                              Polymorphism

                                              AMORPHOUS SOLIDS Solids that donrsquot have a definite geometrical shape are known as Amorphous Solids1 In these solids particles are randomly arranged in three dimension2 They donrsquot have sharp melting points3 Amorphous solids are formed due to sudden cooling of liquid4 Amorphous solids melt over a wide range of temperature

                                              Amorphous Solid

                                              An amorphous solid does not possess a well-defined arrangement and long-range molecular order

                                              Amorphous substances as well as cubic crystal are isotropic that is they exhibit similar properties in all direction

                                              The crystalline from of the antibiotic novobiocin acid is poorly absorbed and has no activity where the amorphous form is readily absorbed and therapeutically active due to different dissolution rate

                                              Amorphous or crystalline amp therapeutic activity

                                              General crystallization conditions 1048698Solvents ndashdifferent polarities 1048698Concentration of the solutions (super saturated saturated diluted) 1048698Cooling speed (quenching slow) 1048698Temperature (room or lower than room temperature)

                                              Crystallization

                                              Final Form

                                              Granulation

                                              Drying

                                              Compaction

                                              Tableting

                                              Drug Product

                                              API

                                              Crystallization

                                              Filtration

                                              Drying

                                              Milling

                                              Bulk API

                                              Stability

                                              Polymorphism and Industry Pharmaceutical

                                              Polymorphism and Industry Pharmaceutical

                                              Fluoxetine HCl the active ingredient in the antidepressant drug Prozac

                                              co crystal which will have increased solubility compared to the crystalline form

                                              Celecoxib

                                              CELECOXIB is a nonsteroidal anti-inflammatory drug

                                              However it was found that the higher bioavailability was shown by the amorphous state

                                              The downfall of the amorphous state was its stability

                                              This was due to the structural relaxation

                                              This was enhanced by mixing it with polymers like PVP which helped in stabilizing the amorphous system (Piyush Gupta et al 2004 Piyush Gupta et al 2005)

                                              A new solid state form was developed by Pharmacia

                                              FurosemideTwo forms with significantly differing aqueous solubility and dissolution rateOral bioavailability compromised

                                              Giron lists gt20 excipients that display polymorphism includingndash Lactose (anhydrous also monohydrate)ndash Aspartame (anhydrous hydrate forms)ndash Magnesium stearate (can affect lubrication of tablets)

                                              Bioavailability

                                              The rate and extent to which the active ingredient or active moiety is absorbed from a drug product and becomes available at the site of action

                                              Bioequivalence

                                              The absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study

                                              Carbamazepine

                                              CHLORPROPAMIDEat least six polymorphic white or almost white crystalline powder It exhibits polymorphism Practically insoluble in water soluble in alcohol freely soluble in acetone and in dichlo-romethane dissolves in dilute solutions of alkali hydroxides Protect from light

                                              blood-glucose-lowering drug

                                              AIDS drug ritonavir

                                              Theobroma oil (cacao butter ) is a polymorphic natural fat

                                              Theobroma oil can exist in 4 different polymorphic forms of which only one is Stabile

                                              1 Unstable gamma form melting at 18degC2 Alpha form melting at 22degC3 Beta prime form melting at 28degC4 Stable beta form melting at 345degC

                                              This is important in the preparation of theobroma suppositories

                                              If the oil is heated to a point where it is completely liquified (about 35 C) the crystals of the stable polymorph are destroyed amp the mass does not crystallize until it is cooled to 15 C

                                              The crystals that form are unstable amp the suppositories melt at 24 C

                                              Theobroma suppositories must be prepared below 33 C

                                              Polymorphism and Industry Pharmaceutical

                                              Polymorphism and Industry Pharmaceutical

                                              Anhydrates together with salts form the majority of all drug formulationsAbout a half of all APIs used today are saltsSalts are stable and well soluble in polar solvents (first of all in water) because they contain ionic bondThere is one more essential advantage of salts ndash their solubility is a function of pH Since pH in the gastrointestinal tract (GIT) vary between 1-75

                                              atorvastatin calcium trihydrateEach tablet contains Atorvastatin Calcium Trihydrate equivalent to Atorvastatin 20 mg

                                              Phase Equilibria amp The Phase Rule

                                              Phase diagram ndash Water

                                              Phase Equilibrium A stable phase structure with lowest free-energy (internal energy) of a system and also randomness or disorder of the atoms or molecules (entropy)

                                              Any change in Temperature Composition and Pressure causes an increase in free energy and away from Equilibrium thus forcing a move to another lsquostatersquo

                                              Phase Equilibria amp The Phase Rule Definitions

                                              A phase is defined as any homogeneous and physically distinct part of a system which is separated from other parts of the system by interfaces

                                              A part of a system is homogeneous if it has identical physical properties and chemical composition throughout the part

                                              A phase may be gas liquid or solid A gas or a gaseous mixture is a single phase Totally miscible liquids constitute a single phase In an immiscible liquid system each layer is counted as a separate phase Every solid constitutes a single phase except when a solid solution is formed A solid solution is considered as a single phase Each polymorphic form constitutes a separate phase

                                              Phase Definition

                                              1 Liquid water pieces of ice and water vapour are present together The number of phases is 3 as each form is a separate phase Ice in the system is a single phase even if it is present as a number of pieces

                                              2 Calcium carbonate undergoes thermal decomposition The chemical reaction is CaCO3(s) CaO(s) + CO2 (g) Number of phases = 3 This system consists of 2 solid phases CaCO3 and CaO and one gaseous phase that of CO2

                                              3 Ammonium chloride undergoes thermal decomposition The chemical reaction is NH4Cl(s) NH3 (g) + HCl (g) Number of phases = 2 This system has two phases one solid NH4Cl and one gaseous a mixture of NH3 and HCl

                                              4 A solution of NaCl in water Number of phases = 1

                                              bull Examples

                                              The number of components of a system at equilibrium is the smallest number of independently varying chemical constituents using which the composition of each and every phase in the system can be expressed

                                              Components

                                              Counting the number of components 1 The sulphur system is a one component system All the phases

                                              monoclinic rhombic liquid and vapour ndash can be expressed in terms of the single constituent ndash sulphur

                                              2 A mixture of ethanol and water is an example of a two component system We need both ethanol and water to express its composition

                                              bull Examples

                                              An example of a system in which a reaction occurs and an equilibrium is established is the thermal decomposition of solid CaCO3

                                              In this system there are three distinct phasesSolid CaCO3

                                              Solid CaOGaseous CO2

                                              Though there are 3 species present the number of components is only two because of the equilibrium CaCO3 (s) CaO(s) + CO2(g)

                                              Any two of the three constituents may be chosen as the components

                                              If CaO and CO2 are chosen then the composition of the phase CaCO3 is expressed as one mole of component CO2 plus one mole of component CaO

                                              If on the other hand CaCO3 and CO2 were chosen then the composition of the phase CaO would be described as one mole of CaCO3 minus one mole of CO2

                                              The degrees of freedom or variance of a system is defined as the minimum number of variables such as

                                              temperaturepressureconcentrationwhich must be fixed in order to define the system completely

                                              Degrees of freedom (or variance)

                                              F = C P + 2

                                              1 A gaseous mixture of CO2 and N2 Three variables pressure temperature and composition are required to define this system This is hence a trivariant system

                                              2 A system having only liquid water has two degrees of freedom or is bivariant Both temperature and pressure need to be mentioned in order to define the system

                                              3 If to the system containing liquid water pieces of ice are added and this system with 2 phases is allowed to come to equilibrium then it is an univariant system

                                              Only one variable either temperature or pressure need to be specified in order to define the systemIf the pressure on the system is maintained at 1 atm then the temperature of the system gets automatically fixed at 0oC the normal melting point of ice

                                              bull Examples

                                              Phase Equilibria amp The Phase Rule

                                              A phase diagram (Equilibrium Phase Diagram) summarizes the conditions at which a substance exists as a solid liquid or gas

                                              OR It is a ldquomaprdquo of the information about the control of phase structure of a particular material system

                                              The relationships between temperature and the compositions and the quantities of phases present at equilibrium are represented

                                              F = C P + 2The phase rule

                                              The phase rule JW Gibbs formulated the phase rule which is a general relation

                                              between the variance F the number of component C and the number of phases P at equilibrium for a system of any composition

                                              For a system in equilibrium

                                              F degree of freedom the least number of intensive variable that must be fixed (known) to describe the system completely

                                              Phase Rule relation to determine the least number of intensive variable that can be changed without changing the equilibrium state of the system or alternately

                                              The least number required to define the state of the system which is called degree of freedom F

                                              Intensive variable independent variable that do not depend on the volume or the size egTemp pressure

                                              Independent chemical species which comprise the system These could be Elements Ions Compounds

                                              Eg Au-Cu system Components rarr Au Cu Ice-water system Component rarr H2O

                                              Al2O3 ndash Cr2O3 system Components rarr Al2O3 Cr2O3

                                              Component the smallest number of constituent by which the composition of each phase in the system at equilibrium can be expressed in form of chemical formula or equation

                                              Phase Equilibria amp The Phase RuleComponents of a system

                                              The number of phases in a system is denoted P

                                              (a)A gas or a gaseous mixture is a single phase P=1

                                              (b) For a solid system an alloy of two metals is a two-phase system (P=2) if the metals are immiscible but a single-phase system (P=1) if they are miscible---a homogeneous mixture of the two substances---is uniform on a molecular scale

                                              (c) For a liquid system according to the solubility to decide whether a system consists of one phase or of two For example a solution of sodium chloride in water is a single phase A pair of liquids that are partially miscible or immiscible is a two-phase system(P=2)

                                              Oil in water

                                              Degrees of Freedom = What you can control What the system controls

                                              F = C + 2 P

                                              Can control the no of components added and P amp T

                                              System decided how many phases to produce given the

                                              conditions

                                              A way of understanding the Gibbs Phase RuleThe degrees of freedom can be thought of as the difference between what you (can) control and

                                              what the system controls

                                              F degree of freedom the least number of intensive variable that must be fixed (known) to describe the system completely

                                              Degree of freedom (or variance) F is the number of variables (T p andor composition) that can be changed independently without changing the phases of the system

                                              a) At the triple pointP = 3 (solid liquid and gas)

                                              C= 1 (water)P + F = C + 2

                                              F = 0 (no degree of freedom)

                                              b) liquid-solid curveP = 2

                                              2+F = 1 + 2F= 1

                                              One variable (T or P) can be changed

                                              c) LiquidP =1

                                              So F =2Two variables (T and P) can be varied independently

                                              and the system will remains a single phase

                                              One-component systemsPhase diagram of water

                                              P (

                                              atm

                                              )

                                              Critical point

                                              374

                                              1

                                              =100=0O--Triple point

                                              0006

                                              218

                                              Curve O -CSublimation

                                              Deposition

                                              Curve O-AVaporizationCondensation

                                              Curve O -BMelting

                                              Freezing

                                              F = C P + 2

                                              F = C P + 2

                                              Phase Diagram of Carbon Dioxide

                                              Condensed system System in which the vapor phase is ignored and only the solid andor liquid phases are considered

                                              Two component system For two component system F can be 3 (3D model is needed) eg T p

                                              and concentration usually we fix p = 1atm the vapor phase is neglected and F is reduced to 2

                                              For three component system the pressure and temperature are fixed

                                              Phenol water phase diagram

                                              eg for point d (24)

                                              Two component system containing liquid phase

                                              Tie Line bc line The line at which the system at equilibrium will separate into phases of constant composition termed lsquoconjugate phasesrsquo

                                              Lever Rule a way to calculate the proportions of each phase present on a phase diagram in a two phase field (at a given temperature and composition)

                                              eg for point d (24)

                                              For every 10 g of liquid system in equilibrium in point d

                                              75 g phase A25 g phase B

                                              ExampleMixed 24g phenol +76g water T 50degC

                                              equilibrium75 g phase A 25 g phase B

                                              11 phenol 63 phenol

                                              011 times75 g=825 g phenol

                                              063 times25 g=1575 g phenol

                                              water rich phasecontains water+ phenol(11)

                                              Phenol rich phasecontains Phenol (63)+ water

                                              The Critical Solution Temperature CST

                                              Is the maximum temperature at which the 2-phase region exists (or upper consolute temperature)

                                              In the case of the phenol-water system this is 668oC (point h)

                                              All combinations of phenol and water gt CST are completely miscible and yield 1-phase liquid systems

                                              Systems Showing a Decrease in Miscibility with Rise in Temperature

                                              A few mixtures exhibit a lower critical solution temperature (low CST) eg triethylamine plus water The miscibility with in temperature

                                              Systems Showing Upper and Lower CSTs

                                              The miscibility with temp

                                              a certain temperature miscibility starts to again with further in temperature

                                              Closed-phase diagram ie nicotine-water system

                                              A salol B thymol

                                              53

                                              Two component system containing solid and liquid phase (Eutectic Mixtures)

                                              A salol B thymol

                                              EMLAreg (lidocaine 25 and prilocaine 25) Cream

                                              EMLA Cream (lidocaine 25 and prilocaine 25) is an emulsion in which the oil phase is a eutectic mixture of lidocaine and prilocaine in a ratio of 11 by weight This eutectic mixture has a melting point below room temperature and therefore both local anesthetics exist as a liquid oil rather than as crystals

                                              Eutectic mixture Pharmaceutical Application

                                              Triangular Diagrams for three ndash component systems

                                              Three component system

                                              Birzeit University Physical Pharmacy PHAR 323 Dr Hani Shtaya

                                              1 Binding Forces Between Molecules2 Repulsive and Attractive Forces3 The Gaseous State The Ideal Gas Law Liquefaction of Gases Aerosols4 Solids and the Crystalline State Crystalline Solids Polymorphism Solvates Amorphous Solids5 Phase Equilibria and the Phase Rule Phase Rule Systems Containing One Component Condensed System Two-Component Systems Containing Liquid Phases Two-Component Systems Containing Solid and Liquid Phases Eutectic Mixtures Rules Relating to Triangular Diagrams

                                              Topics that we have covered

                                              • States of Matter
                                              • States of Matter (2)
                                              • Objectives of the lecture
                                              • Comparison of Gases Liquids and Solids
                                              • Slide 5
                                              • Repulsive and Attractive Forces
                                              • Ideal Gas Equation
                                              • Gaseous state
                                              • Slide 9
                                              • Gaseous state (2)
                                              • Liquefaction of Gases
                                              • Slide 12
                                              • SOLIDS amp CRYSTALLINE STATE Pharmaceutical Drugs more than 80
                                              • Solids and the crystalline state
                                              • Classification of Solids
                                              • Slide 16
                                              • Slide 17
                                              • Crystal forms
                                              • Types of Crystals
                                              • Slide 20
                                              • Slide 21
                                              • Polymorphism
                                              • Slide 23
                                              • Slide 24
                                              • Slide 25
                                              • Slide 26
                                              • Cocrystal
                                              • Principle of polymorphism
                                              • Solvates
                                              • Polymorphism (2)
                                              • Amorphous Solid
                                              • Amorphous or crystalline amp therapeutic activity
                                              • Slide 33
                                              • Slide 34
                                              • Polymorphism and Industry Pharmaceutical
                                              • Celecoxib
                                              • Furosemide
                                              • Bioavailability
                                              • Slide 39
                                              • Slide 40
                                              • Bioequivalence
                                              • Slide 42
                                              • Carbamazepine
                                              • Slide 44
                                              • AIDS drug ritonavir
                                              • Slide 46
                                              • Slide 47
                                              • Phase Equilibria amp The Phase Rule
                                              • Phase diagram ndash Water
                                              • Phase Equilibria amp The Phase Rule Definitions
                                              • Phase Definition
                                              • Examples
                                              • Components
                                              • Examples
                                              • Slide 55
                                              • Degrees of freedom (or variance)
                                              • Examples (2)
                                              • Phase Equilibria amp The Phase Rule
                                              • The phase rule
                                              • Slide 60
                                              • Phase Equilibria amp The Phase Rule (2)
                                              • The number of phases in a system is denoted P
                                              • Slide 63
                                              • Slide 64
                                              • One-component systems
                                              • Slide 66
                                              • Slide 67
                                              • Slide 68
                                              • Slide 69
                                              • Slide 70
                                              • Two component system containing liquid phase
                                              • Slide 72
                                              • The Critical Solution Temperature CST
                                              • Systems Showing a Decrease in Miscibility with Rise in Temperat
                                              • Systems Showing Upper and Lower CSTs
                                              • Two component system containing solid and liquid phase (Eutecti
                                              • Slide 77
                                              • Eutectic mixture Pharmaceutical Application
                                              • Three component system
                                              • Slide 80
                                              • Topics that we have covered

                                                Cocrystal

                                                The simplest definition of a cocrystal is a crystalline structure made up of two or more components in a definite stoichiometric ratio where each component is defined as either an atom ion or molecule

                                                Principle of polymorphism

                                                When the change from one form to another is reversible it is said to be enantiotropic

                                                When the transition takes place in one direction onlymdashfor example from a metastable to a stable formmdashthe change is said to be monotropic

                                                Solvates

                                                Pharmaceutical synthesis include purification and crystallization residual solvent can be trapped in the lattice

                                                This result in the formation of cocrystal or solvate

                                                The presence of residual solvent may affect dramatically the crystalline structure of the solid depending on the type of inter molecular forces that the solvent may have with crystalline solid

                                                Melting pointVapor pressureHardnessOptical electrical magnetic

                                                propertiesColorIR spectraNMR spectra

                                                Photochemical reactivityThermal stabilityFiltration and drying characteristicsDissolution rateBioavailabilityPhysical and chemical stability

                                                Solubility and melting point are very important in pharmaceutical processes including dissolution and

                                                formulation

                                                Polymorphism

                                                AMORPHOUS SOLIDS Solids that donrsquot have a definite geometrical shape are known as Amorphous Solids1 In these solids particles are randomly arranged in three dimension2 They donrsquot have sharp melting points3 Amorphous solids are formed due to sudden cooling of liquid4 Amorphous solids melt over a wide range of temperature

                                                Amorphous Solid

                                                An amorphous solid does not possess a well-defined arrangement and long-range molecular order

                                                Amorphous substances as well as cubic crystal are isotropic that is they exhibit similar properties in all direction

                                                The crystalline from of the antibiotic novobiocin acid is poorly absorbed and has no activity where the amorphous form is readily absorbed and therapeutically active due to different dissolution rate

                                                Amorphous or crystalline amp therapeutic activity

                                                General crystallization conditions 1048698Solvents ndashdifferent polarities 1048698Concentration of the solutions (super saturated saturated diluted) 1048698Cooling speed (quenching slow) 1048698Temperature (room or lower than room temperature)

                                                Crystallization

                                                Final Form

                                                Granulation

                                                Drying

                                                Compaction

                                                Tableting

                                                Drug Product

                                                API

                                                Crystallization

                                                Filtration

                                                Drying

                                                Milling

                                                Bulk API

                                                Stability

                                                Polymorphism and Industry Pharmaceutical

                                                Polymorphism and Industry Pharmaceutical

                                                Fluoxetine HCl the active ingredient in the antidepressant drug Prozac

                                                co crystal which will have increased solubility compared to the crystalline form

                                                Celecoxib

                                                CELECOXIB is a nonsteroidal anti-inflammatory drug

                                                However it was found that the higher bioavailability was shown by the amorphous state

                                                The downfall of the amorphous state was its stability

                                                This was due to the structural relaxation

                                                This was enhanced by mixing it with polymers like PVP which helped in stabilizing the amorphous system (Piyush Gupta et al 2004 Piyush Gupta et al 2005)

                                                A new solid state form was developed by Pharmacia

                                                FurosemideTwo forms with significantly differing aqueous solubility and dissolution rateOral bioavailability compromised

                                                Giron lists gt20 excipients that display polymorphism includingndash Lactose (anhydrous also monohydrate)ndash Aspartame (anhydrous hydrate forms)ndash Magnesium stearate (can affect lubrication of tablets)

                                                Bioavailability

                                                The rate and extent to which the active ingredient or active moiety is absorbed from a drug product and becomes available at the site of action

                                                Bioequivalence

                                                The absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study

                                                Carbamazepine

                                                CHLORPROPAMIDEat least six polymorphic white or almost white crystalline powder It exhibits polymorphism Practically insoluble in water soluble in alcohol freely soluble in acetone and in dichlo-romethane dissolves in dilute solutions of alkali hydroxides Protect from light

                                                blood-glucose-lowering drug

                                                AIDS drug ritonavir

                                                Theobroma oil (cacao butter ) is a polymorphic natural fat

                                                Theobroma oil can exist in 4 different polymorphic forms of which only one is Stabile

                                                1 Unstable gamma form melting at 18degC2 Alpha form melting at 22degC3 Beta prime form melting at 28degC4 Stable beta form melting at 345degC

                                                This is important in the preparation of theobroma suppositories

                                                If the oil is heated to a point where it is completely liquified (about 35 C) the crystals of the stable polymorph are destroyed amp the mass does not crystallize until it is cooled to 15 C

                                                The crystals that form are unstable amp the suppositories melt at 24 C

                                                Theobroma suppositories must be prepared below 33 C

                                                Polymorphism and Industry Pharmaceutical

                                                Polymorphism and Industry Pharmaceutical

                                                Anhydrates together with salts form the majority of all drug formulationsAbout a half of all APIs used today are saltsSalts are stable and well soluble in polar solvents (first of all in water) because they contain ionic bondThere is one more essential advantage of salts ndash their solubility is a function of pH Since pH in the gastrointestinal tract (GIT) vary between 1-75

                                                atorvastatin calcium trihydrateEach tablet contains Atorvastatin Calcium Trihydrate equivalent to Atorvastatin 20 mg

                                                Phase Equilibria amp The Phase Rule

                                                Phase diagram ndash Water

                                                Phase Equilibrium A stable phase structure with lowest free-energy (internal energy) of a system and also randomness or disorder of the atoms or molecules (entropy)

                                                Any change in Temperature Composition and Pressure causes an increase in free energy and away from Equilibrium thus forcing a move to another lsquostatersquo

                                                Phase Equilibria amp The Phase Rule Definitions

                                                A phase is defined as any homogeneous and physically distinct part of a system which is separated from other parts of the system by interfaces

                                                A part of a system is homogeneous if it has identical physical properties and chemical composition throughout the part

                                                A phase may be gas liquid or solid A gas or a gaseous mixture is a single phase Totally miscible liquids constitute a single phase In an immiscible liquid system each layer is counted as a separate phase Every solid constitutes a single phase except when a solid solution is formed A solid solution is considered as a single phase Each polymorphic form constitutes a separate phase

                                                Phase Definition

                                                1 Liquid water pieces of ice and water vapour are present together The number of phases is 3 as each form is a separate phase Ice in the system is a single phase even if it is present as a number of pieces

                                                2 Calcium carbonate undergoes thermal decomposition The chemical reaction is CaCO3(s) CaO(s) + CO2 (g) Number of phases = 3 This system consists of 2 solid phases CaCO3 and CaO and one gaseous phase that of CO2

                                                3 Ammonium chloride undergoes thermal decomposition The chemical reaction is NH4Cl(s) NH3 (g) + HCl (g) Number of phases = 2 This system has two phases one solid NH4Cl and one gaseous a mixture of NH3 and HCl

                                                4 A solution of NaCl in water Number of phases = 1

                                                bull Examples

                                                The number of components of a system at equilibrium is the smallest number of independently varying chemical constituents using which the composition of each and every phase in the system can be expressed

                                                Components

                                                Counting the number of components 1 The sulphur system is a one component system All the phases

                                                monoclinic rhombic liquid and vapour ndash can be expressed in terms of the single constituent ndash sulphur

                                                2 A mixture of ethanol and water is an example of a two component system We need both ethanol and water to express its composition

                                                bull Examples

                                                An example of a system in which a reaction occurs and an equilibrium is established is the thermal decomposition of solid CaCO3

                                                In this system there are three distinct phasesSolid CaCO3

                                                Solid CaOGaseous CO2

                                                Though there are 3 species present the number of components is only two because of the equilibrium CaCO3 (s) CaO(s) + CO2(g)

                                                Any two of the three constituents may be chosen as the components

                                                If CaO and CO2 are chosen then the composition of the phase CaCO3 is expressed as one mole of component CO2 plus one mole of component CaO

                                                If on the other hand CaCO3 and CO2 were chosen then the composition of the phase CaO would be described as one mole of CaCO3 minus one mole of CO2

                                                The degrees of freedom or variance of a system is defined as the minimum number of variables such as

                                                temperaturepressureconcentrationwhich must be fixed in order to define the system completely

                                                Degrees of freedom (or variance)

                                                F = C P + 2

                                                1 A gaseous mixture of CO2 and N2 Three variables pressure temperature and composition are required to define this system This is hence a trivariant system

                                                2 A system having only liquid water has two degrees of freedom or is bivariant Both temperature and pressure need to be mentioned in order to define the system

                                                3 If to the system containing liquid water pieces of ice are added and this system with 2 phases is allowed to come to equilibrium then it is an univariant system

                                                Only one variable either temperature or pressure need to be specified in order to define the systemIf the pressure on the system is maintained at 1 atm then the temperature of the system gets automatically fixed at 0oC the normal melting point of ice

                                                bull Examples

                                                Phase Equilibria amp The Phase Rule

                                                A phase diagram (Equilibrium Phase Diagram) summarizes the conditions at which a substance exists as a solid liquid or gas

                                                OR It is a ldquomaprdquo of the information about the control of phase structure of a particular material system

                                                The relationships between temperature and the compositions and the quantities of phases present at equilibrium are represented

                                                F = C P + 2The phase rule

                                                The phase rule JW Gibbs formulated the phase rule which is a general relation

                                                between the variance F the number of component C and the number of phases P at equilibrium for a system of any composition

                                                For a system in equilibrium

                                                F degree of freedom the least number of intensive variable that must be fixed (known) to describe the system completely

                                                Phase Rule relation to determine the least number of intensive variable that can be changed without changing the equilibrium state of the system or alternately

                                                The least number required to define the state of the system which is called degree of freedom F

                                                Intensive variable independent variable that do not depend on the volume or the size egTemp pressure

                                                Independent chemical species which comprise the system These could be Elements Ions Compounds

                                                Eg Au-Cu system Components rarr Au Cu Ice-water system Component rarr H2O

                                                Al2O3 ndash Cr2O3 system Components rarr Al2O3 Cr2O3

                                                Component the smallest number of constituent by which the composition of each phase in the system at equilibrium can be expressed in form of chemical formula or equation

                                                Phase Equilibria amp The Phase RuleComponents of a system

                                                The number of phases in a system is denoted P

                                                (a)A gas or a gaseous mixture is a single phase P=1

                                                (b) For a solid system an alloy of two metals is a two-phase system (P=2) if the metals are immiscible but a single-phase system (P=1) if they are miscible---a homogeneous mixture of the two substances---is uniform on a molecular scale

                                                (c) For a liquid system according to the solubility to decide whether a system consists of one phase or of two For example a solution of sodium chloride in water is a single phase A pair of liquids that are partially miscible or immiscible is a two-phase system(P=2)

                                                Oil in water

                                                Degrees of Freedom = What you can control What the system controls

                                                F = C + 2 P

                                                Can control the no of components added and P amp T

                                                System decided how many phases to produce given the

                                                conditions

                                                A way of understanding the Gibbs Phase RuleThe degrees of freedom can be thought of as the difference between what you (can) control and

                                                what the system controls

                                                F degree of freedom the least number of intensive variable that must be fixed (known) to describe the system completely

                                                Degree of freedom (or variance) F is the number of variables (T p andor composition) that can be changed independently without changing the phases of the system

                                                a) At the triple pointP = 3 (solid liquid and gas)

                                                C= 1 (water)P + F = C + 2

                                                F = 0 (no degree of freedom)

                                                b) liquid-solid curveP = 2

                                                2+F = 1 + 2F= 1

                                                One variable (T or P) can be changed

                                                c) LiquidP =1

                                                So F =2Two variables (T and P) can be varied independently

                                                and the system will remains a single phase

                                                One-component systemsPhase diagram of water

                                                P (

                                                atm

                                                )

                                                Critical point

                                                374

                                                1

                                                =100=0O--Triple point

                                                0006

                                                218

                                                Curve O -CSublimation

                                                Deposition

                                                Curve O-AVaporizationCondensation

                                                Curve O -BMelting

                                                Freezing

                                                F = C P + 2

                                                F = C P + 2

                                                Phase Diagram of Carbon Dioxide

                                                Condensed system System in which the vapor phase is ignored and only the solid andor liquid phases are considered

                                                Two component system For two component system F can be 3 (3D model is needed) eg T p

                                                and concentration usually we fix p = 1atm the vapor phase is neglected and F is reduced to 2

                                                For three component system the pressure and temperature are fixed

                                                Phenol water phase diagram

                                                eg for point d (24)

                                                Two component system containing liquid phase

                                                Tie Line bc line The line at which the system at equilibrium will separate into phases of constant composition termed lsquoconjugate phasesrsquo

                                                Lever Rule a way to calculate the proportions of each phase present on a phase diagram in a two phase field (at a given temperature and composition)

                                                eg for point d (24)

                                                For every 10 g of liquid system in equilibrium in point d

                                                75 g phase A25 g phase B

                                                ExampleMixed 24g phenol +76g water T 50degC

                                                equilibrium75 g phase A 25 g phase B

                                                11 phenol 63 phenol

                                                011 times75 g=825 g phenol

                                                063 times25 g=1575 g phenol

                                                water rich phasecontains water+ phenol(11)

                                                Phenol rich phasecontains Phenol (63)+ water

                                                The Critical Solution Temperature CST

                                                Is the maximum temperature at which the 2-phase region exists (or upper consolute temperature)

                                                In the case of the phenol-water system this is 668oC (point h)

                                                All combinations of phenol and water gt CST are completely miscible and yield 1-phase liquid systems

                                                Systems Showing a Decrease in Miscibility with Rise in Temperature

                                                A few mixtures exhibit a lower critical solution temperature (low CST) eg triethylamine plus water The miscibility with in temperature

                                                Systems Showing Upper and Lower CSTs

                                                The miscibility with temp

                                                a certain temperature miscibility starts to again with further in temperature

                                                Closed-phase diagram ie nicotine-water system

                                                A salol B thymol

                                                53

                                                Two component system containing solid and liquid phase (Eutectic Mixtures)

                                                A salol B thymol

                                                EMLAreg (lidocaine 25 and prilocaine 25) Cream

                                                EMLA Cream (lidocaine 25 and prilocaine 25) is an emulsion in which the oil phase is a eutectic mixture of lidocaine and prilocaine in a ratio of 11 by weight This eutectic mixture has a melting point below room temperature and therefore both local anesthetics exist as a liquid oil rather than as crystals

                                                Eutectic mixture Pharmaceutical Application

                                                Triangular Diagrams for three ndash component systems

                                                Three component system

                                                Birzeit University Physical Pharmacy PHAR 323 Dr Hani Shtaya

                                                1 Binding Forces Between Molecules2 Repulsive and Attractive Forces3 The Gaseous State The Ideal Gas Law Liquefaction of Gases Aerosols4 Solids and the Crystalline State Crystalline Solids Polymorphism Solvates Amorphous Solids5 Phase Equilibria and the Phase Rule Phase Rule Systems Containing One Component Condensed System Two-Component Systems Containing Liquid Phases Two-Component Systems Containing Solid and Liquid Phases Eutectic Mixtures Rules Relating to Triangular Diagrams

                                                Topics that we have covered

                                                • States of Matter
                                                • States of Matter (2)
                                                • Objectives of the lecture
                                                • Comparison of Gases Liquids and Solids
                                                • Slide 5
                                                • Repulsive and Attractive Forces
                                                • Ideal Gas Equation
                                                • Gaseous state
                                                • Slide 9
                                                • Gaseous state (2)
                                                • Liquefaction of Gases
                                                • Slide 12
                                                • SOLIDS amp CRYSTALLINE STATE Pharmaceutical Drugs more than 80
                                                • Solids and the crystalline state
                                                • Classification of Solids
                                                • Slide 16
                                                • Slide 17
                                                • Crystal forms
                                                • Types of Crystals
                                                • Slide 20
                                                • Slide 21
                                                • Polymorphism
                                                • Slide 23
                                                • Slide 24
                                                • Slide 25
                                                • Slide 26
                                                • Cocrystal
                                                • Principle of polymorphism
                                                • Solvates
                                                • Polymorphism (2)
                                                • Amorphous Solid
                                                • Amorphous or crystalline amp therapeutic activity
                                                • Slide 33
                                                • Slide 34
                                                • Polymorphism and Industry Pharmaceutical
                                                • Celecoxib
                                                • Furosemide
                                                • Bioavailability
                                                • Slide 39
                                                • Slide 40
                                                • Bioequivalence
                                                • Slide 42
                                                • Carbamazepine
                                                • Slide 44
                                                • AIDS drug ritonavir
                                                • Slide 46
                                                • Slide 47
                                                • Phase Equilibria amp The Phase Rule
                                                • Phase diagram ndash Water
                                                • Phase Equilibria amp The Phase Rule Definitions
                                                • Phase Definition
                                                • Examples
                                                • Components
                                                • Examples
                                                • Slide 55
                                                • Degrees of freedom (or variance)
                                                • Examples (2)
                                                • Phase Equilibria amp The Phase Rule
                                                • The phase rule
                                                • Slide 60
                                                • Phase Equilibria amp The Phase Rule (2)
                                                • The number of phases in a system is denoted P
                                                • Slide 63
                                                • Slide 64
                                                • One-component systems
                                                • Slide 66
                                                • Slide 67
                                                • Slide 68
                                                • Slide 69
                                                • Slide 70
                                                • Two component system containing liquid phase
                                                • Slide 72
                                                • The Critical Solution Temperature CST
                                                • Systems Showing a Decrease in Miscibility with Rise in Temperat
                                                • Systems Showing Upper and Lower CSTs
                                                • Two component system containing solid and liquid phase (Eutecti
                                                • Slide 77
                                                • Eutectic mixture Pharmaceutical Application
                                                • Three component system
                                                • Slide 80
                                                • Topics that we have covered

                                                  Principle of polymorphism

                                                  When the change from one form to another is reversible it is said to be enantiotropic

                                                  When the transition takes place in one direction onlymdashfor example from a metastable to a stable formmdashthe change is said to be monotropic

                                                  Solvates

                                                  Pharmaceutical synthesis include purification and crystallization residual solvent can be trapped in the lattice

                                                  This result in the formation of cocrystal or solvate

                                                  The presence of residual solvent may affect dramatically the crystalline structure of the solid depending on the type of inter molecular forces that the solvent may have with crystalline solid

                                                  Melting pointVapor pressureHardnessOptical electrical magnetic

                                                  propertiesColorIR spectraNMR spectra

                                                  Photochemical reactivityThermal stabilityFiltration and drying characteristicsDissolution rateBioavailabilityPhysical and chemical stability

                                                  Solubility and melting point are very important in pharmaceutical processes including dissolution and

                                                  formulation

                                                  Polymorphism

                                                  AMORPHOUS SOLIDS Solids that donrsquot have a definite geometrical shape are known as Amorphous Solids1 In these solids particles are randomly arranged in three dimension2 They donrsquot have sharp melting points3 Amorphous solids are formed due to sudden cooling of liquid4 Amorphous solids melt over a wide range of temperature

                                                  Amorphous Solid

                                                  An amorphous solid does not possess a well-defined arrangement and long-range molecular order

                                                  Amorphous substances as well as cubic crystal are isotropic that is they exhibit similar properties in all direction

                                                  The crystalline from of the antibiotic novobiocin acid is poorly absorbed and has no activity where the amorphous form is readily absorbed and therapeutically active due to different dissolution rate

                                                  Amorphous or crystalline amp therapeutic activity

                                                  General crystallization conditions 1048698Solvents ndashdifferent polarities 1048698Concentration of the solutions (super saturated saturated diluted) 1048698Cooling speed (quenching slow) 1048698Temperature (room or lower than room temperature)

                                                  Crystallization

                                                  Final Form

                                                  Granulation

                                                  Drying

                                                  Compaction

                                                  Tableting

                                                  Drug Product

                                                  API

                                                  Crystallization

                                                  Filtration

                                                  Drying

                                                  Milling

                                                  Bulk API

                                                  Stability

                                                  Polymorphism and Industry Pharmaceutical

                                                  Polymorphism and Industry Pharmaceutical

                                                  Fluoxetine HCl the active ingredient in the antidepressant drug Prozac

                                                  co crystal which will have increased solubility compared to the crystalline form

                                                  Celecoxib

                                                  CELECOXIB is a nonsteroidal anti-inflammatory drug

                                                  However it was found that the higher bioavailability was shown by the amorphous state

                                                  The downfall of the amorphous state was its stability

                                                  This was due to the structural relaxation

                                                  This was enhanced by mixing it with polymers like PVP which helped in stabilizing the amorphous system (Piyush Gupta et al 2004 Piyush Gupta et al 2005)

                                                  A new solid state form was developed by Pharmacia

                                                  FurosemideTwo forms with significantly differing aqueous solubility and dissolution rateOral bioavailability compromised

                                                  Giron lists gt20 excipients that display polymorphism includingndash Lactose (anhydrous also monohydrate)ndash Aspartame (anhydrous hydrate forms)ndash Magnesium stearate (can affect lubrication of tablets)

                                                  Bioavailability

                                                  The rate and extent to which the active ingredient or active moiety is absorbed from a drug product and becomes available at the site of action

                                                  Bioequivalence

                                                  The absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study

                                                  Carbamazepine

                                                  CHLORPROPAMIDEat least six polymorphic white or almost white crystalline powder It exhibits polymorphism Practically insoluble in water soluble in alcohol freely soluble in acetone and in dichlo-romethane dissolves in dilute solutions of alkali hydroxides Protect from light

                                                  blood-glucose-lowering drug

                                                  AIDS drug ritonavir

                                                  Theobroma oil (cacao butter ) is a polymorphic natural fat

                                                  Theobroma oil can exist in 4 different polymorphic forms of which only one is Stabile

                                                  1 Unstable gamma form melting at 18degC2 Alpha form melting at 22degC3 Beta prime form melting at 28degC4 Stable beta form melting at 345degC

                                                  This is important in the preparation of theobroma suppositories

                                                  If the oil is heated to a point where it is completely liquified (about 35 C) the crystals of the stable polymorph are destroyed amp the mass does not crystallize until it is cooled to 15 C

                                                  The crystals that form are unstable amp the suppositories melt at 24 C

                                                  Theobroma suppositories must be prepared below 33 C

                                                  Polymorphism and Industry Pharmaceutical

                                                  Polymorphism and Industry Pharmaceutical

                                                  Anhydrates together with salts form the majority of all drug formulationsAbout a half of all APIs used today are saltsSalts are stable and well soluble in polar solvents (first of all in water) because they contain ionic bondThere is one more essential advantage of salts ndash their solubility is a function of pH Since pH in the gastrointestinal tract (GIT) vary between 1-75

                                                  atorvastatin calcium trihydrateEach tablet contains Atorvastatin Calcium Trihydrate equivalent to Atorvastatin 20 mg

                                                  Phase Equilibria amp The Phase Rule

                                                  Phase diagram ndash Water

                                                  Phase Equilibrium A stable phase structure with lowest free-energy (internal energy) of a system and also randomness or disorder of the atoms or molecules (entropy)

                                                  Any change in Temperature Composition and Pressure causes an increase in free energy and away from Equilibrium thus forcing a move to another lsquostatersquo

                                                  Phase Equilibria amp The Phase Rule Definitions

                                                  A phase is defined as any homogeneous and physically distinct part of a system which is separated from other parts of the system by interfaces

                                                  A part of a system is homogeneous if it has identical physical properties and chemical composition throughout the part

                                                  A phase may be gas liquid or solid A gas or a gaseous mixture is a single phase Totally miscible liquids constitute a single phase In an immiscible liquid system each layer is counted as a separate phase Every solid constitutes a single phase except when a solid solution is formed A solid solution is considered as a single phase Each polymorphic form constitutes a separate phase

                                                  Phase Definition

                                                  1 Liquid water pieces of ice and water vapour are present together The number of phases is 3 as each form is a separate phase Ice in the system is a single phase even if it is present as a number of pieces

                                                  2 Calcium carbonate undergoes thermal decomposition The chemical reaction is CaCO3(s) CaO(s) + CO2 (g) Number of phases = 3 This system consists of 2 solid phases CaCO3 and CaO and one gaseous phase that of CO2

                                                  3 Ammonium chloride undergoes thermal decomposition The chemical reaction is NH4Cl(s) NH3 (g) + HCl (g) Number of phases = 2 This system has two phases one solid NH4Cl and one gaseous a mixture of NH3 and HCl

                                                  4 A solution of NaCl in water Number of phases = 1

                                                  bull Examples

                                                  The number of components of a system at equilibrium is the smallest number of independently varying chemical constituents using which the composition of each and every phase in the system can be expressed

                                                  Components

                                                  Counting the number of components 1 The sulphur system is a one component system All the phases

                                                  monoclinic rhombic liquid and vapour ndash can be expressed in terms of the single constituent ndash sulphur

                                                  2 A mixture of ethanol and water is an example of a two component system We need both ethanol and water to express its composition

                                                  bull Examples

                                                  An example of a system in which a reaction occurs and an equilibrium is established is the thermal decomposition of solid CaCO3

                                                  In this system there are three distinct phasesSolid CaCO3

                                                  Solid CaOGaseous CO2

                                                  Though there are 3 species present the number of components is only two because of the equilibrium CaCO3 (s) CaO(s) + CO2(g)

                                                  Any two of the three constituents may be chosen as the components

                                                  If CaO and CO2 are chosen then the composition of the phase CaCO3 is expressed as one mole of component CO2 plus one mole of component CaO

                                                  If on the other hand CaCO3 and CO2 were chosen then the composition of the phase CaO would be described as one mole of CaCO3 minus one mole of CO2

                                                  The degrees of freedom or variance of a system is defined as the minimum number of variables such as

                                                  temperaturepressureconcentrationwhich must be fixed in order to define the system completely

                                                  Degrees of freedom (or variance)

                                                  F = C P + 2

                                                  1 A gaseous mixture of CO2 and N2 Three variables pressure temperature and composition are required to define this system This is hence a trivariant system

                                                  2 A system having only liquid water has two degrees of freedom or is bivariant Both temperature and pressure need to be mentioned in order to define the system

                                                  3 If to the system containing liquid water pieces of ice are added and this system with 2 phases is allowed to come to equilibrium then it is an univariant system

                                                  Only one variable either temperature or pressure need to be specified in order to define the systemIf the pressure on the system is maintained at 1 atm then the temperature of the system gets automatically fixed at 0oC the normal melting point of ice

                                                  bull Examples

                                                  Phase Equilibria amp The Phase Rule

                                                  A phase diagram (Equilibrium Phase Diagram) summarizes the conditions at which a substance exists as a solid liquid or gas

                                                  OR It is a ldquomaprdquo of the information about the control of phase structure of a particular material system

                                                  The relationships between temperature and the compositions and the quantities of phases present at equilibrium are represented

                                                  F = C P + 2The phase rule

                                                  The phase rule JW Gibbs formulated the phase rule which is a general relation

                                                  between the variance F the number of component C and the number of phases P at equilibrium for a system of any composition

                                                  For a system in equilibrium

                                                  F degree of freedom the least number of intensive variable that must be fixed (known) to describe the system completely

                                                  Phase Rule relation to determine the least number of intensive variable that can be changed without changing the equilibrium state of the system or alternately

                                                  The least number required to define the state of the system which is called degree of freedom F

                                                  Intensive variable independent variable that do not depend on the volume or the size egTemp pressure

                                                  Independent chemical species which comprise the system These could be Elements Ions Compounds

                                                  Eg Au-Cu system Components rarr Au Cu Ice-water system Component rarr H2O

                                                  Al2O3 ndash Cr2O3 system Components rarr Al2O3 Cr2O3

                                                  Component the smallest number of constituent by which the composition of each phase in the system at equilibrium can be expressed in form of chemical formula or equation

                                                  Phase Equilibria amp The Phase RuleComponents of a system

                                                  The number of phases in a system is denoted P

                                                  (a)A gas or a gaseous mixture is a single phase P=1

                                                  (b) For a solid system an alloy of two metals is a two-phase system (P=2) if the metals are immiscible but a single-phase system (P=1) if they are miscible---a homogeneous mixture of the two substances---is uniform on a molecular scale

                                                  (c) For a liquid system according to the solubility to decide whether a system consists of one phase or of two For example a solution of sodium chloride in water is a single phase A pair of liquids that are partially miscible or immiscible is a two-phase system(P=2)

                                                  Oil in water

                                                  Degrees of Freedom = What you can control What the system controls

                                                  F = C + 2 P

                                                  Can control the no of components added and P amp T

                                                  System decided how many phases to produce given the

                                                  conditions

                                                  A way of understanding the Gibbs Phase RuleThe degrees of freedom can be thought of as the difference between what you (can) control and

                                                  what the system controls

                                                  F degree of freedom the least number of intensive variable that must be fixed (known) to describe the system completely

                                                  Degree of freedom (or variance) F is the number of variables (T p andor composition) that can be changed independently without changing the phases of the system

                                                  a) At the triple pointP = 3 (solid liquid and gas)

                                                  C= 1 (water)P + F = C + 2

                                                  F = 0 (no degree of freedom)

                                                  b) liquid-solid curveP = 2

                                                  2+F = 1 + 2F= 1

                                                  One variable (T or P) can be changed

                                                  c) LiquidP =1

                                                  So F =2Two variables (T and P) can be varied independently

                                                  and the system will remains a single phase

                                                  One-component systemsPhase diagram of water

                                                  P (

                                                  atm

                                                  )

                                                  Critical point

                                                  374

                                                  1

                                                  =100=0O--Triple point

                                                  0006

                                                  218

                                                  Curve O -CSublimation

                                                  Deposition

                                                  Curve O-AVaporizationCondensation

                                                  Curve O -BMelting

                                                  Freezing

                                                  F = C P + 2

                                                  F = C P + 2

                                                  Phase Diagram of Carbon Dioxide

                                                  Condensed system System in which the vapor phase is ignored and only the solid andor liquid phases are considered

                                                  Two component system For two component system F can be 3 (3D model is needed) eg T p

                                                  and concentration usually we fix p = 1atm the vapor phase is neglected and F is reduced to 2

                                                  For three component system the pressure and temperature are fixed

                                                  Phenol water phase diagram

                                                  eg for point d (24)

                                                  Two component system containing liquid phase

                                                  Tie Line bc line The line at which the system at equilibrium will separate into phases of constant composition termed lsquoconjugate phasesrsquo

                                                  Lever Rule a way to calculate the proportions of each phase present on a phase diagram in a two phase field (at a given temperature and composition)

                                                  eg for point d (24)

                                                  For every 10 g of liquid system in equilibrium in point d

                                                  75 g phase A25 g phase B

                                                  ExampleMixed 24g phenol +76g water T 50degC

                                                  equilibrium75 g phase A 25 g phase B

                                                  11 phenol 63 phenol

                                                  011 times75 g=825 g phenol

                                                  063 times25 g=1575 g phenol

                                                  water rich phasecontains water+ phenol(11)

                                                  Phenol rich phasecontains Phenol (63)+ water

                                                  The Critical Solution Temperature CST

                                                  Is the maximum temperature at which the 2-phase region exists (or upper consolute temperature)

                                                  In the case of the phenol-water system this is 668oC (point h)

                                                  All combinations of phenol and water gt CST are completely miscible and yield 1-phase liquid systems

                                                  Systems Showing a Decrease in Miscibility with Rise in Temperature

                                                  A few mixtures exhibit a lower critical solution temperature (low CST) eg triethylamine plus water The miscibility with in temperature

                                                  Systems Showing Upper and Lower CSTs

                                                  The miscibility with temp

                                                  a certain temperature miscibility starts to again with further in temperature

                                                  Closed-phase diagram ie nicotine-water system

                                                  A salol B thymol

                                                  53

                                                  Two component system containing solid and liquid phase (Eutectic Mixtures)

                                                  A salol B thymol

                                                  EMLAreg (lidocaine 25 and prilocaine 25) Cream

                                                  EMLA Cream (lidocaine 25 and prilocaine 25) is an emulsion in which the oil phase is a eutectic mixture of lidocaine and prilocaine in a ratio of 11 by weight This eutectic mixture has a melting point below room temperature and therefore both local anesthetics exist as a liquid oil rather than as crystals

                                                  Eutectic mixture Pharmaceutical Application

                                                  Triangular Diagrams for three ndash component systems

                                                  Three component system

                                                  Birzeit University Physical Pharmacy PHAR 323 Dr Hani Shtaya

                                                  1 Binding Forces Between Molecules2 Repulsive and Attractive Forces3 The Gaseous State The Ideal Gas Law Liquefaction of Gases Aerosols4 Solids and the Crystalline State Crystalline Solids Polymorphism Solvates Amorphous Solids5 Phase Equilibria and the Phase Rule Phase Rule Systems Containing One Component Condensed System Two-Component Systems Containing Liquid Phases Two-Component Systems Containing Solid and Liquid Phases Eutectic Mixtures Rules Relating to Triangular Diagrams

                                                  Topics that we have covered

                                                  • States of Matter
                                                  • States of Matter (2)
                                                  • Objectives of the lecture
                                                  • Comparison of Gases Liquids and Solids
                                                  • Slide 5
                                                  • Repulsive and Attractive Forces
                                                  • Ideal Gas Equation
                                                  • Gaseous state
                                                  • Slide 9
                                                  • Gaseous state (2)
                                                  • Liquefaction of Gases
                                                  • Slide 12
                                                  • SOLIDS amp CRYSTALLINE STATE Pharmaceutical Drugs more than 80
                                                  • Solids and the crystalline state
                                                  • Classification of Solids
                                                  • Slide 16
                                                  • Slide 17
                                                  • Crystal forms
                                                  • Types of Crystals
                                                  • Slide 20
                                                  • Slide 21
                                                  • Polymorphism
                                                  • Slide 23
                                                  • Slide 24
                                                  • Slide 25
                                                  • Slide 26
                                                  • Cocrystal
                                                  • Principle of polymorphism
                                                  • Solvates
                                                  • Polymorphism (2)
                                                  • Amorphous Solid
                                                  • Amorphous or crystalline amp therapeutic activity
                                                  • Slide 33
                                                  • Slide 34
                                                  • Polymorphism and Industry Pharmaceutical
                                                  • Celecoxib
                                                  • Furosemide
                                                  • Bioavailability
                                                  • Slide 39
                                                  • Slide 40
                                                  • Bioequivalence
                                                  • Slide 42
                                                  • Carbamazepine
                                                  • Slide 44
                                                  • AIDS drug ritonavir
                                                  • Slide 46
                                                  • Slide 47
                                                  • Phase Equilibria amp The Phase Rule
                                                  • Phase diagram ndash Water
                                                  • Phase Equilibria amp The Phase Rule Definitions
                                                  • Phase Definition
                                                  • Examples
                                                  • Components
                                                  • Examples
                                                  • Slide 55
                                                  • Degrees of freedom (or variance)
                                                  • Examples (2)
                                                  • Phase Equilibria amp The Phase Rule
                                                  • The phase rule
                                                  • Slide 60
                                                  • Phase Equilibria amp The Phase Rule (2)
                                                  • The number of phases in a system is denoted P
                                                  • Slide 63
                                                  • Slide 64
                                                  • One-component systems
                                                  • Slide 66
                                                  • Slide 67
                                                  • Slide 68
                                                  • Slide 69
                                                  • Slide 70
                                                  • Two component system containing liquid phase
                                                  • Slide 72
                                                  • The Critical Solution Temperature CST
                                                  • Systems Showing a Decrease in Miscibility with Rise in Temperat
                                                  • Systems Showing Upper and Lower CSTs
                                                  • Two component system containing solid and liquid phase (Eutecti
                                                  • Slide 77
                                                  • Eutectic mixture Pharmaceutical Application
                                                  • Three component system
                                                  • Slide 80
                                                  • Topics that we have covered

                                                    Solvates

                                                    Pharmaceutical synthesis include purification and crystallization residual solvent can be trapped in the lattice

                                                    This result in the formation of cocrystal or solvate

                                                    The presence of residual solvent may affect dramatically the crystalline structure of the solid depending on the type of inter molecular forces that the solvent may have with crystalline solid

                                                    Melting pointVapor pressureHardnessOptical electrical magnetic

                                                    propertiesColorIR spectraNMR spectra

                                                    Photochemical reactivityThermal stabilityFiltration and drying characteristicsDissolution rateBioavailabilityPhysical and chemical stability

                                                    Solubility and melting point are very important in pharmaceutical processes including dissolution and

                                                    formulation

                                                    Polymorphism

                                                    AMORPHOUS SOLIDS Solids that donrsquot have a definite geometrical shape are known as Amorphous Solids1 In these solids particles are randomly arranged in three dimension2 They donrsquot have sharp melting points3 Amorphous solids are formed due to sudden cooling of liquid4 Amorphous solids melt over a wide range of temperature

                                                    Amorphous Solid

                                                    An amorphous solid does not possess a well-defined arrangement and long-range molecular order

                                                    Amorphous substances as well as cubic crystal are isotropic that is they exhibit similar properties in all direction

                                                    The crystalline from of the antibiotic novobiocin acid is poorly absorbed and has no activity where the amorphous form is readily absorbed and therapeutically active due to different dissolution rate

                                                    Amorphous or crystalline amp therapeutic activity

                                                    General crystallization conditions 1048698Solvents ndashdifferent polarities 1048698Concentration of the solutions (super saturated saturated diluted) 1048698Cooling speed (quenching slow) 1048698Temperature (room or lower than room temperature)

                                                    Crystallization

                                                    Final Form

                                                    Granulation

                                                    Drying

                                                    Compaction

                                                    Tableting

                                                    Drug Product

                                                    API

                                                    Crystallization

                                                    Filtration

                                                    Drying

                                                    Milling

                                                    Bulk API

                                                    Stability

                                                    Polymorphism and Industry Pharmaceutical

                                                    Polymorphism and Industry Pharmaceutical

                                                    Fluoxetine HCl the active ingredient in the antidepressant drug Prozac

                                                    co crystal which will have increased solubility compared to the crystalline form

                                                    Celecoxib

                                                    CELECOXIB is a nonsteroidal anti-inflammatory drug

                                                    However it was found that the higher bioavailability was shown by the amorphous state

                                                    The downfall of the amorphous state was its stability

                                                    This was due to the structural relaxation

                                                    This was enhanced by mixing it with polymers like PVP which helped in stabilizing the amorphous system (Piyush Gupta et al 2004 Piyush Gupta et al 2005)

                                                    A new solid state form was developed by Pharmacia

                                                    FurosemideTwo forms with significantly differing aqueous solubility and dissolution rateOral bioavailability compromised

                                                    Giron lists gt20 excipients that display polymorphism includingndash Lactose (anhydrous also monohydrate)ndash Aspartame (anhydrous hydrate forms)ndash Magnesium stearate (can affect lubrication of tablets)

                                                    Bioavailability

                                                    The rate and extent to which the active ingredient or active moiety is absorbed from a drug product and becomes available at the site of action

                                                    Bioequivalence

                                                    The absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study

                                                    Carbamazepine

                                                    CHLORPROPAMIDEat least six polymorphic white or almost white crystalline powder It exhibits polymorphism Practically insoluble in water soluble in alcohol freely soluble in acetone and in dichlo-romethane dissolves in dilute solutions of alkali hydroxides Protect from light

                                                    blood-glucose-lowering drug

                                                    AIDS drug ritonavir

                                                    Theobroma oil (cacao butter ) is a polymorphic natural fat

                                                    Theobroma oil can exist in 4 different polymorphic forms of which only one is Stabile

                                                    1 Unstable gamma form melting at 18degC2 Alpha form melting at 22degC3 Beta prime form melting at 28degC4 Stable beta form melting at 345degC

                                                    This is important in the preparation of theobroma suppositories

                                                    If the oil is heated to a point where it is completely liquified (about 35 C) the crystals of the stable polymorph are destroyed amp the mass does not crystallize until it is cooled to 15 C

                                                    The crystals that form are unstable amp the suppositories melt at 24 C

                                                    Theobroma suppositories must be prepared below 33 C

                                                    Polymorphism and Industry Pharmaceutical

                                                    Polymorphism and Industry Pharmaceutical

                                                    Anhydrates together with salts form the majority of all drug formulationsAbout a half of all APIs used today are saltsSalts are stable and well soluble in polar solvents (first of all in water) because they contain ionic bondThere is one more essential advantage of salts ndash their solubility is a function of pH Since pH in the gastrointestinal tract (GIT) vary between 1-75

                                                    atorvastatin calcium trihydrateEach tablet contains Atorvastatin Calcium Trihydrate equivalent to Atorvastatin 20 mg

                                                    Phase Equilibria amp The Phase Rule

                                                    Phase diagram ndash Water

                                                    Phase Equilibrium A stable phase structure with lowest free-energy (internal energy) of a system and also randomness or disorder of the atoms or molecules (entropy)

                                                    Any change in Temperature Composition and Pressure causes an increase in free energy and away from Equilibrium thus forcing a move to another lsquostatersquo

                                                    Phase Equilibria amp The Phase Rule Definitions

                                                    A phase is defined as any homogeneous and physically distinct part of a system which is separated from other parts of the system by interfaces

                                                    A part of a system is homogeneous if it has identical physical properties and chemical composition throughout the part

                                                    A phase may be gas liquid or solid A gas or a gaseous mixture is a single phase Totally miscible liquids constitute a single phase In an immiscible liquid system each layer is counted as a separate phase Every solid constitutes a single phase except when a solid solution is formed A solid solution is considered as a single phase Each polymorphic form constitutes a separate phase

                                                    Phase Definition

                                                    1 Liquid water pieces of ice and water vapour are present together The number of phases is 3 as each form is a separate phase Ice in the system is a single phase even if it is present as a number of pieces

                                                    2 Calcium carbonate undergoes thermal decomposition The chemical reaction is CaCO3(s) CaO(s) + CO2 (g) Number of phases = 3 This system consists of 2 solid phases CaCO3 and CaO and one gaseous phase that of CO2

                                                    3 Ammonium chloride undergoes thermal decomposition The chemical reaction is NH4Cl(s) NH3 (g) + HCl (g) Number of phases = 2 This system has two phases one solid NH4Cl and one gaseous a mixture of NH3 and HCl

                                                    4 A solution of NaCl in water Number of phases = 1

                                                    bull Examples

                                                    The number of components of a system at equilibrium is the smallest number of independently varying chemical constituents using which the composition of each and every phase in the system can be expressed

                                                    Components

                                                    Counting the number of components 1 The sulphur system is a one component system All the phases

                                                    monoclinic rhombic liquid and vapour ndash can be expressed in terms of the single constituent ndash sulphur

                                                    2 A mixture of ethanol and water is an example of a two component system We need both ethanol and water to express its composition

                                                    bull Examples

                                                    An example of a system in which a reaction occurs and an equilibrium is established is the thermal decomposition of solid CaCO3

                                                    In this system there are three distinct phasesSolid CaCO3

                                                    Solid CaOGaseous CO2

                                                    Though there are 3 species present the number of components is only two because of the equilibrium CaCO3 (s) CaO(s) + CO2(g)

                                                    Any two of the three constituents may be chosen as the components

                                                    If CaO and CO2 are chosen then the composition of the phase CaCO3 is expressed as one mole of component CO2 plus one mole of component CaO

                                                    If on the other hand CaCO3 and CO2 were chosen then the composition of the phase CaO would be described as one mole of CaCO3 minus one mole of CO2

                                                    The degrees of freedom or variance of a system is defined as the minimum number of variables such as

                                                    temperaturepressureconcentrationwhich must be fixed in order to define the system completely

                                                    Degrees of freedom (or variance)

                                                    F = C P + 2

                                                    1 A gaseous mixture of CO2 and N2 Three variables pressure temperature and composition are required to define this system This is hence a trivariant system

                                                    2 A system having only liquid water has two degrees of freedom or is bivariant Both temperature and pressure need to be mentioned in order to define the system

                                                    3 If to the system containing liquid water pieces of ice are added and this system with 2 phases is allowed to come to equilibrium then it is an univariant system

                                                    Only one variable either temperature or pressure need to be specified in order to define the systemIf the pressure on the system is maintained at 1 atm then the temperature of the system gets automatically fixed at 0oC the normal melting point of ice

                                                    bull Examples

                                                    Phase Equilibria amp The Phase Rule

                                                    A phase diagram (Equilibrium Phase Diagram) summarizes the conditions at which a substance exists as a solid liquid or gas

                                                    OR It is a ldquomaprdquo of the information about the control of phase structure of a particular material system

                                                    The relationships between temperature and the compositions and the quantities of phases present at equilibrium are represented

                                                    F = C P + 2The phase rule

                                                    The phase rule JW Gibbs formulated the phase rule which is a general relation

                                                    between the variance F the number of component C and the number of phases P at equilibrium for a system of any composition

                                                    For a system in equilibrium

                                                    F degree of freedom the least number of intensive variable that must be fixed (known) to describe the system completely

                                                    Phase Rule relation to determine the least number of intensive variable that can be changed without changing the equilibrium state of the system or alternately

                                                    The least number required to define the state of the system which is called degree of freedom F

                                                    Intensive variable independent variable that do not depend on the volume or the size egTemp pressure

                                                    Independent chemical species which comprise the system These could be Elements Ions Compounds

                                                    Eg Au-Cu system Components rarr Au Cu Ice-water system Component rarr H2O

                                                    Al2O3 ndash Cr2O3 system Components rarr Al2O3 Cr2O3

                                                    Component the smallest number of constituent by which the composition of each phase in the system at equilibrium can be expressed in form of chemical formula or equation

                                                    Phase Equilibria amp The Phase RuleComponents of a system

                                                    The number of phases in a system is denoted P

                                                    (a)A gas or a gaseous mixture is a single phase P=1

                                                    (b) For a solid system an alloy of two metals is a two-phase system (P=2) if the metals are immiscible but a single-phase system (P=1) if they are miscible---a homogeneous mixture of the two substances---is uniform on a molecular scale

                                                    (c) For a liquid system according to the solubility to decide whether a system consists of one phase or of two For example a solution of sodium chloride in water is a single phase A pair of liquids that are partially miscible or immiscible is a two-phase system(P=2)

                                                    Oil in water

                                                    Degrees of Freedom = What you can control What the system controls

                                                    F = C + 2 P

                                                    Can control the no of components added and P amp T

                                                    System decided how many phases to produce given the

                                                    conditions

                                                    A way of understanding the Gibbs Phase RuleThe degrees of freedom can be thought of as the difference between what you (can) control and

                                                    what the system controls

                                                    F degree of freedom the least number of intensive variable that must be fixed (known) to describe the system completely

                                                    Degree of freedom (or variance) F is the number of variables (T p andor composition) that can be changed independently without changing the phases of the system

                                                    a) At the triple pointP = 3 (solid liquid and gas)

                                                    C= 1 (water)P + F = C + 2

                                                    F = 0 (no degree of freedom)

                                                    b) liquid-solid curveP = 2

                                                    2+F = 1 + 2F= 1

                                                    One variable (T or P) can be changed

                                                    c) LiquidP =1

                                                    So F =2Two variables (T and P) can be varied independently

                                                    and the system will remains a single phase

                                                    One-component systemsPhase diagram of water

                                                    P (

                                                    atm

                                                    )

                                                    Critical point

                                                    374

                                                    1

                                                    =100=0O--Triple point

                                                    0006

                                                    218

                                                    Curve O -CSublimation

                                                    Deposition

                                                    Curve O-AVaporizationCondensation

                                                    Curve O -BMelting

                                                    Freezing

                                                    F = C P + 2

                                                    F = C P + 2

                                                    Phase Diagram of Carbon Dioxide

                                                    Condensed system System in which the vapor phase is ignored and only the solid andor liquid phases are considered

                                                    Two component system For two component system F can be 3 (3D model is needed) eg T p

                                                    and concentration usually we fix p = 1atm the vapor phase is neglected and F is reduced to 2

                                                    For three component system the pressure and temperature are fixed

                                                    Phenol water phase diagram

                                                    eg for point d (24)

                                                    Two component system containing liquid phase

                                                    Tie Line bc line The line at which the system at equilibrium will separate into phases of constant composition termed lsquoconjugate phasesrsquo

                                                    Lever Rule a way to calculate the proportions of each phase present on a phase diagram in a two phase field (at a given temperature and composition)

                                                    eg for point d (24)

                                                    For every 10 g of liquid system in equilibrium in point d

                                                    75 g phase A25 g phase B

                                                    ExampleMixed 24g phenol +76g water T 50degC

                                                    equilibrium75 g phase A 25 g phase B

                                                    11 phenol 63 phenol

                                                    011 times75 g=825 g phenol

                                                    063 times25 g=1575 g phenol

                                                    water rich phasecontains water+ phenol(11)

                                                    Phenol rich phasecontains Phenol (63)+ water

                                                    The Critical Solution Temperature CST

                                                    Is the maximum temperature at which the 2-phase region exists (or upper consolute temperature)

                                                    In the case of the phenol-water system this is 668oC (point h)

                                                    All combinations of phenol and water gt CST are completely miscible and yield 1-phase liquid systems

                                                    Systems Showing a Decrease in Miscibility with Rise in Temperature

                                                    A few mixtures exhibit a lower critical solution temperature (low CST) eg triethylamine plus water The miscibility with in temperature

                                                    Systems Showing Upper and Lower CSTs

                                                    The miscibility with temp

                                                    a certain temperature miscibility starts to again with further in temperature

                                                    Closed-phase diagram ie nicotine-water system

                                                    A salol B thymol

                                                    53

                                                    Two component system containing solid and liquid phase (Eutectic Mixtures)

                                                    A salol B thymol

                                                    EMLAreg (lidocaine 25 and prilocaine 25) Cream

                                                    EMLA Cream (lidocaine 25 and prilocaine 25) is an emulsion in which the oil phase is a eutectic mixture of lidocaine and prilocaine in a ratio of 11 by weight This eutectic mixture has a melting point below room temperature and therefore both local anesthetics exist as a liquid oil rather than as crystals

                                                    Eutectic mixture Pharmaceutical Application

                                                    Triangular Diagrams for three ndash component systems

                                                    Three component system

                                                    Birzeit University Physical Pharmacy PHAR 323 Dr Hani Shtaya

                                                    1 Binding Forces Between Molecules2 Repulsive and Attractive Forces3 The Gaseous State The Ideal Gas Law Liquefaction of Gases Aerosols4 Solids and the Crystalline State Crystalline Solids Polymorphism Solvates Amorphous Solids5 Phase Equilibria and the Phase Rule Phase Rule Systems Containing One Component Condensed System Two-Component Systems Containing Liquid Phases Two-Component Systems Containing Solid and Liquid Phases Eutectic Mixtures Rules Relating to Triangular Diagrams

                                                    Topics that we have covered

                                                    • States of Matter
                                                    • States of Matter (2)
                                                    • Objectives of the lecture
                                                    • Comparison of Gases Liquids and Solids
                                                    • Slide 5
                                                    • Repulsive and Attractive Forces
                                                    • Ideal Gas Equation
                                                    • Gaseous state
                                                    • Slide 9
                                                    • Gaseous state (2)
                                                    • Liquefaction of Gases
                                                    • Slide 12
                                                    • SOLIDS amp CRYSTALLINE STATE Pharmaceutical Drugs more than 80
                                                    • Solids and the crystalline state
                                                    • Classification of Solids
                                                    • Slide 16
                                                    • Slide 17
                                                    • Crystal forms
                                                    • Types of Crystals
                                                    • Slide 20
                                                    • Slide 21
                                                    • Polymorphism
                                                    • Slide 23
                                                    • Slide 24
                                                    • Slide 25
                                                    • Slide 26
                                                    • Cocrystal
                                                    • Principle of polymorphism
                                                    • Solvates
                                                    • Polymorphism (2)
                                                    • Amorphous Solid
                                                    • Amorphous or crystalline amp therapeutic activity
                                                    • Slide 33
                                                    • Slide 34
                                                    • Polymorphism and Industry Pharmaceutical
                                                    • Celecoxib
                                                    • Furosemide
                                                    • Bioavailability
                                                    • Slide 39
                                                    • Slide 40
                                                    • Bioequivalence
                                                    • Slide 42
                                                    • Carbamazepine
                                                    • Slide 44
                                                    • AIDS drug ritonavir
                                                    • Slide 46
                                                    • Slide 47
                                                    • Phase Equilibria amp The Phase Rule
                                                    • Phase diagram ndash Water
                                                    • Phase Equilibria amp The Phase Rule Definitions
                                                    • Phase Definition
                                                    • Examples
                                                    • Components
                                                    • Examples
                                                    • Slide 55
                                                    • Degrees of freedom (or variance)
                                                    • Examples (2)
                                                    • Phase Equilibria amp The Phase Rule
                                                    • The phase rule
                                                    • Slide 60
                                                    • Phase Equilibria amp The Phase Rule (2)
                                                    • The number of phases in a system is denoted P
                                                    • Slide 63
                                                    • Slide 64
                                                    • One-component systems
                                                    • Slide 66
                                                    • Slide 67
                                                    • Slide 68
                                                    • Slide 69
                                                    • Slide 70
                                                    • Two component system containing liquid phase
                                                    • Slide 72
                                                    • The Critical Solution Temperature CST
                                                    • Systems Showing a Decrease in Miscibility with Rise in Temperat
                                                    • Systems Showing Upper and Lower CSTs
                                                    • Two component system containing solid and liquid phase (Eutecti
                                                    • Slide 77
                                                    • Eutectic mixture Pharmaceutical Application
                                                    • Three component system
                                                    • Slide 80
                                                    • Topics that we have covered

                                                      Melting pointVapor pressureHardnessOptical electrical magnetic

                                                      propertiesColorIR spectraNMR spectra

                                                      Photochemical reactivityThermal stabilityFiltration and drying characteristicsDissolution rateBioavailabilityPhysical and chemical stability

                                                      Solubility and melting point are very important in pharmaceutical processes including dissolution and

                                                      formulation

                                                      Polymorphism

                                                      AMORPHOUS SOLIDS Solids that donrsquot have a definite geometrical shape are known as Amorphous Solids1 In these solids particles are randomly arranged in three dimension2 They donrsquot have sharp melting points3 Amorphous solids are formed due to sudden cooling of liquid4 Amorphous solids melt over a wide range of temperature

                                                      Amorphous Solid

                                                      An amorphous solid does not possess a well-defined arrangement and long-range molecular order

                                                      Amorphous substances as well as cubic crystal are isotropic that is they exhibit similar properties in all direction

                                                      The crystalline from of the antibiotic novobiocin acid is poorly absorbed and has no activity where the amorphous form is readily absorbed and therapeutically active due to different dissolution rate

                                                      Amorphous or crystalline amp therapeutic activity

                                                      General crystallization conditions 1048698Solvents ndashdifferent polarities 1048698Concentration of the solutions (super saturated saturated diluted) 1048698Cooling speed (quenching slow) 1048698Temperature (room or lower than room temperature)

                                                      Crystallization

                                                      Final Form

                                                      Granulation

                                                      Drying

                                                      Compaction

                                                      Tableting

                                                      Drug Product

                                                      API

                                                      Crystallization

                                                      Filtration

                                                      Drying

                                                      Milling

                                                      Bulk API

                                                      Stability

                                                      Polymorphism and Industry Pharmaceutical

                                                      Polymorphism and Industry Pharmaceutical

                                                      Fluoxetine HCl the active ingredient in the antidepressant drug Prozac

                                                      co crystal which will have increased solubility compared to the crystalline form

                                                      Celecoxib

                                                      CELECOXIB is a nonsteroidal anti-inflammatory drug

                                                      However it was found that the higher bioavailability was shown by the amorphous state

                                                      The downfall of the amorphous state was its stability

                                                      This was due to the structural relaxation

                                                      This was enhanced by mixing it with polymers like PVP which helped in stabilizing the amorphous system (Piyush Gupta et al 2004 Piyush Gupta et al 2005)

                                                      A new solid state form was developed by Pharmacia

                                                      FurosemideTwo forms with significantly differing aqueous solubility and dissolution rateOral bioavailability compromised

                                                      Giron lists gt20 excipients that display polymorphism includingndash Lactose (anhydrous also monohydrate)ndash Aspartame (anhydrous hydrate forms)ndash Magnesium stearate (can affect lubrication of tablets)

                                                      Bioavailability

                                                      The rate and extent to which the active ingredient or active moiety is absorbed from a drug product and becomes available at the site of action

                                                      Bioequivalence

                                                      The absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study

                                                      Carbamazepine

                                                      CHLORPROPAMIDEat least six polymorphic white or almost white crystalline powder It exhibits polymorphism Practically insoluble in water soluble in alcohol freely soluble in acetone and in dichlo-romethane dissolves in dilute solutions of alkali hydroxides Protect from light

                                                      blood-glucose-lowering drug

                                                      AIDS drug ritonavir

                                                      Theobroma oil (cacao butter ) is a polymorphic natural fat

                                                      Theobroma oil can exist in 4 different polymorphic forms of which only one is Stabile

                                                      1 Unstable gamma form melting at 18degC2 Alpha form melting at 22degC3 Beta prime form melting at 28degC4 Stable beta form melting at 345degC

                                                      This is important in the preparation of theobroma suppositories

                                                      If the oil is heated to a point where it is completely liquified (about 35 C) the crystals of the stable polymorph are destroyed amp the mass does not crystallize until it is cooled to 15 C

                                                      The crystals that form are unstable amp the suppositories melt at 24 C

                                                      Theobroma suppositories must be prepared below 33 C

                                                      Polymorphism and Industry Pharmaceutical

                                                      Polymorphism and Industry Pharmaceutical

                                                      Anhydrates together with salts form the majority of all drug formulationsAbout a half of all APIs used today are saltsSalts are stable and well soluble in polar solvents (first of all in water) because they contain ionic bondThere is one more essential advantage of salts ndash their solubility is a function of pH Since pH in the gastrointestinal tract (GIT) vary between 1-75

                                                      atorvastatin calcium trihydrateEach tablet contains Atorvastatin Calcium Trihydrate equivalent to Atorvastatin 20 mg

                                                      Phase Equilibria amp The Phase Rule

                                                      Phase diagram ndash Water

                                                      Phase Equilibrium A stable phase structure with lowest free-energy (internal energy) of a system and also randomness or disorder of the atoms or molecules (entropy)

                                                      Any change in Temperature Composition and Pressure causes an increase in free energy and away from Equilibrium thus forcing a move to another lsquostatersquo

                                                      Phase Equilibria amp The Phase Rule Definitions

                                                      A phase is defined as any homogeneous and physically distinct part of a system which is separated from other parts of the system by interfaces

                                                      A part of a system is homogeneous if it has identical physical properties and chemical composition throughout the part

                                                      A phase may be gas liquid or solid A gas or a gaseous mixture is a single phase Totally miscible liquids constitute a single phase In an immiscible liquid system each layer is counted as a separate phase Every solid constitutes a single phase except when a solid solution is formed A solid solution is considered as a single phase Each polymorphic form constitutes a separate phase

                                                      Phase Definition

                                                      1 Liquid water pieces of ice and water vapour are present together The number of phases is 3 as each form is a separate phase Ice in the system is a single phase even if it is present as a number of pieces

                                                      2 Calcium carbonate undergoes thermal decomposition The chemical reaction is CaCO3(s) CaO(s) + CO2 (g) Number of phases = 3 This system consists of 2 solid phases CaCO3 and CaO and one gaseous phase that of CO2

                                                      3 Ammonium chloride undergoes thermal decomposition The chemical reaction is NH4Cl(s) NH3 (g) + HCl (g) Number of phases = 2 This system has two phases one solid NH4Cl and one gaseous a mixture of NH3 and HCl

                                                      4 A solution of NaCl in water Number of phases = 1

                                                      bull Examples

                                                      The number of components of a system at equilibrium is the smallest number of independently varying chemical constituents using which the composition of each and every phase in the system can be expressed

                                                      Components

                                                      Counting the number of components 1 The sulphur system is a one component system All the phases

                                                      monoclinic rhombic liquid and vapour ndash can be expressed in terms of the single constituent ndash sulphur

                                                      2 A mixture of ethanol and water is an example of a two component system We need both ethanol and water to express its composition

                                                      bull Examples

                                                      An example of a system in which a reaction occurs and an equilibrium is established is the thermal decomposition of solid CaCO3

                                                      In this system there are three distinct phasesSolid CaCO3

                                                      Solid CaOGaseous CO2

                                                      Though there are 3 species present the number of components is only two because of the equilibrium CaCO3 (s) CaO(s) + CO2(g)

                                                      Any two of the three constituents may be chosen as the components

                                                      If CaO and CO2 are chosen then the composition of the phase CaCO3 is expressed as one mole of component CO2 plus one mole of component CaO

                                                      If on the other hand CaCO3 and CO2 were chosen then the composition of the phase CaO would be described as one mole of CaCO3 minus one mole of CO2

                                                      The degrees of freedom or variance of a system is defined as the minimum number of variables such as

                                                      temperaturepressureconcentrationwhich must be fixed in order to define the system completely

                                                      Degrees of freedom (or variance)

                                                      F = C P + 2

                                                      1 A gaseous mixture of CO2 and N2 Three variables pressure temperature and composition are required to define this system This is hence a trivariant system

                                                      2 A system having only liquid water has two degrees of freedom or is bivariant Both temperature and pressure need to be mentioned in order to define the system

                                                      3 If to the system containing liquid water pieces of ice are added and this system with 2 phases is allowed to come to equilibrium then it is an univariant system

                                                      Only one variable either temperature or pressure need to be specified in order to define the systemIf the pressure on the system is maintained at 1 atm then the temperature of the system gets automatically fixed at 0oC the normal melting point of ice

                                                      bull Examples

                                                      Phase Equilibria amp The Phase Rule

                                                      A phase diagram (Equilibrium Phase Diagram) summarizes the conditions at which a substance exists as a solid liquid or gas

                                                      OR It is a ldquomaprdquo of the information about the control of phase structure of a particular material system

                                                      The relationships between temperature and the compositions and the quantities of phases present at equilibrium are represented

                                                      F = C P + 2The phase rule

                                                      The phase rule JW Gibbs formulated the phase rule which is a general relation

                                                      between the variance F the number of component C and the number of phases P at equilibrium for a system of any composition

                                                      For a system in equilibrium

                                                      F degree of freedom the least number of intensive variable that must be fixed (known) to describe the system completely

                                                      Phase Rule relation to determine the least number of intensive variable that can be changed without changing the equilibrium state of the system or alternately

                                                      The least number required to define the state of the system which is called degree of freedom F

                                                      Intensive variable independent variable that do not depend on the volume or the size egTemp pressure

                                                      Independent chemical species which comprise the system These could be Elements Ions Compounds

                                                      Eg Au-Cu system Components rarr Au Cu Ice-water system Component rarr H2O

                                                      Al2O3 ndash Cr2O3 system Components rarr Al2O3 Cr2O3

                                                      Component the smallest number of constituent by which the composition of each phase in the system at equilibrium can be expressed in form of chemical formula or equation

                                                      Phase Equilibria amp The Phase RuleComponents of a system

                                                      The number of phases in a system is denoted P

                                                      (a)A gas or a gaseous mixture is a single phase P=1

                                                      (b) For a solid system an alloy of two metals is a two-phase system (P=2) if the metals are immiscible but a single-phase system (P=1) if they are miscible---a homogeneous mixture of the two substances---is uniform on a molecular scale

                                                      (c) For a liquid system according to the solubility to decide whether a system consists of one phase or of two For example a solution of sodium chloride in water is a single phase A pair of liquids that are partially miscible or immiscible is a two-phase system(P=2)

                                                      Oil in water

                                                      Degrees of Freedom = What you can control What the system controls

                                                      F = C + 2 P

                                                      Can control the no of components added and P amp T

                                                      System decided how many phases to produce given the

                                                      conditions

                                                      A way of understanding the Gibbs Phase RuleThe degrees of freedom can be thought of as the difference between what you (can) control and

                                                      what the system controls

                                                      F degree of freedom the least number of intensive variable that must be fixed (known) to describe the system completely

                                                      Degree of freedom (or variance) F is the number of variables (T p andor composition) that can be changed independently without changing the phases of the system

                                                      a) At the triple pointP = 3 (solid liquid and gas)

                                                      C= 1 (water)P + F = C + 2

                                                      F = 0 (no degree of freedom)

                                                      b) liquid-solid curveP = 2

                                                      2+F = 1 + 2F= 1

                                                      One variable (T or P) can be changed

                                                      c) LiquidP =1

                                                      So F =2Two variables (T and P) can be varied independently

                                                      and the system will remains a single phase

                                                      One-component systemsPhase diagram of water

                                                      P (

                                                      atm

                                                      )

                                                      Critical point

                                                      374

                                                      1

                                                      =100=0O--Triple point

                                                      0006

                                                      218

                                                      Curve O -CSublimation

                                                      Deposition

                                                      Curve O-AVaporizationCondensation

                                                      Curve O -BMelting

                                                      Freezing

                                                      F = C P + 2

                                                      F = C P + 2

                                                      Phase Diagram of Carbon Dioxide

                                                      Condensed system System in which the vapor phase is ignored and only the solid andor liquid phases are considered

                                                      Two component system For two component system F can be 3 (3D model is needed) eg T p

                                                      and concentration usually we fix p = 1atm the vapor phase is neglected and F is reduced to 2

                                                      For three component system the pressure and temperature are fixed

                                                      Phenol water phase diagram

                                                      eg for point d (24)

                                                      Two component system containing liquid phase

                                                      Tie Line bc line The line at which the system at equilibrium will separate into phases of constant composition termed lsquoconjugate phasesrsquo

                                                      Lever Rule a way to calculate the proportions of each phase present on a phase diagram in a two phase field (at a given temperature and composition)

                                                      eg for point d (24)

                                                      For every 10 g of liquid system in equilibrium in point d

                                                      75 g phase A25 g phase B

                                                      ExampleMixed 24g phenol +76g water T 50degC

                                                      equilibrium75 g phase A 25 g phase B

                                                      11 phenol 63 phenol

                                                      011 times75 g=825 g phenol

                                                      063 times25 g=1575 g phenol

                                                      water rich phasecontains water+ phenol(11)

                                                      Phenol rich phasecontains Phenol (63)+ water

                                                      The Critical Solution Temperature CST

                                                      Is the maximum temperature at which the 2-phase region exists (or upper consolute temperature)

                                                      In the case of the phenol-water system this is 668oC (point h)

                                                      All combinations of phenol and water gt CST are completely miscible and yield 1-phase liquid systems

                                                      Systems Showing a Decrease in Miscibility with Rise in Temperature

                                                      A few mixtures exhibit a lower critical solution temperature (low CST) eg triethylamine plus water The miscibility with in temperature

                                                      Systems Showing Upper and Lower CSTs

                                                      The miscibility with temp

                                                      a certain temperature miscibility starts to again with further in temperature

                                                      Closed-phase diagram ie nicotine-water system

                                                      A salol B thymol

                                                      53

                                                      Two component system containing solid and liquid phase (Eutectic Mixtures)

                                                      A salol B thymol

                                                      EMLAreg (lidocaine 25 and prilocaine 25) Cream

                                                      EMLA Cream (lidocaine 25 and prilocaine 25) is an emulsion in which the oil phase is a eutectic mixture of lidocaine and prilocaine in a ratio of 11 by weight This eutectic mixture has a melting point below room temperature and therefore both local anesthetics exist as a liquid oil rather than as crystals

                                                      Eutectic mixture Pharmaceutical Application

                                                      Triangular Diagrams for three ndash component systems

                                                      Three component system

                                                      Birzeit University Physical Pharmacy PHAR 323 Dr Hani Shtaya

                                                      1 Binding Forces Between Molecules2 Repulsive and Attractive Forces3 The Gaseous State The Ideal Gas Law Liquefaction of Gases Aerosols4 Solids and the Crystalline State Crystalline Solids Polymorphism Solvates Amorphous Solids5 Phase Equilibria and the Phase Rule Phase Rule Systems Containing One Component Condensed System Two-Component Systems Containing Liquid Phases Two-Component Systems Containing Solid and Liquid Phases Eutectic Mixtures Rules Relating to Triangular Diagrams

                                                      Topics that we have covered

                                                      • States of Matter
                                                      • States of Matter (2)
                                                      • Objectives of the lecture
                                                      • Comparison of Gases Liquids and Solids
                                                      • Slide 5
                                                      • Repulsive and Attractive Forces
                                                      • Ideal Gas Equation
                                                      • Gaseous state
                                                      • Slide 9
                                                      • Gaseous state (2)
                                                      • Liquefaction of Gases
                                                      • Slide 12
                                                      • SOLIDS amp CRYSTALLINE STATE Pharmaceutical Drugs more than 80
                                                      • Solids and the crystalline state
                                                      • Classification of Solids
                                                      • Slide 16
                                                      • Slide 17
                                                      • Crystal forms
                                                      • Types of Crystals
                                                      • Slide 20
                                                      • Slide 21
                                                      • Polymorphism
                                                      • Slide 23
                                                      • Slide 24
                                                      • Slide 25
                                                      • Slide 26
                                                      • Cocrystal
                                                      • Principle of polymorphism
                                                      • Solvates
                                                      • Polymorphism (2)
                                                      • Amorphous Solid
                                                      • Amorphous or crystalline amp therapeutic activity
                                                      • Slide 33
                                                      • Slide 34
                                                      • Polymorphism and Industry Pharmaceutical
                                                      • Celecoxib
                                                      • Furosemide
                                                      • Bioavailability
                                                      • Slide 39
                                                      • Slide 40
                                                      • Bioequivalence
                                                      • Slide 42
                                                      • Carbamazepine
                                                      • Slide 44
                                                      • AIDS drug ritonavir
                                                      • Slide 46
                                                      • Slide 47
                                                      • Phase Equilibria amp The Phase Rule
                                                      • Phase diagram ndash Water
                                                      • Phase Equilibria amp The Phase Rule Definitions
                                                      • Phase Definition
                                                      • Examples
                                                      • Components
                                                      • Examples
                                                      • Slide 55
                                                      • Degrees of freedom (or variance)
                                                      • Examples (2)
                                                      • Phase Equilibria amp The Phase Rule
                                                      • The phase rule
                                                      • Slide 60
                                                      • Phase Equilibria amp The Phase Rule (2)
                                                      • The number of phases in a system is denoted P
                                                      • Slide 63
                                                      • Slide 64
                                                      • One-component systems
                                                      • Slide 66
                                                      • Slide 67
                                                      • Slide 68
                                                      • Slide 69
                                                      • Slide 70
                                                      • Two component system containing liquid phase
                                                      • Slide 72
                                                      • The Critical Solution Temperature CST
                                                      • Systems Showing a Decrease in Miscibility with Rise in Temperat
                                                      • Systems Showing Upper and Lower CSTs
                                                      • Two component system containing solid and liquid phase (Eutecti
                                                      • Slide 77
                                                      • Eutectic mixture Pharmaceutical Application
                                                      • Three component system
                                                      • Slide 80
                                                      • Topics that we have covered

                                                        AMORPHOUS SOLIDS Solids that donrsquot have a definite geometrical shape are known as Amorphous Solids1 In these solids particles are randomly arranged in three dimension2 They donrsquot have sharp melting points3 Amorphous solids are formed due to sudden cooling of liquid4 Amorphous solids melt over a wide range of temperature

                                                        Amorphous Solid

                                                        An amorphous solid does not possess a well-defined arrangement and long-range molecular order

                                                        Amorphous substances as well as cubic crystal are isotropic that is they exhibit similar properties in all direction

                                                        The crystalline from of the antibiotic novobiocin acid is poorly absorbed and has no activity where the amorphous form is readily absorbed and therapeutically active due to different dissolution rate

                                                        Amorphous or crystalline amp therapeutic activity

                                                        General crystallization conditions 1048698Solvents ndashdifferent polarities 1048698Concentration of the solutions (super saturated saturated diluted) 1048698Cooling speed (quenching slow) 1048698Temperature (room or lower than room temperature)

                                                        Crystallization

                                                        Final Form

                                                        Granulation

                                                        Drying

                                                        Compaction

                                                        Tableting

                                                        Drug Product

                                                        API

                                                        Crystallization

                                                        Filtration

                                                        Drying

                                                        Milling

                                                        Bulk API

                                                        Stability

                                                        Polymorphism and Industry Pharmaceutical

                                                        Polymorphism and Industry Pharmaceutical

                                                        Fluoxetine HCl the active ingredient in the antidepressant drug Prozac

                                                        co crystal which will have increased solubility compared to the crystalline form

                                                        Celecoxib

                                                        CELECOXIB is a nonsteroidal anti-inflammatory drug

                                                        However it was found that the higher bioavailability was shown by the amorphous state

                                                        The downfall of the amorphous state was its stability

                                                        This was due to the structural relaxation

                                                        This was enhanced by mixing it with polymers like PVP which helped in stabilizing the amorphous system (Piyush Gupta et al 2004 Piyush Gupta et al 2005)

                                                        A new solid state form was developed by Pharmacia

                                                        FurosemideTwo forms with significantly differing aqueous solubility and dissolution rateOral bioavailability compromised

                                                        Giron lists gt20 excipients that display polymorphism includingndash Lactose (anhydrous also monohydrate)ndash Aspartame (anhydrous hydrate forms)ndash Magnesium stearate (can affect lubrication of tablets)

                                                        Bioavailability

                                                        The rate and extent to which the active ingredient or active moiety is absorbed from a drug product and becomes available at the site of action

                                                        Bioequivalence

                                                        The absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study

                                                        Carbamazepine

                                                        CHLORPROPAMIDEat least six polymorphic white or almost white crystalline powder It exhibits polymorphism Practically insoluble in water soluble in alcohol freely soluble in acetone and in dichlo-romethane dissolves in dilute solutions of alkali hydroxides Protect from light

                                                        blood-glucose-lowering drug

                                                        AIDS drug ritonavir

                                                        Theobroma oil (cacao butter ) is a polymorphic natural fat

                                                        Theobroma oil can exist in 4 different polymorphic forms of which only one is Stabile

                                                        1 Unstable gamma form melting at 18degC2 Alpha form melting at 22degC3 Beta prime form melting at 28degC4 Stable beta form melting at 345degC

                                                        This is important in the preparation of theobroma suppositories

                                                        If the oil is heated to a point where it is completely liquified (about 35 C) the crystals of the stable polymorph are destroyed amp the mass does not crystallize until it is cooled to 15 C

                                                        The crystals that form are unstable amp the suppositories melt at 24 C

                                                        Theobroma suppositories must be prepared below 33 C

                                                        Polymorphism and Industry Pharmaceutical

                                                        Polymorphism and Industry Pharmaceutical

                                                        Anhydrates together with salts form the majority of all drug formulationsAbout a half of all APIs used today are saltsSalts are stable and well soluble in polar solvents (first of all in water) because they contain ionic bondThere is one more essential advantage of salts ndash their solubility is a function of pH Since pH in the gastrointestinal tract (GIT) vary between 1-75

                                                        atorvastatin calcium trihydrateEach tablet contains Atorvastatin Calcium Trihydrate equivalent to Atorvastatin 20 mg

                                                        Phase Equilibria amp The Phase Rule

                                                        Phase diagram ndash Water

                                                        Phase Equilibrium A stable phase structure with lowest free-energy (internal energy) of a system and also randomness or disorder of the atoms or molecules (entropy)

                                                        Any change in Temperature Composition and Pressure causes an increase in free energy and away from Equilibrium thus forcing a move to another lsquostatersquo

                                                        Phase Equilibria amp The Phase Rule Definitions

                                                        A phase is defined as any homogeneous and physically distinct part of a system which is separated from other parts of the system by interfaces

                                                        A part of a system is homogeneous if it has identical physical properties and chemical composition throughout the part

                                                        A phase may be gas liquid or solid A gas or a gaseous mixture is a single phase Totally miscible liquids constitute a single phase In an immiscible liquid system each layer is counted as a separate phase Every solid constitutes a single phase except when a solid solution is formed A solid solution is considered as a single phase Each polymorphic form constitutes a separate phase

                                                        Phase Definition

                                                        1 Liquid water pieces of ice and water vapour are present together The number of phases is 3 as each form is a separate phase Ice in the system is a single phase even if it is present as a number of pieces

                                                        2 Calcium carbonate undergoes thermal decomposition The chemical reaction is CaCO3(s) CaO(s) + CO2 (g) Number of phases = 3 This system consists of 2 solid phases CaCO3 and CaO and one gaseous phase that of CO2

                                                        3 Ammonium chloride undergoes thermal decomposition The chemical reaction is NH4Cl(s) NH3 (g) + HCl (g) Number of phases = 2 This system has two phases one solid NH4Cl and one gaseous a mixture of NH3 and HCl

                                                        4 A solution of NaCl in water Number of phases = 1

                                                        bull Examples

                                                        The number of components of a system at equilibrium is the smallest number of independently varying chemical constituents using which the composition of each and every phase in the system can be expressed

                                                        Components

                                                        Counting the number of components 1 The sulphur system is a one component system All the phases

                                                        monoclinic rhombic liquid and vapour ndash can be expressed in terms of the single constituent ndash sulphur

                                                        2 A mixture of ethanol and water is an example of a two component system We need both ethanol and water to express its composition

                                                        bull Examples

                                                        An example of a system in which a reaction occurs and an equilibrium is established is the thermal decomposition of solid CaCO3

                                                        In this system there are three distinct phasesSolid CaCO3

                                                        Solid CaOGaseous CO2

                                                        Though there are 3 species present the number of components is only two because of the equilibrium CaCO3 (s) CaO(s) + CO2(g)

                                                        Any two of the three constituents may be chosen as the components

                                                        If CaO and CO2 are chosen then the composition of the phase CaCO3 is expressed as one mole of component CO2 plus one mole of component CaO

                                                        If on the other hand CaCO3 and CO2 were chosen then the composition of the phase CaO would be described as one mole of CaCO3 minus one mole of CO2

                                                        The degrees of freedom or variance of a system is defined as the minimum number of variables such as

                                                        temperaturepressureconcentrationwhich must be fixed in order to define the system completely

                                                        Degrees of freedom (or variance)

                                                        F = C P + 2

                                                        1 A gaseous mixture of CO2 and N2 Three variables pressure temperature and composition are required to define this system This is hence a trivariant system

                                                        2 A system having only liquid water has two degrees of freedom or is bivariant Both temperature and pressure need to be mentioned in order to define the system

                                                        3 If to the system containing liquid water pieces of ice are added and this system with 2 phases is allowed to come to equilibrium then it is an univariant system

                                                        Only one variable either temperature or pressure need to be specified in order to define the systemIf the pressure on the system is maintained at 1 atm then the temperature of the system gets automatically fixed at 0oC the normal melting point of ice

                                                        bull Examples

                                                        Phase Equilibria amp The Phase Rule

                                                        A phase diagram (Equilibrium Phase Diagram) summarizes the conditions at which a substance exists as a solid liquid or gas

                                                        OR It is a ldquomaprdquo of the information about the control of phase structure of a particular material system

                                                        The relationships between temperature and the compositions and the quantities of phases present at equilibrium are represented

                                                        F = C P + 2The phase rule

                                                        The phase rule JW Gibbs formulated the phase rule which is a general relation

                                                        between the variance F the number of component C and the number of phases P at equilibrium for a system of any composition

                                                        For a system in equilibrium

                                                        F degree of freedom the least number of intensive variable that must be fixed (known) to describe the system completely

                                                        Phase Rule relation to determine the least number of intensive variable that can be changed without changing the equilibrium state of the system or alternately

                                                        The least number required to define the state of the system which is called degree of freedom F

                                                        Intensive variable independent variable that do not depend on the volume or the size egTemp pressure

                                                        Independent chemical species which comprise the system These could be Elements Ions Compounds

                                                        Eg Au-Cu system Components rarr Au Cu Ice-water system Component rarr H2O

                                                        Al2O3 ndash Cr2O3 system Components rarr Al2O3 Cr2O3

                                                        Component the smallest number of constituent by which the composition of each phase in the system at equilibrium can be expressed in form of chemical formula or equation

                                                        Phase Equilibria amp The Phase RuleComponents of a system

                                                        The number of phases in a system is denoted P

                                                        (a)A gas or a gaseous mixture is a single phase P=1

                                                        (b) For a solid system an alloy of two metals is a two-phase system (P=2) if the metals are immiscible but a single-phase system (P=1) if they are miscible---a homogeneous mixture of the two substances---is uniform on a molecular scale

                                                        (c) For a liquid system according to the solubility to decide whether a system consists of one phase or of two For example a solution of sodium chloride in water is a single phase A pair of liquids that are partially miscible or immiscible is a two-phase system(P=2)

                                                        Oil in water

                                                        Degrees of Freedom = What you can control What the system controls

                                                        F = C + 2 P

                                                        Can control the no of components added and P amp T

                                                        System decided how many phases to produce given the

                                                        conditions

                                                        A way of understanding the Gibbs Phase RuleThe degrees of freedom can be thought of as the difference between what you (can) control and

                                                        what the system controls

                                                        F degree of freedom the least number of intensive variable that must be fixed (known) to describe the system completely

                                                        Degree of freedom (or variance) F is the number of variables (T p andor composition) that can be changed independently without changing the phases of the system

                                                        a) At the triple pointP = 3 (solid liquid and gas)

                                                        C= 1 (water)P + F = C + 2

                                                        F = 0 (no degree of freedom)

                                                        b) liquid-solid curveP = 2

                                                        2+F = 1 + 2F= 1

                                                        One variable (T or P) can be changed

                                                        c) LiquidP =1

                                                        So F =2Two variables (T and P) can be varied independently

                                                        and the system will remains a single phase

                                                        One-component systemsPhase diagram of water

                                                        P (

                                                        atm

                                                        )

                                                        Critical point

                                                        374

                                                        1

                                                        =100=0O--Triple point

                                                        0006

                                                        218

                                                        Curve O -CSublimation

                                                        Deposition

                                                        Curve O-AVaporizationCondensation

                                                        Curve O -BMelting

                                                        Freezing

                                                        F = C P + 2

                                                        F = C P + 2

                                                        Phase Diagram of Carbon Dioxide

                                                        Condensed system System in which the vapor phase is ignored and only the solid andor liquid phases are considered

                                                        Two component system For two component system F can be 3 (3D model is needed) eg T p

                                                        and concentration usually we fix p = 1atm the vapor phase is neglected and F is reduced to 2

                                                        For three component system the pressure and temperature are fixed

                                                        Phenol water phase diagram

                                                        eg for point d (24)

                                                        Two component system containing liquid phase

                                                        Tie Line bc line The line at which the system at equilibrium will separate into phases of constant composition termed lsquoconjugate phasesrsquo

                                                        Lever Rule a way to calculate the proportions of each phase present on a phase diagram in a two phase field (at a given temperature and composition)

                                                        eg for point d (24)

                                                        For every 10 g of liquid system in equilibrium in point d

                                                        75 g phase A25 g phase B

                                                        ExampleMixed 24g phenol +76g water T 50degC

                                                        equilibrium75 g phase A 25 g phase B

                                                        11 phenol 63 phenol

                                                        011 times75 g=825 g phenol

                                                        063 times25 g=1575 g phenol

                                                        water rich phasecontains water+ phenol(11)

                                                        Phenol rich phasecontains Phenol (63)+ water

                                                        The Critical Solution Temperature CST

                                                        Is the maximum temperature at which the 2-phase region exists (or upper consolute temperature)

                                                        In the case of the phenol-water system this is 668oC (point h)

                                                        All combinations of phenol and water gt CST are completely miscible and yield 1-phase liquid systems

                                                        Systems Showing a Decrease in Miscibility with Rise in Temperature

                                                        A few mixtures exhibit a lower critical solution temperature (low CST) eg triethylamine plus water The miscibility with in temperature

                                                        Systems Showing Upper and Lower CSTs

                                                        The miscibility with temp

                                                        a certain temperature miscibility starts to again with further in temperature

                                                        Closed-phase diagram ie nicotine-water system

                                                        A salol B thymol

                                                        53

                                                        Two component system containing solid and liquid phase (Eutectic Mixtures)

                                                        A salol B thymol

                                                        EMLAreg (lidocaine 25 and prilocaine 25) Cream

                                                        EMLA Cream (lidocaine 25 and prilocaine 25) is an emulsion in which the oil phase is a eutectic mixture of lidocaine and prilocaine in a ratio of 11 by weight This eutectic mixture has a melting point below room temperature and therefore both local anesthetics exist as a liquid oil rather than as crystals

                                                        Eutectic mixture Pharmaceutical Application

                                                        Triangular Diagrams for three ndash component systems

                                                        Three component system

                                                        Birzeit University Physical Pharmacy PHAR 323 Dr Hani Shtaya

                                                        1 Binding Forces Between Molecules2 Repulsive and Attractive Forces3 The Gaseous State The Ideal Gas Law Liquefaction of Gases Aerosols4 Solids and the Crystalline State Crystalline Solids Polymorphism Solvates Amorphous Solids5 Phase Equilibria and the Phase Rule Phase Rule Systems Containing One Component Condensed System Two-Component Systems Containing Liquid Phases Two-Component Systems Containing Solid and Liquid Phases Eutectic Mixtures Rules Relating to Triangular Diagrams

                                                        Topics that we have covered

                                                        • States of Matter
                                                        • States of Matter (2)
                                                        • Objectives of the lecture
                                                        • Comparison of Gases Liquids and Solids
                                                        • Slide 5
                                                        • Repulsive and Attractive Forces
                                                        • Ideal Gas Equation
                                                        • Gaseous state
                                                        • Slide 9
                                                        • Gaseous state (2)
                                                        • Liquefaction of Gases
                                                        • Slide 12
                                                        • SOLIDS amp CRYSTALLINE STATE Pharmaceutical Drugs more than 80
                                                        • Solids and the crystalline state
                                                        • Classification of Solids
                                                        • Slide 16
                                                        • Slide 17
                                                        • Crystal forms
                                                        • Types of Crystals
                                                        • Slide 20
                                                        • Slide 21
                                                        • Polymorphism
                                                        • Slide 23
                                                        • Slide 24
                                                        • Slide 25
                                                        • Slide 26
                                                        • Cocrystal
                                                        • Principle of polymorphism
                                                        • Solvates
                                                        • Polymorphism (2)
                                                        • Amorphous Solid
                                                        • Amorphous or crystalline amp therapeutic activity
                                                        • Slide 33
                                                        • Slide 34
                                                        • Polymorphism and Industry Pharmaceutical
                                                        • Celecoxib
                                                        • Furosemide
                                                        • Bioavailability
                                                        • Slide 39
                                                        • Slide 40
                                                        • Bioequivalence
                                                        • Slide 42
                                                        • Carbamazepine
                                                        • Slide 44
                                                        • AIDS drug ritonavir
                                                        • Slide 46
                                                        • Slide 47
                                                        • Phase Equilibria amp The Phase Rule
                                                        • Phase diagram ndash Water
                                                        • Phase Equilibria amp The Phase Rule Definitions
                                                        • Phase Definition
                                                        • Examples
                                                        • Components
                                                        • Examples
                                                        • Slide 55
                                                        • Degrees of freedom (or variance)
                                                        • Examples (2)
                                                        • Phase Equilibria amp The Phase Rule
                                                        • The phase rule
                                                        • Slide 60
                                                        • Phase Equilibria amp The Phase Rule (2)
                                                        • The number of phases in a system is denoted P
                                                        • Slide 63
                                                        • Slide 64
                                                        • One-component systems
                                                        • Slide 66
                                                        • Slide 67
                                                        • Slide 68
                                                        • Slide 69
                                                        • Slide 70
                                                        • Two component system containing liquid phase
                                                        • Slide 72
                                                        • The Critical Solution Temperature CST
                                                        • Systems Showing a Decrease in Miscibility with Rise in Temperat
                                                        • Systems Showing Upper and Lower CSTs
                                                        • Two component system containing solid and liquid phase (Eutecti
                                                        • Slide 77
                                                        • Eutectic mixture Pharmaceutical Application
                                                        • Three component system
                                                        • Slide 80
                                                        • Topics that we have covered

                                                          The crystalline from of the antibiotic novobiocin acid is poorly absorbed and has no activity where the amorphous form is readily absorbed and therapeutically active due to different dissolution rate

                                                          Amorphous or crystalline amp therapeutic activity

                                                          General crystallization conditions 1048698Solvents ndashdifferent polarities 1048698Concentration of the solutions (super saturated saturated diluted) 1048698Cooling speed (quenching slow) 1048698Temperature (room or lower than room temperature)

                                                          Crystallization

                                                          Final Form

                                                          Granulation

                                                          Drying

                                                          Compaction

                                                          Tableting

                                                          Drug Product

                                                          API

                                                          Crystallization

                                                          Filtration

                                                          Drying

                                                          Milling

                                                          Bulk API

                                                          Stability

                                                          Polymorphism and Industry Pharmaceutical

                                                          Polymorphism and Industry Pharmaceutical

                                                          Fluoxetine HCl the active ingredient in the antidepressant drug Prozac

                                                          co crystal which will have increased solubility compared to the crystalline form

                                                          Celecoxib

                                                          CELECOXIB is a nonsteroidal anti-inflammatory drug

                                                          However it was found that the higher bioavailability was shown by the amorphous state

                                                          The downfall of the amorphous state was its stability

                                                          This was due to the structural relaxation

                                                          This was enhanced by mixing it with polymers like PVP which helped in stabilizing the amorphous system (Piyush Gupta et al 2004 Piyush Gupta et al 2005)

                                                          A new solid state form was developed by Pharmacia

                                                          FurosemideTwo forms with significantly differing aqueous solubility and dissolution rateOral bioavailability compromised

                                                          Giron lists gt20 excipients that display polymorphism includingndash Lactose (anhydrous also monohydrate)ndash Aspartame (anhydrous hydrate forms)ndash Magnesium stearate (can affect lubrication of tablets)

                                                          Bioavailability

                                                          The rate and extent to which the active ingredient or active moiety is absorbed from a drug product and becomes available at the site of action

                                                          Bioequivalence

                                                          The absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study

                                                          Carbamazepine

                                                          CHLORPROPAMIDEat least six polymorphic white or almost white crystalline powder It exhibits polymorphism Practically insoluble in water soluble in alcohol freely soluble in acetone and in dichlo-romethane dissolves in dilute solutions of alkali hydroxides Protect from light

                                                          blood-glucose-lowering drug

                                                          AIDS drug ritonavir

                                                          Theobroma oil (cacao butter ) is a polymorphic natural fat

                                                          Theobroma oil can exist in 4 different polymorphic forms of which only one is Stabile

                                                          1 Unstable gamma form melting at 18degC2 Alpha form melting at 22degC3 Beta prime form melting at 28degC4 Stable beta form melting at 345degC

                                                          This is important in the preparation of theobroma suppositories

                                                          If the oil is heated to a point where it is completely liquified (about 35 C) the crystals of the stable polymorph are destroyed amp the mass does not crystallize until it is cooled to 15 C

                                                          The crystals that form are unstable amp the suppositories melt at 24 C

                                                          Theobroma suppositories must be prepared below 33 C

                                                          Polymorphism and Industry Pharmaceutical

                                                          Polymorphism and Industry Pharmaceutical

                                                          Anhydrates together with salts form the majority of all drug formulationsAbout a half of all APIs used today are saltsSalts are stable and well soluble in polar solvents (first of all in water) because they contain ionic bondThere is one more essential advantage of salts ndash their solubility is a function of pH Since pH in the gastrointestinal tract (GIT) vary between 1-75

                                                          atorvastatin calcium trihydrateEach tablet contains Atorvastatin Calcium Trihydrate equivalent to Atorvastatin 20 mg

                                                          Phase Equilibria amp The Phase Rule

                                                          Phase diagram ndash Water

                                                          Phase Equilibrium A stable phase structure with lowest free-energy (internal energy) of a system and also randomness or disorder of the atoms or molecules (entropy)

                                                          Any change in Temperature Composition and Pressure causes an increase in free energy and away from Equilibrium thus forcing a move to another lsquostatersquo

                                                          Phase Equilibria amp The Phase Rule Definitions

                                                          A phase is defined as any homogeneous and physically distinct part of a system which is separated from other parts of the system by interfaces

                                                          A part of a system is homogeneous if it has identical physical properties and chemical composition throughout the part

                                                          A phase may be gas liquid or solid A gas or a gaseous mixture is a single phase Totally miscible liquids constitute a single phase In an immiscible liquid system each layer is counted as a separate phase Every solid constitutes a single phase except when a solid solution is formed A solid solution is considered as a single phase Each polymorphic form constitutes a separate phase

                                                          Phase Definition

                                                          1 Liquid water pieces of ice and water vapour are present together The number of phases is 3 as each form is a separate phase Ice in the system is a single phase even if it is present as a number of pieces

                                                          2 Calcium carbonate undergoes thermal decomposition The chemical reaction is CaCO3(s) CaO(s) + CO2 (g) Number of phases = 3 This system consists of 2 solid phases CaCO3 and CaO and one gaseous phase that of CO2

                                                          3 Ammonium chloride undergoes thermal decomposition The chemical reaction is NH4Cl(s) NH3 (g) + HCl (g) Number of phases = 2 This system has two phases one solid NH4Cl and one gaseous a mixture of NH3 and HCl

                                                          4 A solution of NaCl in water Number of phases = 1

                                                          bull Examples

                                                          The number of components of a system at equilibrium is the smallest number of independently varying chemical constituents using which the composition of each and every phase in the system can be expressed

                                                          Components

                                                          Counting the number of components 1 The sulphur system is a one component system All the phases

                                                          monoclinic rhombic liquid and vapour ndash can be expressed in terms of the single constituent ndash sulphur

                                                          2 A mixture of ethanol and water is an example of a two component system We need both ethanol and water to express its composition

                                                          bull Examples

                                                          An example of a system in which a reaction occurs and an equilibrium is established is the thermal decomposition of solid CaCO3

                                                          In this system there are three distinct phasesSolid CaCO3

                                                          Solid CaOGaseous CO2

                                                          Though there are 3 species present the number of components is only two because of the equilibrium CaCO3 (s) CaO(s) + CO2(g)

                                                          Any two of the three constituents may be chosen as the components

                                                          If CaO and CO2 are chosen then the composition of the phase CaCO3 is expressed as one mole of component CO2 plus one mole of component CaO

                                                          If on the other hand CaCO3 and CO2 were chosen then the composition of the phase CaO would be described as one mole of CaCO3 minus one mole of CO2

                                                          The degrees of freedom or variance of a system is defined as the minimum number of variables such as

                                                          temperaturepressureconcentrationwhich must be fixed in order to define the system completely

                                                          Degrees of freedom (or variance)

                                                          F = C P + 2

                                                          1 A gaseous mixture of CO2 and N2 Three variables pressure temperature and composition are required to define this system This is hence a trivariant system

                                                          2 A system having only liquid water has two degrees of freedom or is bivariant Both temperature and pressure need to be mentioned in order to define the system

                                                          3 If to the system containing liquid water pieces of ice are added and this system with 2 phases is allowed to come to equilibrium then it is an univariant system

                                                          Only one variable either temperature or pressure need to be specified in order to define the systemIf the pressure on the system is maintained at 1 atm then the temperature of the system gets automatically fixed at 0oC the normal melting point of ice

                                                          bull Examples

                                                          Phase Equilibria amp The Phase Rule

                                                          A phase diagram (Equilibrium Phase Diagram) summarizes the conditions at which a substance exists as a solid liquid or gas

                                                          OR It is a ldquomaprdquo of the information about the control of phase structure of a particular material system

                                                          The relationships between temperature and the compositions and the quantities of phases present at equilibrium are represented

                                                          F = C P + 2The phase rule

                                                          The phase rule JW Gibbs formulated the phase rule which is a general relation

                                                          between the variance F the number of component C and the number of phases P at equilibrium for a system of any composition

                                                          For a system in equilibrium

                                                          F degree of freedom the least number of intensive variable that must be fixed (known) to describe the system completely

                                                          Phase Rule relation to determine the least number of intensive variable that can be changed without changing the equilibrium state of the system or alternately

                                                          The least number required to define the state of the system which is called degree of freedom F

                                                          Intensive variable independent variable that do not depend on the volume or the size egTemp pressure

                                                          Independent chemical species which comprise the system These could be Elements Ions Compounds

                                                          Eg Au-Cu system Components rarr Au Cu Ice-water system Component rarr H2O

                                                          Al2O3 ndash Cr2O3 system Components rarr Al2O3 Cr2O3

                                                          Component the smallest number of constituent by which the composition of each phase in the system at equilibrium can be expressed in form of chemical formula or equation

                                                          Phase Equilibria amp The Phase RuleComponents of a system

                                                          The number of phases in a system is denoted P

                                                          (a)A gas or a gaseous mixture is a single phase P=1

                                                          (b) For a solid system an alloy of two metals is a two-phase system (P=2) if the metals are immiscible but a single-phase system (P=1) if they are miscible---a homogeneous mixture of the two substances---is uniform on a molecular scale

                                                          (c) For a liquid system according to the solubility to decide whether a system consists of one phase or of two For example a solution of sodium chloride in water is a single phase A pair of liquids that are partially miscible or immiscible is a two-phase system(P=2)

                                                          Oil in water

                                                          Degrees of Freedom = What you can control What the system controls

                                                          F = C + 2 P

                                                          Can control the no of components added and P amp T

                                                          System decided how many phases to produce given the

                                                          conditions

                                                          A way of understanding the Gibbs Phase RuleThe degrees of freedom can be thought of as the difference between what you (can) control and

                                                          what the system controls

                                                          F degree of freedom the least number of intensive variable that must be fixed (known) to describe the system completely

                                                          Degree of freedom (or variance) F is the number of variables (T p andor composition) that can be changed independently without changing the phases of the system

                                                          a) At the triple pointP = 3 (solid liquid and gas)

                                                          C= 1 (water)P + F = C + 2

                                                          F = 0 (no degree of freedom)

                                                          b) liquid-solid curveP = 2

                                                          2+F = 1 + 2F= 1

                                                          One variable (T or P) can be changed

                                                          c) LiquidP =1

                                                          So F =2Two variables (T and P) can be varied independently

                                                          and the system will remains a single phase

                                                          One-component systemsPhase diagram of water

                                                          P (

                                                          atm

                                                          )

                                                          Critical point

                                                          374

                                                          1

                                                          =100=0O--Triple point

                                                          0006

                                                          218

                                                          Curve O -CSublimation

                                                          Deposition

                                                          Curve O-AVaporizationCondensation

                                                          Curve O -BMelting

                                                          Freezing

                                                          F = C P + 2

                                                          F = C P + 2

                                                          Phase Diagram of Carbon Dioxide

                                                          Condensed system System in which the vapor phase is ignored and only the solid andor liquid phases are considered

                                                          Two component system For two component system F can be 3 (3D model is needed) eg T p

                                                          and concentration usually we fix p = 1atm the vapor phase is neglected and F is reduced to 2

                                                          For three component system the pressure and temperature are fixed

                                                          Phenol water phase diagram

                                                          eg for point d (24)

                                                          Two component system containing liquid phase

                                                          Tie Line bc line The line at which the system at equilibrium will separate into phases of constant composition termed lsquoconjugate phasesrsquo

                                                          Lever Rule a way to calculate the proportions of each phase present on a phase diagram in a two phase field (at a given temperature and composition)

                                                          eg for point d (24)

                                                          For every 10 g of liquid system in equilibrium in point d

                                                          75 g phase A25 g phase B

                                                          ExampleMixed 24g phenol +76g water T 50degC

                                                          equilibrium75 g phase A 25 g phase B

                                                          11 phenol 63 phenol

                                                          011 times75 g=825 g phenol

                                                          063 times25 g=1575 g phenol

                                                          water rich phasecontains water+ phenol(11)

                                                          Phenol rich phasecontains Phenol (63)+ water

                                                          The Critical Solution Temperature CST

                                                          Is the maximum temperature at which the 2-phase region exists (or upper consolute temperature)

                                                          In the case of the phenol-water system this is 668oC (point h)

                                                          All combinations of phenol and water gt CST are completely miscible and yield 1-phase liquid systems

                                                          Systems Showing a Decrease in Miscibility with Rise in Temperature

                                                          A few mixtures exhibit a lower critical solution temperature (low CST) eg triethylamine plus water The miscibility with in temperature

                                                          Systems Showing Upper and Lower CSTs

                                                          The miscibility with temp

                                                          a certain temperature miscibility starts to again with further in temperature

                                                          Closed-phase diagram ie nicotine-water system

                                                          A salol B thymol

                                                          53

                                                          Two component system containing solid and liquid phase (Eutectic Mixtures)

                                                          A salol B thymol

                                                          EMLAreg (lidocaine 25 and prilocaine 25) Cream

                                                          EMLA Cream (lidocaine 25 and prilocaine 25) is an emulsion in which the oil phase is a eutectic mixture of lidocaine and prilocaine in a ratio of 11 by weight This eutectic mixture has a melting point below room temperature and therefore both local anesthetics exist as a liquid oil rather than as crystals

                                                          Eutectic mixture Pharmaceutical Application

                                                          Triangular Diagrams for three ndash component systems

                                                          Three component system

                                                          Birzeit University Physical Pharmacy PHAR 323 Dr Hani Shtaya

                                                          1 Binding Forces Between Molecules2 Repulsive and Attractive Forces3 The Gaseous State The Ideal Gas Law Liquefaction of Gases Aerosols4 Solids and the Crystalline State Crystalline Solids Polymorphism Solvates Amorphous Solids5 Phase Equilibria and the Phase Rule Phase Rule Systems Containing One Component Condensed System Two-Component Systems Containing Liquid Phases Two-Component Systems Containing Solid and Liquid Phases Eutectic Mixtures Rules Relating to Triangular Diagrams

                                                          Topics that we have covered

                                                          • States of Matter
                                                          • States of Matter (2)
                                                          • Objectives of the lecture
                                                          • Comparison of Gases Liquids and Solids
                                                          • Slide 5
                                                          • Repulsive and Attractive Forces
                                                          • Ideal Gas Equation
                                                          • Gaseous state
                                                          • Slide 9
                                                          • Gaseous state (2)
                                                          • Liquefaction of Gases
                                                          • Slide 12
                                                          • SOLIDS amp CRYSTALLINE STATE Pharmaceutical Drugs more than 80
                                                          • Solids and the crystalline state
                                                          • Classification of Solids
                                                          • Slide 16
                                                          • Slide 17
                                                          • Crystal forms
                                                          • Types of Crystals
                                                          • Slide 20
                                                          • Slide 21
                                                          • Polymorphism
                                                          • Slide 23
                                                          • Slide 24
                                                          • Slide 25
                                                          • Slide 26
                                                          • Cocrystal
                                                          • Principle of polymorphism
                                                          • Solvates
                                                          • Polymorphism (2)
                                                          • Amorphous Solid
                                                          • Amorphous or crystalline amp therapeutic activity
                                                          • Slide 33
                                                          • Slide 34
                                                          • Polymorphism and Industry Pharmaceutical
                                                          • Celecoxib
                                                          • Furosemide
                                                          • Bioavailability
                                                          • Slide 39
                                                          • Slide 40
                                                          • Bioequivalence
                                                          • Slide 42
                                                          • Carbamazepine
                                                          • Slide 44
                                                          • AIDS drug ritonavir
                                                          • Slide 46
                                                          • Slide 47
                                                          • Phase Equilibria amp The Phase Rule
                                                          • Phase diagram ndash Water
                                                          • Phase Equilibria amp The Phase Rule Definitions
                                                          • Phase Definition
                                                          • Examples
                                                          • Components
                                                          • Examples
                                                          • Slide 55
                                                          • Degrees of freedom (or variance)
                                                          • Examples (2)
                                                          • Phase Equilibria amp The Phase Rule
                                                          • The phase rule
                                                          • Slide 60
                                                          • Phase Equilibria amp The Phase Rule (2)
                                                          • The number of phases in a system is denoted P
                                                          • Slide 63
                                                          • Slide 64
                                                          • One-component systems
                                                          • Slide 66
                                                          • Slide 67
                                                          • Slide 68
                                                          • Slide 69
                                                          • Slide 70
                                                          • Two component system containing liquid phase
                                                          • Slide 72
                                                          • The Critical Solution Temperature CST
                                                          • Systems Showing a Decrease in Miscibility with Rise in Temperat
                                                          • Systems Showing Upper and Lower CSTs
                                                          • Two component system containing solid and liquid phase (Eutecti
                                                          • Slide 77
                                                          • Eutectic mixture Pharmaceutical Application
                                                          • Three component system
                                                          • Slide 80
                                                          • Topics that we have covered

                                                            General crystallization conditions 1048698Solvents ndashdifferent polarities 1048698Concentration of the solutions (super saturated saturated diluted) 1048698Cooling speed (quenching slow) 1048698Temperature (room or lower than room temperature)

                                                            Crystallization

                                                            Final Form

                                                            Granulation

                                                            Drying

                                                            Compaction

                                                            Tableting

                                                            Drug Product

                                                            API

                                                            Crystallization

                                                            Filtration

                                                            Drying

                                                            Milling

                                                            Bulk API

                                                            Stability

                                                            Polymorphism and Industry Pharmaceutical

                                                            Polymorphism and Industry Pharmaceutical

                                                            Fluoxetine HCl the active ingredient in the antidepressant drug Prozac

                                                            co crystal which will have increased solubility compared to the crystalline form

                                                            Celecoxib

                                                            CELECOXIB is a nonsteroidal anti-inflammatory drug

                                                            However it was found that the higher bioavailability was shown by the amorphous state

                                                            The downfall of the amorphous state was its stability

                                                            This was due to the structural relaxation

                                                            This was enhanced by mixing it with polymers like PVP which helped in stabilizing the amorphous system (Piyush Gupta et al 2004 Piyush Gupta et al 2005)

                                                            A new solid state form was developed by Pharmacia

                                                            FurosemideTwo forms with significantly differing aqueous solubility and dissolution rateOral bioavailability compromised

                                                            Giron lists gt20 excipients that display polymorphism includingndash Lactose (anhydrous also monohydrate)ndash Aspartame (anhydrous hydrate forms)ndash Magnesium stearate (can affect lubrication of tablets)

                                                            Bioavailability

                                                            The rate and extent to which the active ingredient or active moiety is absorbed from a drug product and becomes available at the site of action

                                                            Bioequivalence

                                                            The absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study

                                                            Carbamazepine

                                                            CHLORPROPAMIDEat least six polymorphic white or almost white crystalline powder It exhibits polymorphism Practically insoluble in water soluble in alcohol freely soluble in acetone and in dichlo-romethane dissolves in dilute solutions of alkali hydroxides Protect from light

                                                            blood-glucose-lowering drug

                                                            AIDS drug ritonavir

                                                            Theobroma oil (cacao butter ) is a polymorphic natural fat

                                                            Theobroma oil can exist in 4 different polymorphic forms of which only one is Stabile

                                                            1 Unstable gamma form melting at 18degC2 Alpha form melting at 22degC3 Beta prime form melting at 28degC4 Stable beta form melting at 345degC

                                                            This is important in the preparation of theobroma suppositories

                                                            If the oil is heated to a point where it is completely liquified (about 35 C) the crystals of the stable polymorph are destroyed amp the mass does not crystallize until it is cooled to 15 C

                                                            The crystals that form are unstable amp the suppositories melt at 24 C

                                                            Theobroma suppositories must be prepared below 33 C

                                                            Polymorphism and Industry Pharmaceutical

                                                            Polymorphism and Industry Pharmaceutical

                                                            Anhydrates together with salts form the majority of all drug formulationsAbout a half of all APIs used today are saltsSalts are stable and well soluble in polar solvents (first of all in water) because they contain ionic bondThere is one more essential advantage of salts ndash their solubility is a function of pH Since pH in the gastrointestinal tract (GIT) vary between 1-75

                                                            atorvastatin calcium trihydrateEach tablet contains Atorvastatin Calcium Trihydrate equivalent to Atorvastatin 20 mg

                                                            Phase Equilibria amp The Phase Rule

                                                            Phase diagram ndash Water

                                                            Phase Equilibrium A stable phase structure with lowest free-energy (internal energy) of a system and also randomness or disorder of the atoms or molecules (entropy)

                                                            Any change in Temperature Composition and Pressure causes an increase in free energy and away from Equilibrium thus forcing a move to another lsquostatersquo

                                                            Phase Equilibria amp The Phase Rule Definitions

                                                            A phase is defined as any homogeneous and physically distinct part of a system which is separated from other parts of the system by interfaces

                                                            A part of a system is homogeneous if it has identical physical properties and chemical composition throughout the part

                                                            A phase may be gas liquid or solid A gas or a gaseous mixture is a single phase Totally miscible liquids constitute a single phase In an immiscible liquid system each layer is counted as a separate phase Every solid constitutes a single phase except when a solid solution is formed A solid solution is considered as a single phase Each polymorphic form constitutes a separate phase

                                                            Phase Definition

                                                            1 Liquid water pieces of ice and water vapour are present together The number of phases is 3 as each form is a separate phase Ice in the system is a single phase even if it is present as a number of pieces

                                                            2 Calcium carbonate undergoes thermal decomposition The chemical reaction is CaCO3(s) CaO(s) + CO2 (g) Number of phases = 3 This system consists of 2 solid phases CaCO3 and CaO and one gaseous phase that of CO2

                                                            3 Ammonium chloride undergoes thermal decomposition The chemical reaction is NH4Cl(s) NH3 (g) + HCl (g) Number of phases = 2 This system has two phases one solid NH4Cl and one gaseous a mixture of NH3 and HCl

                                                            4 A solution of NaCl in water Number of phases = 1

                                                            bull Examples

                                                            The number of components of a system at equilibrium is the smallest number of independently varying chemical constituents using which the composition of each and every phase in the system can be expressed

                                                            Components

                                                            Counting the number of components 1 The sulphur system is a one component system All the phases

                                                            monoclinic rhombic liquid and vapour ndash can be expressed in terms of the single constituent ndash sulphur

                                                            2 A mixture of ethanol and water is an example of a two component system We need both ethanol and water to express its composition

                                                            bull Examples

                                                            An example of a system in which a reaction occurs and an equilibrium is established is the thermal decomposition of solid CaCO3

                                                            In this system there are three distinct phasesSolid CaCO3

                                                            Solid CaOGaseous CO2

                                                            Though there are 3 species present the number of components is only two because of the equilibrium CaCO3 (s) CaO(s) + CO2(g)

                                                            Any two of the three constituents may be chosen as the components

                                                            If CaO and CO2 are chosen then the composition of the phase CaCO3 is expressed as one mole of component CO2 plus one mole of component CaO

                                                            If on the other hand CaCO3 and CO2 were chosen then the composition of the phase CaO would be described as one mole of CaCO3 minus one mole of CO2

                                                            The degrees of freedom or variance of a system is defined as the minimum number of variables such as

                                                            temperaturepressureconcentrationwhich must be fixed in order to define the system completely

                                                            Degrees of freedom (or variance)

                                                            F = C P + 2

                                                            1 A gaseous mixture of CO2 and N2 Three variables pressure temperature and composition are required to define this system This is hence a trivariant system

                                                            2 A system having only liquid water has two degrees of freedom or is bivariant Both temperature and pressure need to be mentioned in order to define the system

                                                            3 If to the system containing liquid water pieces of ice are added and this system with 2 phases is allowed to come to equilibrium then it is an univariant system

                                                            Only one variable either temperature or pressure need to be specified in order to define the systemIf the pressure on the system is maintained at 1 atm then the temperature of the system gets automatically fixed at 0oC the normal melting point of ice

                                                            bull Examples

                                                            Phase Equilibria amp The Phase Rule

                                                            A phase diagram (Equilibrium Phase Diagram) summarizes the conditions at which a substance exists as a solid liquid or gas

                                                            OR It is a ldquomaprdquo of the information about the control of phase structure of a particular material system

                                                            The relationships between temperature and the compositions and the quantities of phases present at equilibrium are represented

                                                            F = C P + 2The phase rule

                                                            The phase rule JW Gibbs formulated the phase rule which is a general relation

                                                            between the variance F the number of component C and the number of phases P at equilibrium for a system of any composition

                                                            For a system in equilibrium

                                                            F degree of freedom the least number of intensive variable that must be fixed (known) to describe the system completely

                                                            Phase Rule relation to determine the least number of intensive variable that can be changed without changing the equilibrium state of the system or alternately

                                                            The least number required to define the state of the system which is called degree of freedom F

                                                            Intensive variable independent variable that do not depend on the volume or the size egTemp pressure

                                                            Independent chemical species which comprise the system These could be Elements Ions Compounds

                                                            Eg Au-Cu system Components rarr Au Cu Ice-water system Component rarr H2O

                                                            Al2O3 ndash Cr2O3 system Components rarr Al2O3 Cr2O3

                                                            Component the smallest number of constituent by which the composition of each phase in the system at equilibrium can be expressed in form of chemical formula or equation

                                                            Phase Equilibria amp The Phase RuleComponents of a system

                                                            The number of phases in a system is denoted P

                                                            (a)A gas or a gaseous mixture is a single phase P=1

                                                            (b) For a solid system an alloy of two metals is a two-phase system (P=2) if the metals are immiscible but a single-phase system (P=1) if they are miscible---a homogeneous mixture of the two substances---is uniform on a molecular scale

                                                            (c) For a liquid system according to the solubility to decide whether a system consists of one phase or of two For example a solution of sodium chloride in water is a single phase A pair of liquids that are partially miscible or immiscible is a two-phase system(P=2)

                                                            Oil in water

                                                            Degrees of Freedom = What you can control What the system controls

                                                            F = C + 2 P

                                                            Can control the no of components added and P amp T

                                                            System decided how many phases to produce given the

                                                            conditions

                                                            A way of understanding the Gibbs Phase RuleThe degrees of freedom can be thought of as the difference between what you (can) control and

                                                            what the system controls

                                                            F degree of freedom the least number of intensive variable that must be fixed (known) to describe the system completely

                                                            Degree of freedom (or variance) F is the number of variables (T p andor composition) that can be changed independently without changing the phases of the system

                                                            a) At the triple pointP = 3 (solid liquid and gas)

                                                            C= 1 (water)P + F = C + 2

                                                            F = 0 (no degree of freedom)

                                                            b) liquid-solid curveP = 2

                                                            2+F = 1 + 2F= 1

                                                            One variable (T or P) can be changed

                                                            c) LiquidP =1

                                                            So F =2Two variables (T and P) can be varied independently

                                                            and the system will remains a single phase

                                                            One-component systemsPhase diagram of water

                                                            P (

                                                            atm

                                                            )

                                                            Critical point

                                                            374

                                                            1

                                                            =100=0O--Triple point

                                                            0006

                                                            218

                                                            Curve O -CSublimation

                                                            Deposition

                                                            Curve O-AVaporizationCondensation

                                                            Curve O -BMelting

                                                            Freezing

                                                            F = C P + 2

                                                            F = C P + 2

                                                            Phase Diagram of Carbon Dioxide

                                                            Condensed system System in which the vapor phase is ignored and only the solid andor liquid phases are considered

                                                            Two component system For two component system F can be 3 (3D model is needed) eg T p

                                                            and concentration usually we fix p = 1atm the vapor phase is neglected and F is reduced to 2

                                                            For three component system the pressure and temperature are fixed

                                                            Phenol water phase diagram

                                                            eg for point d (24)

                                                            Two component system containing liquid phase

                                                            Tie Line bc line The line at which the system at equilibrium will separate into phases of constant composition termed lsquoconjugate phasesrsquo

                                                            Lever Rule a way to calculate the proportions of each phase present on a phase diagram in a two phase field (at a given temperature and composition)

                                                            eg for point d (24)

                                                            For every 10 g of liquid system in equilibrium in point d

                                                            75 g phase A25 g phase B

                                                            ExampleMixed 24g phenol +76g water T 50degC

                                                            equilibrium75 g phase A 25 g phase B

                                                            11 phenol 63 phenol

                                                            011 times75 g=825 g phenol

                                                            063 times25 g=1575 g phenol

                                                            water rich phasecontains water+ phenol(11)

                                                            Phenol rich phasecontains Phenol (63)+ water

                                                            The Critical Solution Temperature CST

                                                            Is the maximum temperature at which the 2-phase region exists (or upper consolute temperature)

                                                            In the case of the phenol-water system this is 668oC (point h)

                                                            All combinations of phenol and water gt CST are completely miscible and yield 1-phase liquid systems

                                                            Systems Showing a Decrease in Miscibility with Rise in Temperature

                                                            A few mixtures exhibit a lower critical solution temperature (low CST) eg triethylamine plus water The miscibility with in temperature

                                                            Systems Showing Upper and Lower CSTs

                                                            The miscibility with temp

                                                            a certain temperature miscibility starts to again with further in temperature

                                                            Closed-phase diagram ie nicotine-water system

                                                            A salol B thymol

                                                            53

                                                            Two component system containing solid and liquid phase (Eutectic Mixtures)

                                                            A salol B thymol

                                                            EMLAreg (lidocaine 25 and prilocaine 25) Cream

                                                            EMLA Cream (lidocaine 25 and prilocaine 25) is an emulsion in which the oil phase is a eutectic mixture of lidocaine and prilocaine in a ratio of 11 by weight This eutectic mixture has a melting point below room temperature and therefore both local anesthetics exist as a liquid oil rather than as crystals

                                                            Eutectic mixture Pharmaceutical Application

                                                            Triangular Diagrams for three ndash component systems

                                                            Three component system

                                                            Birzeit University Physical Pharmacy PHAR 323 Dr Hani Shtaya

                                                            1 Binding Forces Between Molecules2 Repulsive and Attractive Forces3 The Gaseous State The Ideal Gas Law Liquefaction of Gases Aerosols4 Solids and the Crystalline State Crystalline Solids Polymorphism Solvates Amorphous Solids5 Phase Equilibria and the Phase Rule Phase Rule Systems Containing One Component Condensed System Two-Component Systems Containing Liquid Phases Two-Component Systems Containing Solid and Liquid Phases Eutectic Mixtures Rules Relating to Triangular Diagrams

                                                            Topics that we have covered

                                                            • States of Matter
                                                            • States of Matter (2)
                                                            • Objectives of the lecture
                                                            • Comparison of Gases Liquids and Solids
                                                            • Slide 5
                                                            • Repulsive and Attractive Forces
                                                            • Ideal Gas Equation
                                                            • Gaseous state
                                                            • Slide 9
                                                            • Gaseous state (2)
                                                            • Liquefaction of Gases
                                                            • Slide 12
                                                            • SOLIDS amp CRYSTALLINE STATE Pharmaceutical Drugs more than 80
                                                            • Solids and the crystalline state
                                                            • Classification of Solids
                                                            • Slide 16
                                                            • Slide 17
                                                            • Crystal forms
                                                            • Types of Crystals
                                                            • Slide 20
                                                            • Slide 21
                                                            • Polymorphism
                                                            • Slide 23
                                                            • Slide 24
                                                            • Slide 25
                                                            • Slide 26
                                                            • Cocrystal
                                                            • Principle of polymorphism
                                                            • Solvates
                                                            • Polymorphism (2)
                                                            • Amorphous Solid
                                                            • Amorphous or crystalline amp therapeutic activity
                                                            • Slide 33
                                                            • Slide 34
                                                            • Polymorphism and Industry Pharmaceutical
                                                            • Celecoxib
                                                            • Furosemide
                                                            • Bioavailability
                                                            • Slide 39
                                                            • Slide 40
                                                            • Bioequivalence
                                                            • Slide 42
                                                            • Carbamazepine
                                                            • Slide 44
                                                            • AIDS drug ritonavir
                                                            • Slide 46
                                                            • Slide 47
                                                            • Phase Equilibria amp The Phase Rule
                                                            • Phase diagram ndash Water
                                                            • Phase Equilibria amp The Phase Rule Definitions
                                                            • Phase Definition
                                                            • Examples
                                                            • Components
                                                            • Examples
                                                            • Slide 55
                                                            • Degrees of freedom (or variance)
                                                            • Examples (2)
                                                            • Phase Equilibria amp The Phase Rule
                                                            • The phase rule
                                                            • Slide 60
                                                            • Phase Equilibria amp The Phase Rule (2)
                                                            • The number of phases in a system is denoted P
                                                            • Slide 63
                                                            • Slide 64
                                                            • One-component systems
                                                            • Slide 66
                                                            • Slide 67
                                                            • Slide 68
                                                            • Slide 69
                                                            • Slide 70
                                                            • Two component system containing liquid phase
                                                            • Slide 72
                                                            • The Critical Solution Temperature CST
                                                            • Systems Showing a Decrease in Miscibility with Rise in Temperat
                                                            • Systems Showing Upper and Lower CSTs
                                                            • Two component system containing solid and liquid phase (Eutecti
                                                            • Slide 77
                                                            • Eutectic mixture Pharmaceutical Application
                                                            • Three component system
                                                            • Slide 80
                                                            • Topics that we have covered

                                                              Final Form

                                                              Granulation

                                                              Drying

                                                              Compaction

                                                              Tableting

                                                              Drug Product

                                                              API

                                                              Crystallization

                                                              Filtration

                                                              Drying

                                                              Milling

                                                              Bulk API

                                                              Stability

                                                              Polymorphism and Industry Pharmaceutical

                                                              Polymorphism and Industry Pharmaceutical

                                                              Fluoxetine HCl the active ingredient in the antidepressant drug Prozac

                                                              co crystal which will have increased solubility compared to the crystalline form

                                                              Celecoxib

                                                              CELECOXIB is a nonsteroidal anti-inflammatory drug

                                                              However it was found that the higher bioavailability was shown by the amorphous state

                                                              The downfall of the amorphous state was its stability

                                                              This was due to the structural relaxation

                                                              This was enhanced by mixing it with polymers like PVP which helped in stabilizing the amorphous system (Piyush Gupta et al 2004 Piyush Gupta et al 2005)

                                                              A new solid state form was developed by Pharmacia

                                                              FurosemideTwo forms with significantly differing aqueous solubility and dissolution rateOral bioavailability compromised

                                                              Giron lists gt20 excipients that display polymorphism includingndash Lactose (anhydrous also monohydrate)ndash Aspartame (anhydrous hydrate forms)ndash Magnesium stearate (can affect lubrication of tablets)

                                                              Bioavailability

                                                              The rate and extent to which the active ingredient or active moiety is absorbed from a drug product and becomes available at the site of action

                                                              Bioequivalence

                                                              The absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study

                                                              Carbamazepine

                                                              CHLORPROPAMIDEat least six polymorphic white or almost white crystalline powder It exhibits polymorphism Practically insoluble in water soluble in alcohol freely soluble in acetone and in dichlo-romethane dissolves in dilute solutions of alkali hydroxides Protect from light

                                                              blood-glucose-lowering drug

                                                              AIDS drug ritonavir

                                                              Theobroma oil (cacao butter ) is a polymorphic natural fat

                                                              Theobroma oil can exist in 4 different polymorphic forms of which only one is Stabile

                                                              1 Unstable gamma form melting at 18degC2 Alpha form melting at 22degC3 Beta prime form melting at 28degC4 Stable beta form melting at 345degC

                                                              This is important in the preparation of theobroma suppositories

                                                              If the oil is heated to a point where it is completely liquified (about 35 C) the crystals of the stable polymorph are destroyed amp the mass does not crystallize until it is cooled to 15 C

                                                              The crystals that form are unstable amp the suppositories melt at 24 C

                                                              Theobroma suppositories must be prepared below 33 C

                                                              Polymorphism and Industry Pharmaceutical

                                                              Polymorphism and Industry Pharmaceutical

                                                              Anhydrates together with salts form the majority of all drug formulationsAbout a half of all APIs used today are saltsSalts are stable and well soluble in polar solvents (first of all in water) because they contain ionic bondThere is one more essential advantage of salts ndash their solubility is a function of pH Since pH in the gastrointestinal tract (GIT) vary between 1-75

                                                              atorvastatin calcium trihydrateEach tablet contains Atorvastatin Calcium Trihydrate equivalent to Atorvastatin 20 mg

                                                              Phase Equilibria amp The Phase Rule

                                                              Phase diagram ndash Water

                                                              Phase Equilibrium A stable phase structure with lowest free-energy (internal energy) of a system and also randomness or disorder of the atoms or molecules (entropy)

                                                              Any change in Temperature Composition and Pressure causes an increase in free energy and away from Equilibrium thus forcing a move to another lsquostatersquo

                                                              Phase Equilibria amp The Phase Rule Definitions

                                                              A phase is defined as any homogeneous and physically distinct part of a system which is separated from other parts of the system by interfaces

                                                              A part of a system is homogeneous if it has identical physical properties and chemical composition throughout the part

                                                              A phase may be gas liquid or solid A gas or a gaseous mixture is a single phase Totally miscible liquids constitute a single phase In an immiscible liquid system each layer is counted as a separate phase Every solid constitutes a single phase except when a solid solution is formed A solid solution is considered as a single phase Each polymorphic form constitutes a separate phase

                                                              Phase Definition

                                                              1 Liquid water pieces of ice and water vapour are present together The number of phases is 3 as each form is a separate phase Ice in the system is a single phase even if it is present as a number of pieces

                                                              2 Calcium carbonate undergoes thermal decomposition The chemical reaction is CaCO3(s) CaO(s) + CO2 (g) Number of phases = 3 This system consists of 2 solid phases CaCO3 and CaO and one gaseous phase that of CO2

                                                              3 Ammonium chloride undergoes thermal decomposition The chemical reaction is NH4Cl(s) NH3 (g) + HCl (g) Number of phases = 2 This system has two phases one solid NH4Cl and one gaseous a mixture of NH3 and HCl

                                                              4 A solution of NaCl in water Number of phases = 1

                                                              bull Examples

                                                              The number of components of a system at equilibrium is the smallest number of independently varying chemical constituents using which the composition of each and every phase in the system can be expressed

                                                              Components

                                                              Counting the number of components 1 The sulphur system is a one component system All the phases

                                                              monoclinic rhombic liquid and vapour ndash can be expressed in terms of the single constituent ndash sulphur

                                                              2 A mixture of ethanol and water is an example of a two component system We need both ethanol and water to express its composition

                                                              bull Examples

                                                              An example of a system in which a reaction occurs and an equilibrium is established is the thermal decomposition of solid CaCO3

                                                              In this system there are three distinct phasesSolid CaCO3

                                                              Solid CaOGaseous CO2

                                                              Though there are 3 species present the number of components is only two because of the equilibrium CaCO3 (s) CaO(s) + CO2(g)

                                                              Any two of the three constituents may be chosen as the components

                                                              If CaO and CO2 are chosen then the composition of the phase CaCO3 is expressed as one mole of component CO2 plus one mole of component CaO

                                                              If on the other hand CaCO3 and CO2 were chosen then the composition of the phase CaO would be described as one mole of CaCO3 minus one mole of CO2

                                                              The degrees of freedom or variance of a system is defined as the minimum number of variables such as

                                                              temperaturepressureconcentrationwhich must be fixed in order to define the system completely

                                                              Degrees of freedom (or variance)

                                                              F = C P + 2

                                                              1 A gaseous mixture of CO2 and N2 Three variables pressure temperature and composition are required to define this system This is hence a trivariant system

                                                              2 A system having only liquid water has two degrees of freedom or is bivariant Both temperature and pressure need to be mentioned in order to define the system

                                                              3 If to the system containing liquid water pieces of ice are added and this system with 2 phases is allowed to come to equilibrium then it is an univariant system

                                                              Only one variable either temperature or pressure need to be specified in order to define the systemIf the pressure on the system is maintained at 1 atm then the temperature of the system gets automatically fixed at 0oC the normal melting point of ice

                                                              bull Examples

                                                              Phase Equilibria amp The Phase Rule

                                                              A phase diagram (Equilibrium Phase Diagram) summarizes the conditions at which a substance exists as a solid liquid or gas

                                                              OR It is a ldquomaprdquo of the information about the control of phase structure of a particular material system

                                                              The relationships between temperature and the compositions and the quantities of phases present at equilibrium are represented

                                                              F = C P + 2The phase rule

                                                              The phase rule JW Gibbs formulated the phase rule which is a general relation

                                                              between the variance F the number of component C and the number of phases P at equilibrium for a system of any composition

                                                              For a system in equilibrium

                                                              F degree of freedom the least number of intensive variable that must be fixed (known) to describe the system completely

                                                              Phase Rule relation to determine the least number of intensive variable that can be changed without changing the equilibrium state of the system or alternately

                                                              The least number required to define the state of the system which is called degree of freedom F

                                                              Intensive variable independent variable that do not depend on the volume or the size egTemp pressure

                                                              Independent chemical species which comprise the system These could be Elements Ions Compounds

                                                              Eg Au-Cu system Components rarr Au Cu Ice-water system Component rarr H2O

                                                              Al2O3 ndash Cr2O3 system Components rarr Al2O3 Cr2O3

                                                              Component the smallest number of constituent by which the composition of each phase in the system at equilibrium can be expressed in form of chemical formula or equation

                                                              Phase Equilibria amp The Phase RuleComponents of a system

                                                              The number of phases in a system is denoted P

                                                              (a)A gas or a gaseous mixture is a single phase P=1

                                                              (b) For a solid system an alloy of two metals is a two-phase system (P=2) if the metals are immiscible but a single-phase system (P=1) if they are miscible---a homogeneous mixture of the two substances---is uniform on a molecular scale

                                                              (c) For a liquid system according to the solubility to decide whether a system consists of one phase or of two For example a solution of sodium chloride in water is a single phase A pair of liquids that are partially miscible or immiscible is a two-phase system(P=2)

                                                              Oil in water

                                                              Degrees of Freedom = What you can control What the system controls

                                                              F = C + 2 P

                                                              Can control the no of components added and P amp T

                                                              System decided how many phases to produce given the

                                                              conditions

                                                              A way of understanding the Gibbs Phase RuleThe degrees of freedom can be thought of as the difference between what you (can) control and

                                                              what the system controls

                                                              F degree of freedom the least number of intensive variable that must be fixed (known) to describe the system completely

                                                              Degree of freedom (or variance) F is the number of variables (T p andor composition) that can be changed independently without changing the phases of the system

                                                              a) At the triple pointP = 3 (solid liquid and gas)

                                                              C= 1 (water)P + F = C + 2

                                                              F = 0 (no degree of freedom)

                                                              b) liquid-solid curveP = 2

                                                              2+F = 1 + 2F= 1

                                                              One variable (T or P) can be changed

                                                              c) LiquidP =1

                                                              So F =2Two variables (T and P) can be varied independently

                                                              and the system will remains a single phase

                                                              One-component systemsPhase diagram of water

                                                              P (

                                                              atm

                                                              )

                                                              Critical point

                                                              374

                                                              1

                                                              =100=0O--Triple point

                                                              0006

                                                              218

                                                              Curve O -CSublimation

                                                              Deposition

                                                              Curve O-AVaporizationCondensation

                                                              Curve O -BMelting

                                                              Freezing

                                                              F = C P + 2

                                                              F = C P + 2

                                                              Phase Diagram of Carbon Dioxide

                                                              Condensed system System in which the vapor phase is ignored and only the solid andor liquid phases are considered

                                                              Two component system For two component system F can be 3 (3D model is needed) eg T p

                                                              and concentration usually we fix p = 1atm the vapor phase is neglected and F is reduced to 2

                                                              For three component system the pressure and temperature are fixed

                                                              Phenol water phase diagram

                                                              eg for point d (24)

                                                              Two component system containing liquid phase

                                                              Tie Line bc line The line at which the system at equilibrium will separate into phases of constant composition termed lsquoconjugate phasesrsquo

                                                              Lever Rule a way to calculate the proportions of each phase present on a phase diagram in a two phase field (at a given temperature and composition)

                                                              eg for point d (24)

                                                              For every 10 g of liquid system in equilibrium in point d

                                                              75 g phase A25 g phase B

                                                              ExampleMixed 24g phenol +76g water T 50degC

                                                              equilibrium75 g phase A 25 g phase B

                                                              11 phenol 63 phenol

                                                              011 times75 g=825 g phenol

                                                              063 times25 g=1575 g phenol

                                                              water rich phasecontains water+ phenol(11)

                                                              Phenol rich phasecontains Phenol (63)+ water

                                                              The Critical Solution Temperature CST

                                                              Is the maximum temperature at which the 2-phase region exists (or upper consolute temperature)

                                                              In the case of the phenol-water system this is 668oC (point h)

                                                              All combinations of phenol and water gt CST are completely miscible and yield 1-phase liquid systems

                                                              Systems Showing a Decrease in Miscibility with Rise in Temperature

                                                              A few mixtures exhibit a lower critical solution temperature (low CST) eg triethylamine plus water The miscibility with in temperature

                                                              Systems Showing Upper and Lower CSTs

                                                              The miscibility with temp

                                                              a certain temperature miscibility starts to again with further in temperature

                                                              Closed-phase diagram ie nicotine-water system

                                                              A salol B thymol

                                                              53

                                                              Two component system containing solid and liquid phase (Eutectic Mixtures)

                                                              A salol B thymol

                                                              EMLAreg (lidocaine 25 and prilocaine 25) Cream

                                                              EMLA Cream (lidocaine 25 and prilocaine 25) is an emulsion in which the oil phase is a eutectic mixture of lidocaine and prilocaine in a ratio of 11 by weight This eutectic mixture has a melting point below room temperature and therefore both local anesthetics exist as a liquid oil rather than as crystals

                                                              Eutectic mixture Pharmaceutical Application

                                                              Triangular Diagrams for three ndash component systems

                                                              Three component system

                                                              Birzeit University Physical Pharmacy PHAR 323 Dr Hani Shtaya

                                                              1 Binding Forces Between Molecules2 Repulsive and Attractive Forces3 The Gaseous State The Ideal Gas Law Liquefaction of Gases Aerosols4 Solids and the Crystalline State Crystalline Solids Polymorphism Solvates Amorphous Solids5 Phase Equilibria and the Phase Rule Phase Rule Systems Containing One Component Condensed System Two-Component Systems Containing Liquid Phases Two-Component Systems Containing Solid and Liquid Phases Eutectic Mixtures Rules Relating to Triangular Diagrams

                                                              Topics that we have covered

                                                              • States of Matter
                                                              • States of Matter (2)
                                                              • Objectives of the lecture
                                                              • Comparison of Gases Liquids and Solids
                                                              • Slide 5
                                                              • Repulsive and Attractive Forces
                                                              • Ideal Gas Equation
                                                              • Gaseous state
                                                              • Slide 9
                                                              • Gaseous state (2)
                                                              • Liquefaction of Gases
                                                              • Slide 12
                                                              • SOLIDS amp CRYSTALLINE STATE Pharmaceutical Drugs more than 80
                                                              • Solids and the crystalline state
                                                              • Classification of Solids
                                                              • Slide 16
                                                              • Slide 17
                                                              • Crystal forms
                                                              • Types of Crystals
                                                              • Slide 20
                                                              • Slide 21
                                                              • Polymorphism
                                                              • Slide 23
                                                              • Slide 24
                                                              • Slide 25
                                                              • Slide 26
                                                              • Cocrystal
                                                              • Principle of polymorphism
                                                              • Solvates
                                                              • Polymorphism (2)
                                                              • Amorphous Solid
                                                              • Amorphous or crystalline amp therapeutic activity
                                                              • Slide 33
                                                              • Slide 34
                                                              • Polymorphism and Industry Pharmaceutical
                                                              • Celecoxib
                                                              • Furosemide
                                                              • Bioavailability
                                                              • Slide 39
                                                              • Slide 40
                                                              • Bioequivalence
                                                              • Slide 42
                                                              • Carbamazepine
                                                              • Slide 44
                                                              • AIDS drug ritonavir
                                                              • Slide 46
                                                              • Slide 47
                                                              • Phase Equilibria amp The Phase Rule
                                                              • Phase diagram ndash Water
                                                              • Phase Equilibria amp The Phase Rule Definitions
                                                              • Phase Definition
                                                              • Examples
                                                              • Components
                                                              • Examples
                                                              • Slide 55
                                                              • Degrees of freedom (or variance)
                                                              • Examples (2)
                                                              • Phase Equilibria amp The Phase Rule
                                                              • The phase rule
                                                              • Slide 60
                                                              • Phase Equilibria amp The Phase Rule (2)
                                                              • The number of phases in a system is denoted P
                                                              • Slide 63
                                                              • Slide 64
                                                              • One-component systems
                                                              • Slide 66
                                                              • Slide 67
                                                              • Slide 68
                                                              • Slide 69
                                                              • Slide 70
                                                              • Two component system containing liquid phase
                                                              • Slide 72
                                                              • The Critical Solution Temperature CST
                                                              • Systems Showing a Decrease in Miscibility with Rise in Temperat
                                                              • Systems Showing Upper and Lower CSTs
                                                              • Two component system containing solid and liquid phase (Eutecti
                                                              • Slide 77
                                                              • Eutectic mixture Pharmaceutical Application
                                                              • Three component system
                                                              • Slide 80
                                                              • Topics that we have covered

                                                                Polymorphism and Industry Pharmaceutical

                                                                Fluoxetine HCl the active ingredient in the antidepressant drug Prozac

                                                                co crystal which will have increased solubility compared to the crystalline form

                                                                Celecoxib

                                                                CELECOXIB is a nonsteroidal anti-inflammatory drug

                                                                However it was found that the higher bioavailability was shown by the amorphous state

                                                                The downfall of the amorphous state was its stability

                                                                This was due to the structural relaxation

                                                                This was enhanced by mixing it with polymers like PVP which helped in stabilizing the amorphous system (Piyush Gupta et al 2004 Piyush Gupta et al 2005)

                                                                A new solid state form was developed by Pharmacia

                                                                FurosemideTwo forms with significantly differing aqueous solubility and dissolution rateOral bioavailability compromised

                                                                Giron lists gt20 excipients that display polymorphism includingndash Lactose (anhydrous also monohydrate)ndash Aspartame (anhydrous hydrate forms)ndash Magnesium stearate (can affect lubrication of tablets)

                                                                Bioavailability

                                                                The rate and extent to which the active ingredient or active moiety is absorbed from a drug product and becomes available at the site of action

                                                                Bioequivalence

                                                                The absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study

                                                                Carbamazepine

                                                                CHLORPROPAMIDEat least six polymorphic white or almost white crystalline powder It exhibits polymorphism Practically insoluble in water soluble in alcohol freely soluble in acetone and in dichlo-romethane dissolves in dilute solutions of alkali hydroxides Protect from light

                                                                blood-glucose-lowering drug

                                                                AIDS drug ritonavir

                                                                Theobroma oil (cacao butter ) is a polymorphic natural fat

                                                                Theobroma oil can exist in 4 different polymorphic forms of which only one is Stabile

                                                                1 Unstable gamma form melting at 18degC2 Alpha form melting at 22degC3 Beta prime form melting at 28degC4 Stable beta form melting at 345degC

                                                                This is important in the preparation of theobroma suppositories

                                                                If the oil is heated to a point where it is completely liquified (about 35 C) the crystals of the stable polymorph are destroyed amp the mass does not crystallize until it is cooled to 15 C

                                                                The crystals that form are unstable amp the suppositories melt at 24 C

                                                                Theobroma suppositories must be prepared below 33 C

                                                                Polymorphism and Industry Pharmaceutical

                                                                Polymorphism and Industry Pharmaceutical

                                                                Anhydrates together with salts form the majority of all drug formulationsAbout a half of all APIs used today are saltsSalts are stable and well soluble in polar solvents (first of all in water) because they contain ionic bondThere is one more essential advantage of salts ndash their solubility is a function of pH Since pH in the gastrointestinal tract (GIT) vary between 1-75

                                                                atorvastatin calcium trihydrateEach tablet contains Atorvastatin Calcium Trihydrate equivalent to Atorvastatin 20 mg

                                                                Phase Equilibria amp The Phase Rule

                                                                Phase diagram ndash Water

                                                                Phase Equilibrium A stable phase structure with lowest free-energy (internal energy) of a system and also randomness or disorder of the atoms or molecules (entropy)

                                                                Any change in Temperature Composition and Pressure causes an increase in free energy and away from Equilibrium thus forcing a move to another lsquostatersquo

                                                                Phase Equilibria amp The Phase Rule Definitions

                                                                A phase is defined as any homogeneous and physically distinct part of a system which is separated from other parts of the system by interfaces

                                                                A part of a system is homogeneous if it has identical physical properties and chemical composition throughout the part

                                                                A phase may be gas liquid or solid A gas or a gaseous mixture is a single phase Totally miscible liquids constitute a single phase In an immiscible liquid system each layer is counted as a separate phase Every solid constitutes a single phase except when a solid solution is formed A solid solution is considered as a single phase Each polymorphic form constitutes a separate phase

                                                                Phase Definition

                                                                1 Liquid water pieces of ice and water vapour are present together The number of phases is 3 as each form is a separate phase Ice in the system is a single phase even if it is present as a number of pieces

                                                                2 Calcium carbonate undergoes thermal decomposition The chemical reaction is CaCO3(s) CaO(s) + CO2 (g) Number of phases = 3 This system consists of 2 solid phases CaCO3 and CaO and one gaseous phase that of CO2

                                                                3 Ammonium chloride undergoes thermal decomposition The chemical reaction is NH4Cl(s) NH3 (g) + HCl (g) Number of phases = 2 This system has two phases one solid NH4Cl and one gaseous a mixture of NH3 and HCl

                                                                4 A solution of NaCl in water Number of phases = 1

                                                                bull Examples

                                                                The number of components of a system at equilibrium is the smallest number of independently varying chemical constituents using which the composition of each and every phase in the system can be expressed

                                                                Components

                                                                Counting the number of components 1 The sulphur system is a one component system All the phases

                                                                monoclinic rhombic liquid and vapour ndash can be expressed in terms of the single constituent ndash sulphur

                                                                2 A mixture of ethanol and water is an example of a two component system We need both ethanol and water to express its composition

                                                                bull Examples

                                                                An example of a system in which a reaction occurs and an equilibrium is established is the thermal decomposition of solid CaCO3

                                                                In this system there are three distinct phasesSolid CaCO3

                                                                Solid CaOGaseous CO2

                                                                Though there are 3 species present the number of components is only two because of the equilibrium CaCO3 (s) CaO(s) + CO2(g)

                                                                Any two of the three constituents may be chosen as the components

                                                                If CaO and CO2 are chosen then the composition of the phase CaCO3 is expressed as one mole of component CO2 plus one mole of component CaO

                                                                If on the other hand CaCO3 and CO2 were chosen then the composition of the phase CaO would be described as one mole of CaCO3 minus one mole of CO2

                                                                The degrees of freedom or variance of a system is defined as the minimum number of variables such as

                                                                temperaturepressureconcentrationwhich must be fixed in order to define the system completely

                                                                Degrees of freedom (or variance)

                                                                F = C P + 2

                                                                1 A gaseous mixture of CO2 and N2 Three variables pressure temperature and composition are required to define this system This is hence a trivariant system

                                                                2 A system having only liquid water has two degrees of freedom or is bivariant Both temperature and pressure need to be mentioned in order to define the system

                                                                3 If to the system containing liquid water pieces of ice are added and this system with 2 phases is allowed to come to equilibrium then it is an univariant system

                                                                Only one variable either temperature or pressure need to be specified in order to define the systemIf the pressure on the system is maintained at 1 atm then the temperature of the system gets automatically fixed at 0oC the normal melting point of ice

                                                                bull Examples

                                                                Phase Equilibria amp The Phase Rule

                                                                A phase diagram (Equilibrium Phase Diagram) summarizes the conditions at which a substance exists as a solid liquid or gas

                                                                OR It is a ldquomaprdquo of the information about the control of phase structure of a particular material system

                                                                The relationships between temperature and the compositions and the quantities of phases present at equilibrium are represented

                                                                F = C P + 2The phase rule

                                                                The phase rule JW Gibbs formulated the phase rule which is a general relation

                                                                between the variance F the number of component C and the number of phases P at equilibrium for a system of any composition

                                                                For a system in equilibrium

                                                                F degree of freedom the least number of intensive variable that must be fixed (known) to describe the system completely

                                                                Phase Rule relation to determine the least number of intensive variable that can be changed without changing the equilibrium state of the system or alternately

                                                                The least number required to define the state of the system which is called degree of freedom F

                                                                Intensive variable independent variable that do not depend on the volume or the size egTemp pressure

                                                                Independent chemical species which comprise the system These could be Elements Ions Compounds

                                                                Eg Au-Cu system Components rarr Au Cu Ice-water system Component rarr H2O

                                                                Al2O3 ndash Cr2O3 system Components rarr Al2O3 Cr2O3

                                                                Component the smallest number of constituent by which the composition of each phase in the system at equilibrium can be expressed in form of chemical formula or equation

                                                                Phase Equilibria amp The Phase RuleComponents of a system

                                                                The number of phases in a system is denoted P

                                                                (a)A gas or a gaseous mixture is a single phase P=1

                                                                (b) For a solid system an alloy of two metals is a two-phase system (P=2) if the metals are immiscible but a single-phase system (P=1) if they are miscible---a homogeneous mixture of the two substances---is uniform on a molecular scale

                                                                (c) For a liquid system according to the solubility to decide whether a system consists of one phase or of two For example a solution of sodium chloride in water is a single phase A pair of liquids that are partially miscible or immiscible is a two-phase system(P=2)

                                                                Oil in water

                                                                Degrees of Freedom = What you can control What the system controls

                                                                F = C + 2 P

                                                                Can control the no of components added and P amp T

                                                                System decided how many phases to produce given the

                                                                conditions

                                                                A way of understanding the Gibbs Phase RuleThe degrees of freedom can be thought of as the difference between what you (can) control and

                                                                what the system controls

                                                                F degree of freedom the least number of intensive variable that must be fixed (known) to describe the system completely

                                                                Degree of freedom (or variance) F is the number of variables (T p andor composition) that can be changed independently without changing the phases of the system

                                                                a) At the triple pointP = 3 (solid liquid and gas)

                                                                C= 1 (water)P + F = C + 2

                                                                F = 0 (no degree of freedom)

                                                                b) liquid-solid curveP = 2

                                                                2+F = 1 + 2F= 1

                                                                One variable (T or P) can be changed

                                                                c) LiquidP =1

                                                                So F =2Two variables (T and P) can be varied independently

                                                                and the system will remains a single phase

                                                                One-component systemsPhase diagram of water

                                                                P (

                                                                atm

                                                                )

                                                                Critical point

                                                                374

                                                                1

                                                                =100=0O--Triple point

                                                                0006

                                                                218

                                                                Curve O -CSublimation

                                                                Deposition

                                                                Curve O-AVaporizationCondensation

                                                                Curve O -BMelting

                                                                Freezing

                                                                F = C P + 2

                                                                F = C P + 2

                                                                Phase Diagram of Carbon Dioxide

                                                                Condensed system System in which the vapor phase is ignored and only the solid andor liquid phases are considered

                                                                Two component system For two component system F can be 3 (3D model is needed) eg T p

                                                                and concentration usually we fix p = 1atm the vapor phase is neglected and F is reduced to 2

                                                                For three component system the pressure and temperature are fixed

                                                                Phenol water phase diagram

                                                                eg for point d (24)

                                                                Two component system containing liquid phase

                                                                Tie Line bc line The line at which the system at equilibrium will separate into phases of constant composition termed lsquoconjugate phasesrsquo

                                                                Lever Rule a way to calculate the proportions of each phase present on a phase diagram in a two phase field (at a given temperature and composition)

                                                                eg for point d (24)

                                                                For every 10 g of liquid system in equilibrium in point d

                                                                75 g phase A25 g phase B

                                                                ExampleMixed 24g phenol +76g water T 50degC

                                                                equilibrium75 g phase A 25 g phase B

                                                                11 phenol 63 phenol

                                                                011 times75 g=825 g phenol

                                                                063 times25 g=1575 g phenol

                                                                water rich phasecontains water+ phenol(11)

                                                                Phenol rich phasecontains Phenol (63)+ water

                                                                The Critical Solution Temperature CST

                                                                Is the maximum temperature at which the 2-phase region exists (or upper consolute temperature)

                                                                In the case of the phenol-water system this is 668oC (point h)

                                                                All combinations of phenol and water gt CST are completely miscible and yield 1-phase liquid systems

                                                                Systems Showing a Decrease in Miscibility with Rise in Temperature

                                                                A few mixtures exhibit a lower critical solution temperature (low CST) eg triethylamine plus water The miscibility with in temperature

                                                                Systems Showing Upper and Lower CSTs

                                                                The miscibility with temp

                                                                a certain temperature miscibility starts to again with further in temperature

                                                                Closed-phase diagram ie nicotine-water system

                                                                A salol B thymol

                                                                53

                                                                Two component system containing solid and liquid phase (Eutectic Mixtures)

                                                                A salol B thymol

                                                                EMLAreg (lidocaine 25 and prilocaine 25) Cream

                                                                EMLA Cream (lidocaine 25 and prilocaine 25) is an emulsion in which the oil phase is a eutectic mixture of lidocaine and prilocaine in a ratio of 11 by weight This eutectic mixture has a melting point below room temperature and therefore both local anesthetics exist as a liquid oil rather than as crystals

                                                                Eutectic mixture Pharmaceutical Application

                                                                Triangular Diagrams for three ndash component systems

                                                                Three component system

                                                                Birzeit University Physical Pharmacy PHAR 323 Dr Hani Shtaya

                                                                1 Binding Forces Between Molecules2 Repulsive and Attractive Forces3 The Gaseous State The Ideal Gas Law Liquefaction of Gases Aerosols4 Solids and the Crystalline State Crystalline Solids Polymorphism Solvates Amorphous Solids5 Phase Equilibria and the Phase Rule Phase Rule Systems Containing One Component Condensed System Two-Component Systems Containing Liquid Phases Two-Component Systems Containing Solid and Liquid Phases Eutectic Mixtures Rules Relating to Triangular Diagrams

                                                                Topics that we have covered

                                                                • States of Matter
                                                                • States of Matter (2)
                                                                • Objectives of the lecture
                                                                • Comparison of Gases Liquids and Solids
                                                                • Slide 5
                                                                • Repulsive and Attractive Forces
                                                                • Ideal Gas Equation
                                                                • Gaseous state
                                                                • Slide 9
                                                                • Gaseous state (2)
                                                                • Liquefaction of Gases
                                                                • Slide 12
                                                                • SOLIDS amp CRYSTALLINE STATE Pharmaceutical Drugs more than 80
                                                                • Solids and the crystalline state
                                                                • Classification of Solids
                                                                • Slide 16
                                                                • Slide 17
                                                                • Crystal forms
                                                                • Types of Crystals
                                                                • Slide 20
                                                                • Slide 21
                                                                • Polymorphism
                                                                • Slide 23
                                                                • Slide 24
                                                                • Slide 25
                                                                • Slide 26
                                                                • Cocrystal
                                                                • Principle of polymorphism
                                                                • Solvates
                                                                • Polymorphism (2)
                                                                • Amorphous Solid
                                                                • Amorphous or crystalline amp therapeutic activity
                                                                • Slide 33
                                                                • Slide 34
                                                                • Polymorphism and Industry Pharmaceutical
                                                                • Celecoxib
                                                                • Furosemide
                                                                • Bioavailability
                                                                • Slide 39
                                                                • Slide 40
                                                                • Bioequivalence
                                                                • Slide 42
                                                                • Carbamazepine
                                                                • Slide 44
                                                                • AIDS drug ritonavir
                                                                • Slide 46
                                                                • Slide 47
                                                                • Phase Equilibria amp The Phase Rule
                                                                • Phase diagram ndash Water
                                                                • Phase Equilibria amp The Phase Rule Definitions
                                                                • Phase Definition
                                                                • Examples
                                                                • Components
                                                                • Examples
                                                                • Slide 55
                                                                • Degrees of freedom (or variance)
                                                                • Examples (2)
                                                                • Phase Equilibria amp The Phase Rule
                                                                • The phase rule
                                                                • Slide 60
                                                                • Phase Equilibria amp The Phase Rule (2)
                                                                • The number of phases in a system is denoted P
                                                                • Slide 63
                                                                • Slide 64
                                                                • One-component systems
                                                                • Slide 66
                                                                • Slide 67
                                                                • Slide 68
                                                                • Slide 69
                                                                • Slide 70
                                                                • Two component system containing liquid phase
                                                                • Slide 72
                                                                • The Critical Solution Temperature CST
                                                                • Systems Showing a Decrease in Miscibility with Rise in Temperat
                                                                • Systems Showing Upper and Lower CSTs
                                                                • Two component system containing solid and liquid phase (Eutecti
                                                                • Slide 77
                                                                • Eutectic mixture Pharmaceutical Application
                                                                • Three component system
                                                                • Slide 80
                                                                • Topics that we have covered

                                                                  Celecoxib

                                                                  CELECOXIB is a nonsteroidal anti-inflammatory drug

                                                                  However it was found that the higher bioavailability was shown by the amorphous state

                                                                  The downfall of the amorphous state was its stability

                                                                  This was due to the structural relaxation

                                                                  This was enhanced by mixing it with polymers like PVP which helped in stabilizing the amorphous system (Piyush Gupta et al 2004 Piyush Gupta et al 2005)

                                                                  A new solid state form was developed by Pharmacia

                                                                  FurosemideTwo forms with significantly differing aqueous solubility and dissolution rateOral bioavailability compromised

                                                                  Giron lists gt20 excipients that display polymorphism includingndash Lactose (anhydrous also monohydrate)ndash Aspartame (anhydrous hydrate forms)ndash Magnesium stearate (can affect lubrication of tablets)

                                                                  Bioavailability

                                                                  The rate and extent to which the active ingredient or active moiety is absorbed from a drug product and becomes available at the site of action

                                                                  Bioequivalence

                                                                  The absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study

                                                                  Carbamazepine

                                                                  CHLORPROPAMIDEat least six polymorphic white or almost white crystalline powder It exhibits polymorphism Practically insoluble in water soluble in alcohol freely soluble in acetone and in dichlo-romethane dissolves in dilute solutions of alkali hydroxides Protect from light

                                                                  blood-glucose-lowering drug

                                                                  AIDS drug ritonavir

                                                                  Theobroma oil (cacao butter ) is a polymorphic natural fat

                                                                  Theobroma oil can exist in 4 different polymorphic forms of which only one is Stabile

                                                                  1 Unstable gamma form melting at 18degC2 Alpha form melting at 22degC3 Beta prime form melting at 28degC4 Stable beta form melting at 345degC

                                                                  This is important in the preparation of theobroma suppositories

                                                                  If the oil is heated to a point where it is completely liquified (about 35 C) the crystals of the stable polymorph are destroyed amp the mass does not crystallize until it is cooled to 15 C

                                                                  The crystals that form are unstable amp the suppositories melt at 24 C

                                                                  Theobroma suppositories must be prepared below 33 C

                                                                  Polymorphism and Industry Pharmaceutical

                                                                  Polymorphism and Industry Pharmaceutical

                                                                  Anhydrates together with salts form the majority of all drug formulationsAbout a half of all APIs used today are saltsSalts are stable and well soluble in polar solvents (first of all in water) because they contain ionic bondThere is one more essential advantage of salts ndash their solubility is a function of pH Since pH in the gastrointestinal tract (GIT) vary between 1-75

                                                                  atorvastatin calcium trihydrateEach tablet contains Atorvastatin Calcium Trihydrate equivalent to Atorvastatin 20 mg

                                                                  Phase Equilibria amp The Phase Rule

                                                                  Phase diagram ndash Water

                                                                  Phase Equilibrium A stable phase structure with lowest free-energy (internal energy) of a system and also randomness or disorder of the atoms or molecules (entropy)

                                                                  Any change in Temperature Composition and Pressure causes an increase in free energy and away from Equilibrium thus forcing a move to another lsquostatersquo

                                                                  Phase Equilibria amp The Phase Rule Definitions

                                                                  A phase is defined as any homogeneous and physically distinct part of a system which is separated from other parts of the system by interfaces

                                                                  A part of a system is homogeneous if it has identical physical properties and chemical composition throughout the part

                                                                  A phase may be gas liquid or solid A gas or a gaseous mixture is a single phase Totally miscible liquids constitute a single phase In an immiscible liquid system each layer is counted as a separate phase Every solid constitutes a single phase except when a solid solution is formed A solid solution is considered as a single phase Each polymorphic form constitutes a separate phase

                                                                  Phase Definition

                                                                  1 Liquid water pieces of ice and water vapour are present together The number of phases is 3 as each form is a separate phase Ice in the system is a single phase even if it is present as a number of pieces

                                                                  2 Calcium carbonate undergoes thermal decomposition The chemical reaction is CaCO3(s) CaO(s) + CO2 (g) Number of phases = 3 This system consists of 2 solid phases CaCO3 and CaO and one gaseous phase that of CO2

                                                                  3 Ammonium chloride undergoes thermal decomposition The chemical reaction is NH4Cl(s) NH3 (g) + HCl (g) Number of phases = 2 This system has two phases one solid NH4Cl and one gaseous a mixture of NH3 and HCl

                                                                  4 A solution of NaCl in water Number of phases = 1

                                                                  bull Examples

                                                                  The number of components of a system at equilibrium is the smallest number of independently varying chemical constituents using which the composition of each and every phase in the system can be expressed

                                                                  Components

                                                                  Counting the number of components 1 The sulphur system is a one component system All the phases

                                                                  monoclinic rhombic liquid and vapour ndash can be expressed in terms of the single constituent ndash sulphur

                                                                  2 A mixture of ethanol and water is an example of a two component system We need both ethanol and water to express its composition

                                                                  bull Examples

                                                                  An example of a system in which a reaction occurs and an equilibrium is established is the thermal decomposition of solid CaCO3

                                                                  In this system there are three distinct phasesSolid CaCO3

                                                                  Solid CaOGaseous CO2

                                                                  Though there are 3 species present the number of components is only two because of the equilibrium CaCO3 (s) CaO(s) + CO2(g)

                                                                  Any two of the three constituents may be chosen as the components

                                                                  If CaO and CO2 are chosen then the composition of the phase CaCO3 is expressed as one mole of component CO2 plus one mole of component CaO

                                                                  If on the other hand CaCO3 and CO2 were chosen then the composition of the phase CaO would be described as one mole of CaCO3 minus one mole of CO2

                                                                  The degrees of freedom or variance of a system is defined as the minimum number of variables such as

                                                                  temperaturepressureconcentrationwhich must be fixed in order to define the system completely

                                                                  Degrees of freedom (or variance)

                                                                  F = C P + 2

                                                                  1 A gaseous mixture of CO2 and N2 Three variables pressure temperature and composition are required to define this system This is hence a trivariant system

                                                                  2 A system having only liquid water has two degrees of freedom or is bivariant Both temperature and pressure need to be mentioned in order to define the system

                                                                  3 If to the system containing liquid water pieces of ice are added and this system with 2 phases is allowed to come to equilibrium then it is an univariant system

                                                                  Only one variable either temperature or pressure need to be specified in order to define the systemIf the pressure on the system is maintained at 1 atm then the temperature of the system gets automatically fixed at 0oC the normal melting point of ice

                                                                  bull Examples

                                                                  Phase Equilibria amp The Phase Rule

                                                                  A phase diagram (Equilibrium Phase Diagram) summarizes the conditions at which a substance exists as a solid liquid or gas

                                                                  OR It is a ldquomaprdquo of the information about the control of phase structure of a particular material system

                                                                  The relationships between temperature and the compositions and the quantities of phases present at equilibrium are represented

                                                                  F = C P + 2The phase rule

                                                                  The phase rule JW Gibbs formulated the phase rule which is a general relation

                                                                  between the variance F the number of component C and the number of phases P at equilibrium for a system of any composition

                                                                  For a system in equilibrium

                                                                  F degree of freedom the least number of intensive variable that must be fixed (known) to describe the system completely

                                                                  Phase Rule relation to determine the least number of intensive variable that can be changed without changing the equilibrium state of the system or alternately

                                                                  The least number required to define the state of the system which is called degree of freedom F

                                                                  Intensive variable independent variable that do not depend on the volume or the size egTemp pressure

                                                                  Independent chemical species which comprise the system These could be Elements Ions Compounds

                                                                  Eg Au-Cu system Components rarr Au Cu Ice-water system Component rarr H2O

                                                                  Al2O3 ndash Cr2O3 system Components rarr Al2O3 Cr2O3

                                                                  Component the smallest number of constituent by which the composition of each phase in the system at equilibrium can be expressed in form of chemical formula or equation

                                                                  Phase Equilibria amp The Phase RuleComponents of a system

                                                                  The number of phases in a system is denoted P

                                                                  (a)A gas or a gaseous mixture is a single phase P=1

                                                                  (b) For a solid system an alloy of two metals is a two-phase system (P=2) if the metals are immiscible but a single-phase system (P=1) if they are miscible---a homogeneous mixture of the two substances---is uniform on a molecular scale

                                                                  (c) For a liquid system according to the solubility to decide whether a system consists of one phase or of two For example a solution of sodium chloride in water is a single phase A pair of liquids that are partially miscible or immiscible is a two-phase system(P=2)

                                                                  Oil in water

                                                                  Degrees of Freedom = What you can control What the system controls

                                                                  F = C + 2 P

                                                                  Can control the no of components added and P amp T

                                                                  System decided how many phases to produce given the

                                                                  conditions

                                                                  A way of understanding the Gibbs Phase RuleThe degrees of freedom can be thought of as the difference between what you (can) control and

                                                                  what the system controls

                                                                  F degree of freedom the least number of intensive variable that must be fixed (known) to describe the system completely

                                                                  Degree of freedom (or variance) F is the number of variables (T p andor composition) that can be changed independently without changing the phases of the system

                                                                  a) At the triple pointP = 3 (solid liquid and gas)

                                                                  C= 1 (water)P + F = C + 2

                                                                  F = 0 (no degree of freedom)

                                                                  b) liquid-solid curveP = 2

                                                                  2+F = 1 + 2F= 1

                                                                  One variable (T or P) can be changed

                                                                  c) LiquidP =1

                                                                  So F =2Two variables (T and P) can be varied independently

                                                                  and the system will remains a single phase

                                                                  One-component systemsPhase diagram of water

                                                                  P (

                                                                  atm

                                                                  )

                                                                  Critical point

                                                                  374

                                                                  1

                                                                  =100=0O--Triple point

                                                                  0006

                                                                  218

                                                                  Curve O -CSublimation

                                                                  Deposition

                                                                  Curve O-AVaporizationCondensation

                                                                  Curve O -BMelting

                                                                  Freezing

                                                                  F = C P + 2

                                                                  F = C P + 2

                                                                  Phase Diagram of Carbon Dioxide

                                                                  Condensed system System in which the vapor phase is ignored and only the solid andor liquid phases are considered

                                                                  Two component system For two component system F can be 3 (3D model is needed) eg T p

                                                                  and concentration usually we fix p = 1atm the vapor phase is neglected and F is reduced to 2

                                                                  For three component system the pressure and temperature are fixed

                                                                  Phenol water phase diagram

                                                                  eg for point d (24)

                                                                  Two component system containing liquid phase

                                                                  Tie Line bc line The line at which the system at equilibrium will separate into phases of constant composition termed lsquoconjugate phasesrsquo

                                                                  Lever Rule a way to calculate the proportions of each phase present on a phase diagram in a two phase field (at a given temperature and composition)

                                                                  eg for point d (24)

                                                                  For every 10 g of liquid system in equilibrium in point d

                                                                  75 g phase A25 g phase B

                                                                  ExampleMixed 24g phenol +76g water T 50degC

                                                                  equilibrium75 g phase A 25 g phase B

                                                                  11 phenol 63 phenol

                                                                  011 times75 g=825 g phenol

                                                                  063 times25 g=1575 g phenol

                                                                  water rich phasecontains water+ phenol(11)

                                                                  Phenol rich phasecontains Phenol (63)+ water

                                                                  The Critical Solution Temperature CST

                                                                  Is the maximum temperature at which the 2-phase region exists (or upper consolute temperature)

                                                                  In the case of the phenol-water system this is 668oC (point h)

                                                                  All combinations of phenol and water gt CST are completely miscible and yield 1-phase liquid systems

                                                                  Systems Showing a Decrease in Miscibility with Rise in Temperature

                                                                  A few mixtures exhibit a lower critical solution temperature (low CST) eg triethylamine plus water The miscibility with in temperature

                                                                  Systems Showing Upper and Lower CSTs

                                                                  The miscibility with temp

                                                                  a certain temperature miscibility starts to again with further in temperature

                                                                  Closed-phase diagram ie nicotine-water system

                                                                  A salol B thymol

                                                                  53

                                                                  Two component system containing solid and liquid phase (Eutectic Mixtures)

                                                                  A salol B thymol

                                                                  EMLAreg (lidocaine 25 and prilocaine 25) Cream

                                                                  EMLA Cream (lidocaine 25 and prilocaine 25) is an emulsion in which the oil phase is a eutectic mixture of lidocaine and prilocaine in a ratio of 11 by weight This eutectic mixture has a melting point below room temperature and therefore both local anesthetics exist as a liquid oil rather than as crystals

                                                                  Eutectic mixture Pharmaceutical Application

                                                                  Triangular Diagrams for three ndash component systems

                                                                  Three component system

                                                                  Birzeit University Physical Pharmacy PHAR 323 Dr Hani Shtaya

                                                                  1 Binding Forces Between Molecules2 Repulsive and Attractive Forces3 The Gaseous State The Ideal Gas Law Liquefaction of Gases Aerosols4 Solids and the Crystalline State Crystalline Solids Polymorphism Solvates Amorphous Solids5 Phase Equilibria and the Phase Rule Phase Rule Systems Containing One Component Condensed System Two-Component Systems Containing Liquid Phases Two-Component Systems Containing Solid and Liquid Phases Eutectic Mixtures Rules Relating to Triangular Diagrams

                                                                  Topics that we have covered

                                                                  • States of Matter
                                                                  • States of Matter (2)
                                                                  • Objectives of the lecture
                                                                  • Comparison of Gases Liquids and Solids
                                                                  • Slide 5
                                                                  • Repulsive and Attractive Forces
                                                                  • Ideal Gas Equation
                                                                  • Gaseous state
                                                                  • Slide 9
                                                                  • Gaseous state (2)
                                                                  • Liquefaction of Gases
                                                                  • Slide 12
                                                                  • SOLIDS amp CRYSTALLINE STATE Pharmaceutical Drugs more than 80
                                                                  • Solids and the crystalline state
                                                                  • Classification of Solids
                                                                  • Slide 16
                                                                  • Slide 17
                                                                  • Crystal forms
                                                                  • Types of Crystals
                                                                  • Slide 20
                                                                  • Slide 21
                                                                  • Polymorphism
                                                                  • Slide 23
                                                                  • Slide 24
                                                                  • Slide 25
                                                                  • Slide 26
                                                                  • Cocrystal
                                                                  • Principle of polymorphism
                                                                  • Solvates
                                                                  • Polymorphism (2)
                                                                  • Amorphous Solid
                                                                  • Amorphous or crystalline amp therapeutic activity
                                                                  • Slide 33
                                                                  • Slide 34
                                                                  • Polymorphism and Industry Pharmaceutical
                                                                  • Celecoxib
                                                                  • Furosemide
                                                                  • Bioavailability
                                                                  • Slide 39
                                                                  • Slide 40
                                                                  • Bioequivalence
                                                                  • Slide 42
                                                                  • Carbamazepine
                                                                  • Slide 44
                                                                  • AIDS drug ritonavir
                                                                  • Slide 46
                                                                  • Slide 47
                                                                  • Phase Equilibria amp The Phase Rule
                                                                  • Phase diagram ndash Water
                                                                  • Phase Equilibria amp The Phase Rule Definitions
                                                                  • Phase Definition
                                                                  • Examples
                                                                  • Components
                                                                  • Examples
                                                                  • Slide 55
                                                                  • Degrees of freedom (or variance)
                                                                  • Examples (2)
                                                                  • Phase Equilibria amp The Phase Rule
                                                                  • The phase rule
                                                                  • Slide 60
                                                                  • Phase Equilibria amp The Phase Rule (2)
                                                                  • The number of phases in a system is denoted P
                                                                  • Slide 63
                                                                  • Slide 64
                                                                  • One-component systems
                                                                  • Slide 66
                                                                  • Slide 67
                                                                  • Slide 68
                                                                  • Slide 69
                                                                  • Slide 70
                                                                  • Two component system containing liquid phase
                                                                  • Slide 72
                                                                  • The Critical Solution Temperature CST
                                                                  • Systems Showing a Decrease in Miscibility with Rise in Temperat
                                                                  • Systems Showing Upper and Lower CSTs
                                                                  • Two component system containing solid and liquid phase (Eutecti
                                                                  • Slide 77
                                                                  • Eutectic mixture Pharmaceutical Application
                                                                  • Three component system
                                                                  • Slide 80
                                                                  • Topics that we have covered

                                                                    FurosemideTwo forms with significantly differing aqueous solubility and dissolution rateOral bioavailability compromised

                                                                    Giron lists gt20 excipients that display polymorphism includingndash Lactose (anhydrous also monohydrate)ndash Aspartame (anhydrous hydrate forms)ndash Magnesium stearate (can affect lubrication of tablets)

                                                                    Bioavailability

                                                                    The rate and extent to which the active ingredient or active moiety is absorbed from a drug product and becomes available at the site of action

                                                                    Bioequivalence

                                                                    The absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study

                                                                    Carbamazepine

                                                                    CHLORPROPAMIDEat least six polymorphic white or almost white crystalline powder It exhibits polymorphism Practically insoluble in water soluble in alcohol freely soluble in acetone and in dichlo-romethane dissolves in dilute solutions of alkali hydroxides Protect from light

                                                                    blood-glucose-lowering drug

                                                                    AIDS drug ritonavir

                                                                    Theobroma oil (cacao butter ) is a polymorphic natural fat

                                                                    Theobroma oil can exist in 4 different polymorphic forms of which only one is Stabile

                                                                    1 Unstable gamma form melting at 18degC2 Alpha form melting at 22degC3 Beta prime form melting at 28degC4 Stable beta form melting at 345degC

                                                                    This is important in the preparation of theobroma suppositories

                                                                    If the oil is heated to a point where it is completely liquified (about 35 C) the crystals of the stable polymorph are destroyed amp the mass does not crystallize until it is cooled to 15 C

                                                                    The crystals that form are unstable amp the suppositories melt at 24 C

                                                                    Theobroma suppositories must be prepared below 33 C

                                                                    Polymorphism and Industry Pharmaceutical

                                                                    Polymorphism and Industry Pharmaceutical

                                                                    Anhydrates together with salts form the majority of all drug formulationsAbout a half of all APIs used today are saltsSalts are stable and well soluble in polar solvents (first of all in water) because they contain ionic bondThere is one more essential advantage of salts ndash their solubility is a function of pH Since pH in the gastrointestinal tract (GIT) vary between 1-75

                                                                    atorvastatin calcium trihydrateEach tablet contains Atorvastatin Calcium Trihydrate equivalent to Atorvastatin 20 mg

                                                                    Phase Equilibria amp The Phase Rule

                                                                    Phase diagram ndash Water

                                                                    Phase Equilibrium A stable phase structure with lowest free-energy (internal energy) of a system and also randomness or disorder of the atoms or molecules (entropy)

                                                                    Any change in Temperature Composition and Pressure causes an increase in free energy and away from Equilibrium thus forcing a move to another lsquostatersquo

                                                                    Phase Equilibria amp The Phase Rule Definitions

                                                                    A phase is defined as any homogeneous and physically distinct part of a system which is separated from other parts of the system by interfaces

                                                                    A part of a system is homogeneous if it has identical physical properties and chemical composition throughout the part

                                                                    A phase may be gas liquid or solid A gas or a gaseous mixture is a single phase Totally miscible liquids constitute a single phase In an immiscible liquid system each layer is counted as a separate phase Every solid constitutes a single phase except when a solid solution is formed A solid solution is considered as a single phase Each polymorphic form constitutes a separate phase

                                                                    Phase Definition

                                                                    1 Liquid water pieces of ice and water vapour are present together The number of phases is 3 as each form is a separate phase Ice in the system is a single phase even if it is present as a number of pieces

                                                                    2 Calcium carbonate undergoes thermal decomposition The chemical reaction is CaCO3(s) CaO(s) + CO2 (g) Number of phases = 3 This system consists of 2 solid phases CaCO3 and CaO and one gaseous phase that of CO2

                                                                    3 Ammonium chloride undergoes thermal decomposition The chemical reaction is NH4Cl(s) NH3 (g) + HCl (g) Number of phases = 2 This system has two phases one solid NH4Cl and one gaseous a mixture of NH3 and HCl

                                                                    4 A solution of NaCl in water Number of phases = 1

                                                                    bull Examples

                                                                    The number of components of a system at equilibrium is the smallest number of independently varying chemical constituents using which the composition of each and every phase in the system can be expressed

                                                                    Components

                                                                    Counting the number of components 1 The sulphur system is a one component system All the phases

                                                                    monoclinic rhombic liquid and vapour ndash can be expressed in terms of the single constituent ndash sulphur

                                                                    2 A mixture of ethanol and water is an example of a two component system We need both ethanol and water to express its composition

                                                                    bull Examples

                                                                    An example of a system in which a reaction occurs and an equilibrium is established is the thermal decomposition of solid CaCO3

                                                                    In this system there are three distinct phasesSolid CaCO3

                                                                    Solid CaOGaseous CO2

                                                                    Though there are 3 species present the number of components is only two because of the equilibrium CaCO3 (s) CaO(s) + CO2(g)

                                                                    Any two of the three constituents may be chosen as the components

                                                                    If CaO and CO2 are chosen then the composition of the phase CaCO3 is expressed as one mole of component CO2 plus one mole of component CaO

                                                                    If on the other hand CaCO3 and CO2 were chosen then the composition of the phase CaO would be described as one mole of CaCO3 minus one mole of CO2

                                                                    The degrees of freedom or variance of a system is defined as the minimum number of variables such as

                                                                    temperaturepressureconcentrationwhich must be fixed in order to define the system completely

                                                                    Degrees of freedom (or variance)

                                                                    F = C P + 2

                                                                    1 A gaseous mixture of CO2 and N2 Three variables pressure temperature and composition are required to define this system This is hence a trivariant system

                                                                    2 A system having only liquid water has two degrees of freedom or is bivariant Both temperature and pressure need to be mentioned in order to define the system

                                                                    3 If to the system containing liquid water pieces of ice are added and this system with 2 phases is allowed to come to equilibrium then it is an univariant system

                                                                    Only one variable either temperature or pressure need to be specified in order to define the systemIf the pressure on the system is maintained at 1 atm then the temperature of the system gets automatically fixed at 0oC the normal melting point of ice

                                                                    bull Examples

                                                                    Phase Equilibria amp The Phase Rule

                                                                    A phase diagram (Equilibrium Phase Diagram) summarizes the conditions at which a substance exists as a solid liquid or gas

                                                                    OR It is a ldquomaprdquo of the information about the control of phase structure of a particular material system

                                                                    The relationships between temperature and the compositions and the quantities of phases present at equilibrium are represented

                                                                    F = C P + 2The phase rule

                                                                    The phase rule JW Gibbs formulated the phase rule which is a general relation

                                                                    between the variance F the number of component C and the number of phases P at equilibrium for a system of any composition

                                                                    For a system in equilibrium

                                                                    F degree of freedom the least number of intensive variable that must be fixed (known) to describe the system completely

                                                                    Phase Rule relation to determine the least number of intensive variable that can be changed without changing the equilibrium state of the system or alternately

                                                                    The least number required to define the state of the system which is called degree of freedom F

                                                                    Intensive variable independent variable that do not depend on the volume or the size egTemp pressure

                                                                    Independent chemical species which comprise the system These could be Elements Ions Compounds

                                                                    Eg Au-Cu system Components rarr Au Cu Ice-water system Component rarr H2O

                                                                    Al2O3 ndash Cr2O3 system Components rarr Al2O3 Cr2O3

                                                                    Component the smallest number of constituent by which the composition of each phase in the system at equilibrium can be expressed in form of chemical formula or equation

                                                                    Phase Equilibria amp The Phase RuleComponents of a system

                                                                    The number of phases in a system is denoted P

                                                                    (a)A gas or a gaseous mixture is a single phase P=1

                                                                    (b) For a solid system an alloy of two metals is a two-phase system (P=2) if the metals are immiscible but a single-phase system (P=1) if they are miscible---a homogeneous mixture of the two substances---is uniform on a molecular scale

                                                                    (c) For a liquid system according to the solubility to decide whether a system consists of one phase or of two For example a solution of sodium chloride in water is a single phase A pair of liquids that are partially miscible or immiscible is a two-phase system(P=2)

                                                                    Oil in water

                                                                    Degrees of Freedom = What you can control What the system controls

                                                                    F = C + 2 P

                                                                    Can control the no of components added and P amp T

                                                                    System decided how many phases to produce given the

                                                                    conditions

                                                                    A way of understanding the Gibbs Phase RuleThe degrees of freedom can be thought of as the difference between what you (can) control and

                                                                    what the system controls

                                                                    F degree of freedom the least number of intensive variable that must be fixed (known) to describe the system completely

                                                                    Degree of freedom (or variance) F is the number of variables (T p andor composition) that can be changed independently without changing the phases of the system

                                                                    a) At the triple pointP = 3 (solid liquid and gas)

                                                                    C= 1 (water)P + F = C + 2

                                                                    F = 0 (no degree of freedom)

                                                                    b) liquid-solid curveP = 2

                                                                    2+F = 1 + 2F= 1

                                                                    One variable (T or P) can be changed

                                                                    c) LiquidP =1

                                                                    So F =2Two variables (T and P) can be varied independently

                                                                    and the system will remains a single phase

                                                                    One-component systemsPhase diagram of water

                                                                    P (

                                                                    atm

                                                                    )

                                                                    Critical point

                                                                    374

                                                                    1

                                                                    =100=0O--Triple point

                                                                    0006

                                                                    218

                                                                    Curve O -CSublimation

                                                                    Deposition

                                                                    Curve O-AVaporizationCondensation

                                                                    Curve O -BMelting

                                                                    Freezing

                                                                    F = C P + 2

                                                                    F = C P + 2

                                                                    Phase Diagram of Carbon Dioxide

                                                                    Condensed system System in which the vapor phase is ignored and only the solid andor liquid phases are considered

                                                                    Two component system For two component system F can be 3 (3D model is needed) eg T p

                                                                    and concentration usually we fix p = 1atm the vapor phase is neglected and F is reduced to 2

                                                                    For three component system the pressure and temperature are fixed

                                                                    Phenol water phase diagram

                                                                    eg for point d (24)

                                                                    Two component system containing liquid phase

                                                                    Tie Line bc line The line at which the system at equilibrium will separate into phases of constant composition termed lsquoconjugate phasesrsquo

                                                                    Lever Rule a way to calculate the proportions of each phase present on a phase diagram in a two phase field (at a given temperature and composition)

                                                                    eg for point d (24)

                                                                    For every 10 g of liquid system in equilibrium in point d

                                                                    75 g phase A25 g phase B

                                                                    ExampleMixed 24g phenol +76g water T 50degC

                                                                    equilibrium75 g phase A 25 g phase B

                                                                    11 phenol 63 phenol

                                                                    011 times75 g=825 g phenol

                                                                    063 times25 g=1575 g phenol

                                                                    water rich phasecontains water+ phenol(11)

                                                                    Phenol rich phasecontains Phenol (63)+ water

                                                                    The Critical Solution Temperature CST

                                                                    Is the maximum temperature at which the 2-phase region exists (or upper consolute temperature)

                                                                    In the case of the phenol-water system this is 668oC (point h)

                                                                    All combinations of phenol and water gt CST are completely miscible and yield 1-phase liquid systems

                                                                    Systems Showing a Decrease in Miscibility with Rise in Temperature

                                                                    A few mixtures exhibit a lower critical solution temperature (low CST) eg triethylamine plus water The miscibility with in temperature

                                                                    Systems Showing Upper and Lower CSTs

                                                                    The miscibility with temp

                                                                    a certain temperature miscibility starts to again with further in temperature

                                                                    Closed-phase diagram ie nicotine-water system

                                                                    A salol B thymol

                                                                    53

                                                                    Two component system containing solid and liquid phase (Eutectic Mixtures)

                                                                    A salol B thymol

                                                                    EMLAreg (lidocaine 25 and prilocaine 25) Cream

                                                                    EMLA Cream (lidocaine 25 and prilocaine 25) is an emulsion in which the oil phase is a eutectic mixture of lidocaine and prilocaine in a ratio of 11 by weight This eutectic mixture has a melting point below room temperature and therefore both local anesthetics exist as a liquid oil rather than as crystals

                                                                    Eutectic mixture Pharmaceutical Application

                                                                    Triangular Diagrams for three ndash component systems

                                                                    Three component system

                                                                    Birzeit University Physical Pharmacy PHAR 323 Dr Hani Shtaya

                                                                    1 Binding Forces Between Molecules2 Repulsive and Attractive Forces3 The Gaseous State The Ideal Gas Law Liquefaction of Gases Aerosols4 Solids and the Crystalline State Crystalline Solids Polymorphism Solvates Amorphous Solids5 Phase Equilibria and the Phase Rule Phase Rule Systems Containing One Component Condensed System Two-Component Systems Containing Liquid Phases Two-Component Systems Containing Solid and Liquid Phases Eutectic Mixtures Rules Relating to Triangular Diagrams

                                                                    Topics that we have covered

                                                                    • States of Matter
                                                                    • States of Matter (2)
                                                                    • Objectives of the lecture
                                                                    • Comparison of Gases Liquids and Solids
                                                                    • Slide 5
                                                                    • Repulsive and Attractive Forces
                                                                    • Ideal Gas Equation
                                                                    • Gaseous state
                                                                    • Slide 9
                                                                    • Gaseous state (2)
                                                                    • Liquefaction of Gases
                                                                    • Slide 12
                                                                    • SOLIDS amp CRYSTALLINE STATE Pharmaceutical Drugs more than 80
                                                                    • Solids and the crystalline state
                                                                    • Classification of Solids
                                                                    • Slide 16
                                                                    • Slide 17
                                                                    • Crystal forms
                                                                    • Types of Crystals
                                                                    • Slide 20
                                                                    • Slide 21
                                                                    • Polymorphism
                                                                    • Slide 23
                                                                    • Slide 24
                                                                    • Slide 25
                                                                    • Slide 26
                                                                    • Cocrystal
                                                                    • Principle of polymorphism
                                                                    • Solvates
                                                                    • Polymorphism (2)
                                                                    • Amorphous Solid
                                                                    • Amorphous or crystalline amp therapeutic activity
                                                                    • Slide 33
                                                                    • Slide 34
                                                                    • Polymorphism and Industry Pharmaceutical
                                                                    • Celecoxib
                                                                    • Furosemide
                                                                    • Bioavailability
                                                                    • Slide 39
                                                                    • Slide 40
                                                                    • Bioequivalence
                                                                    • Slide 42
                                                                    • Carbamazepine
                                                                    • Slide 44
                                                                    • AIDS drug ritonavir
                                                                    • Slide 46
                                                                    • Slide 47
                                                                    • Phase Equilibria amp The Phase Rule
                                                                    • Phase diagram ndash Water
                                                                    • Phase Equilibria amp The Phase Rule Definitions
                                                                    • Phase Definition
                                                                    • Examples
                                                                    • Components
                                                                    • Examples
                                                                    • Slide 55
                                                                    • Degrees of freedom (or variance)
                                                                    • Examples (2)
                                                                    • Phase Equilibria amp The Phase Rule
                                                                    • The phase rule
                                                                    • Slide 60
                                                                    • Phase Equilibria amp The Phase Rule (2)
                                                                    • The number of phases in a system is denoted P
                                                                    • Slide 63
                                                                    • Slide 64
                                                                    • One-component systems
                                                                    • Slide 66
                                                                    • Slide 67
                                                                    • Slide 68
                                                                    • Slide 69
                                                                    • Slide 70
                                                                    • Two component system containing liquid phase
                                                                    • Slide 72
                                                                    • The Critical Solution Temperature CST
                                                                    • Systems Showing a Decrease in Miscibility with Rise in Temperat
                                                                    • Systems Showing Upper and Lower CSTs
                                                                    • Two component system containing solid and liquid phase (Eutecti
                                                                    • Slide 77
                                                                    • Eutectic mixture Pharmaceutical Application
                                                                    • Three component system
                                                                    • Slide 80
                                                                    • Topics that we have covered

                                                                      Bioavailability

                                                                      The rate and extent to which the active ingredient or active moiety is absorbed from a drug product and becomes available at the site of action

                                                                      Bioequivalence

                                                                      The absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study

                                                                      Carbamazepine

                                                                      CHLORPROPAMIDEat least six polymorphic white or almost white crystalline powder It exhibits polymorphism Practically insoluble in water soluble in alcohol freely soluble in acetone and in dichlo-romethane dissolves in dilute solutions of alkali hydroxides Protect from light

                                                                      blood-glucose-lowering drug

                                                                      AIDS drug ritonavir

                                                                      Theobroma oil (cacao butter ) is a polymorphic natural fat

                                                                      Theobroma oil can exist in 4 different polymorphic forms of which only one is Stabile

                                                                      1 Unstable gamma form melting at 18degC2 Alpha form melting at 22degC3 Beta prime form melting at 28degC4 Stable beta form melting at 345degC

                                                                      This is important in the preparation of theobroma suppositories

                                                                      If the oil is heated to a point where it is completely liquified (about 35 C) the crystals of the stable polymorph are destroyed amp the mass does not crystallize until it is cooled to 15 C

                                                                      The crystals that form are unstable amp the suppositories melt at 24 C

                                                                      Theobroma suppositories must be prepared below 33 C

                                                                      Polymorphism and Industry Pharmaceutical

                                                                      Polymorphism and Industry Pharmaceutical

                                                                      Anhydrates together with salts form the majority of all drug formulationsAbout a half of all APIs used today are saltsSalts are stable and well soluble in polar solvents (first of all in water) because they contain ionic bondThere is one more essential advantage of salts ndash their solubility is a function of pH Since pH in the gastrointestinal tract (GIT) vary between 1-75

                                                                      atorvastatin calcium trihydrateEach tablet contains Atorvastatin Calcium Trihydrate equivalent to Atorvastatin 20 mg

                                                                      Phase Equilibria amp The Phase Rule

                                                                      Phase diagram ndash Water

                                                                      Phase Equilibrium A stable phase structure with lowest free-energy (internal energy) of a system and also randomness or disorder of the atoms or molecules (entropy)

                                                                      Any change in Temperature Composition and Pressure causes an increase in free energy and away from Equilibrium thus forcing a move to another lsquostatersquo

                                                                      Phase Equilibria amp The Phase Rule Definitions

                                                                      A phase is defined as any homogeneous and physically distinct part of a system which is separated from other parts of the system by interfaces

                                                                      A part of a system is homogeneous if it has identical physical properties and chemical composition throughout the part

                                                                      A phase may be gas liquid or solid A gas or a gaseous mixture is a single phase Totally miscible liquids constitute a single phase In an immiscible liquid system each layer is counted as a separate phase Every solid constitutes a single phase except when a solid solution is formed A solid solution is considered as a single phase Each polymorphic form constitutes a separate phase

                                                                      Phase Definition

                                                                      1 Liquid water pieces of ice and water vapour are present together The number of phases is 3 as each form is a separate phase Ice in the system is a single phase even if it is present as a number of pieces

                                                                      2 Calcium carbonate undergoes thermal decomposition The chemical reaction is CaCO3(s) CaO(s) + CO2 (g) Number of phases = 3 This system consists of 2 solid phases CaCO3 and CaO and one gaseous phase that of CO2

                                                                      3 Ammonium chloride undergoes thermal decomposition The chemical reaction is NH4Cl(s) NH3 (g) + HCl (g) Number of phases = 2 This system has two phases one solid NH4Cl and one gaseous a mixture of NH3 and HCl

                                                                      4 A solution of NaCl in water Number of phases = 1

                                                                      bull Examples

                                                                      The number of components of a system at equilibrium is the smallest number of independently varying chemical constituents using which the composition of each and every phase in the system can be expressed

                                                                      Components

                                                                      Counting the number of components 1 The sulphur system is a one component system All the phases

                                                                      monoclinic rhombic liquid and vapour ndash can be expressed in terms of the single constituent ndash sulphur

                                                                      2 A mixture of ethanol and water is an example of a two component system We need both ethanol and water to express its composition

                                                                      bull Examples

                                                                      An example of a system in which a reaction occurs and an equilibrium is established is the thermal decomposition of solid CaCO3

                                                                      In this system there are three distinct phasesSolid CaCO3

                                                                      Solid CaOGaseous CO2

                                                                      Though there are 3 species present the number of components is only two because of the equilibrium CaCO3 (s) CaO(s) + CO2(g)

                                                                      Any two of the three constituents may be chosen as the components

                                                                      If CaO and CO2 are chosen then the composition of the phase CaCO3 is expressed as one mole of component CO2 plus one mole of component CaO

                                                                      If on the other hand CaCO3 and CO2 were chosen then the composition of the phase CaO would be described as one mole of CaCO3 minus one mole of CO2

                                                                      The degrees of freedom or variance of a system is defined as the minimum number of variables such as

                                                                      temperaturepressureconcentrationwhich must be fixed in order to define the system completely

                                                                      Degrees of freedom (or variance)

                                                                      F = C P + 2

                                                                      1 A gaseous mixture of CO2 and N2 Three variables pressure temperature and composition are required to define this system This is hence a trivariant system

                                                                      2 A system having only liquid water has two degrees of freedom or is bivariant Both temperature and pressure need to be mentioned in order to define the system

                                                                      3 If to the system containing liquid water pieces of ice are added and this system with 2 phases is allowed to come to equilibrium then it is an univariant system

                                                                      Only one variable either temperature or pressure need to be specified in order to define the systemIf the pressure on the system is maintained at 1 atm then the temperature of the system gets automatically fixed at 0oC the normal melting point of ice

                                                                      bull Examples

                                                                      Phase Equilibria amp The Phase Rule

                                                                      A phase diagram (Equilibrium Phase Diagram) summarizes the conditions at which a substance exists as a solid liquid or gas

                                                                      OR It is a ldquomaprdquo of the information about the control of phase structure of a particular material system

                                                                      The relationships between temperature and the compositions and the quantities of phases present at equilibrium are represented

                                                                      F = C P + 2The phase rule

                                                                      The phase rule JW Gibbs formulated the phase rule which is a general relation

                                                                      between the variance F the number of component C and the number of phases P at equilibrium for a system of any composition

                                                                      For a system in equilibrium

                                                                      F degree of freedom the least number of intensive variable that must be fixed (known) to describe the system completely

                                                                      Phase Rule relation to determine the least number of intensive variable that can be changed without changing the equilibrium state of the system or alternately

                                                                      The least number required to define the state of the system which is called degree of freedom F

                                                                      Intensive variable independent variable that do not depend on the volume or the size egTemp pressure

                                                                      Independent chemical species which comprise the system These could be Elements Ions Compounds

                                                                      Eg Au-Cu system Components rarr Au Cu Ice-water system Component rarr H2O

                                                                      Al2O3 ndash Cr2O3 system Components rarr Al2O3 Cr2O3

                                                                      Component the smallest number of constituent by which the composition of each phase in the system at equilibrium can be expressed in form of chemical formula or equation

                                                                      Phase Equilibria amp The Phase RuleComponents of a system

                                                                      The number of phases in a system is denoted P

                                                                      (a)A gas or a gaseous mixture is a single phase P=1

                                                                      (b) For a solid system an alloy of two metals is a two-phase system (P=2) if the metals are immiscible but a single-phase system (P=1) if they are miscible---a homogeneous mixture of the two substances---is uniform on a molecular scale

                                                                      (c) For a liquid system according to the solubility to decide whether a system consists of one phase or of two For example a solution of sodium chloride in water is a single phase A pair of liquids that are partially miscible or immiscible is a two-phase system(P=2)

                                                                      Oil in water

                                                                      Degrees of Freedom = What you can control What the system controls

                                                                      F = C + 2 P

                                                                      Can control the no of components added and P amp T

                                                                      System decided how many phases to produce given the

                                                                      conditions

                                                                      A way of understanding the Gibbs Phase RuleThe degrees of freedom can be thought of as the difference between what you (can) control and

                                                                      what the system controls

                                                                      F degree of freedom the least number of intensive variable that must be fixed (known) to describe the system completely

                                                                      Degree of freedom (or variance) F is the number of variables (T p andor composition) that can be changed independently without changing the phases of the system

                                                                      a) At the triple pointP = 3 (solid liquid and gas)

                                                                      C= 1 (water)P + F = C + 2

                                                                      F = 0 (no degree of freedom)

                                                                      b) liquid-solid curveP = 2

                                                                      2+F = 1 + 2F= 1

                                                                      One variable (T or P) can be changed

                                                                      c) LiquidP =1

                                                                      So F =2Two variables (T and P) can be varied independently

                                                                      and the system will remains a single phase

                                                                      One-component systemsPhase diagram of water

                                                                      P (

                                                                      atm

                                                                      )

                                                                      Critical point

                                                                      374

                                                                      1

                                                                      =100=0O--Triple point

                                                                      0006

                                                                      218

                                                                      Curve O -CSublimation

                                                                      Deposition

                                                                      Curve O-AVaporizationCondensation

                                                                      Curve O -BMelting

                                                                      Freezing

                                                                      F = C P + 2

                                                                      F = C P + 2

                                                                      Phase Diagram of Carbon Dioxide

                                                                      Condensed system System in which the vapor phase is ignored and only the solid andor liquid phases are considered

                                                                      Two component system For two component system F can be 3 (3D model is needed) eg T p

                                                                      and concentration usually we fix p = 1atm the vapor phase is neglected and F is reduced to 2

                                                                      For three component system the pressure and temperature are fixed

                                                                      Phenol water phase diagram

                                                                      eg for point d (24)

                                                                      Two component system containing liquid phase

                                                                      Tie Line bc line The line at which the system at equilibrium will separate into phases of constant composition termed lsquoconjugate phasesrsquo

                                                                      Lever Rule a way to calculate the proportions of each phase present on a phase diagram in a two phase field (at a given temperature and composition)

                                                                      eg for point d (24)

                                                                      For every 10 g of liquid system in equilibrium in point d

                                                                      75 g phase A25 g phase B

                                                                      ExampleMixed 24g phenol +76g water T 50degC

                                                                      equilibrium75 g phase A 25 g phase B

                                                                      11 phenol 63 phenol

                                                                      011 times75 g=825 g phenol

                                                                      063 times25 g=1575 g phenol

                                                                      water rich phasecontains water+ phenol(11)

                                                                      Phenol rich phasecontains Phenol (63)+ water

                                                                      The Critical Solution Temperature CST

                                                                      Is the maximum temperature at which the 2-phase region exists (or upper consolute temperature)

                                                                      In the case of the phenol-water system this is 668oC (point h)

                                                                      All combinations of phenol and water gt CST are completely miscible and yield 1-phase liquid systems

                                                                      Systems Showing a Decrease in Miscibility with Rise in Temperature

                                                                      A few mixtures exhibit a lower critical solution temperature (low CST) eg triethylamine plus water The miscibility with in temperature

                                                                      Systems Showing Upper and Lower CSTs

                                                                      The miscibility with temp

                                                                      a certain temperature miscibility starts to again with further in temperature

                                                                      Closed-phase diagram ie nicotine-water system

                                                                      A salol B thymol

                                                                      53

                                                                      Two component system containing solid and liquid phase (Eutectic Mixtures)

                                                                      A salol B thymol

                                                                      EMLAreg (lidocaine 25 and prilocaine 25) Cream

                                                                      EMLA Cream (lidocaine 25 and prilocaine 25) is an emulsion in which the oil phase is a eutectic mixture of lidocaine and prilocaine in a ratio of 11 by weight This eutectic mixture has a melting point below room temperature and therefore both local anesthetics exist as a liquid oil rather than as crystals

                                                                      Eutectic mixture Pharmaceutical Application

                                                                      Triangular Diagrams for three ndash component systems

                                                                      Three component system

                                                                      Birzeit University Physical Pharmacy PHAR 323 Dr Hani Shtaya

                                                                      1 Binding Forces Between Molecules2 Repulsive and Attractive Forces3 The Gaseous State The Ideal Gas Law Liquefaction of Gases Aerosols4 Solids and the Crystalline State Crystalline Solids Polymorphism Solvates Amorphous Solids5 Phase Equilibria and the Phase Rule Phase Rule Systems Containing One Component Condensed System Two-Component Systems Containing Liquid Phases Two-Component Systems Containing Solid and Liquid Phases Eutectic Mixtures Rules Relating to Triangular Diagrams

                                                                      Topics that we have covered

                                                                      • States of Matter
                                                                      • States of Matter (2)
                                                                      • Objectives of the lecture
                                                                      • Comparison of Gases Liquids and Solids
                                                                      • Slide 5
                                                                      • Repulsive and Attractive Forces
                                                                      • Ideal Gas Equation
                                                                      • Gaseous state
                                                                      • Slide 9
                                                                      • Gaseous state (2)
                                                                      • Liquefaction of Gases
                                                                      • Slide 12
                                                                      • SOLIDS amp CRYSTALLINE STATE Pharmaceutical Drugs more than 80
                                                                      • Solids and the crystalline state
                                                                      • Classification of Solids
                                                                      • Slide 16
                                                                      • Slide 17
                                                                      • Crystal forms
                                                                      • Types of Crystals
                                                                      • Slide 20
                                                                      • Slide 21
                                                                      • Polymorphism
                                                                      • Slide 23
                                                                      • Slide 24
                                                                      • Slide 25
                                                                      • Slide 26
                                                                      • Cocrystal
                                                                      • Principle of polymorphism
                                                                      • Solvates
                                                                      • Polymorphism (2)
                                                                      • Amorphous Solid
                                                                      • Amorphous or crystalline amp therapeutic activity
                                                                      • Slide 33
                                                                      • Slide 34
                                                                      • Polymorphism and Industry Pharmaceutical
                                                                      • Celecoxib
                                                                      • Furosemide
                                                                      • Bioavailability
                                                                      • Slide 39
                                                                      • Slide 40
                                                                      • Bioequivalence
                                                                      • Slide 42
                                                                      • Carbamazepine
                                                                      • Slide 44
                                                                      • AIDS drug ritonavir
                                                                      • Slide 46
                                                                      • Slide 47
                                                                      • Phase Equilibria amp The Phase Rule
                                                                      • Phase diagram ndash Water
                                                                      • Phase Equilibria amp The Phase Rule Definitions
                                                                      • Phase Definition
                                                                      • Examples
                                                                      • Components
                                                                      • Examples
                                                                      • Slide 55
                                                                      • Degrees of freedom (or variance)
                                                                      • Examples (2)
                                                                      • Phase Equilibria amp The Phase Rule
                                                                      • The phase rule
                                                                      • Slide 60
                                                                      • Phase Equilibria amp The Phase Rule (2)
                                                                      • The number of phases in a system is denoted P
                                                                      • Slide 63
                                                                      • Slide 64
                                                                      • One-component systems
                                                                      • Slide 66
                                                                      • Slide 67
                                                                      • Slide 68
                                                                      • Slide 69
                                                                      • Slide 70
                                                                      • Two component system containing liquid phase
                                                                      • Slide 72
                                                                      • The Critical Solution Temperature CST
                                                                      • Systems Showing a Decrease in Miscibility with Rise in Temperat
                                                                      • Systems Showing Upper and Lower CSTs
                                                                      • Two component system containing solid and liquid phase (Eutecti
                                                                      • Slide 77
                                                                      • Eutectic mixture Pharmaceutical Application
                                                                      • Three component system
                                                                      • Slide 80
                                                                      • Topics that we have covered

                                                                        Bioequivalence

                                                                        The absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study

                                                                        Carbamazepine

                                                                        CHLORPROPAMIDEat least six polymorphic white or almost white crystalline powder It exhibits polymorphism Practically insoluble in water soluble in alcohol freely soluble in acetone and in dichlo-romethane dissolves in dilute solutions of alkali hydroxides Protect from light

                                                                        blood-glucose-lowering drug

                                                                        AIDS drug ritonavir

                                                                        Theobroma oil (cacao butter ) is a polymorphic natural fat

                                                                        Theobroma oil can exist in 4 different polymorphic forms of which only one is Stabile

                                                                        1 Unstable gamma form melting at 18degC2 Alpha form melting at 22degC3 Beta prime form melting at 28degC4 Stable beta form melting at 345degC

                                                                        This is important in the preparation of theobroma suppositories

                                                                        If the oil is heated to a point where it is completely liquified (about 35 C) the crystals of the stable polymorph are destroyed amp the mass does not crystallize until it is cooled to 15 C

                                                                        The crystals that form are unstable amp the suppositories melt at 24 C

                                                                        Theobroma suppositories must be prepared below 33 C

                                                                        Polymorphism and Industry Pharmaceutical

                                                                        Polymorphism and Industry Pharmaceutical

                                                                        Anhydrates together with salts form the majority of all drug formulationsAbout a half of all APIs used today are saltsSalts are stable and well soluble in polar solvents (first of all in water) because they contain ionic bondThere is one more essential advantage of salts ndash their solubility is a function of pH Since pH in the gastrointestinal tract (GIT) vary between 1-75

                                                                        atorvastatin calcium trihydrateEach tablet contains Atorvastatin Calcium Trihydrate equivalent to Atorvastatin 20 mg

                                                                        Phase Equilibria amp The Phase Rule

                                                                        Phase diagram ndash Water

                                                                        Phase Equilibrium A stable phase structure with lowest free-energy (internal energy) of a system and also randomness or disorder of the atoms or molecules (entropy)

                                                                        Any change in Temperature Composition and Pressure causes an increase in free energy and away from Equilibrium thus forcing a move to another lsquostatersquo

                                                                        Phase Equilibria amp The Phase Rule Definitions

                                                                        A phase is defined as any homogeneous and physically distinct part of a system which is separated from other parts of the system by interfaces

                                                                        A part of a system is homogeneous if it has identical physical properties and chemical composition throughout the part

                                                                        A phase may be gas liquid or solid A gas or a gaseous mixture is a single phase Totally miscible liquids constitute a single phase In an immiscible liquid system each layer is counted as a separate phase Every solid constitutes a single phase except when a solid solution is formed A solid solution is considered as a single phase Each polymorphic form constitutes a separate phase

                                                                        Phase Definition

                                                                        1 Liquid water pieces of ice and water vapour are present together The number of phases is 3 as each form is a separate phase Ice in the system is a single phase even if it is present as a number of pieces

                                                                        2 Calcium carbonate undergoes thermal decomposition The chemical reaction is CaCO3(s) CaO(s) + CO2 (g) Number of phases = 3 This system consists of 2 solid phases CaCO3 and CaO and one gaseous phase that of CO2

                                                                        3 Ammonium chloride undergoes thermal decomposition The chemical reaction is NH4Cl(s) NH3 (g) + HCl (g) Number of phases = 2 This system has two phases one solid NH4Cl and one gaseous a mixture of NH3 and HCl

                                                                        4 A solution of NaCl in water Number of phases = 1

                                                                        bull Examples

                                                                        The number of components of a system at equilibrium is the smallest number of independently varying chemical constituents using which the composition of each and every phase in the system can be expressed

                                                                        Components

                                                                        Counting the number of components 1 The sulphur system is a one component system All the phases

                                                                        monoclinic rhombic liquid and vapour ndash can be expressed in terms of the single constituent ndash sulphur

                                                                        2 A mixture of ethanol and water is an example of a two component system We need both ethanol and water to express its composition

                                                                        bull Examples

                                                                        An example of a system in which a reaction occurs and an equilibrium is established is the thermal decomposition of solid CaCO3

                                                                        In this system there are three distinct phasesSolid CaCO3

                                                                        Solid CaOGaseous CO2

                                                                        Though there are 3 species present the number of components is only two because of the equilibrium CaCO3 (s) CaO(s) + CO2(g)

                                                                        Any two of the three constituents may be chosen as the components

                                                                        If CaO and CO2 are chosen then the composition of the phase CaCO3 is expressed as one mole of component CO2 plus one mole of component CaO

                                                                        If on the other hand CaCO3 and CO2 were chosen then the composition of the phase CaO would be described as one mole of CaCO3 minus one mole of CO2

                                                                        The degrees of freedom or variance of a system is defined as the minimum number of variables such as

                                                                        temperaturepressureconcentrationwhich must be fixed in order to define the system completely

                                                                        Degrees of freedom (or variance)

                                                                        F = C P + 2

                                                                        1 A gaseous mixture of CO2 and N2 Three variables pressure temperature and composition are required to define this system This is hence a trivariant system

                                                                        2 A system having only liquid water has two degrees of freedom or is bivariant Both temperature and pressure need to be mentioned in order to define the system

                                                                        3 If to the system containing liquid water pieces of ice are added and this system with 2 phases is allowed to come to equilibrium then it is an univariant system

                                                                        Only one variable either temperature or pressure need to be specified in order to define the systemIf the pressure on the system is maintained at 1 atm then the temperature of the system gets automatically fixed at 0oC the normal melting point of ice

                                                                        bull Examples

                                                                        Phase Equilibria amp The Phase Rule

                                                                        A phase diagram (Equilibrium Phase Diagram) summarizes the conditions at which a substance exists as a solid liquid or gas

                                                                        OR It is a ldquomaprdquo of the information about the control of phase structure of a particular material system

                                                                        The relationships between temperature and the compositions and the quantities of phases present at equilibrium are represented

                                                                        F = C P + 2The phase rule

                                                                        The phase rule JW Gibbs formulated the phase rule which is a general relation

                                                                        between the variance F the number of component C and the number of phases P at equilibrium for a system of any composition

                                                                        For a system in equilibrium

                                                                        F degree of freedom the least number of intensive variable that must be fixed (known) to describe the system completely

                                                                        Phase Rule relation to determine the least number of intensive variable that can be changed without changing the equilibrium state of the system or alternately

                                                                        The least number required to define the state of the system which is called degree of freedom F

                                                                        Intensive variable independent variable that do not depend on the volume or the size egTemp pressure

                                                                        Independent chemical species which comprise the system These could be Elements Ions Compounds

                                                                        Eg Au-Cu system Components rarr Au Cu Ice-water system Component rarr H2O

                                                                        Al2O3 ndash Cr2O3 system Components rarr Al2O3 Cr2O3

                                                                        Component the smallest number of constituent by which the composition of each phase in the system at equilibrium can be expressed in form of chemical formula or equation

                                                                        Phase Equilibria amp The Phase RuleComponents of a system

                                                                        The number of phases in a system is denoted P

                                                                        (a)A gas or a gaseous mixture is a single phase P=1

                                                                        (b) For a solid system an alloy of two metals is a two-phase system (P=2) if the metals are immiscible but a single-phase system (P=1) if they are miscible---a homogeneous mixture of the two substances---is uniform on a molecular scale

                                                                        (c) For a liquid system according to the solubility to decide whether a system consists of one phase or of two For example a solution of sodium chloride in water is a single phase A pair of liquids that are partially miscible or immiscible is a two-phase system(P=2)

                                                                        Oil in water

                                                                        Degrees of Freedom = What you can control What the system controls

                                                                        F = C + 2 P

                                                                        Can control the no of components added and P amp T

                                                                        System decided how many phases to produce given the

                                                                        conditions

                                                                        A way of understanding the Gibbs Phase RuleThe degrees of freedom can be thought of as the difference between what you (can) control and

                                                                        what the system controls

                                                                        F degree of freedom the least number of intensive variable that must be fixed (known) to describe the system completely

                                                                        Degree of freedom (or variance) F is the number of variables (T p andor composition) that can be changed independently without changing the phases of the system

                                                                        a) At the triple pointP = 3 (solid liquid and gas)

                                                                        C= 1 (water)P + F = C + 2

                                                                        F = 0 (no degree of freedom)

                                                                        b) liquid-solid curveP = 2

                                                                        2+F = 1 + 2F= 1

                                                                        One variable (T or P) can be changed

                                                                        c) LiquidP =1

                                                                        So F =2Two variables (T and P) can be varied independently

                                                                        and the system will remains a single phase

                                                                        One-component systemsPhase diagram of water

                                                                        P (

                                                                        atm

                                                                        )

                                                                        Critical point

                                                                        374

                                                                        1

                                                                        =100=0O--Triple point

                                                                        0006

                                                                        218

                                                                        Curve O -CSublimation

                                                                        Deposition

                                                                        Curve O-AVaporizationCondensation

                                                                        Curve O -BMelting

                                                                        Freezing

                                                                        F = C P + 2

                                                                        F = C P + 2

                                                                        Phase Diagram of Carbon Dioxide

                                                                        Condensed system System in which the vapor phase is ignored and only the solid andor liquid phases are considered

                                                                        Two component system For two component system F can be 3 (3D model is needed) eg T p

                                                                        and concentration usually we fix p = 1atm the vapor phase is neglected and F is reduced to 2

                                                                        For three component system the pressure and temperature are fixed

                                                                        Phenol water phase diagram

                                                                        eg for point d (24)

                                                                        Two component system containing liquid phase

                                                                        Tie Line bc line The line at which the system at equilibrium will separate into phases of constant composition termed lsquoconjugate phasesrsquo

                                                                        Lever Rule a way to calculate the proportions of each phase present on a phase diagram in a two phase field (at a given temperature and composition)

                                                                        eg for point d (24)

                                                                        For every 10 g of liquid system in equilibrium in point d

                                                                        75 g phase A25 g phase B

                                                                        ExampleMixed 24g phenol +76g water T 50degC

                                                                        equilibrium75 g phase A 25 g phase B

                                                                        11 phenol 63 phenol

                                                                        011 times75 g=825 g phenol

                                                                        063 times25 g=1575 g phenol

                                                                        water rich phasecontains water+ phenol(11)

                                                                        Phenol rich phasecontains Phenol (63)+ water

                                                                        The Critical Solution Temperature CST

                                                                        Is the maximum temperature at which the 2-phase region exists (or upper consolute temperature)

                                                                        In the case of the phenol-water system this is 668oC (point h)

                                                                        All combinations of phenol and water gt CST are completely miscible and yield 1-phase liquid systems

                                                                        Systems Showing a Decrease in Miscibility with Rise in Temperature

                                                                        A few mixtures exhibit a lower critical solution temperature (low CST) eg triethylamine plus water The miscibility with in temperature

                                                                        Systems Showing Upper and Lower CSTs

                                                                        The miscibility with temp

                                                                        a certain temperature miscibility starts to again with further in temperature

                                                                        Closed-phase diagram ie nicotine-water system

                                                                        A salol B thymol

                                                                        53

                                                                        Two component system containing solid and liquid phase (Eutectic Mixtures)

                                                                        A salol B thymol

                                                                        EMLAreg (lidocaine 25 and prilocaine 25) Cream

                                                                        EMLA Cream (lidocaine 25 and prilocaine 25) is an emulsion in which the oil phase is a eutectic mixture of lidocaine and prilocaine in a ratio of 11 by weight This eutectic mixture has a melting point below room temperature and therefore both local anesthetics exist as a liquid oil rather than as crystals

                                                                        Eutectic mixture Pharmaceutical Application

                                                                        Triangular Diagrams for three ndash component systems

                                                                        Three component system

                                                                        Birzeit University Physical Pharmacy PHAR 323 Dr Hani Shtaya

                                                                        1 Binding Forces Between Molecules2 Repulsive and Attractive Forces3 The Gaseous State The Ideal Gas Law Liquefaction of Gases Aerosols4 Solids and the Crystalline State Crystalline Solids Polymorphism Solvates Amorphous Solids5 Phase Equilibria and the Phase Rule Phase Rule Systems Containing One Component Condensed System Two-Component Systems Containing Liquid Phases Two-Component Systems Containing Solid and Liquid Phases Eutectic Mixtures Rules Relating to Triangular Diagrams

                                                                        Topics that we have covered

                                                                        • States of Matter
                                                                        • States of Matter (2)
                                                                        • Objectives of the lecture
                                                                        • Comparison of Gases Liquids and Solids
                                                                        • Slide 5
                                                                        • Repulsive and Attractive Forces
                                                                        • Ideal Gas Equation
                                                                        • Gaseous state
                                                                        • Slide 9
                                                                        • Gaseous state (2)
                                                                        • Liquefaction of Gases
                                                                        • Slide 12
                                                                        • SOLIDS amp CRYSTALLINE STATE Pharmaceutical Drugs more than 80
                                                                        • Solids and the crystalline state
                                                                        • Classification of Solids
                                                                        • Slide 16
                                                                        • Slide 17
                                                                        • Crystal forms
                                                                        • Types of Crystals
                                                                        • Slide 20
                                                                        • Slide 21
                                                                        • Polymorphism
                                                                        • Slide 23
                                                                        • Slide 24
                                                                        • Slide 25
                                                                        • Slide 26
                                                                        • Cocrystal
                                                                        • Principle of polymorphism
                                                                        • Solvates
                                                                        • Polymorphism (2)
                                                                        • Amorphous Solid
                                                                        • Amorphous or crystalline amp therapeutic activity
                                                                        • Slide 33
                                                                        • Slide 34
                                                                        • Polymorphism and Industry Pharmaceutical
                                                                        • Celecoxib
                                                                        • Furosemide
                                                                        • Bioavailability
                                                                        • Slide 39
                                                                        • Slide 40
                                                                        • Bioequivalence
                                                                        • Slide 42
                                                                        • Carbamazepine
                                                                        • Slide 44
                                                                        • AIDS drug ritonavir
                                                                        • Slide 46
                                                                        • Slide 47
                                                                        • Phase Equilibria amp The Phase Rule
                                                                        • Phase diagram ndash Water
                                                                        • Phase Equilibria amp The Phase Rule Definitions
                                                                        • Phase Definition
                                                                        • Examples
                                                                        • Components
                                                                        • Examples
                                                                        • Slide 55
                                                                        • Degrees of freedom (or variance)
                                                                        • Examples (2)
                                                                        • Phase Equilibria amp The Phase Rule
                                                                        • The phase rule
                                                                        • Slide 60
                                                                        • Phase Equilibria amp The Phase Rule (2)
                                                                        • The number of phases in a system is denoted P
                                                                        • Slide 63
                                                                        • Slide 64
                                                                        • One-component systems
                                                                        • Slide 66
                                                                        • Slide 67
                                                                        • Slide 68
                                                                        • Slide 69
                                                                        • Slide 70
                                                                        • Two component system containing liquid phase
                                                                        • Slide 72
                                                                        • The Critical Solution Temperature CST
                                                                        • Systems Showing a Decrease in Miscibility with Rise in Temperat
                                                                        • Systems Showing Upper and Lower CSTs
                                                                        • Two component system containing solid and liquid phase (Eutecti
                                                                        • Slide 77
                                                                        • Eutectic mixture Pharmaceutical Application
                                                                        • Three component system
                                                                        • Slide 80
                                                                        • Topics that we have covered

                                                                          Carbamazepine

                                                                          CHLORPROPAMIDEat least six polymorphic white or almost white crystalline powder It exhibits polymorphism Practically insoluble in water soluble in alcohol freely soluble in acetone and in dichlo-romethane dissolves in dilute solutions of alkali hydroxides Protect from light

                                                                          blood-glucose-lowering drug

                                                                          AIDS drug ritonavir

                                                                          Theobroma oil (cacao butter ) is a polymorphic natural fat

                                                                          Theobroma oil can exist in 4 different polymorphic forms of which only one is Stabile

                                                                          1 Unstable gamma form melting at 18degC2 Alpha form melting at 22degC3 Beta prime form melting at 28degC4 Stable beta form melting at 345degC

                                                                          This is important in the preparation of theobroma suppositories

                                                                          If the oil is heated to a point where it is completely liquified (about 35 C) the crystals of the stable polymorph are destroyed amp the mass does not crystallize until it is cooled to 15 C

                                                                          The crystals that form are unstable amp the suppositories melt at 24 C

                                                                          Theobroma suppositories must be prepared below 33 C

                                                                          Polymorphism and Industry Pharmaceutical

                                                                          Polymorphism and Industry Pharmaceutical

                                                                          Anhydrates together with salts form the majority of all drug formulationsAbout a half of all APIs used today are saltsSalts are stable and well soluble in polar solvents (first of all in water) because they contain ionic bondThere is one more essential advantage of salts ndash their solubility is a function of pH Since pH in the gastrointestinal tract (GIT) vary between 1-75

                                                                          atorvastatin calcium trihydrateEach tablet contains Atorvastatin Calcium Trihydrate equivalent to Atorvastatin 20 mg

                                                                          Phase Equilibria amp The Phase Rule

                                                                          Phase diagram ndash Water

                                                                          Phase Equilibrium A stable phase structure with lowest free-energy (internal energy) of a system and also randomness or disorder of the atoms or molecules (entropy)

                                                                          Any change in Temperature Composition and Pressure causes an increase in free energy and away from Equilibrium thus forcing a move to another lsquostatersquo

                                                                          Phase Equilibria amp The Phase Rule Definitions

                                                                          A phase is defined as any homogeneous and physically distinct part of a system which is separated from other parts of the system by interfaces

                                                                          A part of a system is homogeneous if it has identical physical properties and chemical composition throughout the part

                                                                          A phase may be gas liquid or solid A gas or a gaseous mixture is a single phase Totally miscible liquids constitute a single phase In an immiscible liquid system each layer is counted as a separate phase Every solid constitutes a single phase except when a solid solution is formed A solid solution is considered as a single phase Each polymorphic form constitutes a separate phase

                                                                          Phase Definition

                                                                          1 Liquid water pieces of ice and water vapour are present together The number of phases is 3 as each form is a separate phase Ice in the system is a single phase even if it is present as a number of pieces

                                                                          2 Calcium carbonate undergoes thermal decomposition The chemical reaction is CaCO3(s) CaO(s) + CO2 (g) Number of phases = 3 This system consists of 2 solid phases CaCO3 and CaO and one gaseous phase that of CO2

                                                                          3 Ammonium chloride undergoes thermal decomposition The chemical reaction is NH4Cl(s) NH3 (g) + HCl (g) Number of phases = 2 This system has two phases one solid NH4Cl and one gaseous a mixture of NH3 and HCl

                                                                          4 A solution of NaCl in water Number of phases = 1

                                                                          bull Examples

                                                                          The number of components of a system at equilibrium is the smallest number of independently varying chemical constituents using which the composition of each and every phase in the system can be expressed

                                                                          Components

                                                                          Counting the number of components 1 The sulphur system is a one component system All the phases

                                                                          monoclinic rhombic liquid and vapour ndash can be expressed in terms of the single constituent ndash sulphur

                                                                          2 A mixture of ethanol and water is an example of a two component system We need both ethanol and water to express its composition

                                                                          bull Examples

                                                                          An example of a system in which a reaction occurs and an equilibrium is established is the thermal decomposition of solid CaCO3

                                                                          In this system there are three distinct phasesSolid CaCO3

                                                                          Solid CaOGaseous CO2

                                                                          Though there are 3 species present the number of components is only two because of the equilibrium CaCO3 (s) CaO(s) + CO2(g)

                                                                          Any two of the three constituents may be chosen as the components

                                                                          If CaO and CO2 are chosen then the composition of the phase CaCO3 is expressed as one mole of component CO2 plus one mole of component CaO

                                                                          If on the other hand CaCO3 and CO2 were chosen then the composition of the phase CaO would be described as one mole of CaCO3 minus one mole of CO2

                                                                          The degrees of freedom or variance of a system is defined as the minimum number of variables such as

                                                                          temperaturepressureconcentrationwhich must be fixed in order to define the system completely

                                                                          Degrees of freedom (or variance)

                                                                          F = C P + 2

                                                                          1 A gaseous mixture of CO2 and N2 Three variables pressure temperature and composition are required to define this system This is hence a trivariant system

                                                                          2 A system having only liquid water has two degrees of freedom or is bivariant Both temperature and pressure need to be mentioned in order to define the system

                                                                          3 If to the system containing liquid water pieces of ice are added and this system with 2 phases is allowed to come to equilibrium then it is an univariant system

                                                                          Only one variable either temperature or pressure need to be specified in order to define the systemIf the pressure on the system is maintained at 1 atm then the temperature of the system gets automatically fixed at 0oC the normal melting point of ice

                                                                          bull Examples

                                                                          Phase Equilibria amp The Phase Rule

                                                                          A phase diagram (Equilibrium Phase Diagram) summarizes the conditions at which a substance exists as a solid liquid or gas

                                                                          OR It is a ldquomaprdquo of the information about the control of phase structure of a particular material system

                                                                          The relationships between temperature and the compositions and the quantities of phases present at equilibrium are represented

                                                                          F = C P + 2The phase rule

                                                                          The phase rule JW Gibbs formulated the phase rule which is a general relation

                                                                          between the variance F the number of component C and the number of phases P at equilibrium for a system of any composition

                                                                          For a system in equilibrium

                                                                          F degree of freedom the least number of intensive variable that must be fixed (known) to describe the system completely

                                                                          Phase Rule relation to determine the least number of intensive variable that can be changed without changing the equilibrium state of the system or alternately

                                                                          The least number required to define the state of the system which is called degree of freedom F

                                                                          Intensive variable independent variable that do not depend on the volume or the size egTemp pressure

                                                                          Independent chemical species which comprise the system These could be Elements Ions Compounds

                                                                          Eg Au-Cu system Components rarr Au Cu Ice-water system Component rarr H2O

                                                                          Al2O3 ndash Cr2O3 system Components rarr Al2O3 Cr2O3

                                                                          Component the smallest number of constituent by which the composition of each phase in the system at equilibrium can be expressed in form of chemical formula or equation

                                                                          Phase Equilibria amp The Phase RuleComponents of a system

                                                                          The number of phases in a system is denoted P

                                                                          (a)A gas or a gaseous mixture is a single phase P=1

                                                                          (b) For a solid system an alloy of two metals is a two-phase system (P=2) if the metals are immiscible but a single-phase system (P=1) if they are miscible---a homogeneous mixture of the two substances---is uniform on a molecular scale

                                                                          (c) For a liquid system according to the solubility to decide whether a system consists of one phase or of two For example a solution of sodium chloride in water is a single phase A pair of liquids that are partially miscible or immiscible is a two-phase system(P=2)

                                                                          Oil in water

                                                                          Degrees of Freedom = What you can control What the system controls

                                                                          F = C + 2 P

                                                                          Can control the no of components added and P amp T

                                                                          System decided how many phases to produce given the

                                                                          conditions

                                                                          A way of understanding the Gibbs Phase RuleThe degrees of freedom can be thought of as the difference between what you (can) control and

                                                                          what the system controls

                                                                          F degree of freedom the least number of intensive variable that must be fixed (known) to describe the system completely

                                                                          Degree of freedom (or variance) F is the number of variables (T p andor composition) that can be changed independently without changing the phases of the system

                                                                          a) At the triple pointP = 3 (solid liquid and gas)

                                                                          C= 1 (water)P + F = C + 2

                                                                          F = 0 (no degree of freedom)

                                                                          b) liquid-solid curveP = 2

                                                                          2+F = 1 + 2F= 1

                                                                          One variable (T or P) can be changed

                                                                          c) LiquidP =1

                                                                          So F =2Two variables (T and P) can be varied independently

                                                                          and the system will remains a single phase

                                                                          One-component systemsPhase diagram of water

                                                                          P (

                                                                          atm

                                                                          )

                                                                          Critical point

                                                                          374

                                                                          1

                                                                          =100=0O--Triple point

                                                                          0006

                                                                          218

                                                                          Curve O -CSublimation

                                                                          Deposition

                                                                          Curve O-AVaporizationCondensation

                                                                          Curve O -BMelting

                                                                          Freezing

                                                                          F = C P + 2

                                                                          F = C P + 2

                                                                          Phase Diagram of Carbon Dioxide

                                                                          Condensed system System in which the vapor phase is ignored and only the solid andor liquid phases are considered

                                                                          Two component system For two component system F can be 3 (3D model is needed) eg T p

                                                                          and concentration usually we fix p = 1atm the vapor phase is neglected and F is reduced to 2

                                                                          For three component system the pressure and temperature are fixed

                                                                          Phenol water phase diagram

                                                                          eg for point d (24)

                                                                          Two component system containing liquid phase

                                                                          Tie Line bc line The line at which the system at equilibrium will separate into phases of constant composition termed lsquoconjugate phasesrsquo

                                                                          Lever Rule a way to calculate the proportions of each phase present on a phase diagram in a two phase field (at a given temperature and composition)

                                                                          eg for point d (24)

                                                                          For every 10 g of liquid system in equilibrium in point d

                                                                          75 g phase A25 g phase B

                                                                          ExampleMixed 24g phenol +76g water T 50degC

                                                                          equilibrium75 g phase A 25 g phase B

                                                                          11 phenol 63 phenol

                                                                          011 times75 g=825 g phenol

                                                                          063 times25 g=1575 g phenol

                                                                          water rich phasecontains water+ phenol(11)

                                                                          Phenol rich phasecontains Phenol (63)+ water

                                                                          The Critical Solution Temperature CST

                                                                          Is the maximum temperature at which the 2-phase region exists (or upper consolute temperature)

                                                                          In the case of the phenol-water system this is 668oC (point h)

                                                                          All combinations of phenol and water gt CST are completely miscible and yield 1-phase liquid systems

                                                                          Systems Showing a Decrease in Miscibility with Rise in Temperature

                                                                          A few mixtures exhibit a lower critical solution temperature (low CST) eg triethylamine plus water The miscibility with in temperature

                                                                          Systems Showing Upper and Lower CSTs

                                                                          The miscibility with temp

                                                                          a certain temperature miscibility starts to again with further in temperature

                                                                          Closed-phase diagram ie nicotine-water system

                                                                          A salol B thymol

                                                                          53

                                                                          Two component system containing solid and liquid phase (Eutectic Mixtures)

                                                                          A salol B thymol

                                                                          EMLAreg (lidocaine 25 and prilocaine 25) Cream

                                                                          EMLA Cream (lidocaine 25 and prilocaine 25) is an emulsion in which the oil phase is a eutectic mixture of lidocaine and prilocaine in a ratio of 11 by weight This eutectic mixture has a melting point below room temperature and therefore both local anesthetics exist as a liquid oil rather than as crystals

                                                                          Eutectic mixture Pharmaceutical Application

                                                                          Triangular Diagrams for three ndash component systems

                                                                          Three component system

                                                                          Birzeit University Physical Pharmacy PHAR 323 Dr Hani Shtaya

                                                                          1 Binding Forces Between Molecules2 Repulsive and Attractive Forces3 The Gaseous State The Ideal Gas Law Liquefaction of Gases Aerosols4 Solids and the Crystalline State Crystalline Solids Polymorphism Solvates Amorphous Solids5 Phase Equilibria and the Phase Rule Phase Rule Systems Containing One Component Condensed System Two-Component Systems Containing Liquid Phases Two-Component Systems Containing Solid and Liquid Phases Eutectic Mixtures Rules Relating to Triangular Diagrams

                                                                          Topics that we have covered

                                                                          • States of Matter
                                                                          • States of Matter (2)
                                                                          • Objectives of the lecture
                                                                          • Comparison of Gases Liquids and Solids
                                                                          • Slide 5
                                                                          • Repulsive and Attractive Forces
                                                                          • Ideal Gas Equation
                                                                          • Gaseous state
                                                                          • Slide 9
                                                                          • Gaseous state (2)
                                                                          • Liquefaction of Gases
                                                                          • Slide 12
                                                                          • SOLIDS amp CRYSTALLINE STATE Pharmaceutical Drugs more than 80
                                                                          • Solids and the crystalline state
                                                                          • Classification of Solids
                                                                          • Slide 16
                                                                          • Slide 17
                                                                          • Crystal forms
                                                                          • Types of Crystals
                                                                          • Slide 20
                                                                          • Slide 21
                                                                          • Polymorphism
                                                                          • Slide 23
                                                                          • Slide 24
                                                                          • Slide 25
                                                                          • Slide 26
                                                                          • Cocrystal
                                                                          • Principle of polymorphism
                                                                          • Solvates
                                                                          • Polymorphism (2)
                                                                          • Amorphous Solid
                                                                          • Amorphous or crystalline amp therapeutic activity
                                                                          • Slide 33
                                                                          • Slide 34
                                                                          • Polymorphism and Industry Pharmaceutical
                                                                          • Celecoxib
                                                                          • Furosemide
                                                                          • Bioavailability
                                                                          • Slide 39
                                                                          • Slide 40
                                                                          • Bioequivalence
                                                                          • Slide 42
                                                                          • Carbamazepine
                                                                          • Slide 44
                                                                          • AIDS drug ritonavir
                                                                          • Slide 46
                                                                          • Slide 47
                                                                          • Phase Equilibria amp The Phase Rule
                                                                          • Phase diagram ndash Water
                                                                          • Phase Equilibria amp The Phase Rule Definitions
                                                                          • Phase Definition
                                                                          • Examples
                                                                          • Components
                                                                          • Examples
                                                                          • Slide 55
                                                                          • Degrees of freedom (or variance)
                                                                          • Examples (2)
                                                                          • Phase Equilibria amp The Phase Rule
                                                                          • The phase rule
                                                                          • Slide 60
                                                                          • Phase Equilibria amp The Phase Rule (2)
                                                                          • The number of phases in a system is denoted P
                                                                          • Slide 63
                                                                          • Slide 64
                                                                          • One-component systems
                                                                          • Slide 66
                                                                          • Slide 67
                                                                          • Slide 68
                                                                          • Slide 69
                                                                          • Slide 70
                                                                          • Two component system containing liquid phase
                                                                          • Slide 72
                                                                          • The Critical Solution Temperature CST
                                                                          • Systems Showing a Decrease in Miscibility with Rise in Temperat
                                                                          • Systems Showing Upper and Lower CSTs
                                                                          • Two component system containing solid and liquid phase (Eutecti
                                                                          • Slide 77
                                                                          • Eutectic mixture Pharmaceutical Application
                                                                          • Three component system
                                                                          • Slide 80
                                                                          • Topics that we have covered

                                                                            CHLORPROPAMIDEat least six polymorphic white or almost white crystalline powder It exhibits polymorphism Practically insoluble in water soluble in alcohol freely soluble in acetone and in dichlo-romethane dissolves in dilute solutions of alkali hydroxides Protect from light

                                                                            blood-glucose-lowering drug

                                                                            AIDS drug ritonavir

                                                                            Theobroma oil (cacao butter ) is a polymorphic natural fat

                                                                            Theobroma oil can exist in 4 different polymorphic forms of which only one is Stabile

                                                                            1 Unstable gamma form melting at 18degC2 Alpha form melting at 22degC3 Beta prime form melting at 28degC4 Stable beta form melting at 345degC

                                                                            This is important in the preparation of theobroma suppositories

                                                                            If the oil is heated to a point where it is completely liquified (about 35 C) the crystals of the stable polymorph are destroyed amp the mass does not crystallize until it is cooled to 15 C

                                                                            The crystals that form are unstable amp the suppositories melt at 24 C

                                                                            Theobroma suppositories must be prepared below 33 C

                                                                            Polymorphism and Industry Pharmaceutical

                                                                            Polymorphism and Industry Pharmaceutical

                                                                            Anhydrates together with salts form the majority of all drug formulationsAbout a half of all APIs used today are saltsSalts are stable and well soluble in polar solvents (first of all in water) because they contain ionic bondThere is one more essential advantage of salts ndash their solubility is a function of pH Since pH in the gastrointestinal tract (GIT) vary between 1-75

                                                                            atorvastatin calcium trihydrateEach tablet contains Atorvastatin Calcium Trihydrate equivalent to Atorvastatin 20 mg

                                                                            Phase Equilibria amp The Phase Rule

                                                                            Phase diagram ndash Water

                                                                            Phase Equilibrium A stable phase structure with lowest free-energy (internal energy) of a system and also randomness or disorder of the atoms or molecules (entropy)

                                                                            Any change in Temperature Composition and Pressure causes an increase in free energy and away from Equilibrium thus forcing a move to another lsquostatersquo

                                                                            Phase Equilibria amp The Phase Rule Definitions

                                                                            A phase is defined as any homogeneous and physically distinct part of a system which is separated from other parts of the system by interfaces

                                                                            A part of a system is homogeneous if it has identical physical properties and chemical composition throughout the part

                                                                            A phase may be gas liquid or solid A gas or a gaseous mixture is a single phase Totally miscible liquids constitute a single phase In an immiscible liquid system each layer is counted as a separate phase Every solid constitutes a single phase except when a solid solution is formed A solid solution is considered as a single phase Each polymorphic form constitutes a separate phase

                                                                            Phase Definition

                                                                            1 Liquid water pieces of ice and water vapour are present together The number of phases is 3 as each form is a separate phase Ice in the system is a single phase even if it is present as a number of pieces

                                                                            2 Calcium carbonate undergoes thermal decomposition The chemical reaction is CaCO3(s) CaO(s) + CO2 (g) Number of phases = 3 This system consists of 2 solid phases CaCO3 and CaO and one gaseous phase that of CO2

                                                                            3 Ammonium chloride undergoes thermal decomposition The chemical reaction is NH4Cl(s) NH3 (g) + HCl (g) Number of phases = 2 This system has two phases one solid NH4Cl and one gaseous a mixture of NH3 and HCl

                                                                            4 A solution of NaCl in water Number of phases = 1

                                                                            bull Examples

                                                                            The number of components of a system at equilibrium is the smallest number of independently varying chemical constituents using which the composition of each and every phase in the system can be expressed

                                                                            Components

                                                                            Counting the number of components 1 The sulphur system is a one component system All the phases

                                                                            monoclinic rhombic liquid and vapour ndash can be expressed in terms of the single constituent ndash sulphur

                                                                            2 A mixture of ethanol and water is an example of a two component system We need both ethanol and water to express its composition

                                                                            bull Examples

                                                                            An example of a system in which a reaction occurs and an equilibrium is established is the thermal decomposition of solid CaCO3

                                                                            In this system there are three distinct phasesSolid CaCO3

                                                                            Solid CaOGaseous CO2

                                                                            Though there are 3 species present the number of components is only two because of the equilibrium CaCO3 (s) CaO(s) + CO2(g)

                                                                            Any two of the three constituents may be chosen as the components

                                                                            If CaO and CO2 are chosen then the composition of the phase CaCO3 is expressed as one mole of component CO2 plus one mole of component CaO

                                                                            If on the other hand CaCO3 and CO2 were chosen then the composition of the phase CaO would be described as one mole of CaCO3 minus one mole of CO2

                                                                            The degrees of freedom or variance of a system is defined as the minimum number of variables such as

                                                                            temperaturepressureconcentrationwhich must be fixed in order to define the system completely

                                                                            Degrees of freedom (or variance)

                                                                            F = C P + 2

                                                                            1 A gaseous mixture of CO2 and N2 Three variables pressure temperature and composition are required to define this system This is hence a trivariant system

                                                                            2 A system having only liquid water has two degrees of freedom or is bivariant Both temperature and pressure need to be mentioned in order to define the system

                                                                            3 If to the system containing liquid water pieces of ice are added and this system with 2 phases is allowed to come to equilibrium then it is an univariant system

                                                                            Only one variable either temperature or pressure need to be specified in order to define the systemIf the pressure on the system is maintained at 1 atm then the temperature of the system gets automatically fixed at 0oC the normal melting point of ice

                                                                            bull Examples

                                                                            Phase Equilibria amp The Phase Rule

                                                                            A phase diagram (Equilibrium Phase Diagram) summarizes the conditions at which a substance exists as a solid liquid or gas

                                                                            OR It is a ldquomaprdquo of the information about the control of phase structure of a particular material system

                                                                            The relationships between temperature and the compositions and the quantities of phases present at equilibrium are represented

                                                                            F = C P + 2The phase rule

                                                                            The phase rule JW Gibbs formulated the phase rule which is a general relation

                                                                            between the variance F the number of component C and the number of phases P at equilibrium for a system of any composition

                                                                            For a system in equilibrium

                                                                            F degree of freedom the least number of intensive variable that must be fixed (known) to describe the system completely

                                                                            Phase Rule relation to determine the least number of intensive variable that can be changed without changing the equilibrium state of the system or alternately

                                                                            The least number required to define the state of the system which is called degree of freedom F

                                                                            Intensive variable independent variable that do not depend on the volume or the size egTemp pressure

                                                                            Independent chemical species which comprise the system These could be Elements Ions Compounds

                                                                            Eg Au-Cu system Components rarr Au Cu Ice-water system Component rarr H2O

                                                                            Al2O3 ndash Cr2O3 system Components rarr Al2O3 Cr2O3

                                                                            Component the smallest number of constituent by which the composition of each phase in the system at equilibrium can be expressed in form of chemical formula or equation

                                                                            Phase Equilibria amp The Phase RuleComponents of a system

                                                                            The number of phases in a system is denoted P

                                                                            (a)A gas or a gaseous mixture is a single phase P=1

                                                                            (b) For a solid system an alloy of two metals is a two-phase system (P=2) if the metals are immiscible but a single-phase system (P=1) if they are miscible---a homogeneous mixture of the two substances---is uniform on a molecular scale

                                                                            (c) For a liquid system according to the solubility to decide whether a system consists of one phase or of two For example a solution of sodium chloride in water is a single phase A pair of liquids that are partially miscible or immiscible is a two-phase system(P=2)

                                                                            Oil in water

                                                                            Degrees of Freedom = What you can control What the system controls

                                                                            F = C + 2 P

                                                                            Can control the no of components added and P amp T

                                                                            System decided how many phases to produce given the

                                                                            conditions

                                                                            A way of understanding the Gibbs Phase RuleThe degrees of freedom can be thought of as the difference between what you (can) control and

                                                                            what the system controls

                                                                            F degree of freedom the least number of intensive variable that must be fixed (known) to describe the system completely

                                                                            Degree of freedom (or variance) F is the number of variables (T p andor composition) that can be changed independently without changing the phases of the system

                                                                            a) At the triple pointP = 3 (solid liquid and gas)

                                                                            C= 1 (water)P + F = C + 2

                                                                            F = 0 (no degree of freedom)

                                                                            b) liquid-solid curveP = 2

                                                                            2+F = 1 + 2F= 1

                                                                            One variable (T or P) can be changed

                                                                            c) LiquidP =1

                                                                            So F =2Two variables (T and P) can be varied independently

                                                                            and the system will remains a single phase

                                                                            One-component systemsPhase diagram of water

                                                                            P (

                                                                            atm

                                                                            )

                                                                            Critical point

                                                                            374

                                                                            1

                                                                            =100=0O--Triple point

                                                                            0006

                                                                            218

                                                                            Curve O -CSublimation

                                                                            Deposition

                                                                            Curve O-AVaporizationCondensation

                                                                            Curve O -BMelting

                                                                            Freezing

                                                                            F = C P + 2

                                                                            F = C P + 2

                                                                            Phase Diagram of Carbon Dioxide

                                                                            Condensed system System in which the vapor phase is ignored and only the solid andor liquid phases are considered

                                                                            Two component system For two component system F can be 3 (3D model is needed) eg T p

                                                                            and concentration usually we fix p = 1atm the vapor phase is neglected and F is reduced to 2

                                                                            For three component system the pressure and temperature are fixed

                                                                            Phenol water phase diagram

                                                                            eg for point d (24)

                                                                            Two component system containing liquid phase

                                                                            Tie Line bc line The line at which the system at equilibrium will separate into phases of constant composition termed lsquoconjugate phasesrsquo

                                                                            Lever Rule a way to calculate the proportions of each phase present on a phase diagram in a two phase field (at a given temperature and composition)

                                                                            eg for point d (24)

                                                                            For every 10 g of liquid system in equilibrium in point d

                                                                            75 g phase A25 g phase B

                                                                            ExampleMixed 24g phenol +76g water T 50degC

                                                                            equilibrium75 g phase A 25 g phase B

                                                                            11 phenol 63 phenol

                                                                            011 times75 g=825 g phenol

                                                                            063 times25 g=1575 g phenol

                                                                            water rich phasecontains water+ phenol(11)

                                                                            Phenol rich phasecontains Phenol (63)+ water

                                                                            The Critical Solution Temperature CST

                                                                            Is the maximum temperature at which the 2-phase region exists (or upper consolute temperature)

                                                                            In the case of the phenol-water system this is 668oC (point h)

                                                                            All combinations of phenol and water gt CST are completely miscible and yield 1-phase liquid systems

                                                                            Systems Showing a Decrease in Miscibility with Rise in Temperature

                                                                            A few mixtures exhibit a lower critical solution temperature (low CST) eg triethylamine plus water The miscibility with in temperature

                                                                            Systems Showing Upper and Lower CSTs

                                                                            The miscibility with temp

                                                                            a certain temperature miscibility starts to again with further in temperature

                                                                            Closed-phase diagram ie nicotine-water system

                                                                            A salol B thymol

                                                                            53

                                                                            Two component system containing solid and liquid phase (Eutectic Mixtures)

                                                                            A salol B thymol

                                                                            EMLAreg (lidocaine 25 and prilocaine 25) Cream

                                                                            EMLA Cream (lidocaine 25 and prilocaine 25) is an emulsion in which the oil phase is a eutectic mixture of lidocaine and prilocaine in a ratio of 11 by weight This eutectic mixture has a melting point below room temperature and therefore both local anesthetics exist as a liquid oil rather than as crystals

                                                                            Eutectic mixture Pharmaceutical Application

                                                                            Triangular Diagrams for three ndash component systems

                                                                            Three component system

                                                                            Birzeit University Physical Pharmacy PHAR 323 Dr Hani Shtaya

                                                                            1 Binding Forces Between Molecules2 Repulsive and Attractive Forces3 The Gaseous State The Ideal Gas Law Liquefaction of Gases Aerosols4 Solids and the Crystalline State Crystalline Solids Polymorphism Solvates Amorphous Solids5 Phase Equilibria and the Phase Rule Phase Rule Systems Containing One Component Condensed System Two-Component Systems Containing Liquid Phases Two-Component Systems Containing Solid and Liquid Phases Eutectic Mixtures Rules Relating to Triangular Diagrams

                                                                            Topics that we have covered

                                                                            • States of Matter
                                                                            • States of Matter (2)
                                                                            • Objectives of the lecture
                                                                            • Comparison of Gases Liquids and Solids
                                                                            • Slide 5
                                                                            • Repulsive and Attractive Forces
                                                                            • Ideal Gas Equation
                                                                            • Gaseous state
                                                                            • Slide 9
                                                                            • Gaseous state (2)
                                                                            • Liquefaction of Gases
                                                                            • Slide 12
                                                                            • SOLIDS amp CRYSTALLINE STATE Pharmaceutical Drugs more than 80
                                                                            • Solids and the crystalline state
                                                                            • Classification of Solids
                                                                            • Slide 16
                                                                            • Slide 17
                                                                            • Crystal forms
                                                                            • Types of Crystals
                                                                            • Slide 20
                                                                            • Slide 21
                                                                            • Polymorphism
                                                                            • Slide 23
                                                                            • Slide 24
                                                                            • Slide 25
                                                                            • Slide 26
                                                                            • Cocrystal
                                                                            • Principle of polymorphism
                                                                            • Solvates
                                                                            • Polymorphism (2)
                                                                            • Amorphous Solid
                                                                            • Amorphous or crystalline amp therapeutic activity
                                                                            • Slide 33
                                                                            • Slide 34
                                                                            • Polymorphism and Industry Pharmaceutical
                                                                            • Celecoxib
                                                                            • Furosemide
                                                                            • Bioavailability
                                                                            • Slide 39
                                                                            • Slide 40
                                                                            • Bioequivalence
                                                                            • Slide 42
                                                                            • Carbamazepine
                                                                            • Slide 44
                                                                            • AIDS drug ritonavir
                                                                            • Slide 46
                                                                            • Slide 47
                                                                            • Phase Equilibria amp The Phase Rule
                                                                            • Phase diagram ndash Water
                                                                            • Phase Equilibria amp The Phase Rule Definitions
                                                                            • Phase Definition
                                                                            • Examples
                                                                            • Components
                                                                            • Examples
                                                                            • Slide 55
                                                                            • Degrees of freedom (or variance)
                                                                            • Examples (2)
                                                                            • Phase Equilibria amp The Phase Rule
                                                                            • The phase rule
                                                                            • Slide 60
                                                                            • Phase Equilibria amp The Phase Rule (2)
                                                                            • The number of phases in a system is denoted P
                                                                            • Slide 63
                                                                            • Slide 64
                                                                            • One-component systems
                                                                            • Slide 66
                                                                            • Slide 67
                                                                            • Slide 68
                                                                            • Slide 69
                                                                            • Slide 70
                                                                            • Two component system containing liquid phase
                                                                            • Slide 72
                                                                            • The Critical Solution Temperature CST
                                                                            • Systems Showing a Decrease in Miscibility with Rise in Temperat
                                                                            • Systems Showing Upper and Lower CSTs
                                                                            • Two component system containing solid and liquid phase (Eutecti
                                                                            • Slide 77
                                                                            • Eutectic mixture Pharmaceutical Application
                                                                            • Three component system
                                                                            • Slide 80
                                                                            • Topics that we have covered

                                                                              AIDS drug ritonavir

                                                                              Theobroma oil (cacao butter ) is a polymorphic natural fat

                                                                              Theobroma oil can exist in 4 different polymorphic forms of which only one is Stabile

                                                                              1 Unstable gamma form melting at 18degC2 Alpha form melting at 22degC3 Beta prime form melting at 28degC4 Stable beta form melting at 345degC

                                                                              This is important in the preparation of theobroma suppositories

                                                                              If the oil is heated to a point where it is completely liquified (about 35 C) the crystals of the stable polymorph are destroyed amp the mass does not crystallize until it is cooled to 15 C

                                                                              The crystals that form are unstable amp the suppositories melt at 24 C

                                                                              Theobroma suppositories must be prepared below 33 C

                                                                              Polymorphism and Industry Pharmaceutical

                                                                              Polymorphism and Industry Pharmaceutical

                                                                              Anhydrates together with salts form the majority of all drug formulationsAbout a half of all APIs used today are saltsSalts are stable and well soluble in polar solvents (first of all in water) because they contain ionic bondThere is one more essential advantage of salts ndash their solubility is a function of pH Since pH in the gastrointestinal tract (GIT) vary between 1-75

                                                                              atorvastatin calcium trihydrateEach tablet contains Atorvastatin Calcium Trihydrate equivalent to Atorvastatin 20 mg

                                                                              Phase Equilibria amp The Phase Rule

                                                                              Phase diagram ndash Water

                                                                              Phase Equilibrium A stable phase structure with lowest free-energy (internal energy) of a system and also randomness or disorder of the atoms or molecules (entropy)

                                                                              Any change in Temperature Composition and Pressure causes an increase in free energy and away from Equilibrium thus forcing a move to another lsquostatersquo

                                                                              Phase Equilibria amp The Phase Rule Definitions

                                                                              A phase is defined as any homogeneous and physically distinct part of a system which is separated from other parts of the system by interfaces

                                                                              A part of a system is homogeneous if it has identical physical properties and chemical composition throughout the part

                                                                              A phase may be gas liquid or solid A gas or a gaseous mixture is a single phase Totally miscible liquids constitute a single phase In an immiscible liquid system each layer is counted as a separate phase Every solid constitutes a single phase except when a solid solution is formed A solid solution is considered as a single phase Each polymorphic form constitutes a separate phase

                                                                              Phase Definition

                                                                              1 Liquid water pieces of ice and water vapour are present together The number of phases is 3 as each form is a separate phase Ice in the system is a single phase even if it is present as a number of pieces

                                                                              2 Calcium carbonate undergoes thermal decomposition The chemical reaction is CaCO3(s) CaO(s) + CO2 (g) Number of phases = 3 This system consists of 2 solid phases CaCO3 and CaO and one gaseous phase that of CO2

                                                                              3 Ammonium chloride undergoes thermal decomposition The chemical reaction is NH4Cl(s) NH3 (g) + HCl (g) Number of phases = 2 This system has two phases one solid NH4Cl and one gaseous a mixture of NH3 and HCl

                                                                              4 A solution of NaCl in water Number of phases = 1

                                                                              bull Examples

                                                                              The number of components of a system at equilibrium is the smallest number of independently varying chemical constituents using which the composition of each and every phase in the system can be expressed

                                                                              Components

                                                                              Counting the number of components 1 The sulphur system is a one component system All the phases

                                                                              monoclinic rhombic liquid and vapour ndash can be expressed in terms of the single constituent ndash sulphur

                                                                              2 A mixture of ethanol and water is an example of a two component system We need both ethanol and water to express its composition

                                                                              bull Examples

                                                                              An example of a system in which a reaction occurs and an equilibrium is established is the thermal decomposition of solid CaCO3

                                                                              In this system there are three distinct phasesSolid CaCO3

                                                                              Solid CaOGaseous CO2

                                                                              Though there are 3 species present the number of components is only two because of the equilibrium CaCO3 (s) CaO(s) + CO2(g)

                                                                              Any two of the three constituents may be chosen as the components

                                                                              If CaO and CO2 are chosen then the composition of the phase CaCO3 is expressed as one mole of component CO2 plus one mole of component CaO

                                                                              If on the other hand CaCO3 and CO2 were chosen then the composition of the phase CaO would be described as one mole of CaCO3 minus one mole of CO2

                                                                              The degrees of freedom or variance of a system is defined as the minimum number of variables such as

                                                                              temperaturepressureconcentrationwhich must be fixed in order to define the system completely

                                                                              Degrees of freedom (or variance)

                                                                              F = C P + 2

                                                                              1 A gaseous mixture of CO2 and N2 Three variables pressure temperature and composition are required to define this system This is hence a trivariant system

                                                                              2 A system having only liquid water has two degrees of freedom or is bivariant Both temperature and pressure need to be mentioned in order to define the system

                                                                              3 If to the system containing liquid water pieces of ice are added and this system with 2 phases is allowed to come to equilibrium then it is an univariant system

                                                                              Only one variable either temperature or pressure need to be specified in order to define the systemIf the pressure on the system is maintained at 1 atm then the temperature of the system gets automatically fixed at 0oC the normal melting point of ice

                                                                              bull Examples

                                                                              Phase Equilibria amp The Phase Rule

                                                                              A phase diagram (Equilibrium Phase Diagram) summarizes the conditions at which a substance exists as a solid liquid or gas

                                                                              OR It is a ldquomaprdquo of the information about the control of phase structure of a particular material system

                                                                              The relationships between temperature and the compositions and the quantities of phases present at equilibrium are represented

                                                                              F = C P + 2The phase rule

                                                                              The phase rule JW Gibbs formulated the phase rule which is a general relation

                                                                              between the variance F the number of component C and the number of phases P at equilibrium for a system of any composition

                                                                              For a system in equilibrium

                                                                              F degree of freedom the least number of intensive variable that must be fixed (known) to describe the system completely

                                                                              Phase Rule relation to determine the least number of intensive variable that can be changed without changing the equilibrium state of the system or alternately

                                                                              The least number required to define the state of the system which is called degree of freedom F

                                                                              Intensive variable independent variable that do not depend on the volume or the size egTemp pressure

                                                                              Independent chemical species which comprise the system These could be Elements Ions Compounds

                                                                              Eg Au-Cu system Components rarr Au Cu Ice-water system Component rarr H2O

                                                                              Al2O3 ndash Cr2O3 system Components rarr Al2O3 Cr2O3

                                                                              Component the smallest number of constituent by which the composition of each phase in the system at equilibrium can be expressed in form of chemical formula or equation

                                                                              Phase Equilibria amp The Phase RuleComponents of a system

                                                                              The number of phases in a system is denoted P

                                                                              (a)A gas or a gaseous mixture is a single phase P=1

                                                                              (b) For a solid system an alloy of two metals is a two-phase system (P=2) if the metals are immiscible but a single-phase system (P=1) if they are miscible---a homogeneous mixture of the two substances---is uniform on a molecular scale

                                                                              (c) For a liquid system according to the solubility to decide whether a system consists of one phase or of two For example a solution of sodium chloride in water is a single phase A pair of liquids that are partially miscible or immiscible is a two-phase system(P=2)

                                                                              Oil in water

                                                                              Degrees of Freedom = What you can control What the system controls

                                                                              F = C + 2 P

                                                                              Can control the no of components added and P amp T

                                                                              System decided how many phases to produce given the

                                                                              conditions

                                                                              A way of understanding the Gibbs Phase RuleThe degrees of freedom can be thought of as the difference between what you (can) control and

                                                                              what the system controls

                                                                              F degree of freedom the least number of intensive variable that must be fixed (known) to describe the system completely

                                                                              Degree of freedom (or variance) F is the number of variables (T p andor composition) that can be changed independently without changing the phases of the system

                                                                              a) At the triple pointP = 3 (solid liquid and gas)

                                                                              C= 1 (water)P + F = C + 2

                                                                              F = 0 (no degree of freedom)

                                                                              b) liquid-solid curveP = 2

                                                                              2+F = 1 + 2F= 1

                                                                              One variable (T or P) can be changed

                                                                              c) LiquidP =1

                                                                              So F =2Two variables (T and P) can be varied independently

                                                                              and the system will remains a single phase

                                                                              One-component systemsPhase diagram of water

                                                                              P (

                                                                              atm

                                                                              )

                                                                              Critical point

                                                                              374

                                                                              1

                                                                              =100=0O--Triple point

                                                                              0006

                                                                              218

                                                                              Curve O -CSublimation

                                                                              Deposition

                                                                              Curve O-AVaporizationCondensation

                                                                              Curve O -BMelting

                                                                              Freezing

                                                                              F = C P + 2

                                                                              F = C P + 2

                                                                              Phase Diagram of Carbon Dioxide

                                                                              Condensed system System in which the vapor phase is ignored and only the solid andor liquid phases are considered

                                                                              Two component system For two component system F can be 3 (3D model is needed) eg T p

                                                                              and concentration usually we fix p = 1atm the vapor phase is neglected and F is reduced to 2

                                                                              For three component system the pressure and temperature are fixed

                                                                              Phenol water phase diagram

                                                                              eg for point d (24)

                                                                              Two component system containing liquid phase

                                                                              Tie Line bc line The line at which the system at equilibrium will separate into phases of constant composition termed lsquoconjugate phasesrsquo

                                                                              Lever Rule a way to calculate the proportions of each phase present on a phase diagram in a two phase field (at a given temperature and composition)

                                                                              eg for point d (24)

                                                                              For every 10 g of liquid system in equilibrium in point d

                                                                              75 g phase A25 g phase B

                                                                              ExampleMixed 24g phenol +76g water T 50degC

                                                                              equilibrium75 g phase A 25 g phase B

                                                                              11 phenol 63 phenol

                                                                              011 times75 g=825 g phenol

                                                                              063 times25 g=1575 g phenol

                                                                              water rich phasecontains water+ phenol(11)

                                                                              Phenol rich phasecontains Phenol (63)+ water

                                                                              The Critical Solution Temperature CST

                                                                              Is the maximum temperature at which the 2-phase region exists (or upper consolute temperature)

                                                                              In the case of the phenol-water system this is 668oC (point h)

                                                                              All combinations of phenol and water gt CST are completely miscible and yield 1-phase liquid systems

                                                                              Systems Showing a Decrease in Miscibility with Rise in Temperature

                                                                              A few mixtures exhibit a lower critical solution temperature (low CST) eg triethylamine plus water The miscibility with in temperature

                                                                              Systems Showing Upper and Lower CSTs

                                                                              The miscibility with temp

                                                                              a certain temperature miscibility starts to again with further in temperature

                                                                              Closed-phase diagram ie nicotine-water system

                                                                              A salol B thymol

                                                                              53

                                                                              Two component system containing solid and liquid phase (Eutectic Mixtures)

                                                                              A salol B thymol

                                                                              EMLAreg (lidocaine 25 and prilocaine 25) Cream

                                                                              EMLA Cream (lidocaine 25 and prilocaine 25) is an emulsion in which the oil phase is a eutectic mixture of lidocaine and prilocaine in a ratio of 11 by weight This eutectic mixture has a melting point below room temperature and therefore both local anesthetics exist as a liquid oil rather than as crystals

                                                                              Eutectic mixture Pharmaceutical Application

                                                                              Triangular Diagrams for three ndash component systems

                                                                              Three component system

                                                                              Birzeit University Physical Pharmacy PHAR 323 Dr Hani Shtaya

                                                                              1 Binding Forces Between Molecules2 Repulsive and Attractive Forces3 The Gaseous State The Ideal Gas Law Liquefaction of Gases Aerosols4 Solids and the Crystalline State Crystalline Solids Polymorphism Solvates Amorphous Solids5 Phase Equilibria and the Phase Rule Phase Rule Systems Containing One Component Condensed System Two-Component Systems Containing Liquid Phases Two-Component Systems Containing Solid and Liquid Phases Eutectic Mixtures Rules Relating to Triangular Diagrams

                                                                              Topics that we have covered

                                                                              • States of Matter
                                                                              • States of Matter (2)
                                                                              • Objectives of the lecture
                                                                              • Comparison of Gases Liquids and Solids
                                                                              • Slide 5
                                                                              • Repulsive and Attractive Forces
                                                                              • Ideal Gas Equation
                                                                              • Gaseous state
                                                                              • Slide 9
                                                                              • Gaseous state (2)
                                                                              • Liquefaction of Gases
                                                                              • Slide 12
                                                                              • SOLIDS amp CRYSTALLINE STATE Pharmaceutical Drugs more than 80
                                                                              • Solids and the crystalline state
                                                                              • Classification of Solids
                                                                              • Slide 16
                                                                              • Slide 17
                                                                              • Crystal forms
                                                                              • Types of Crystals
                                                                              • Slide 20
                                                                              • Slide 21
                                                                              • Polymorphism
                                                                              • Slide 23
                                                                              • Slide 24
                                                                              • Slide 25
                                                                              • Slide 26
                                                                              • Cocrystal
                                                                              • Principle of polymorphism
                                                                              • Solvates
                                                                              • Polymorphism (2)
                                                                              • Amorphous Solid
                                                                              • Amorphous or crystalline amp therapeutic activity
                                                                              • Slide 33
                                                                              • Slide 34
                                                                              • Polymorphism and Industry Pharmaceutical
                                                                              • Celecoxib
                                                                              • Furosemide
                                                                              • Bioavailability
                                                                              • Slide 39
                                                                              • Slide 40
                                                                              • Bioequivalence
                                                                              • Slide 42
                                                                              • Carbamazepine
                                                                              • Slide 44
                                                                              • AIDS drug ritonavir
                                                                              • Slide 46
                                                                              • Slide 47
                                                                              • Phase Equilibria amp The Phase Rule
                                                                              • Phase diagram ndash Water
                                                                              • Phase Equilibria amp The Phase Rule Definitions
                                                                              • Phase Definition
                                                                              • Examples
                                                                              • Components
                                                                              • Examples
                                                                              • Slide 55
                                                                              • Degrees of freedom (or variance)
                                                                              • Examples (2)
                                                                              • Phase Equilibria amp The Phase Rule
                                                                              • The phase rule
                                                                              • Slide 60
                                                                              • Phase Equilibria amp The Phase Rule (2)
                                                                              • The number of phases in a system is denoted P
                                                                              • Slide 63
                                                                              • Slide 64
                                                                              • One-component systems
                                                                              • Slide 66
                                                                              • Slide 67
                                                                              • Slide 68
                                                                              • Slide 69
                                                                              • Slide 70
                                                                              • Two component system containing liquid phase
                                                                              • Slide 72
                                                                              • The Critical Solution Temperature CST
                                                                              • Systems Showing a Decrease in Miscibility with Rise in Temperat
                                                                              • Systems Showing Upper and Lower CSTs
                                                                              • Two component system containing solid and liquid phase (Eutecti
                                                                              • Slide 77
                                                                              • Eutectic mixture Pharmaceutical Application
                                                                              • Three component system
                                                                              • Slide 80
                                                                              • Topics that we have covered

                                                                                Theobroma oil (cacao butter ) is a polymorphic natural fat

                                                                                Theobroma oil can exist in 4 different polymorphic forms of which only one is Stabile

                                                                                1 Unstable gamma form melting at 18degC2 Alpha form melting at 22degC3 Beta prime form melting at 28degC4 Stable beta form melting at 345degC

                                                                                This is important in the preparation of theobroma suppositories

                                                                                If the oil is heated to a point where it is completely liquified (about 35 C) the crystals of the stable polymorph are destroyed amp the mass does not crystallize until it is cooled to 15 C

                                                                                The crystals that form are unstable amp the suppositories melt at 24 C

                                                                                Theobroma suppositories must be prepared below 33 C

                                                                                Polymorphism and Industry Pharmaceutical

                                                                                Polymorphism and Industry Pharmaceutical

                                                                                Anhydrates together with salts form the majority of all drug formulationsAbout a half of all APIs used today are saltsSalts are stable and well soluble in polar solvents (first of all in water) because they contain ionic bondThere is one more essential advantage of salts ndash their solubility is a function of pH Since pH in the gastrointestinal tract (GIT) vary between 1-75

                                                                                atorvastatin calcium trihydrateEach tablet contains Atorvastatin Calcium Trihydrate equivalent to Atorvastatin 20 mg

                                                                                Phase Equilibria amp The Phase Rule

                                                                                Phase diagram ndash Water

                                                                                Phase Equilibrium A stable phase structure with lowest free-energy (internal energy) of a system and also randomness or disorder of the atoms or molecules (entropy)

                                                                                Any change in Temperature Composition and Pressure causes an increase in free energy and away from Equilibrium thus forcing a move to another lsquostatersquo

                                                                                Phase Equilibria amp The Phase Rule Definitions

                                                                                A phase is defined as any homogeneous and physically distinct part of a system which is separated from other parts of the system by interfaces

                                                                                A part of a system is homogeneous if it has identical physical properties and chemical composition throughout the part

                                                                                A phase may be gas liquid or solid A gas or a gaseous mixture is a single phase Totally miscible liquids constitute a single phase In an immiscible liquid system each layer is counted as a separate phase Every solid constitutes a single phase except when a solid solution is formed A solid solution is considered as a single phase Each polymorphic form constitutes a separate phase

                                                                                Phase Definition

                                                                                1 Liquid water pieces of ice and water vapour are present together The number of phases is 3 as each form is a separate phase Ice in the system is a single phase even if it is present as a number of pieces

                                                                                2 Calcium carbonate undergoes thermal decomposition The chemical reaction is CaCO3(s) CaO(s) + CO2 (g) Number of phases = 3 This system consists of 2 solid phases CaCO3 and CaO and one gaseous phase that of CO2

                                                                                3 Ammonium chloride undergoes thermal decomposition The chemical reaction is NH4Cl(s) NH3 (g) + HCl (g) Number of phases = 2 This system has two phases one solid NH4Cl and one gaseous a mixture of NH3 and HCl

                                                                                4 A solution of NaCl in water Number of phases = 1

                                                                                bull Examples

                                                                                The number of components of a system at equilibrium is the smallest number of independently varying chemical constituents using which the composition of each and every phase in the system can be expressed

                                                                                Components

                                                                                Counting the number of components 1 The sulphur system is a one component system All the phases

                                                                                monoclinic rhombic liquid and vapour ndash can be expressed in terms of the single constituent ndash sulphur

                                                                                2 A mixture of ethanol and water is an example of a two component system We need both ethanol and water to express its composition

                                                                                bull Examples

                                                                                An example of a system in which a reaction occurs and an equilibrium is established is the thermal decomposition of solid CaCO3

                                                                                In this system there are three distinct phasesSolid CaCO3

                                                                                Solid CaOGaseous CO2

                                                                                Though there are 3 species present the number of components is only two because of the equilibrium CaCO3 (s) CaO(s) + CO2(g)

                                                                                Any two of the three constituents may be chosen as the components

                                                                                If CaO and CO2 are chosen then the composition of the phase CaCO3 is expressed as one mole of component CO2 plus one mole of component CaO

                                                                                If on the other hand CaCO3 and CO2 were chosen then the composition of the phase CaO would be described as one mole of CaCO3 minus one mole of CO2

                                                                                The degrees of freedom or variance of a system is defined as the minimum number of variables such as

                                                                                temperaturepressureconcentrationwhich must be fixed in order to define the system completely

                                                                                Degrees of freedom (or variance)

                                                                                F = C P + 2

                                                                                1 A gaseous mixture of CO2 and N2 Three variables pressure temperature and composition are required to define this system This is hence a trivariant system

                                                                                2 A system having only liquid water has two degrees of freedom or is bivariant Both temperature and pressure need to be mentioned in order to define the system

                                                                                3 If to the system containing liquid water pieces of ice are added and this system with 2 phases is allowed to come to equilibrium then it is an univariant system

                                                                                Only one variable either temperature or pressure need to be specified in order to define the systemIf the pressure on the system is maintained at 1 atm then the temperature of the system gets automatically fixed at 0oC the normal melting point of ice

                                                                                bull Examples

                                                                                Phase Equilibria amp The Phase Rule

                                                                                A phase diagram (Equilibrium Phase Diagram) summarizes the conditions at which a substance exists as a solid liquid or gas

                                                                                OR It is a ldquomaprdquo of the information about the control of phase structure of a particular material system

                                                                                The relationships between temperature and the compositions and the quantities of phases present at equilibrium are represented

                                                                                F = C P + 2The phase rule

                                                                                The phase rule JW Gibbs formulated the phase rule which is a general relation

                                                                                between the variance F the number of component C and the number of phases P at equilibrium for a system of any composition

                                                                                For a system in equilibrium

                                                                                F degree of freedom the least number of intensive variable that must be fixed (known) to describe the system completely

                                                                                Phase Rule relation to determine the least number of intensive variable that can be changed without changing the equilibrium state of the system or alternately

                                                                                The least number required to define the state of the system which is called degree of freedom F

                                                                                Intensive variable independent variable that do not depend on the volume or the size egTemp pressure

                                                                                Independent chemical species which comprise the system These could be Elements Ions Compounds

                                                                                Eg Au-Cu system Components rarr Au Cu Ice-water system Component rarr H2O

                                                                                Al2O3 ndash Cr2O3 system Components rarr Al2O3 Cr2O3

                                                                                Component the smallest number of constituent by which the composition of each phase in the system at equilibrium can be expressed in form of chemical formula or equation

                                                                                Phase Equilibria amp The Phase RuleComponents of a system

                                                                                The number of phases in a system is denoted P

                                                                                (a)A gas or a gaseous mixture is a single phase P=1

                                                                                (b) For a solid system an alloy of two metals is a two-phase system (P=2) if the metals are immiscible but a single-phase system (P=1) if they are miscible---a homogeneous mixture of the two substances---is uniform on a molecular scale

                                                                                (c) For a liquid system according to the solubility to decide whether a system consists of one phase or of two For example a solution of sodium chloride in water is a single phase A pair of liquids that are partially miscible or immiscible is a two-phase system(P=2)

                                                                                Oil in water

                                                                                Degrees of Freedom = What you can control What the system controls

                                                                                F = C + 2 P

                                                                                Can control the no of components added and P amp T

                                                                                System decided how many phases to produce given the

                                                                                conditions

                                                                                A way of understanding the Gibbs Phase RuleThe degrees of freedom can be thought of as the difference between what you (can) control and

                                                                                what the system controls

                                                                                F degree of freedom the least number of intensive variable that must be fixed (known) to describe the system completely

                                                                                Degree of freedom (or variance) F is the number of variables (T p andor composition) that can be changed independently without changing the phases of the system

                                                                                a) At the triple pointP = 3 (solid liquid and gas)

                                                                                C= 1 (water)P + F = C + 2

                                                                                F = 0 (no degree of freedom)

                                                                                b) liquid-solid curveP = 2

                                                                                2+F = 1 + 2F= 1

                                                                                One variable (T or P) can be changed

                                                                                c) LiquidP =1

                                                                                So F =2Two variables (T and P) can be varied independently

                                                                                and the system will remains a single phase

                                                                                One-component systemsPhase diagram of water

                                                                                P (

                                                                                atm

                                                                                )

                                                                                Critical point

                                                                                374

                                                                                1

                                                                                =100=0O--Triple point

                                                                                0006

                                                                                218

                                                                                Curve O -CSublimation

                                                                                Deposition

                                                                                Curve O-AVaporizationCondensation

                                                                                Curve O -BMelting

                                                                                Freezing

                                                                                F = C P + 2

                                                                                F = C P + 2

                                                                                Phase Diagram of Carbon Dioxide

                                                                                Condensed system System in which the vapor phase is ignored and only the solid andor liquid phases are considered

                                                                                Two component system For two component system F can be 3 (3D model is needed) eg T p

                                                                                and concentration usually we fix p = 1atm the vapor phase is neglected and F is reduced to 2

                                                                                For three component system the pressure and temperature are fixed

                                                                                Phenol water phase diagram

                                                                                eg for point d (24)

                                                                                Two component system containing liquid phase

                                                                                Tie Line bc line The line at which the system at equilibrium will separate into phases of constant composition termed lsquoconjugate phasesrsquo

                                                                                Lever Rule a way to calculate the proportions of each phase present on a phase diagram in a two phase field (at a given temperature and composition)

                                                                                eg for point d (24)

                                                                                For every 10 g of liquid system in equilibrium in point d

                                                                                75 g phase A25 g phase B

                                                                                ExampleMixed 24g phenol +76g water T 50degC

                                                                                equilibrium75 g phase A 25 g phase B

                                                                                11 phenol 63 phenol

                                                                                011 times75 g=825 g phenol

                                                                                063 times25 g=1575 g phenol

                                                                                water rich phasecontains water+ phenol(11)

                                                                                Phenol rich phasecontains Phenol (63)+ water

                                                                                The Critical Solution Temperature CST

                                                                                Is the maximum temperature at which the 2-phase region exists (or upper consolute temperature)

                                                                                In the case of the phenol-water system this is 668oC (point h)

                                                                                All combinations of phenol and water gt CST are completely miscible and yield 1-phase liquid systems

                                                                                Systems Showing a Decrease in Miscibility with Rise in Temperature

                                                                                A few mixtures exhibit a lower critical solution temperature (low CST) eg triethylamine plus water The miscibility with in temperature

                                                                                Systems Showing Upper and Lower CSTs

                                                                                The miscibility with temp

                                                                                a certain temperature miscibility starts to again with further in temperature

                                                                                Closed-phase diagram ie nicotine-water system

                                                                                A salol B thymol

                                                                                53

                                                                                Two component system containing solid and liquid phase (Eutectic Mixtures)

                                                                                A salol B thymol

                                                                                EMLAreg (lidocaine 25 and prilocaine 25) Cream

                                                                                EMLA Cream (lidocaine 25 and prilocaine 25) is an emulsion in which the oil phase is a eutectic mixture of lidocaine and prilocaine in a ratio of 11 by weight This eutectic mixture has a melting point below room temperature and therefore both local anesthetics exist as a liquid oil rather than as crystals

                                                                                Eutectic mixture Pharmaceutical Application

                                                                                Triangular Diagrams for three ndash component systems

                                                                                Three component system

                                                                                Birzeit University Physical Pharmacy PHAR 323 Dr Hani Shtaya

                                                                                1 Binding Forces Between Molecules2 Repulsive and Attractive Forces3 The Gaseous State The Ideal Gas Law Liquefaction of Gases Aerosols4 Solids and the Crystalline State Crystalline Solids Polymorphism Solvates Amorphous Solids5 Phase Equilibria and the Phase Rule Phase Rule Systems Containing One Component Condensed System Two-Component Systems Containing Liquid Phases Two-Component Systems Containing Solid and Liquid Phases Eutectic Mixtures Rules Relating to Triangular Diagrams

                                                                                Topics that we have covered

                                                                                • States of Matter
                                                                                • States of Matter (2)
                                                                                • Objectives of the lecture
                                                                                • Comparison of Gases Liquids and Solids
                                                                                • Slide 5
                                                                                • Repulsive and Attractive Forces
                                                                                • Ideal Gas Equation
                                                                                • Gaseous state
                                                                                • Slide 9
                                                                                • Gaseous state (2)
                                                                                • Liquefaction of Gases
                                                                                • Slide 12
                                                                                • SOLIDS amp CRYSTALLINE STATE Pharmaceutical Drugs more than 80
                                                                                • Solids and the crystalline state
                                                                                • Classification of Solids
                                                                                • Slide 16
                                                                                • Slide 17
                                                                                • Crystal forms
                                                                                • Types of Crystals
                                                                                • Slide 20
                                                                                • Slide 21
                                                                                • Polymorphism
                                                                                • Slide 23
                                                                                • Slide 24
                                                                                • Slide 25
                                                                                • Slide 26
                                                                                • Cocrystal
                                                                                • Principle of polymorphism
                                                                                • Solvates
                                                                                • Polymorphism (2)
                                                                                • Amorphous Solid
                                                                                • Amorphous or crystalline amp therapeutic activity
                                                                                • Slide 33
                                                                                • Slide 34
                                                                                • Polymorphism and Industry Pharmaceutical
                                                                                • Celecoxib
                                                                                • Furosemide
                                                                                • Bioavailability
                                                                                • Slide 39
                                                                                • Slide 40
                                                                                • Bioequivalence
                                                                                • Slide 42
                                                                                • Carbamazepine
                                                                                • Slide 44
                                                                                • AIDS drug ritonavir
                                                                                • Slide 46
                                                                                • Slide 47
                                                                                • Phase Equilibria amp The Phase Rule
                                                                                • Phase diagram ndash Water
                                                                                • Phase Equilibria amp The Phase Rule Definitions
                                                                                • Phase Definition
                                                                                • Examples
                                                                                • Components
                                                                                • Examples
                                                                                • Slide 55
                                                                                • Degrees of freedom (or variance)
                                                                                • Examples (2)
                                                                                • Phase Equilibria amp The Phase Rule
                                                                                • The phase rule
                                                                                • Slide 60
                                                                                • Phase Equilibria amp The Phase Rule (2)
                                                                                • The number of phases in a system is denoted P
                                                                                • Slide 63
                                                                                • Slide 64
                                                                                • One-component systems
                                                                                • Slide 66
                                                                                • Slide 67
                                                                                • Slide 68
                                                                                • Slide 69
                                                                                • Slide 70
                                                                                • Two component system containing liquid phase
                                                                                • Slide 72
                                                                                • The Critical Solution Temperature CST
                                                                                • Systems Showing a Decrease in Miscibility with Rise in Temperat
                                                                                • Systems Showing Upper and Lower CSTs
                                                                                • Two component system containing solid and liquid phase (Eutecti
                                                                                • Slide 77
                                                                                • Eutectic mixture Pharmaceutical Application
                                                                                • Three component system
                                                                                • Slide 80
                                                                                • Topics that we have covered

                                                                                  Polymorphism and Industry Pharmaceutical

                                                                                  Anhydrates together with salts form the majority of all drug formulationsAbout a half of all APIs used today are saltsSalts are stable and well soluble in polar solvents (first of all in water) because they contain ionic bondThere is one more essential advantage of salts ndash their solubility is a function of pH Since pH in the gastrointestinal tract (GIT) vary between 1-75

                                                                                  atorvastatin calcium trihydrateEach tablet contains Atorvastatin Calcium Trihydrate equivalent to Atorvastatin 20 mg

                                                                                  Phase Equilibria amp The Phase Rule

                                                                                  Phase diagram ndash Water

                                                                                  Phase Equilibrium A stable phase structure with lowest free-energy (internal energy) of a system and also randomness or disorder of the atoms or molecules (entropy)

                                                                                  Any change in Temperature Composition and Pressure causes an increase in free energy and away from Equilibrium thus forcing a move to another lsquostatersquo

                                                                                  Phase Equilibria amp The Phase Rule Definitions

                                                                                  A phase is defined as any homogeneous and physically distinct part of a system which is separated from other parts of the system by interfaces

                                                                                  A part of a system is homogeneous if it has identical physical properties and chemical composition throughout the part

                                                                                  A phase may be gas liquid or solid A gas or a gaseous mixture is a single phase Totally miscible liquids constitute a single phase In an immiscible liquid system each layer is counted as a separate phase Every solid constitutes a single phase except when a solid solution is formed A solid solution is considered as a single phase Each polymorphic form constitutes a separate phase

                                                                                  Phase Definition

                                                                                  1 Liquid water pieces of ice and water vapour are present together The number of phases is 3 as each form is a separate phase Ice in the system is a single phase even if it is present as a number of pieces

                                                                                  2 Calcium carbonate undergoes thermal decomposition The chemical reaction is CaCO3(s) CaO(s) + CO2 (g) Number of phases = 3 This system consists of 2 solid phases CaCO3 and CaO and one gaseous phase that of CO2

                                                                                  3 Ammonium chloride undergoes thermal decomposition The chemical reaction is NH4Cl(s) NH3 (g) + HCl (g) Number of phases = 2 This system has two phases one solid NH4Cl and one gaseous a mixture of NH3 and HCl

                                                                                  4 A solution of NaCl in water Number of phases = 1

                                                                                  bull Examples

                                                                                  The number of components of a system at equilibrium is the smallest number of independently varying chemical constituents using which the composition of each and every phase in the system can be expressed

                                                                                  Components

                                                                                  Counting the number of components 1 The sulphur system is a one component system All the phases

                                                                                  monoclinic rhombic liquid and vapour ndash can be expressed in terms of the single constituent ndash sulphur

                                                                                  2 A mixture of ethanol and water is an example of a two component system We need both ethanol and water to express its composition

                                                                                  bull Examples

                                                                                  An example of a system in which a reaction occurs and an equilibrium is established is the thermal decomposition of solid CaCO3

                                                                                  In this system there are three distinct phasesSolid CaCO3

                                                                                  Solid CaOGaseous CO2

                                                                                  Though there are 3 species present the number of components is only two because of the equilibrium CaCO3 (s) CaO(s) + CO2(g)

                                                                                  Any two of the three constituents may be chosen as the components

                                                                                  If CaO and CO2 are chosen then the composition of the phase CaCO3 is expressed as one mole of component CO2 plus one mole of component CaO

                                                                                  If on the other hand CaCO3 and CO2 were chosen then the composition of the phase CaO would be described as one mole of CaCO3 minus one mole of CO2

                                                                                  The degrees of freedom or variance of a system is defined as the minimum number of variables such as

                                                                                  temperaturepressureconcentrationwhich must be fixed in order to define the system completely

                                                                                  Degrees of freedom (or variance)

                                                                                  F = C P + 2

                                                                                  1 A gaseous mixture of CO2 and N2 Three variables pressure temperature and composition are required to define this system This is hence a trivariant system

                                                                                  2 A system having only liquid water has two degrees of freedom or is bivariant Both temperature and pressure need to be mentioned in order to define the system

                                                                                  3 If to the system containing liquid water pieces of ice are added and this system with 2 phases is allowed to come to equilibrium then it is an univariant system

                                                                                  Only one variable either temperature or pressure need to be specified in order to define the systemIf the pressure on the system is maintained at 1 atm then the temperature of the system gets automatically fixed at 0oC the normal melting point of ice

                                                                                  bull Examples

                                                                                  Phase Equilibria amp The Phase Rule

                                                                                  A phase diagram (Equilibrium Phase Diagram) summarizes the conditions at which a substance exists as a solid liquid or gas

                                                                                  OR It is a ldquomaprdquo of the information about the control of phase structure of a particular material system

                                                                                  The relationships between temperature and the compositions and the quantities of phases present at equilibrium are represented

                                                                                  F = C P + 2The phase rule

                                                                                  The phase rule JW Gibbs formulated the phase rule which is a general relation

                                                                                  between the variance F the number of component C and the number of phases P at equilibrium for a system of any composition

                                                                                  For a system in equilibrium

                                                                                  F degree of freedom the least number of intensive variable that must be fixed (known) to describe the system completely

                                                                                  Phase Rule relation to determine the least number of intensive variable that can be changed without changing the equilibrium state of the system or alternately

                                                                                  The least number required to define the state of the system which is called degree of freedom F

                                                                                  Intensive variable independent variable that do not depend on the volume or the size egTemp pressure

                                                                                  Independent chemical species which comprise the system These could be Elements Ions Compounds

                                                                                  Eg Au-Cu system Components rarr Au Cu Ice-water system Component rarr H2O

                                                                                  Al2O3 ndash Cr2O3 system Components rarr Al2O3 Cr2O3

                                                                                  Component the smallest number of constituent by which the composition of each phase in the system at equilibrium can be expressed in form of chemical formula or equation

                                                                                  Phase Equilibria amp The Phase RuleComponents of a system

                                                                                  The number of phases in a system is denoted P

                                                                                  (a)A gas or a gaseous mixture is a single phase P=1

                                                                                  (b) For a solid system an alloy of two metals is a two-phase system (P=2) if the metals are immiscible but a single-phase system (P=1) if they are miscible---a homogeneous mixture of the two substances---is uniform on a molecular scale

                                                                                  (c) For a liquid system according to the solubility to decide whether a system consists of one phase or of two For example a solution of sodium chloride in water is a single phase A pair of liquids that are partially miscible or immiscible is a two-phase system(P=2)

                                                                                  Oil in water

                                                                                  Degrees of Freedom = What you can control What the system controls

                                                                                  F = C + 2 P

                                                                                  Can control the no of components added and P amp T

                                                                                  System decided how many phases to produce given the

                                                                                  conditions

                                                                                  A way of understanding the Gibbs Phase RuleThe degrees of freedom can be thought of as the difference between what you (can) control and

                                                                                  what the system controls

                                                                                  F degree of freedom the least number of intensive variable that must be fixed (known) to describe the system completely

                                                                                  Degree of freedom (or variance) F is the number of variables (T p andor composition) that can be changed independently without changing the phases of the system

                                                                                  a) At the triple pointP = 3 (solid liquid and gas)

                                                                                  C= 1 (water)P + F = C + 2

                                                                                  F = 0 (no degree of freedom)

                                                                                  b) liquid-solid curveP = 2

                                                                                  2+F = 1 + 2F= 1

                                                                                  One variable (T or P) can be changed

                                                                                  c) LiquidP =1

                                                                                  So F =2Two variables (T and P) can be varied independently

                                                                                  and the system will remains a single phase

                                                                                  One-component systemsPhase diagram of water

                                                                                  P (

                                                                                  atm

                                                                                  )

                                                                                  Critical point

                                                                                  374

                                                                                  1

                                                                                  =100=0O--Triple point

                                                                                  0006

                                                                                  218

                                                                                  Curve O -CSublimation

                                                                                  Deposition

                                                                                  Curve O-AVaporizationCondensation

                                                                                  Curve O -BMelting

                                                                                  Freezing

                                                                                  F = C P + 2

                                                                                  F = C P + 2

                                                                                  Phase Diagram of Carbon Dioxide

                                                                                  Condensed system System in which the vapor phase is ignored and only the solid andor liquid phases are considered

                                                                                  Two component system For two component system F can be 3 (3D model is needed) eg T p

                                                                                  and concentration usually we fix p = 1atm the vapor phase is neglected and F is reduced to 2

                                                                                  For three component system the pressure and temperature are fixed

                                                                                  Phenol water phase diagram

                                                                                  eg for point d (24)

                                                                                  Two component system containing liquid phase

                                                                                  Tie Line bc line The line at which the system at equilibrium will separate into phases of constant composition termed lsquoconjugate phasesrsquo

                                                                                  Lever Rule a way to calculate the proportions of each phase present on a phase diagram in a two phase field (at a given temperature and composition)

                                                                                  eg for point d (24)

                                                                                  For every 10 g of liquid system in equilibrium in point d

                                                                                  75 g phase A25 g phase B

                                                                                  ExampleMixed 24g phenol +76g water T 50degC

                                                                                  equilibrium75 g phase A 25 g phase B

                                                                                  11 phenol 63 phenol

                                                                                  011 times75 g=825 g phenol

                                                                                  063 times25 g=1575 g phenol

                                                                                  water rich phasecontains water+ phenol(11)

                                                                                  Phenol rich phasecontains Phenol (63)+ water

                                                                                  The Critical Solution Temperature CST

                                                                                  Is the maximum temperature at which the 2-phase region exists (or upper consolute temperature)

                                                                                  In the case of the phenol-water system this is 668oC (point h)

                                                                                  All combinations of phenol and water gt CST are completely miscible and yield 1-phase liquid systems

                                                                                  Systems Showing a Decrease in Miscibility with Rise in Temperature

                                                                                  A few mixtures exhibit a lower critical solution temperature (low CST) eg triethylamine plus water The miscibility with in temperature

                                                                                  Systems Showing Upper and Lower CSTs

                                                                                  The miscibility with temp

                                                                                  a certain temperature miscibility starts to again with further in temperature

                                                                                  Closed-phase diagram ie nicotine-water system

                                                                                  A salol B thymol

                                                                                  53

                                                                                  Two component system containing solid and liquid phase (Eutectic Mixtures)

                                                                                  A salol B thymol

                                                                                  EMLAreg (lidocaine 25 and prilocaine 25) Cream

                                                                                  EMLA Cream (lidocaine 25 and prilocaine 25) is an emulsion in which the oil phase is a eutectic mixture of lidocaine and prilocaine in a ratio of 11 by weight This eutectic mixture has a melting point below room temperature and therefore both local anesthetics exist as a liquid oil rather than as crystals

                                                                                  Eutectic mixture Pharmaceutical Application

                                                                                  Triangular Diagrams for three ndash component systems

                                                                                  Three component system

                                                                                  Birzeit University Physical Pharmacy PHAR 323 Dr Hani Shtaya

                                                                                  1 Binding Forces Between Molecules2 Repulsive and Attractive Forces3 The Gaseous State The Ideal Gas Law Liquefaction of Gases Aerosols4 Solids and the Crystalline State Crystalline Solids Polymorphism Solvates Amorphous Solids5 Phase Equilibria and the Phase Rule Phase Rule Systems Containing One Component Condensed System Two-Component Systems Containing Liquid Phases Two-Component Systems Containing Solid and Liquid Phases Eutectic Mixtures Rules Relating to Triangular Diagrams

                                                                                  Topics that we have covered

                                                                                  • States of Matter
                                                                                  • States of Matter (2)
                                                                                  • Objectives of the lecture
                                                                                  • Comparison of Gases Liquids and Solids
                                                                                  • Slide 5
                                                                                  • Repulsive and Attractive Forces
                                                                                  • Ideal Gas Equation
                                                                                  • Gaseous state
                                                                                  • Slide 9
                                                                                  • Gaseous state (2)
                                                                                  • Liquefaction of Gases
                                                                                  • Slide 12
                                                                                  • SOLIDS amp CRYSTALLINE STATE Pharmaceutical Drugs more than 80
                                                                                  • Solids and the crystalline state
                                                                                  • Classification of Solids
                                                                                  • Slide 16
                                                                                  • Slide 17
                                                                                  • Crystal forms
                                                                                  • Types of Crystals
                                                                                  • Slide 20
                                                                                  • Slide 21
                                                                                  • Polymorphism
                                                                                  • Slide 23
                                                                                  • Slide 24
                                                                                  • Slide 25
                                                                                  • Slide 26
                                                                                  • Cocrystal
                                                                                  • Principle of polymorphism
                                                                                  • Solvates
                                                                                  • Polymorphism (2)
                                                                                  • Amorphous Solid
                                                                                  • Amorphous or crystalline amp therapeutic activity
                                                                                  • Slide 33
                                                                                  • Slide 34
                                                                                  • Polymorphism and Industry Pharmaceutical
                                                                                  • Celecoxib
                                                                                  • Furosemide
                                                                                  • Bioavailability
                                                                                  • Slide 39
                                                                                  • Slide 40
                                                                                  • Bioequivalence
                                                                                  • Slide 42
                                                                                  • Carbamazepine
                                                                                  • Slide 44
                                                                                  • AIDS drug ritonavir
                                                                                  • Slide 46
                                                                                  • Slide 47
                                                                                  • Phase Equilibria amp The Phase Rule
                                                                                  • Phase diagram ndash Water
                                                                                  • Phase Equilibria amp The Phase Rule Definitions
                                                                                  • Phase Definition
                                                                                  • Examples
                                                                                  • Components
                                                                                  • Examples
                                                                                  • Slide 55
                                                                                  • Degrees of freedom (or variance)
                                                                                  • Examples (2)
                                                                                  • Phase Equilibria amp The Phase Rule
                                                                                  • The phase rule
                                                                                  • Slide 60
                                                                                  • Phase Equilibria amp The Phase Rule (2)
                                                                                  • The number of phases in a system is denoted P
                                                                                  • Slide 63
                                                                                  • Slide 64
                                                                                  • One-component systems
                                                                                  • Slide 66
                                                                                  • Slide 67
                                                                                  • Slide 68
                                                                                  • Slide 69
                                                                                  • Slide 70
                                                                                  • Two component system containing liquid phase
                                                                                  • Slide 72
                                                                                  • The Critical Solution Temperature CST
                                                                                  • Systems Showing a Decrease in Miscibility with Rise in Temperat
                                                                                  • Systems Showing Upper and Lower CSTs
                                                                                  • Two component system containing solid and liquid phase (Eutecti
                                                                                  • Slide 77
                                                                                  • Eutectic mixture Pharmaceutical Application
                                                                                  • Three component system
                                                                                  • Slide 80
                                                                                  • Topics that we have covered

                                                                                    Phase Equilibria amp The Phase Rule

                                                                                    Phase diagram ndash Water

                                                                                    Phase Equilibrium A stable phase structure with lowest free-energy (internal energy) of a system and also randomness or disorder of the atoms or molecules (entropy)

                                                                                    Any change in Temperature Composition and Pressure causes an increase in free energy and away from Equilibrium thus forcing a move to another lsquostatersquo

                                                                                    Phase Equilibria amp The Phase Rule Definitions

                                                                                    A phase is defined as any homogeneous and physically distinct part of a system which is separated from other parts of the system by interfaces

                                                                                    A part of a system is homogeneous if it has identical physical properties and chemical composition throughout the part

                                                                                    A phase may be gas liquid or solid A gas or a gaseous mixture is a single phase Totally miscible liquids constitute a single phase In an immiscible liquid system each layer is counted as a separate phase Every solid constitutes a single phase except when a solid solution is formed A solid solution is considered as a single phase Each polymorphic form constitutes a separate phase

                                                                                    Phase Definition

                                                                                    1 Liquid water pieces of ice and water vapour are present together The number of phases is 3 as each form is a separate phase Ice in the system is a single phase even if it is present as a number of pieces

                                                                                    2 Calcium carbonate undergoes thermal decomposition The chemical reaction is CaCO3(s) CaO(s) + CO2 (g) Number of phases = 3 This system consists of 2 solid phases CaCO3 and CaO and one gaseous phase that of CO2

                                                                                    3 Ammonium chloride undergoes thermal decomposition The chemical reaction is NH4Cl(s) NH3 (g) + HCl (g) Number of phases = 2 This system has two phases one solid NH4Cl and one gaseous a mixture of NH3 and HCl

                                                                                    4 A solution of NaCl in water Number of phases = 1

                                                                                    bull Examples

                                                                                    The number of components of a system at equilibrium is the smallest number of independently varying chemical constituents using which the composition of each and every phase in the system can be expressed

                                                                                    Components

                                                                                    Counting the number of components 1 The sulphur system is a one component system All the phases

                                                                                    monoclinic rhombic liquid and vapour ndash can be expressed in terms of the single constituent ndash sulphur

                                                                                    2 A mixture of ethanol and water is an example of a two component system We need both ethanol and water to express its composition

                                                                                    bull Examples

                                                                                    An example of a system in which a reaction occurs and an equilibrium is established is the thermal decomposition of solid CaCO3

                                                                                    In this system there are three distinct phasesSolid CaCO3

                                                                                    Solid CaOGaseous CO2

                                                                                    Though there are 3 species present the number of components is only two because of the equilibrium CaCO3 (s) CaO(s) + CO2(g)

                                                                                    Any two of the three constituents may be chosen as the components

                                                                                    If CaO and CO2 are chosen then the composition of the phase CaCO3 is expressed as one mole of component CO2 plus one mole of component CaO

                                                                                    If on the other hand CaCO3 and CO2 were chosen then the composition of the phase CaO would be described as one mole of CaCO3 minus one mole of CO2

                                                                                    The degrees of freedom or variance of a system is defined as the minimum number of variables such as

                                                                                    temperaturepressureconcentrationwhich must be fixed in order to define the system completely

                                                                                    Degrees of freedom (or variance)

                                                                                    F = C P + 2

                                                                                    1 A gaseous mixture of CO2 and N2 Three variables pressure temperature and composition are required to define this system This is hence a trivariant system

                                                                                    2 A system having only liquid water has two degrees of freedom or is bivariant Both temperature and pressure need to be mentioned in order to define the system

                                                                                    3 If to the system containing liquid water pieces of ice are added and this system with 2 phases is allowed to come to equilibrium then it is an univariant system

                                                                                    Only one variable either temperature or pressure need to be specified in order to define the systemIf the pressure on the system is maintained at 1 atm then the temperature of the system gets automatically fixed at 0oC the normal melting point of ice

                                                                                    bull Examples

                                                                                    Phase Equilibria amp The Phase Rule

                                                                                    A phase diagram (Equilibrium Phase Diagram) summarizes the conditions at which a substance exists as a solid liquid or gas

                                                                                    OR It is a ldquomaprdquo of the information about the control of phase structure of a particular material system

                                                                                    The relationships between temperature and the compositions and the quantities of phases present at equilibrium are represented

                                                                                    F = C P + 2The phase rule

                                                                                    The phase rule JW Gibbs formulated the phase rule which is a general relation

                                                                                    between the variance F the number of component C and the number of phases P at equilibrium for a system of any composition

                                                                                    For a system in equilibrium

                                                                                    F degree of freedom the least number of intensive variable that must be fixed (known) to describe the system completely

                                                                                    Phase Rule relation to determine the least number of intensive variable that can be changed without changing the equilibrium state of the system or alternately

                                                                                    The least number required to define the state of the system which is called degree of freedom F

                                                                                    Intensive variable independent variable that do not depend on the volume or the size egTemp pressure

                                                                                    Independent chemical species which comprise the system These could be Elements Ions Compounds

                                                                                    Eg Au-Cu system Components rarr Au Cu Ice-water system Component rarr H2O

                                                                                    Al2O3 ndash Cr2O3 system Components rarr Al2O3 Cr2O3

                                                                                    Component the smallest number of constituent by which the composition of each phase in the system at equilibrium can be expressed in form of chemical formula or equation

                                                                                    Phase Equilibria amp The Phase RuleComponents of a system

                                                                                    The number of phases in a system is denoted P

                                                                                    (a)A gas or a gaseous mixture is a single phase P=1

                                                                                    (b) For a solid system an alloy of two metals is a two-phase system (P=2) if the metals are immiscible but a single-phase system (P=1) if they are miscible---a homogeneous mixture of the two substances---is uniform on a molecular scale

                                                                                    (c) For a liquid system according to the solubility to decide whether a system consists of one phase or of two For example a solution of sodium chloride in water is a single phase A pair of liquids that are partially miscible or immiscible is a two-phase system(P=2)

                                                                                    Oil in water

                                                                                    Degrees of Freedom = What you can control What the system controls

                                                                                    F = C + 2 P

                                                                                    Can control the no of components added and P amp T

                                                                                    System decided how many phases to produce given the

                                                                                    conditions

                                                                                    A way of understanding the Gibbs Phase RuleThe degrees of freedom can be thought of as the difference between what you (can) control and

                                                                                    what the system controls

                                                                                    F degree of freedom the least number of intensive variable that must be fixed (known) to describe the system completely

                                                                                    Degree of freedom (or variance) F is the number of variables (T p andor composition) that can be changed independently without changing the phases of the system

                                                                                    a) At the triple pointP = 3 (solid liquid and gas)

                                                                                    C= 1 (water)P + F = C + 2

                                                                                    F = 0 (no degree of freedom)

                                                                                    b) liquid-solid curveP = 2

                                                                                    2+F = 1 + 2F= 1

                                                                                    One variable (T or P) can be changed

                                                                                    c) LiquidP =1

                                                                                    So F =2Two variables (T and P) can be varied independently

                                                                                    and the system will remains a single phase

                                                                                    One-component systemsPhase diagram of water

                                                                                    P (

                                                                                    atm

                                                                                    )

                                                                                    Critical point

                                                                                    374

                                                                                    1

                                                                                    =100=0O--Triple point

                                                                                    0006

                                                                                    218

                                                                                    Curve O -CSublimation

                                                                                    Deposition

                                                                                    Curve O-AVaporizationCondensation

                                                                                    Curve O -BMelting

                                                                                    Freezing

                                                                                    F = C P + 2

                                                                                    F = C P + 2

                                                                                    Phase Diagram of Carbon Dioxide

                                                                                    Condensed system System in which the vapor phase is ignored and only the solid andor liquid phases are considered

                                                                                    Two component system For two component system F can be 3 (3D model is needed) eg T p

                                                                                    and concentration usually we fix p = 1atm the vapor phase is neglected and F is reduced to 2

                                                                                    For three component system the pressure and temperature are fixed

                                                                                    Phenol water phase diagram

                                                                                    eg for point d (24)

                                                                                    Two component system containing liquid phase

                                                                                    Tie Line bc line The line at which the system at equilibrium will separate into phases of constant composition termed lsquoconjugate phasesrsquo

                                                                                    Lever Rule a way to calculate the proportions of each phase present on a phase diagram in a two phase field (at a given temperature and composition)

                                                                                    eg for point d (24)

                                                                                    For every 10 g of liquid system in equilibrium in point d

                                                                                    75 g phase A25 g phase B

                                                                                    ExampleMixed 24g phenol +76g water T 50degC

                                                                                    equilibrium75 g phase A 25 g phase B

                                                                                    11 phenol 63 phenol

                                                                                    011 times75 g=825 g phenol

                                                                                    063 times25 g=1575 g phenol

                                                                                    water rich phasecontains water+ phenol(11)

                                                                                    Phenol rich phasecontains Phenol (63)+ water

                                                                                    The Critical Solution Temperature CST

                                                                                    Is the maximum temperature at which the 2-phase region exists (or upper consolute temperature)

                                                                                    In the case of the phenol-water system this is 668oC (point h)

                                                                                    All combinations of phenol and water gt CST are completely miscible and yield 1-phase liquid systems

                                                                                    Systems Showing a Decrease in Miscibility with Rise in Temperature

                                                                                    A few mixtures exhibit a lower critical solution temperature (low CST) eg triethylamine plus water The miscibility with in temperature

                                                                                    Systems Showing Upper and Lower CSTs

                                                                                    The miscibility with temp

                                                                                    a certain temperature miscibility starts to again with further in temperature

                                                                                    Closed-phase diagram ie nicotine-water system

                                                                                    A salol B thymol

                                                                                    53

                                                                                    Two component system containing solid and liquid phase (Eutectic Mixtures)

                                                                                    A salol B thymol

                                                                                    EMLAreg (lidocaine 25 and prilocaine 25) Cream

                                                                                    EMLA Cream (lidocaine 25 and prilocaine 25) is an emulsion in which the oil phase is a eutectic mixture of lidocaine and prilocaine in a ratio of 11 by weight This eutectic mixture has a melting point below room temperature and therefore both local anesthetics exist as a liquid oil rather than as crystals

                                                                                    Eutectic mixture Pharmaceutical Application

                                                                                    Triangular Diagrams for three ndash component systems

                                                                                    Three component system

                                                                                    Birzeit University Physical Pharmacy PHAR 323 Dr Hani Shtaya

                                                                                    1 Binding Forces Between Molecules2 Repulsive and Attractive Forces3 The Gaseous State The Ideal Gas Law Liquefaction of Gases Aerosols4 Solids and the Crystalline State Crystalline Solids Polymorphism Solvates Amorphous Solids5 Phase Equilibria and the Phase Rule Phase Rule Systems Containing One Component Condensed System Two-Component Systems Containing Liquid Phases Two-Component Systems Containing Solid and Liquid Phases Eutectic Mixtures Rules Relating to Triangular Diagrams

                                                                                    Topics that we have covered

                                                                                    • States of Matter
                                                                                    • States of Matter (2)
                                                                                    • Objectives of the lecture
                                                                                    • Comparison of Gases Liquids and Solids
                                                                                    • Slide 5
                                                                                    • Repulsive and Attractive Forces
                                                                                    • Ideal Gas Equation
                                                                                    • Gaseous state
                                                                                    • Slide 9
                                                                                    • Gaseous state (2)
                                                                                    • Liquefaction of Gases
                                                                                    • Slide 12
                                                                                    • SOLIDS amp CRYSTALLINE STATE Pharmaceutical Drugs more than 80
                                                                                    • Solids and the crystalline state
                                                                                    • Classification of Solids
                                                                                    • Slide 16
                                                                                    • Slide 17
                                                                                    • Crystal forms
                                                                                    • Types of Crystals
                                                                                    • Slide 20
                                                                                    • Slide 21
                                                                                    • Polymorphism
                                                                                    • Slide 23
                                                                                    • Slide 24
                                                                                    • Slide 25
                                                                                    • Slide 26
                                                                                    • Cocrystal
                                                                                    • Principle of polymorphism
                                                                                    • Solvates
                                                                                    • Polymorphism (2)
                                                                                    • Amorphous Solid
                                                                                    • Amorphous or crystalline amp therapeutic activity
                                                                                    • Slide 33
                                                                                    • Slide 34
                                                                                    • Polymorphism and Industry Pharmaceutical
                                                                                    • Celecoxib
                                                                                    • Furosemide
                                                                                    • Bioavailability
                                                                                    • Slide 39
                                                                                    • Slide 40
                                                                                    • Bioequivalence
                                                                                    • Slide 42
                                                                                    • Carbamazepine
                                                                                    • Slide 44
                                                                                    • AIDS drug ritonavir
                                                                                    • Slide 46
                                                                                    • Slide 47
                                                                                    • Phase Equilibria amp The Phase Rule
                                                                                    • Phase diagram ndash Water
                                                                                    • Phase Equilibria amp The Phase Rule Definitions
                                                                                    • Phase Definition
                                                                                    • Examples
                                                                                    • Components
                                                                                    • Examples
                                                                                    • Slide 55
                                                                                    • Degrees of freedom (or variance)
                                                                                    • Examples (2)
                                                                                    • Phase Equilibria amp The Phase Rule
                                                                                    • The phase rule
                                                                                    • Slide 60
                                                                                    • Phase Equilibria amp The Phase Rule (2)
                                                                                    • The number of phases in a system is denoted P
                                                                                    • Slide 63
                                                                                    • Slide 64
                                                                                    • One-component systems
                                                                                    • Slide 66
                                                                                    • Slide 67
                                                                                    • Slide 68
                                                                                    • Slide 69
                                                                                    • Slide 70
                                                                                    • Two component system containing liquid phase
                                                                                    • Slide 72
                                                                                    • The Critical Solution Temperature CST
                                                                                    • Systems Showing a Decrease in Miscibility with Rise in Temperat
                                                                                    • Systems Showing Upper and Lower CSTs
                                                                                    • Two component system containing solid and liquid phase (Eutecti
                                                                                    • Slide 77
                                                                                    • Eutectic mixture Pharmaceutical Application
                                                                                    • Three component system
                                                                                    • Slide 80
                                                                                    • Topics that we have covered

                                                                                      Phase diagram ndash Water

                                                                                      Phase Equilibrium A stable phase structure with lowest free-energy (internal energy) of a system and also randomness or disorder of the atoms or molecules (entropy)

                                                                                      Any change in Temperature Composition and Pressure causes an increase in free energy and away from Equilibrium thus forcing a move to another lsquostatersquo

                                                                                      Phase Equilibria amp The Phase Rule Definitions

                                                                                      A phase is defined as any homogeneous and physically distinct part of a system which is separated from other parts of the system by interfaces

                                                                                      A part of a system is homogeneous if it has identical physical properties and chemical composition throughout the part

                                                                                      A phase may be gas liquid or solid A gas or a gaseous mixture is a single phase Totally miscible liquids constitute a single phase In an immiscible liquid system each layer is counted as a separate phase Every solid constitutes a single phase except when a solid solution is formed A solid solution is considered as a single phase Each polymorphic form constitutes a separate phase

                                                                                      Phase Definition

                                                                                      1 Liquid water pieces of ice and water vapour are present together The number of phases is 3 as each form is a separate phase Ice in the system is a single phase even if it is present as a number of pieces

                                                                                      2 Calcium carbonate undergoes thermal decomposition The chemical reaction is CaCO3(s) CaO(s) + CO2 (g) Number of phases = 3 This system consists of 2 solid phases CaCO3 and CaO and one gaseous phase that of CO2

                                                                                      3 Ammonium chloride undergoes thermal decomposition The chemical reaction is NH4Cl(s) NH3 (g) + HCl (g) Number of phases = 2 This system has two phases one solid NH4Cl and one gaseous a mixture of NH3 and HCl

                                                                                      4 A solution of NaCl in water Number of phases = 1

                                                                                      bull Examples

                                                                                      The number of components of a system at equilibrium is the smallest number of independently varying chemical constituents using which the composition of each and every phase in the system can be expressed

                                                                                      Components

                                                                                      Counting the number of components 1 The sulphur system is a one component system All the phases

                                                                                      monoclinic rhombic liquid and vapour ndash can be expressed in terms of the single constituent ndash sulphur

                                                                                      2 A mixture of ethanol and water is an example of a two component system We need both ethanol and water to express its composition

                                                                                      bull Examples

                                                                                      An example of a system in which a reaction occurs and an equilibrium is established is the thermal decomposition of solid CaCO3

                                                                                      In this system there are three distinct phasesSolid CaCO3

                                                                                      Solid CaOGaseous CO2

                                                                                      Though there are 3 species present the number of components is only two because of the equilibrium CaCO3 (s) CaO(s) + CO2(g)

                                                                                      Any two of the three constituents may be chosen as the components

                                                                                      If CaO and CO2 are chosen then the composition of the phase CaCO3 is expressed as one mole of component CO2 plus one mole of component CaO

                                                                                      If on the other hand CaCO3 and CO2 were chosen then the composition of the phase CaO would be described as one mole of CaCO3 minus one mole of CO2

                                                                                      The degrees of freedom or variance of a system is defined as the minimum number of variables such as

                                                                                      temperaturepressureconcentrationwhich must be fixed in order to define the system completely

                                                                                      Degrees of freedom (or variance)

                                                                                      F = C P + 2

                                                                                      1 A gaseous mixture of CO2 and N2 Three variables pressure temperature and composition are required to define this system This is hence a trivariant system

                                                                                      2 A system having only liquid water has two degrees of freedom or is bivariant Both temperature and pressure need to be mentioned in order to define the system

                                                                                      3 If to the system containing liquid water pieces of ice are added and this system with 2 phases is allowed to come to equilibrium then it is an univariant system

                                                                                      Only one variable either temperature or pressure need to be specified in order to define the systemIf the pressure on the system is maintained at 1 atm then the temperature of the system gets automatically fixed at 0oC the normal melting point of ice

                                                                                      bull Examples

                                                                                      Phase Equilibria amp The Phase Rule

                                                                                      A phase diagram (Equilibrium Phase Diagram) summarizes the conditions at which a substance exists as a solid liquid or gas

                                                                                      OR It is a ldquomaprdquo of the information about the control of phase structure of a particular material system

                                                                                      The relationships between temperature and the compositions and the quantities of phases present at equilibrium are represented

                                                                                      F = C P + 2The phase rule

                                                                                      The phase rule JW Gibbs formulated the phase rule which is a general relation

                                                                                      between the variance F the number of component C and the number of phases P at equilibrium for a system of any composition

                                                                                      For a system in equilibrium

                                                                                      F degree of freedom the least number of intensive variable that must be fixed (known) to describe the system completely

                                                                                      Phase Rule relation to determine the least number of intensive variable that can be changed without changing the equilibrium state of the system or alternately

                                                                                      The least number required to define the state of the system which is called degree of freedom F

                                                                                      Intensive variable independent variable that do not depend on the volume or the size egTemp pressure

                                                                                      Independent chemical species which comprise the system These could be Elements Ions Compounds

                                                                                      Eg Au-Cu system Components rarr Au Cu Ice-water system Component rarr H2O

                                                                                      Al2O3 ndash Cr2O3 system Components rarr Al2O3 Cr2O3

                                                                                      Component the smallest number of constituent by which the composition of each phase in the system at equilibrium can be expressed in form of chemical formula or equation

                                                                                      Phase Equilibria amp The Phase RuleComponents of a system

                                                                                      The number of phases in a system is denoted P

                                                                                      (a)A gas or a gaseous mixture is a single phase P=1

                                                                                      (b) For a solid system an alloy of two metals is a two-phase system (P=2) if the metals are immiscible but a single-phase system (P=1) if they are miscible---a homogeneous mixture of the two substances---is uniform on a molecular scale

                                                                                      (c) For a liquid system according to the solubility to decide whether a system consists of one phase or of two For example a solution of sodium chloride in water is a single phase A pair of liquids that are partially miscible or immiscible is a two-phase system(P=2)

                                                                                      Oil in water

                                                                                      Degrees of Freedom = What you can control What the system controls

                                                                                      F = C + 2 P

                                                                                      Can control the no of components added and P amp T

                                                                                      System decided how many phases to produce given the

                                                                                      conditions

                                                                                      A way of understanding the Gibbs Phase RuleThe degrees of freedom can be thought of as the difference between what you (can) control and

                                                                                      what the system controls

                                                                                      F degree of freedom the least number of intensive variable that must be fixed (known) to describe the system completely

                                                                                      Degree of freedom (or variance) F is the number of variables (T p andor composition) that can be changed independently without changing the phases of the system

                                                                                      a) At the triple pointP = 3 (solid liquid and gas)

                                                                                      C= 1 (water)P + F = C + 2

                                                                                      F = 0 (no degree of freedom)

                                                                                      b) liquid-solid curveP = 2

                                                                                      2+F = 1 + 2F= 1

                                                                                      One variable (T or P) can be changed

                                                                                      c) LiquidP =1

                                                                                      So F =2Two variables (T and P) can be varied independently

                                                                                      and the system will remains a single phase

                                                                                      One-component systemsPhase diagram of water

                                                                                      P (

                                                                                      atm

                                                                                      )

                                                                                      Critical point

                                                                                      374

                                                                                      1

                                                                                      =100=0O--Triple point

                                                                                      0006

                                                                                      218

                                                                                      Curve O -CSublimation

                                                                                      Deposition

                                                                                      Curve O-AVaporizationCondensation

                                                                                      Curve O -BMelting

                                                                                      Freezing

                                                                                      F = C P + 2

                                                                                      F = C P + 2

                                                                                      Phase Diagram of Carbon Dioxide

                                                                                      Condensed system System in which the vapor phase is ignored and only the solid andor liquid phases are considered

                                                                                      Two component system For two component system F can be 3 (3D model is needed) eg T p

                                                                                      and concentration usually we fix p = 1atm the vapor phase is neglected and F is reduced to 2

                                                                                      For three component system the pressure and temperature are fixed

                                                                                      Phenol water phase diagram

                                                                                      eg for point d (24)

                                                                                      Two component system containing liquid phase

                                                                                      Tie Line bc line The line at which the system at equilibrium will separate into phases of constant composition termed lsquoconjugate phasesrsquo

                                                                                      Lever Rule a way to calculate the proportions of each phase present on a phase diagram in a two phase field (at a given temperature and composition)

                                                                                      eg for point d (24)

                                                                                      For every 10 g of liquid system in equilibrium in point d

                                                                                      75 g phase A25 g phase B

                                                                                      ExampleMixed 24g phenol +76g water T 50degC

                                                                                      equilibrium75 g phase A 25 g phase B

                                                                                      11 phenol 63 phenol

                                                                                      011 times75 g=825 g phenol

                                                                                      063 times25 g=1575 g phenol

                                                                                      water rich phasecontains water+ phenol(11)

                                                                                      Phenol rich phasecontains Phenol (63)+ water

                                                                                      The Critical Solution Temperature CST

                                                                                      Is the maximum temperature at which the 2-phase region exists (or upper consolute temperature)

                                                                                      In the case of the phenol-water system this is 668oC (point h)

                                                                                      All combinations of phenol and water gt CST are completely miscible and yield 1-phase liquid systems

                                                                                      Systems Showing a Decrease in Miscibility with Rise in Temperature

                                                                                      A few mixtures exhibit a lower critical solution temperature (low CST) eg triethylamine plus water The miscibility with in temperature

                                                                                      Systems Showing Upper and Lower CSTs

                                                                                      The miscibility with temp

                                                                                      a certain temperature miscibility starts to again with further in temperature

                                                                                      Closed-phase diagram ie nicotine-water system

                                                                                      A salol B thymol

                                                                                      53

                                                                                      Two component system containing solid and liquid phase (Eutectic Mixtures)

                                                                                      A salol B thymol

                                                                                      EMLAreg (lidocaine 25 and prilocaine 25) Cream

                                                                                      EMLA Cream (lidocaine 25 and prilocaine 25) is an emulsion in which the oil phase is a eutectic mixture of lidocaine and prilocaine in a ratio of 11 by weight This eutectic mixture has a melting point below room temperature and therefore both local anesthetics exist as a liquid oil rather than as crystals

                                                                                      Eutectic mixture Pharmaceutical Application

                                                                                      Triangular Diagrams for three ndash component systems

                                                                                      Three component system

                                                                                      Birzeit University Physical Pharmacy PHAR 323 Dr Hani Shtaya

                                                                                      1 Binding Forces Between Molecules2 Repulsive and Attractive Forces3 The Gaseous State The Ideal Gas Law Liquefaction of Gases Aerosols4 Solids and the Crystalline State Crystalline Solids Polymorphism Solvates Amorphous Solids5 Phase Equilibria and the Phase Rule Phase Rule Systems Containing One Component Condensed System Two-Component Systems Containing Liquid Phases Two-Component Systems Containing Solid and Liquid Phases Eutectic Mixtures Rules Relating to Triangular Diagrams

                                                                                      Topics that we have covered

                                                                                      • States of Matter
                                                                                      • States of Matter (2)
                                                                                      • Objectives of the lecture
                                                                                      • Comparison of Gases Liquids and Solids
                                                                                      • Slide 5
                                                                                      • Repulsive and Attractive Forces
                                                                                      • Ideal Gas Equation
                                                                                      • Gaseous state
                                                                                      • Slide 9
                                                                                      • Gaseous state (2)
                                                                                      • Liquefaction of Gases
                                                                                      • Slide 12
                                                                                      • SOLIDS amp CRYSTALLINE STATE Pharmaceutical Drugs more than 80
                                                                                      • Solids and the crystalline state
                                                                                      • Classification of Solids
                                                                                      • Slide 16
                                                                                      • Slide 17
                                                                                      • Crystal forms
                                                                                      • Types of Crystals
                                                                                      • Slide 20
                                                                                      • Slide 21
                                                                                      • Polymorphism
                                                                                      • Slide 23
                                                                                      • Slide 24
                                                                                      • Slide 25
                                                                                      • Slide 26
                                                                                      • Cocrystal
                                                                                      • Principle of polymorphism
                                                                                      • Solvates
                                                                                      • Polymorphism (2)
                                                                                      • Amorphous Solid
                                                                                      • Amorphous or crystalline amp therapeutic activity
                                                                                      • Slide 33
                                                                                      • Slide 34
                                                                                      • Polymorphism and Industry Pharmaceutical
                                                                                      • Celecoxib
                                                                                      • Furosemide
                                                                                      • Bioavailability
                                                                                      • Slide 39
                                                                                      • Slide 40
                                                                                      • Bioequivalence
                                                                                      • Slide 42
                                                                                      • Carbamazepine
                                                                                      • Slide 44
                                                                                      • AIDS drug ritonavir
                                                                                      • Slide 46
                                                                                      • Slide 47
                                                                                      • Phase Equilibria amp The Phase Rule
                                                                                      • Phase diagram ndash Water
                                                                                      • Phase Equilibria amp The Phase Rule Definitions
                                                                                      • Phase Definition
                                                                                      • Examples
                                                                                      • Components
                                                                                      • Examples
                                                                                      • Slide 55
                                                                                      • Degrees of freedom (or variance)
                                                                                      • Examples (2)
                                                                                      • Phase Equilibria amp The Phase Rule
                                                                                      • The phase rule
                                                                                      • Slide 60
                                                                                      • Phase Equilibria amp The Phase Rule (2)
                                                                                      • The number of phases in a system is denoted P
                                                                                      • Slide 63
                                                                                      • Slide 64
                                                                                      • One-component systems
                                                                                      • Slide 66
                                                                                      • Slide 67
                                                                                      • Slide 68
                                                                                      • Slide 69
                                                                                      • Slide 70
                                                                                      • Two component system containing liquid phase
                                                                                      • Slide 72
                                                                                      • The Critical Solution Temperature CST
                                                                                      • Systems Showing a Decrease in Miscibility with Rise in Temperat
                                                                                      • Systems Showing Upper and Lower CSTs
                                                                                      • Two component system containing solid and liquid phase (Eutecti
                                                                                      • Slide 77
                                                                                      • Eutectic mixture Pharmaceutical Application
                                                                                      • Three component system
                                                                                      • Slide 80
                                                                                      • Topics that we have covered

                                                                                        Phase Equilibrium A stable phase structure with lowest free-energy (internal energy) of a system and also randomness or disorder of the atoms or molecules (entropy)

                                                                                        Any change in Temperature Composition and Pressure causes an increase in free energy and away from Equilibrium thus forcing a move to another lsquostatersquo

                                                                                        Phase Equilibria amp The Phase Rule Definitions

                                                                                        A phase is defined as any homogeneous and physically distinct part of a system which is separated from other parts of the system by interfaces

                                                                                        A part of a system is homogeneous if it has identical physical properties and chemical composition throughout the part

                                                                                        A phase may be gas liquid or solid A gas or a gaseous mixture is a single phase Totally miscible liquids constitute a single phase In an immiscible liquid system each layer is counted as a separate phase Every solid constitutes a single phase except when a solid solution is formed A solid solution is considered as a single phase Each polymorphic form constitutes a separate phase

                                                                                        Phase Definition

                                                                                        1 Liquid water pieces of ice and water vapour are present together The number of phases is 3 as each form is a separate phase Ice in the system is a single phase even if it is present as a number of pieces

                                                                                        2 Calcium carbonate undergoes thermal decomposition The chemical reaction is CaCO3(s) CaO(s) + CO2 (g) Number of phases = 3 This system consists of 2 solid phases CaCO3 and CaO and one gaseous phase that of CO2

                                                                                        3 Ammonium chloride undergoes thermal decomposition The chemical reaction is NH4Cl(s) NH3 (g) + HCl (g) Number of phases = 2 This system has two phases one solid NH4Cl and one gaseous a mixture of NH3 and HCl

                                                                                        4 A solution of NaCl in water Number of phases = 1

                                                                                        bull Examples

                                                                                        The number of components of a system at equilibrium is the smallest number of independently varying chemical constituents using which the composition of each and every phase in the system can be expressed

                                                                                        Components

                                                                                        Counting the number of components 1 The sulphur system is a one component system All the phases

                                                                                        monoclinic rhombic liquid and vapour ndash can be expressed in terms of the single constituent ndash sulphur

                                                                                        2 A mixture of ethanol and water is an example of a two component system We need both ethanol and water to express its composition

                                                                                        bull Examples

                                                                                        An example of a system in which a reaction occurs and an equilibrium is established is the thermal decomposition of solid CaCO3

                                                                                        In this system there are three distinct phasesSolid CaCO3

                                                                                        Solid CaOGaseous CO2

                                                                                        Though there are 3 species present the number of components is only two because of the equilibrium CaCO3 (s) CaO(s) + CO2(g)

                                                                                        Any two of the three constituents may be chosen as the components

                                                                                        If CaO and CO2 are chosen then the composition of the phase CaCO3 is expressed as one mole of component CO2 plus one mole of component CaO

                                                                                        If on the other hand CaCO3 and CO2 were chosen then the composition of the phase CaO would be described as one mole of CaCO3 minus one mole of CO2

                                                                                        The degrees of freedom or variance of a system is defined as the minimum number of variables such as

                                                                                        temperaturepressureconcentrationwhich must be fixed in order to define the system completely

                                                                                        Degrees of freedom (or variance)

                                                                                        F = C P + 2

                                                                                        1 A gaseous mixture of CO2 and N2 Three variables pressure temperature and composition are required to define this system This is hence a trivariant system

                                                                                        2 A system having only liquid water has two degrees of freedom or is bivariant Both temperature and pressure need to be mentioned in order to define the system

                                                                                        3 If to the system containing liquid water pieces of ice are added and this system with 2 phases is allowed to come to equilibrium then it is an univariant system

                                                                                        Only one variable either temperature or pressure need to be specified in order to define the systemIf the pressure on the system is maintained at 1 atm then the temperature of the system gets automatically fixed at 0oC the normal melting point of ice

                                                                                        bull Examples

                                                                                        Phase Equilibria amp The Phase Rule

                                                                                        A phase diagram (Equilibrium Phase Diagram) summarizes the conditions at which a substance exists as a solid liquid or gas

                                                                                        OR It is a ldquomaprdquo of the information about the control of phase structure of a particular material system

                                                                                        The relationships between temperature and the compositions and the quantities of phases present at equilibrium are represented

                                                                                        F = C P + 2The phase rule

                                                                                        The phase rule JW Gibbs formulated the phase rule which is a general relation

                                                                                        between the variance F the number of component C and the number of phases P at equilibrium for a system of any composition

                                                                                        For a system in equilibrium

                                                                                        F degree of freedom the least number of intensive variable that must be fixed (known) to describe the system completely

                                                                                        Phase Rule relation to determine the least number of intensive variable that can be changed without changing the equilibrium state of the system or alternately

                                                                                        The least number required to define the state of the system which is called degree of freedom F

                                                                                        Intensive variable independent variable that do not depend on the volume or the size egTemp pressure

                                                                                        Independent chemical species which comprise the system These could be Elements Ions Compounds

                                                                                        Eg Au-Cu system Components rarr Au Cu Ice-water system Component rarr H2O

                                                                                        Al2O3 ndash Cr2O3 system Components rarr Al2O3 Cr2O3

                                                                                        Component the smallest number of constituent by which the composition of each phase in the system at equilibrium can be expressed in form of chemical formula or equation

                                                                                        Phase Equilibria amp The Phase RuleComponents of a system

                                                                                        The number of phases in a system is denoted P

                                                                                        (a)A gas or a gaseous mixture is a single phase P=1

                                                                                        (b) For a solid system an alloy of two metals is a two-phase system (P=2) if the metals are immiscible but a single-phase system (P=1) if they are miscible---a homogeneous mixture of the two substances---is uniform on a molecular scale

                                                                                        (c) For a liquid system according to the solubility to decide whether a system consists of one phase or of two For example a solution of sodium chloride in water is a single phase A pair of liquids that are partially miscible or immiscible is a two-phase system(P=2)

                                                                                        Oil in water

                                                                                        Degrees of Freedom = What you can control What the system controls

                                                                                        F = C + 2 P

                                                                                        Can control the no of components added and P amp T

                                                                                        System decided how many phases to produce given the

                                                                                        conditions

                                                                                        A way of understanding the Gibbs Phase RuleThe degrees of freedom can be thought of as the difference between what you (can) control and

                                                                                        what the system controls

                                                                                        F degree of freedom the least number of intensive variable that must be fixed (known) to describe the system completely

                                                                                        Degree of freedom (or variance) F is the number of variables (T p andor composition) that can be changed independently without changing the phases of the system

                                                                                        a) At the triple pointP = 3 (solid liquid and gas)

                                                                                        C= 1 (water)P + F = C + 2

                                                                                        F = 0 (no degree of freedom)

                                                                                        b) liquid-solid curveP = 2

                                                                                        2+F = 1 + 2F= 1

                                                                                        One variable (T or P) can be changed

                                                                                        c) LiquidP =1

                                                                                        So F =2Two variables (T and P) can be varied independently

                                                                                        and the system will remains a single phase

                                                                                        One-component systemsPhase diagram of water

                                                                                        P (

                                                                                        atm

                                                                                        )

                                                                                        Critical point

                                                                                        374

                                                                                        1

                                                                                        =100=0O--Triple point

                                                                                        0006

                                                                                        218

                                                                                        Curve O -CSublimation

                                                                                        Deposition

                                                                                        Curve O-AVaporizationCondensation

                                                                                        Curve O -BMelting

                                                                                        Freezing

                                                                                        F = C P + 2

                                                                                        F = C P + 2

                                                                                        Phase Diagram of Carbon Dioxide

                                                                                        Condensed system System in which the vapor phase is ignored and only the solid andor liquid phases are considered

                                                                                        Two component system For two component system F can be 3 (3D model is needed) eg T p

                                                                                        and concentration usually we fix p = 1atm the vapor phase is neglected and F is reduced to 2

                                                                                        For three component system the pressure and temperature are fixed

                                                                                        Phenol water phase diagram

                                                                                        eg for point d (24)

                                                                                        Two component system containing liquid phase

                                                                                        Tie Line bc line The line at which the system at equilibrium will separate into phases of constant composition termed lsquoconjugate phasesrsquo

                                                                                        Lever Rule a way to calculate the proportions of each phase present on a phase diagram in a two phase field (at a given temperature and composition)

                                                                                        eg for point d (24)

                                                                                        For every 10 g of liquid system in equilibrium in point d

                                                                                        75 g phase A25 g phase B

                                                                                        ExampleMixed 24g phenol +76g water T 50degC

                                                                                        equilibrium75 g phase A 25 g phase B

                                                                                        11 phenol 63 phenol

                                                                                        011 times75 g=825 g phenol

                                                                                        063 times25 g=1575 g phenol

                                                                                        water rich phasecontains water+ phenol(11)

                                                                                        Phenol rich phasecontains Phenol (63)+ water

                                                                                        The Critical Solution Temperature CST

                                                                                        Is the maximum temperature at which the 2-phase region exists (or upper consolute temperature)

                                                                                        In the case of the phenol-water system this is 668oC (point h)

                                                                                        All combinations of phenol and water gt CST are completely miscible and yield 1-phase liquid systems

                                                                                        Systems Showing a Decrease in Miscibility with Rise in Temperature

                                                                                        A few mixtures exhibit a lower critical solution temperature (low CST) eg triethylamine plus water The miscibility with in temperature

                                                                                        Systems Showing Upper and Lower CSTs

                                                                                        The miscibility with temp

                                                                                        a certain temperature miscibility starts to again with further in temperature

                                                                                        Closed-phase diagram ie nicotine-water system

                                                                                        A salol B thymol

                                                                                        53

                                                                                        Two component system containing solid and liquid phase (Eutectic Mixtures)

                                                                                        A salol B thymol

                                                                                        EMLAreg (lidocaine 25 and prilocaine 25) Cream

                                                                                        EMLA Cream (lidocaine 25 and prilocaine 25) is an emulsion in which the oil phase is a eutectic mixture of lidocaine and prilocaine in a ratio of 11 by weight This eutectic mixture has a melting point below room temperature and therefore both local anesthetics exist as a liquid oil rather than as crystals

                                                                                        Eutectic mixture Pharmaceutical Application

                                                                                        Triangular Diagrams for three ndash component systems

                                                                                        Three component system

                                                                                        Birzeit University Physical Pharmacy PHAR 323 Dr Hani Shtaya

                                                                                        1 Binding Forces Between Molecules2 Repulsive and Attractive Forces3 The Gaseous State The Ideal Gas Law Liquefaction of Gases Aerosols4 Solids and the Crystalline State Crystalline Solids Polymorphism Solvates Amorphous Solids5 Phase Equilibria and the Phase Rule Phase Rule Systems Containing One Component Condensed System Two-Component Systems Containing Liquid Phases Two-Component Systems Containing Solid and Liquid Phases Eutectic Mixtures Rules Relating to Triangular Diagrams

                                                                                        Topics that we have covered

                                                                                        • States of Matter
                                                                                        • States of Matter (2)
                                                                                        • Objectives of the lecture
                                                                                        • Comparison of Gases Liquids and Solids
                                                                                        • Slide 5
                                                                                        • Repulsive and Attractive Forces
                                                                                        • Ideal Gas Equation
                                                                                        • Gaseous state
                                                                                        • Slide 9
                                                                                        • Gaseous state (2)
                                                                                        • Liquefaction of Gases
                                                                                        • Slide 12
                                                                                        • SOLIDS amp CRYSTALLINE STATE Pharmaceutical Drugs more than 80
                                                                                        • Solids and the crystalline state
                                                                                        • Classification of Solids
                                                                                        • Slide 16
                                                                                        • Slide 17
                                                                                        • Crystal forms
                                                                                        • Types of Crystals
                                                                                        • Slide 20
                                                                                        • Slide 21
                                                                                        • Polymorphism
                                                                                        • Slide 23
                                                                                        • Slide 24
                                                                                        • Slide 25
                                                                                        • Slide 26
                                                                                        • Cocrystal
                                                                                        • Principle of polymorphism
                                                                                        • Solvates
                                                                                        • Polymorphism (2)
                                                                                        • Amorphous Solid
                                                                                        • Amorphous or crystalline amp therapeutic activity
                                                                                        • Slide 33
                                                                                        • Slide 34
                                                                                        • Polymorphism and Industry Pharmaceutical
                                                                                        • Celecoxib
                                                                                        • Furosemide
                                                                                        • Bioavailability
                                                                                        • Slide 39
                                                                                        • Slide 40
                                                                                        • Bioequivalence
                                                                                        • Slide 42
                                                                                        • Carbamazepine
                                                                                        • Slide 44
                                                                                        • AIDS drug ritonavir
                                                                                        • Slide 46
                                                                                        • Slide 47
                                                                                        • Phase Equilibria amp The Phase Rule
                                                                                        • Phase diagram ndash Water
                                                                                        • Phase Equilibria amp The Phase Rule Definitions
                                                                                        • Phase Definition
                                                                                        • Examples
                                                                                        • Components
                                                                                        • Examples
                                                                                        • Slide 55
                                                                                        • Degrees of freedom (or variance)
                                                                                        • Examples (2)
                                                                                        • Phase Equilibria amp The Phase Rule
                                                                                        • The phase rule
                                                                                        • Slide 60
                                                                                        • Phase Equilibria amp The Phase Rule (2)
                                                                                        • The number of phases in a system is denoted P
                                                                                        • Slide 63
                                                                                        • Slide 64
                                                                                        • One-component systems
                                                                                        • Slide 66
                                                                                        • Slide 67
                                                                                        • Slide 68
                                                                                        • Slide 69
                                                                                        • Slide 70
                                                                                        • Two component system containing liquid phase
                                                                                        • Slide 72
                                                                                        • The Critical Solution Temperature CST
                                                                                        • Systems Showing a Decrease in Miscibility with Rise in Temperat
                                                                                        • Systems Showing Upper and Lower CSTs
                                                                                        • Two component system containing solid and liquid phase (Eutecti
                                                                                        • Slide 77
                                                                                        • Eutectic mixture Pharmaceutical Application
                                                                                        • Three component system
                                                                                        • Slide 80
                                                                                        • Topics that we have covered

                                                                                          A phase is defined as any homogeneous and physically distinct part of a system which is separated from other parts of the system by interfaces

                                                                                          A part of a system is homogeneous if it has identical physical properties and chemical composition throughout the part

                                                                                          A phase may be gas liquid or solid A gas or a gaseous mixture is a single phase Totally miscible liquids constitute a single phase In an immiscible liquid system each layer is counted as a separate phase Every solid constitutes a single phase except when a solid solution is formed A solid solution is considered as a single phase Each polymorphic form constitutes a separate phase

                                                                                          Phase Definition

                                                                                          1 Liquid water pieces of ice and water vapour are present together The number of phases is 3 as each form is a separate phase Ice in the system is a single phase even if it is present as a number of pieces

                                                                                          2 Calcium carbonate undergoes thermal decomposition The chemical reaction is CaCO3(s) CaO(s) + CO2 (g) Number of phases = 3 This system consists of 2 solid phases CaCO3 and CaO and one gaseous phase that of CO2

                                                                                          3 Ammonium chloride undergoes thermal decomposition The chemical reaction is NH4Cl(s) NH3 (g) + HCl (g) Number of phases = 2 This system has two phases one solid NH4Cl and one gaseous a mixture of NH3 and HCl

                                                                                          4 A solution of NaCl in water Number of phases = 1

                                                                                          bull Examples

                                                                                          The number of components of a system at equilibrium is the smallest number of independently varying chemical constituents using which the composition of each and every phase in the system can be expressed

                                                                                          Components

                                                                                          Counting the number of components 1 The sulphur system is a one component system All the phases

                                                                                          monoclinic rhombic liquid and vapour ndash can be expressed in terms of the single constituent ndash sulphur

                                                                                          2 A mixture of ethanol and water is an example of a two component system We need both ethanol and water to express its composition

                                                                                          bull Examples

                                                                                          An example of a system in which a reaction occurs and an equilibrium is established is the thermal decomposition of solid CaCO3

                                                                                          In this system there are three distinct phasesSolid CaCO3

                                                                                          Solid CaOGaseous CO2

                                                                                          Though there are 3 species present the number of components is only two because of the equilibrium CaCO3 (s) CaO(s) + CO2(g)

                                                                                          Any two of the three constituents may be chosen as the components

                                                                                          If CaO and CO2 are chosen then the composition of the phase CaCO3 is expressed as one mole of component CO2 plus one mole of component CaO

                                                                                          If on the other hand CaCO3 and CO2 were chosen then the composition of the phase CaO would be described as one mole of CaCO3 minus one mole of CO2

                                                                                          The degrees of freedom or variance of a system is defined as the minimum number of variables such as

                                                                                          temperaturepressureconcentrationwhich must be fixed in order to define the system completely

                                                                                          Degrees of freedom (or variance)

                                                                                          F = C P + 2

                                                                                          1 A gaseous mixture of CO2 and N2 Three variables pressure temperature and composition are required to define this system This is hence a trivariant system

                                                                                          2 A system having only liquid water has two degrees of freedom or is bivariant Both temperature and pressure need to be mentioned in order to define the system

                                                                                          3 If to the system containing liquid water pieces of ice are added and this system with 2 phases is allowed to come to equilibrium then it is an univariant system

                                                                                          Only one variable either temperature or pressure need to be specified in order to define the systemIf the pressure on the system is maintained at 1 atm then the temperature of the system gets automatically fixed at 0oC the normal melting point of ice

                                                                                          bull Examples

                                                                                          Phase Equilibria amp The Phase Rule

                                                                                          A phase diagram (Equilibrium Phase Diagram) summarizes the conditions at which a substance exists as a solid liquid or gas

                                                                                          OR It is a ldquomaprdquo of the information about the control of phase structure of a particular material system

                                                                                          The relationships between temperature and the compositions and the quantities of phases present at equilibrium are represented

                                                                                          F = C P + 2The phase rule

                                                                                          The phase rule JW Gibbs formulated the phase rule which is a general relation

                                                                                          between the variance F the number of component C and the number of phases P at equilibrium for a system of any composition

                                                                                          For a system in equilibrium

                                                                                          F degree of freedom the least number of intensive variable that must be fixed (known) to describe the system completely

                                                                                          Phase Rule relation to determine the least number of intensive variable that can be changed without changing the equilibrium state of the system or alternately

                                                                                          The least number required to define the state of the system which is called degree of freedom F

                                                                                          Intensive variable independent variable that do not depend on the volume or the size egTemp pressure

                                                                                          Independent chemical species which comprise the system These could be Elements Ions Compounds

                                                                                          Eg Au-Cu system Components rarr Au Cu Ice-water system Component rarr H2O

                                                                                          Al2O3 ndash Cr2O3 system Components rarr Al2O3 Cr2O3

                                                                                          Component the smallest number of constituent by which the composition of each phase in the system at equilibrium can be expressed in form of chemical formula or equation

                                                                                          Phase Equilibria amp The Phase RuleComponents of a system

                                                                                          The number of phases in a system is denoted P

                                                                                          (a)A gas or a gaseous mixture is a single phase P=1

                                                                                          (b) For a solid system an alloy of two metals is a two-phase system (P=2) if the metals are immiscible but a single-phase system (P=1) if they are miscible---a homogeneous mixture of the two substances---is uniform on a molecular scale

                                                                                          (c) For a liquid system according to the solubility to decide whether a system consists of one phase or of two For example a solution of sodium chloride in water is a single phase A pair of liquids that are partially miscible or immiscible is a two-phase system(P=2)

                                                                                          Oil in water

                                                                                          Degrees of Freedom = What you can control What the system controls

                                                                                          F = C + 2 P

                                                                                          Can control the no of components added and P amp T

                                                                                          System decided how many phases to produce given the

                                                                                          conditions

                                                                                          A way of understanding the Gibbs Phase RuleThe degrees of freedom can be thought of as the difference between what you (can) control and

                                                                                          what the system controls

                                                                                          F degree of freedom the least number of intensive variable that must be fixed (known) to describe the system completely

                                                                                          Degree of freedom (or variance) F is the number of variables (T p andor composition) that can be changed independently without changing the phases of the system

                                                                                          a) At the triple pointP = 3 (solid liquid and gas)

                                                                                          C= 1 (water)P + F = C + 2

                                                                                          F = 0 (no degree of freedom)

                                                                                          b) liquid-solid curveP = 2

                                                                                          2+F = 1 + 2F= 1

                                                                                          One variable (T or P) can be changed

                                                                                          c) LiquidP =1

                                                                                          So F =2Two variables (T and P) can be varied independently

                                                                                          and the system will remains a single phase

                                                                                          One-component systemsPhase diagram of water

                                                                                          P (

                                                                                          atm

                                                                                          )

                                                                                          Critical point

                                                                                          374

                                                                                          1

                                                                                          =100=0O--Triple point

                                                                                          0006

                                                                                          218

                                                                                          Curve O -CSublimation

                                                                                          Deposition

                                                                                          Curve O-AVaporizationCondensation

                                                                                          Curve O -BMelting

                                                                                          Freezing

                                                                                          F = C P + 2

                                                                                          F = C P + 2

                                                                                          Phase Diagram of Carbon Dioxide

                                                                                          Condensed system System in which the vapor phase is ignored and only the solid andor liquid phases are considered

                                                                                          Two component system For two component system F can be 3 (3D model is needed) eg T p

                                                                                          and concentration usually we fix p = 1atm the vapor phase is neglected and F is reduced to 2

                                                                                          For three component system the pressure and temperature are fixed

                                                                                          Phenol water phase diagram

                                                                                          eg for point d (24)

                                                                                          Two component system containing liquid phase

                                                                                          Tie Line bc line The line at which the system at equilibrium will separate into phases of constant composition termed lsquoconjugate phasesrsquo

                                                                                          Lever Rule a way to calculate the proportions of each phase present on a phase diagram in a two phase field (at a given temperature and composition)

                                                                                          eg for point d (24)

                                                                                          For every 10 g of liquid system in equilibrium in point d

                                                                                          75 g phase A25 g phase B

                                                                                          ExampleMixed 24g phenol +76g water T 50degC

                                                                                          equilibrium75 g phase A 25 g phase B

                                                                                          11 phenol 63 phenol

                                                                                          011 times75 g=825 g phenol

                                                                                          063 times25 g=1575 g phenol

                                                                                          water rich phasecontains water+ phenol(11)

                                                                                          Phenol rich phasecontains Phenol (63)+ water

                                                                                          The Critical Solution Temperature CST

                                                                                          Is the maximum temperature at which the 2-phase region exists (or upper consolute temperature)

                                                                                          In the case of the phenol-water system this is 668oC (point h)

                                                                                          All combinations of phenol and water gt CST are completely miscible and yield 1-phase liquid systems

                                                                                          Systems Showing a Decrease in Miscibility with Rise in Temperature

                                                                                          A few mixtures exhibit a lower critical solution temperature (low CST) eg triethylamine plus water The miscibility with in temperature

                                                                                          Systems Showing Upper and Lower CSTs

                                                                                          The miscibility with temp

                                                                                          a certain temperature miscibility starts to again with further in temperature

                                                                                          Closed-phase diagram ie nicotine-water system

                                                                                          A salol B thymol

                                                                                          53

                                                                                          Two component system containing solid and liquid phase (Eutectic Mixtures)

                                                                                          A salol B thymol

                                                                                          EMLAreg (lidocaine 25 and prilocaine 25) Cream

                                                                                          EMLA Cream (lidocaine 25 and prilocaine 25) is an emulsion in which the oil phase is a eutectic mixture of lidocaine and prilocaine in a ratio of 11 by weight This eutectic mixture has a melting point below room temperature and therefore both local anesthetics exist as a liquid oil rather than as crystals

                                                                                          Eutectic mixture Pharmaceutical Application

                                                                                          Triangular Diagrams for three ndash component systems

                                                                                          Three component system

                                                                                          Birzeit University Physical Pharmacy PHAR 323 Dr Hani Shtaya

                                                                                          1 Binding Forces Between Molecules2 Repulsive and Attractive Forces3 The Gaseous State The Ideal Gas Law Liquefaction of Gases Aerosols4 Solids and the Crystalline State Crystalline Solids Polymorphism Solvates Amorphous Solids5 Phase Equilibria and the Phase Rule Phase Rule Systems Containing One Component Condensed System Two-Component Systems Containing Liquid Phases Two-Component Systems Containing Solid and Liquid Phases Eutectic Mixtures Rules Relating to Triangular Diagrams

                                                                                          Topics that we have covered

                                                                                          • States of Matter
                                                                                          • States of Matter (2)
                                                                                          • Objectives of the lecture
                                                                                          • Comparison of Gases Liquids and Solids
                                                                                          • Slide 5
                                                                                          • Repulsive and Attractive Forces
                                                                                          • Ideal Gas Equation
                                                                                          • Gaseous state
                                                                                          • Slide 9
                                                                                          • Gaseous state (2)
                                                                                          • Liquefaction of Gases
                                                                                          • Slide 12
                                                                                          • SOLIDS amp CRYSTALLINE STATE Pharmaceutical Drugs more than 80
                                                                                          • Solids and the crystalline state
                                                                                          • Classification of Solids
                                                                                          • Slide 16
                                                                                          • Slide 17
                                                                                          • Crystal forms
                                                                                          • Types of Crystals
                                                                                          • Slide 20
                                                                                          • Slide 21
                                                                                          • Polymorphism
                                                                                          • Slide 23
                                                                                          • Slide 24
                                                                                          • Slide 25
                                                                                          • Slide 26
                                                                                          • Cocrystal
                                                                                          • Principle of polymorphism
                                                                                          • Solvates
                                                                                          • Polymorphism (2)
                                                                                          • Amorphous Solid
                                                                                          • Amorphous or crystalline amp therapeutic activity
                                                                                          • Slide 33
                                                                                          • Slide 34
                                                                                          • Polymorphism and Industry Pharmaceutical
                                                                                          • Celecoxib
                                                                                          • Furosemide
                                                                                          • Bioavailability
                                                                                          • Slide 39
                                                                                          • Slide 40
                                                                                          • Bioequivalence
                                                                                          • Slide 42
                                                                                          • Carbamazepine
                                                                                          • Slide 44
                                                                                          • AIDS drug ritonavir
                                                                                          • Slide 46
                                                                                          • Slide 47
                                                                                          • Phase Equilibria amp The Phase Rule
                                                                                          • Phase diagram ndash Water
                                                                                          • Phase Equilibria amp The Phase Rule Definitions
                                                                                          • Phase Definition
                                                                                          • Examples
                                                                                          • Components
                                                                                          • Examples
                                                                                          • Slide 55
                                                                                          • Degrees of freedom (or variance)
                                                                                          • Examples (2)
                                                                                          • Phase Equilibria amp The Phase Rule
                                                                                          • The phase rule
                                                                                          • Slide 60
                                                                                          • Phase Equilibria amp The Phase Rule (2)
                                                                                          • The number of phases in a system is denoted P
                                                                                          • Slide 63
                                                                                          • Slide 64
                                                                                          • One-component systems
                                                                                          • Slide 66
                                                                                          • Slide 67
                                                                                          • Slide 68
                                                                                          • Slide 69
                                                                                          • Slide 70
                                                                                          • Two component system containing liquid phase
                                                                                          • Slide 72
                                                                                          • The Critical Solution Temperature CST
                                                                                          • Systems Showing a Decrease in Miscibility with Rise in Temperat
                                                                                          • Systems Showing Upper and Lower CSTs
                                                                                          • Two component system containing solid and liquid phase (Eutecti
                                                                                          • Slide 77
                                                                                          • Eutectic mixture Pharmaceutical Application
                                                                                          • Three component system
                                                                                          • Slide 80
                                                                                          • Topics that we have covered

                                                                                            1 Liquid water pieces of ice and water vapour are present together The number of phases is 3 as each form is a separate phase Ice in the system is a single phase even if it is present as a number of pieces

                                                                                            2 Calcium carbonate undergoes thermal decomposition The chemical reaction is CaCO3(s) CaO(s) + CO2 (g) Number of phases = 3 This system consists of 2 solid phases CaCO3 and CaO and one gaseous phase that of CO2

                                                                                            3 Ammonium chloride undergoes thermal decomposition The chemical reaction is NH4Cl(s) NH3 (g) + HCl (g) Number of phases = 2 This system has two phases one solid NH4Cl and one gaseous a mixture of NH3 and HCl

                                                                                            4 A solution of NaCl in water Number of phases = 1

                                                                                            bull Examples

                                                                                            The number of components of a system at equilibrium is the smallest number of independently varying chemical constituents using which the composition of each and every phase in the system can be expressed

                                                                                            Components

                                                                                            Counting the number of components 1 The sulphur system is a one component system All the phases

                                                                                            monoclinic rhombic liquid and vapour ndash can be expressed in terms of the single constituent ndash sulphur

                                                                                            2 A mixture of ethanol and water is an example of a two component system We need both ethanol and water to express its composition

                                                                                            bull Examples

                                                                                            An example of a system in which a reaction occurs and an equilibrium is established is the thermal decomposition of solid CaCO3

                                                                                            In this system there are three distinct phasesSolid CaCO3

                                                                                            Solid CaOGaseous CO2

                                                                                            Though there are 3 species present the number of components is only two because of the equilibrium CaCO3 (s) CaO(s) + CO2(g)

                                                                                            Any two of the three constituents may be chosen as the components

                                                                                            If CaO and CO2 are chosen then the composition of the phase CaCO3 is expressed as one mole of component CO2 plus one mole of component CaO

                                                                                            If on the other hand CaCO3 and CO2 were chosen then the composition of the phase CaO would be described as one mole of CaCO3 minus one mole of CO2

                                                                                            The degrees of freedom or variance of a system is defined as the minimum number of variables such as

                                                                                            temperaturepressureconcentrationwhich must be fixed in order to define the system completely

                                                                                            Degrees of freedom (or variance)

                                                                                            F = C P + 2

                                                                                            1 A gaseous mixture of CO2 and N2 Three variables pressure temperature and composition are required to define this system This is hence a trivariant system

                                                                                            2 A system having only liquid water has two degrees of freedom or is bivariant Both temperature and pressure need to be mentioned in order to define the system

                                                                                            3 If to the system containing liquid water pieces of ice are added and this system with 2 phases is allowed to come to equilibrium then it is an univariant system

                                                                                            Only one variable either temperature or pressure need to be specified in order to define the systemIf the pressure on the system is maintained at 1 atm then the temperature of the system gets automatically fixed at 0oC the normal melting point of ice

                                                                                            bull Examples

                                                                                            Phase Equilibria amp The Phase Rule

                                                                                            A phase diagram (Equilibrium Phase Diagram) summarizes the conditions at which a substance exists as a solid liquid or gas

                                                                                            OR It is a ldquomaprdquo of the information about the control of phase structure of a particular material system

                                                                                            The relationships between temperature and the compositions and the quantities of phases present at equilibrium are represented

                                                                                            F = C P + 2The phase rule

                                                                                            The phase rule JW Gibbs formulated the phase rule which is a general relation

                                                                                            between the variance F the number of component C and the number of phases P at equilibrium for a system of any composition

                                                                                            For a system in equilibrium

                                                                                            F degree of freedom the least number of intensive variable that must be fixed (known) to describe the system completely

                                                                                            Phase Rule relation to determine the least number of intensive variable that can be changed without changing the equilibrium state of the system or alternately

                                                                                            The least number required to define the state of the system which is called degree of freedom F

                                                                                            Intensive variable independent variable that do not depend on the volume or the size egTemp pressure

                                                                                            Independent chemical species which comprise the system These could be Elements Ions Compounds

                                                                                            Eg Au-Cu system Components rarr Au Cu Ice-water system Component rarr H2O

                                                                                            Al2O3 ndash Cr2O3 system Components rarr Al2O3 Cr2O3

                                                                                            Component the smallest number of constituent by which the composition of each phase in the system at equilibrium can be expressed in form of chemical formula or equation

                                                                                            Phase Equilibria amp The Phase RuleComponents of a system

                                                                                            The number of phases in a system is denoted P

                                                                                            (a)A gas or a gaseous mixture is a single phase P=1

                                                                                            (b) For a solid system an alloy of two metals is a two-phase system (P=2) if the metals are immiscible but a single-phase system (P=1) if they are miscible---a homogeneous mixture of the two substances---is uniform on a molecular scale

                                                                                            (c) For a liquid system according to the solubility to decide whether a system consists of one phase or of two For example a solution of sodium chloride in water is a single phase A pair of liquids that are partially miscible or immiscible is a two-phase system(P=2)

                                                                                            Oil in water

                                                                                            Degrees of Freedom = What you can control What the system controls

                                                                                            F = C + 2 P

                                                                                            Can control the no of components added and P amp T

                                                                                            System decided how many phases to produce given the

                                                                                            conditions

                                                                                            A way of understanding the Gibbs Phase RuleThe degrees of freedom can be thought of as the difference between what you (can) control and

                                                                                            what the system controls

                                                                                            F degree of freedom the least number of intensive variable that must be fixed (known) to describe the system completely

                                                                                            Degree of freedom (or variance) F is the number of variables (T p andor composition) that can be changed independently without changing the phases of the system

                                                                                            a) At the triple pointP = 3 (solid liquid and gas)

                                                                                            C= 1 (water)P + F = C + 2

                                                                                            F = 0 (no degree of freedom)

                                                                                            b) liquid-solid curveP = 2

                                                                                            2+F = 1 + 2F= 1

                                                                                            One variable (T or P) can be changed

                                                                                            c) LiquidP =1

                                                                                            So F =2Two variables (T and P) can be varied independently

                                                                                            and the system will remains a single phase

                                                                                            One-component systemsPhase diagram of water

                                                                                            P (

                                                                                            atm

                                                                                            )

                                                                                            Critical point

                                                                                            374

                                                                                            1

                                                                                            =100=0O--Triple point

                                                                                            0006

                                                                                            218

                                                                                            Curve O -CSublimation

                                                                                            Deposition

                                                                                            Curve O-AVaporizationCondensation

                                                                                            Curve O -BMelting

                                                                                            Freezing

                                                                                            F = C P + 2

                                                                                            F = C P + 2

                                                                                            Phase Diagram of Carbon Dioxide

                                                                                            Condensed system System in which the vapor phase is ignored and only the solid andor liquid phases are considered

                                                                                            Two component system For two component system F can be 3 (3D model is needed) eg T p

                                                                                            and concentration usually we fix p = 1atm the vapor phase is neglected and F is reduced to 2

                                                                                            For three component system the pressure and temperature are fixed

                                                                                            Phenol water phase diagram

                                                                                            eg for point d (24)

                                                                                            Two component system containing liquid phase

                                                                                            Tie Line bc line The line at which the system at equilibrium will separate into phases of constant composition termed lsquoconjugate phasesrsquo

                                                                                            Lever Rule a way to calculate the proportions of each phase present on a phase diagram in a two phase field (at a given temperature and composition)

                                                                                            eg for point d (24)

                                                                                            For every 10 g of liquid system in equilibrium in point d

                                                                                            75 g phase A25 g phase B

                                                                                            ExampleMixed 24g phenol +76g water T 50degC

                                                                                            equilibrium75 g phase A 25 g phase B

                                                                                            11 phenol 63 phenol

                                                                                            011 times75 g=825 g phenol

                                                                                            063 times25 g=1575 g phenol

                                                                                            water rich phasecontains water+ phenol(11)

                                                                                            Phenol rich phasecontains Phenol (63)+ water

                                                                                            The Critical Solution Temperature CST

                                                                                            Is the maximum temperature at which the 2-phase region exists (or upper consolute temperature)

                                                                                            In the case of the phenol-water system this is 668oC (point h)

                                                                                            All combinations of phenol and water gt CST are completely miscible and yield 1-phase liquid systems

                                                                                            Systems Showing a Decrease in Miscibility with Rise in Temperature

                                                                                            A few mixtures exhibit a lower critical solution temperature (low CST) eg triethylamine plus water The miscibility with in temperature

                                                                                            Systems Showing Upper and Lower CSTs

                                                                                            The miscibility with temp

                                                                                            a certain temperature miscibility starts to again with further in temperature

                                                                                            Closed-phase diagram ie nicotine-water system

                                                                                            A salol B thymol

                                                                                            53

                                                                                            Two component system containing solid and liquid phase (Eutectic Mixtures)

                                                                                            A salol B thymol

                                                                                            EMLAreg (lidocaine 25 and prilocaine 25) Cream

                                                                                            EMLA Cream (lidocaine 25 and prilocaine 25) is an emulsion in which the oil phase is a eutectic mixture of lidocaine and prilocaine in a ratio of 11 by weight This eutectic mixture has a melting point below room temperature and therefore both local anesthetics exist as a liquid oil rather than as crystals

                                                                                            Eutectic mixture Pharmaceutical Application

                                                                                            Triangular Diagrams for three ndash component systems

                                                                                            Three component system

                                                                                            Birzeit University Physical Pharmacy PHAR 323 Dr Hani Shtaya

                                                                                            1 Binding Forces Between Molecules2 Repulsive and Attractive Forces3 The Gaseous State The Ideal Gas Law Liquefaction of Gases Aerosols4 Solids and the Crystalline State Crystalline Solids Polymorphism Solvates Amorphous Solids5 Phase Equilibria and the Phase Rule Phase Rule Systems Containing One Component Condensed System Two-Component Systems Containing Liquid Phases Two-Component Systems Containing Solid and Liquid Phases Eutectic Mixtures Rules Relating to Triangular Diagrams

                                                                                            Topics that we have covered

                                                                                            • States of Matter
                                                                                            • States of Matter (2)
                                                                                            • Objectives of the lecture
                                                                                            • Comparison of Gases Liquids and Solids
                                                                                            • Slide 5
                                                                                            • Repulsive and Attractive Forces
                                                                                            • Ideal Gas Equation
                                                                                            • Gaseous state
                                                                                            • Slide 9
                                                                                            • Gaseous state (2)
                                                                                            • Liquefaction of Gases
                                                                                            • Slide 12
                                                                                            • SOLIDS amp CRYSTALLINE STATE Pharmaceutical Drugs more than 80
                                                                                            • Solids and the crystalline state
                                                                                            • Classification of Solids
                                                                                            • Slide 16
                                                                                            • Slide 17
                                                                                            • Crystal forms
                                                                                            • Types of Crystals
                                                                                            • Slide 20
                                                                                            • Slide 21
                                                                                            • Polymorphism
                                                                                            • Slide 23
                                                                                            • Slide 24
                                                                                            • Slide 25
                                                                                            • Slide 26
                                                                                            • Cocrystal
                                                                                            • Principle of polymorphism
                                                                                            • Solvates
                                                                                            • Polymorphism (2)
                                                                                            • Amorphous Solid
                                                                                            • Amorphous or crystalline amp therapeutic activity
                                                                                            • Slide 33
                                                                                            • Slide 34
                                                                                            • Polymorphism and Industry Pharmaceutical
                                                                                            • Celecoxib
                                                                                            • Furosemide
                                                                                            • Bioavailability
                                                                                            • Slide 39
                                                                                            • Slide 40
                                                                                            • Bioequivalence
                                                                                            • Slide 42
                                                                                            • Carbamazepine
                                                                                            • Slide 44
                                                                                            • AIDS drug ritonavir
                                                                                            • Slide 46
                                                                                            • Slide 47
                                                                                            • Phase Equilibria amp The Phase Rule
                                                                                            • Phase diagram ndash Water
                                                                                            • Phase Equilibria amp The Phase Rule Definitions
                                                                                            • Phase Definition
                                                                                            • Examples
                                                                                            • Components
                                                                                            • Examples
                                                                                            • Slide 55
                                                                                            • Degrees of freedom (or variance)
                                                                                            • Examples (2)
                                                                                            • Phase Equilibria amp The Phase Rule
                                                                                            • The phase rule
                                                                                            • Slide 60
                                                                                            • Phase Equilibria amp The Phase Rule (2)
                                                                                            • The number of phases in a system is denoted P
                                                                                            • Slide 63
                                                                                            • Slide 64
                                                                                            • One-component systems
                                                                                            • Slide 66
                                                                                            • Slide 67
                                                                                            • Slide 68
                                                                                            • Slide 69
                                                                                            • Slide 70
                                                                                            • Two component system containing liquid phase
                                                                                            • Slide 72
                                                                                            • The Critical Solution Temperature CST
                                                                                            • Systems Showing a Decrease in Miscibility with Rise in Temperat
                                                                                            • Systems Showing Upper and Lower CSTs
                                                                                            • Two component system containing solid and liquid phase (Eutecti
                                                                                            • Slide 77
                                                                                            • Eutectic mixture Pharmaceutical Application
                                                                                            • Three component system
                                                                                            • Slide 80
                                                                                            • Topics that we have covered

                                                                                              The number of components of a system at equilibrium is the smallest number of independently varying chemical constituents using which the composition of each and every phase in the system can be expressed

                                                                                              Components

                                                                                              Counting the number of components 1 The sulphur system is a one component system All the phases

                                                                                              monoclinic rhombic liquid and vapour ndash can be expressed in terms of the single constituent ndash sulphur

                                                                                              2 A mixture of ethanol and water is an example of a two component system We need both ethanol and water to express its composition

                                                                                              bull Examples

                                                                                              An example of a system in which a reaction occurs and an equilibrium is established is the thermal decomposition of solid CaCO3

                                                                                              In this system there are three distinct phasesSolid CaCO3

                                                                                              Solid CaOGaseous CO2

                                                                                              Though there are 3 species present the number of components is only two because of the equilibrium CaCO3 (s) CaO(s) + CO2(g)

                                                                                              Any two of the three constituents may be chosen as the components

                                                                                              If CaO and CO2 are chosen then the composition of the phase CaCO3 is expressed as one mole of component CO2 plus one mole of component CaO

                                                                                              If on the other hand CaCO3 and CO2 were chosen then the composition of the phase CaO would be described as one mole of CaCO3 minus one mole of CO2

                                                                                              The degrees of freedom or variance of a system is defined as the minimum number of variables such as

                                                                                              temperaturepressureconcentrationwhich must be fixed in order to define the system completely

                                                                                              Degrees of freedom (or variance)

                                                                                              F = C P + 2

                                                                                              1 A gaseous mixture of CO2 and N2 Three variables pressure temperature and composition are required to define this system This is hence a trivariant system

                                                                                              2 A system having only liquid water has two degrees of freedom or is bivariant Both temperature and pressure need to be mentioned in order to define the system

                                                                                              3 If to the system containing liquid water pieces of ice are added and this system with 2 phases is allowed to come to equilibrium then it is an univariant system

                                                                                              Only one variable either temperature or pressure need to be specified in order to define the systemIf the pressure on the system is maintained at 1 atm then the temperature of the system gets automatically fixed at 0oC the normal melting point of ice

                                                                                              bull Examples

                                                                                              Phase Equilibria amp The Phase Rule

                                                                                              A phase diagram (Equilibrium Phase Diagram) summarizes the conditions at which a substance exists as a solid liquid or gas

                                                                                              OR It is a ldquomaprdquo of the information about the control of phase structure of a particular material system

                                                                                              The relationships between temperature and the compositions and the quantities of phases present at equilibrium are represented

                                                                                              F = C P + 2The phase rule

                                                                                              The phase rule JW Gibbs formulated the phase rule which is a general relation

                                                                                              between the variance F the number of component C and the number of phases P at equilibrium for a system of any composition

                                                                                              For a system in equilibrium

                                                                                              F degree of freedom the least number of intensive variable that must be fixed (known) to describe the system completely

                                                                                              Phase Rule relation to determine the least number of intensive variable that can be changed without changing the equilibrium state of the system or alternately

                                                                                              The least number required to define the state of the system which is called degree of freedom F

                                                                                              Intensive variable independent variable that do not depend on the volume or the size egTemp pressure

                                                                                              Independent chemical species which comprise the system These could be Elements Ions Compounds

                                                                                              Eg Au-Cu system Components rarr Au Cu Ice-water system Component rarr H2O

                                                                                              Al2O3 ndash Cr2O3 system Components rarr Al2O3 Cr2O3

                                                                                              Component the smallest number of constituent by which the composition of each phase in the system at equilibrium can be expressed in form of chemical formula or equation

                                                                                              Phase Equilibria amp The Phase RuleComponents of a system

                                                                                              The number of phases in a system is denoted P

                                                                                              (a)A gas or a gaseous mixture is a single phase P=1

                                                                                              (b) For a solid system an alloy of two metals is a two-phase system (P=2) if the metals are immiscible but a single-phase system (P=1) if they are miscible---a homogeneous mixture of the two substances---is uniform on a molecular scale

                                                                                              (c) For a liquid system according to the solubility to decide whether a system consists of one phase or of two For example a solution of sodium chloride in water is a single phase A pair of liquids that are partially miscible or immiscible is a two-phase system(P=2)

                                                                                              Oil in water

                                                                                              Degrees of Freedom = What you can control What the system controls

                                                                                              F = C + 2 P

                                                                                              Can control the no of components added and P amp T

                                                                                              System decided how many phases to produce given the

                                                                                              conditions

                                                                                              A way of understanding the Gibbs Phase RuleThe degrees of freedom can be thought of as the difference between what you (can) control and

                                                                                              what the system controls

                                                                                              F degree of freedom the least number of intensive variable that must be fixed (known) to describe the system completely

                                                                                              Degree of freedom (or variance) F is the number of variables (T p andor composition) that can be changed independently without changing the phases of the system

                                                                                              a) At the triple pointP = 3 (solid liquid and gas)

                                                                                              C= 1 (water)P + F = C + 2

                                                                                              F = 0 (no degree of freedom)

                                                                                              b) liquid-solid curveP = 2

                                                                                              2+F = 1 + 2F= 1

                                                                                              One variable (T or P) can be changed

                                                                                              c) LiquidP =1

                                                                                              So F =2Two variables (T and P) can be varied independently

                                                                                              and the system will remains a single phase

                                                                                              One-component systemsPhase diagram of water

                                                                                              P (

                                                                                              atm

                                                                                              )

                                                                                              Critical point

                                                                                              374

                                                                                              1

                                                                                              =100=0O--Triple point

                                                                                              0006

                                                                                              218

                                                                                              Curve O -CSublimation

                                                                                              Deposition

                                                                                              Curve O-AVaporizationCondensation

                                                                                              Curve O -BMelting

                                                                                              Freezing

                                                                                              F = C P + 2

                                                                                              F = C P + 2

                                                                                              Phase Diagram of Carbon Dioxide

                                                                                              Condensed system System in which the vapor phase is ignored and only the solid andor liquid phases are considered

                                                                                              Two component system For two component system F can be 3 (3D model is needed) eg T p

                                                                                              and concentration usually we fix p = 1atm the vapor phase is neglected and F is reduced to 2

                                                                                              For three component system the pressure and temperature are fixed

                                                                                              Phenol water phase diagram

                                                                                              eg for point d (24)

                                                                                              Two component system containing liquid phase

                                                                                              Tie Line bc line The line at which the system at equilibrium will separate into phases of constant composition termed lsquoconjugate phasesrsquo

                                                                                              Lever Rule a way to calculate the proportions of each phase present on a phase diagram in a two phase field (at a given temperature and composition)

                                                                                              eg for point d (24)

                                                                                              For every 10 g of liquid system in equilibrium in point d

                                                                                              75 g phase A25 g phase B

                                                                                              ExampleMixed 24g phenol +76g water T 50degC

                                                                                              equilibrium75 g phase A 25 g phase B

                                                                                              11 phenol 63 phenol

                                                                                              011 times75 g=825 g phenol

                                                                                              063 times25 g=1575 g phenol

                                                                                              water rich phasecontains water+ phenol(11)

                                                                                              Phenol rich phasecontains Phenol (63)+ water

                                                                                              The Critical Solution Temperature CST

                                                                                              Is the maximum temperature at which the 2-phase region exists (or upper consolute temperature)

                                                                                              In the case of the phenol-water system this is 668oC (point h)

                                                                                              All combinations of phenol and water gt CST are completely miscible and yield 1-phase liquid systems

                                                                                              Systems Showing a Decrease in Miscibility with Rise in Temperature

                                                                                              A few mixtures exhibit a lower critical solution temperature (low CST) eg triethylamine plus water The miscibility with in temperature

                                                                                              Systems Showing Upper and Lower CSTs

                                                                                              The miscibility with temp

                                                                                              a certain temperature miscibility starts to again with further in temperature

                                                                                              Closed-phase diagram ie nicotine-water system

                                                                                              A salol B thymol

                                                                                              53

                                                                                              Two component system containing solid and liquid phase (Eutectic Mixtures)

                                                                                              A salol B thymol

                                                                                              EMLAreg (lidocaine 25 and prilocaine 25) Cream

                                                                                              EMLA Cream (lidocaine 25 and prilocaine 25) is an emulsion in which the oil phase is a eutectic mixture of lidocaine and prilocaine in a ratio of 11 by weight This eutectic mixture has a melting point below room temperature and therefore both local anesthetics exist as a liquid oil rather than as crystals

                                                                                              Eutectic mixture Pharmaceutical Application

                                                                                              Triangular Diagrams for three ndash component systems

                                                                                              Three component system

                                                                                              Birzeit University Physical Pharmacy PHAR 323 Dr Hani Shtaya

                                                                                              1 Binding Forces Between Molecules2 Repulsive and Attractive Forces3 The Gaseous State The Ideal Gas Law Liquefaction of Gases Aerosols4 Solids and the Crystalline State Crystalline Solids Polymorphism Solvates Amorphous Solids5 Phase Equilibria and the Phase Rule Phase Rule Systems Containing One Component Condensed System Two-Component Systems Containing Liquid Phases Two-Component Systems Containing Solid and Liquid Phases Eutectic Mixtures Rules Relating to Triangular Diagrams

                                                                                              Topics that we have covered

                                                                                              • States of Matter
                                                                                              • States of Matter (2)
                                                                                              • Objectives of the lecture
                                                                                              • Comparison of Gases Liquids and Solids
                                                                                              • Slide 5
                                                                                              • Repulsive and Attractive Forces
                                                                                              • Ideal Gas Equation
                                                                                              • Gaseous state
                                                                                              • Slide 9
                                                                                              • Gaseous state (2)
                                                                                              • Liquefaction of Gases
                                                                                              • Slide 12
                                                                                              • SOLIDS amp CRYSTALLINE STATE Pharmaceutical Drugs more than 80
                                                                                              • Solids and the crystalline state
                                                                                              • Classification of Solids
                                                                                              • Slide 16
                                                                                              • Slide 17
                                                                                              • Crystal forms
                                                                                              • Types of Crystals
                                                                                              • Slide 20
                                                                                              • Slide 21
                                                                                              • Polymorphism
                                                                                              • Slide 23
                                                                                              • Slide 24
                                                                                              • Slide 25
                                                                                              • Slide 26
                                                                                              • Cocrystal
                                                                                              • Principle of polymorphism
                                                                                              • Solvates
                                                                                              • Polymorphism (2)
                                                                                              • Amorphous Solid
                                                                                              • Amorphous or crystalline amp therapeutic activity
                                                                                              • Slide 33
                                                                                              • Slide 34
                                                                                              • Polymorphism and Industry Pharmaceutical
                                                                                              • Celecoxib
                                                                                              • Furosemide
                                                                                              • Bioavailability
                                                                                              • Slide 39
                                                                                              • Slide 40
                                                                                              • Bioequivalence
                                                                                              • Slide 42
                                                                                              • Carbamazepine
                                                                                              • Slide 44
                                                                                              • AIDS drug ritonavir
                                                                                              • Slide 46
                                                                                              • Slide 47
                                                                                              • Phase Equilibria amp The Phase Rule
                                                                                              • Phase diagram ndash Water
                                                                                              • Phase Equilibria amp The Phase Rule Definitions
                                                                                              • Phase Definition
                                                                                              • Examples
                                                                                              • Components
                                                                                              • Examples
                                                                                              • Slide 55
                                                                                              • Degrees of freedom (or variance)
                                                                                              • Examples (2)
                                                                                              • Phase Equilibria amp The Phase Rule
                                                                                              • The phase rule
                                                                                              • Slide 60
                                                                                              • Phase Equilibria amp The Phase Rule (2)
                                                                                              • The number of phases in a system is denoted P
                                                                                              • Slide 63
                                                                                              • Slide 64
                                                                                              • One-component systems
                                                                                              • Slide 66
                                                                                              • Slide 67
                                                                                              • Slide 68
                                                                                              • Slide 69
                                                                                              • Slide 70
                                                                                              • Two component system containing liquid phase
                                                                                              • Slide 72
                                                                                              • The Critical Solution Temperature CST
                                                                                              • Systems Showing a Decrease in Miscibility with Rise in Temperat
                                                                                              • Systems Showing Upper and Lower CSTs
                                                                                              • Two component system containing solid and liquid phase (Eutecti
                                                                                              • Slide 77
                                                                                              • Eutectic mixture Pharmaceutical Application
                                                                                              • Three component system
                                                                                              • Slide 80
                                                                                              • Topics that we have covered

                                                                                                Counting the number of components 1 The sulphur system is a one component system All the phases

                                                                                                monoclinic rhombic liquid and vapour ndash can be expressed in terms of the single constituent ndash sulphur

                                                                                                2 A mixture of ethanol and water is an example of a two component system We need both ethanol and water to express its composition

                                                                                                bull Examples

                                                                                                An example of a system in which a reaction occurs and an equilibrium is established is the thermal decomposition of solid CaCO3

                                                                                                In this system there are three distinct phasesSolid CaCO3

                                                                                                Solid CaOGaseous CO2

                                                                                                Though there are 3 species present the number of components is only two because of the equilibrium CaCO3 (s) CaO(s) + CO2(g)

                                                                                                Any two of the three constituents may be chosen as the components

                                                                                                If CaO and CO2 are chosen then the composition of the phase CaCO3 is expressed as one mole of component CO2 plus one mole of component CaO

                                                                                                If on the other hand CaCO3 and CO2 were chosen then the composition of the phase CaO would be described as one mole of CaCO3 minus one mole of CO2

                                                                                                The degrees of freedom or variance of a system is defined as the minimum number of variables such as

                                                                                                temperaturepressureconcentrationwhich must be fixed in order to define the system completely

                                                                                                Degrees of freedom (or variance)

                                                                                                F = C P + 2

                                                                                                1 A gaseous mixture of CO2 and N2 Three variables pressure temperature and composition are required to define this system This is hence a trivariant system

                                                                                                2 A system having only liquid water has two degrees of freedom or is bivariant Both temperature and pressure need to be mentioned in order to define the system

                                                                                                3 If to the system containing liquid water pieces of ice are added and this system with 2 phases is allowed to come to equilibrium then it is an univariant system

                                                                                                Only one variable either temperature or pressure need to be specified in order to define the systemIf the pressure on the system is maintained at 1 atm then the temperature of the system gets automatically fixed at 0oC the normal melting point of ice

                                                                                                bull Examples

                                                                                                Phase Equilibria amp The Phase Rule

                                                                                                A phase diagram (Equilibrium Phase Diagram) summarizes the conditions at which a substance exists as a solid liquid or gas

                                                                                                OR It is a ldquomaprdquo of the information about the control of phase structure of a particular material system

                                                                                                The relationships between temperature and the compositions and the quantities of phases present at equilibrium are represented

                                                                                                F = C P + 2The phase rule

                                                                                                The phase rule JW Gibbs formulated the phase rule which is a general relation

                                                                                                between the variance F the number of component C and the number of phases P at equilibrium for a system of any composition

                                                                                                For a system in equilibrium

                                                                                                F degree of freedom the least number of intensive variable that must be fixed (known) to describe the system completely

                                                                                                Phase Rule relation to determine the least number of intensive variable that can be changed without changing the equilibrium state of the system or alternately

                                                                                                The least number required to define the state of the system which is called degree of freedom F

                                                                                                Intensive variable independent variable that do not depend on the volume or the size egTemp pressure

                                                                                                Independent chemical species which comprise the system These could be Elements Ions Compounds

                                                                                                Eg Au-Cu system Components rarr Au Cu Ice-water system Component rarr H2O

                                                                                                Al2O3 ndash Cr2O3 system Components rarr Al2O3 Cr2O3

                                                                                                Component the smallest number of constituent by which the composition of each phase in the system at equilibrium can be expressed in form of chemical formula or equation

                                                                                                Phase Equilibria amp The Phase RuleComponents of a system

                                                                                                The number of phases in a system is denoted P

                                                                                                (a)A gas or a gaseous mixture is a single phase P=1

                                                                                                (b) For a solid system an alloy of two metals is a two-phase system (P=2) if the metals are immiscible but a single-phase system (P=1) if they are miscible---a homogeneous mixture of the two substances---is uniform on a molecular scale

                                                                                                (c) For a liquid system according to the solubility to decide whether a system consists of one phase or of two For example a solution of sodium chloride in water is a single phase A pair of liquids that are partially miscible or immiscible is a two-phase system(P=2)

                                                                                                Oil in water

                                                                                                Degrees of Freedom = What you can control What the system controls

                                                                                                F = C + 2 P

                                                                                                Can control the no of components added and P amp T

                                                                                                System decided how many phases to produce given the

                                                                                                conditions

                                                                                                A way of understanding the Gibbs Phase RuleThe degrees of freedom can be thought of as the difference between what you (can) control and

                                                                                                what the system controls

                                                                                                F degree of freedom the least number of intensive variable that must be fixed (known) to describe the system completely

                                                                                                Degree of freedom (or variance) F is the number of variables (T p andor composition) that can be changed independently without changing the phases of the system

                                                                                                a) At the triple pointP = 3 (solid liquid and gas)

                                                                                                C= 1 (water)P + F = C + 2

                                                                                                F = 0 (no degree of freedom)

                                                                                                b) liquid-solid curveP = 2

                                                                                                2+F = 1 + 2F= 1

                                                                                                One variable (T or P) can be changed

                                                                                                c) LiquidP =1

                                                                                                So F =2Two variables (T and P) can be varied independently

                                                                                                and the system will remains a single phase

                                                                                                One-component systemsPhase diagram of water

                                                                                                P (

                                                                                                atm

                                                                                                )

                                                                                                Critical point

                                                                                                374

                                                                                                1

                                                                                                =100=0O--Triple point

                                                                                                0006

                                                                                                218

                                                                                                Curve O -CSublimation

                                                                                                Deposition

                                                                                                Curve O-AVaporizationCondensation

                                                                                                Curve O -BMelting

                                                                                                Freezing

                                                                                                F = C P + 2

                                                                                                F = C P + 2

                                                                                                Phase Diagram of Carbon Dioxide

                                                                                                Condensed system System in which the vapor phase is ignored and only the solid andor liquid phases are considered

                                                                                                Two component system For two component system F can be 3 (3D model is needed) eg T p

                                                                                                and concentration usually we fix p = 1atm the vapor phase is neglected and F is reduced to 2

                                                                                                For three component system the pressure and temperature are fixed

                                                                                                Phenol water phase diagram

                                                                                                eg for point d (24)

                                                                                                Two component system containing liquid phase

                                                                                                Tie Line bc line The line at which the system at equilibrium will separate into phases of constant composition termed lsquoconjugate phasesrsquo

                                                                                                Lever Rule a way to calculate the proportions of each phase present on a phase diagram in a two phase field (at a given temperature and composition)

                                                                                                eg for point d (24)

                                                                                                For every 10 g of liquid system in equilibrium in point d

                                                                                                75 g phase A25 g phase B

                                                                                                ExampleMixed 24g phenol +76g water T 50degC

                                                                                                equilibrium75 g phase A 25 g phase B

                                                                                                11 phenol 63 phenol

                                                                                                011 times75 g=825 g phenol

                                                                                                063 times25 g=1575 g phenol

                                                                                                water rich phasecontains water+ phenol(11)

                                                                                                Phenol rich phasecontains Phenol (63)+ water

                                                                                                The Critical Solution Temperature CST

                                                                                                Is the maximum temperature at which the 2-phase region exists (or upper consolute temperature)

                                                                                                In the case of the phenol-water system this is 668oC (point h)

                                                                                                All combinations of phenol and water gt CST are completely miscible and yield 1-phase liquid systems

                                                                                                Systems Showing a Decrease in Miscibility with Rise in Temperature

                                                                                                A few mixtures exhibit a lower critical solution temperature (low CST) eg triethylamine plus water The miscibility with in temperature

                                                                                                Systems Showing Upper and Lower CSTs

                                                                                                The miscibility with temp

                                                                                                a certain temperature miscibility starts to again with further in temperature

                                                                                                Closed-phase diagram ie nicotine-water system

                                                                                                A salol B thymol

                                                                                                53

                                                                                                Two component system containing solid and liquid phase (Eutectic Mixtures)

                                                                                                A salol B thymol

                                                                                                EMLAreg (lidocaine 25 and prilocaine 25) Cream

                                                                                                EMLA Cream (lidocaine 25 and prilocaine 25) is an emulsion in which the oil phase is a eutectic mixture of lidocaine and prilocaine in a ratio of 11 by weight This eutectic mixture has a melting point below room temperature and therefore both local anesthetics exist as a liquid oil rather than as crystals

                                                                                                Eutectic mixture Pharmaceutical Application

                                                                                                Triangular Diagrams for three ndash component systems

                                                                                                Three component system

                                                                                                Birzeit University Physical Pharmacy PHAR 323 Dr Hani Shtaya

                                                                                                1 Binding Forces Between Molecules2 Repulsive and Attractive Forces3 The Gaseous State The Ideal Gas Law Liquefaction of Gases Aerosols4 Solids and the Crystalline State Crystalline Solids Polymorphism Solvates Amorphous Solids5 Phase Equilibria and the Phase Rule Phase Rule Systems Containing One Component Condensed System Two-Component Systems Containing Liquid Phases Two-Component Systems Containing Solid and Liquid Phases Eutectic Mixtures Rules Relating to Triangular Diagrams

                                                                                                Topics that we have covered

                                                                                                • States of Matter
                                                                                                • States of Matter (2)
                                                                                                • Objectives of the lecture
                                                                                                • Comparison of Gases Liquids and Solids
                                                                                                • Slide 5
                                                                                                • Repulsive and Attractive Forces
                                                                                                • Ideal Gas Equation
                                                                                                • Gaseous state
                                                                                                • Slide 9
                                                                                                • Gaseous state (2)
                                                                                                • Liquefaction of Gases
                                                                                                • Slide 12
                                                                                                • SOLIDS amp CRYSTALLINE STATE Pharmaceutical Drugs more than 80
                                                                                                • Solids and the crystalline state
                                                                                                • Classification of Solids
                                                                                                • Slide 16
                                                                                                • Slide 17
                                                                                                • Crystal forms
                                                                                                • Types of Crystals
                                                                                                • Slide 20
                                                                                                • Slide 21
                                                                                                • Polymorphism
                                                                                                • Slide 23
                                                                                                • Slide 24
                                                                                                • Slide 25
                                                                                                • Slide 26
                                                                                                • Cocrystal
                                                                                                • Principle of polymorphism
                                                                                                • Solvates
                                                                                                • Polymorphism (2)
                                                                                                • Amorphous Solid
                                                                                                • Amorphous or crystalline amp therapeutic activity
                                                                                                • Slide 33
                                                                                                • Slide 34
                                                                                                • Polymorphism and Industry Pharmaceutical
                                                                                                • Celecoxib
                                                                                                • Furosemide
                                                                                                • Bioavailability
                                                                                                • Slide 39
                                                                                                • Slide 40
                                                                                                • Bioequivalence
                                                                                                • Slide 42
                                                                                                • Carbamazepine
                                                                                                • Slide 44
                                                                                                • AIDS drug ritonavir
                                                                                                • Slide 46
                                                                                                • Slide 47
                                                                                                • Phase Equilibria amp The Phase Rule
                                                                                                • Phase diagram ndash Water
                                                                                                • Phase Equilibria amp The Phase Rule Definitions
                                                                                                • Phase Definition
                                                                                                • Examples
                                                                                                • Components
                                                                                                • Examples
                                                                                                • Slide 55
                                                                                                • Degrees of freedom (or variance)
                                                                                                • Examples (2)
                                                                                                • Phase Equilibria amp The Phase Rule
                                                                                                • The phase rule
                                                                                                • Slide 60
                                                                                                • Phase Equilibria amp The Phase Rule (2)
                                                                                                • The number of phases in a system is denoted P
                                                                                                • Slide 63
                                                                                                • Slide 64
                                                                                                • One-component systems
                                                                                                • Slide 66
                                                                                                • Slide 67
                                                                                                • Slide 68
                                                                                                • Slide 69
                                                                                                • Slide 70
                                                                                                • Two component system containing liquid phase
                                                                                                • Slide 72
                                                                                                • The Critical Solution Temperature CST
                                                                                                • Systems Showing a Decrease in Miscibility with Rise in Temperat
                                                                                                • Systems Showing Upper and Lower CSTs
                                                                                                • Two component system containing solid and liquid phase (Eutecti
                                                                                                • Slide 77
                                                                                                • Eutectic mixture Pharmaceutical Application
                                                                                                • Three component system
                                                                                                • Slide 80
                                                                                                • Topics that we have covered

                                                                                                  An example of a system in which a reaction occurs and an equilibrium is established is the thermal decomposition of solid CaCO3

                                                                                                  In this system there are three distinct phasesSolid CaCO3

                                                                                                  Solid CaOGaseous CO2

                                                                                                  Though there are 3 species present the number of components is only two because of the equilibrium CaCO3 (s) CaO(s) + CO2(g)

                                                                                                  Any two of the three constituents may be chosen as the components

                                                                                                  If CaO and CO2 are chosen then the composition of the phase CaCO3 is expressed as one mole of component CO2 plus one mole of component CaO

                                                                                                  If on the other hand CaCO3 and CO2 were chosen then the composition of the phase CaO would be described as one mole of CaCO3 minus one mole of CO2

                                                                                                  The degrees of freedom or variance of a system is defined as the minimum number of variables such as

                                                                                                  temperaturepressureconcentrationwhich must be fixed in order to define the system completely

                                                                                                  Degrees of freedom (or variance)

                                                                                                  F = C P + 2

                                                                                                  1 A gaseous mixture of CO2 and N2 Three variables pressure temperature and composition are required to define this system This is hence a trivariant system

                                                                                                  2 A system having only liquid water has two degrees of freedom or is bivariant Both temperature and pressure need to be mentioned in order to define the system

                                                                                                  3 If to the system containing liquid water pieces of ice are added and this system with 2 phases is allowed to come to equilibrium then it is an univariant system

                                                                                                  Only one variable either temperature or pressure need to be specified in order to define the systemIf the pressure on the system is maintained at 1 atm then the temperature of the system gets automatically fixed at 0oC the normal melting point of ice

                                                                                                  bull Examples

                                                                                                  Phase Equilibria amp The Phase Rule

                                                                                                  A phase diagram (Equilibrium Phase Diagram) summarizes the conditions at which a substance exists as a solid liquid or gas

                                                                                                  OR It is a ldquomaprdquo of the information about the control of phase structure of a particular material system

                                                                                                  The relationships between temperature and the compositions and the quantities of phases present at equilibrium are represented

                                                                                                  F = C P + 2The phase rule

                                                                                                  The phase rule JW Gibbs formulated the phase rule which is a general relation

                                                                                                  between the variance F the number of component C and the number of phases P at equilibrium for a system of any composition

                                                                                                  For a system in equilibrium

                                                                                                  F degree of freedom the least number of intensive variable that must be fixed (known) to describe the system completely

                                                                                                  Phase Rule relation to determine the least number of intensive variable that can be changed without changing the equilibrium state of the system or alternately

                                                                                                  The least number required to define the state of the system which is called degree of freedom F

                                                                                                  Intensive variable independent variable that do not depend on the volume or the size egTemp pressure

                                                                                                  Independent chemical species which comprise the system These could be Elements Ions Compounds

                                                                                                  Eg Au-Cu system Components rarr Au Cu Ice-water system Component rarr H2O

                                                                                                  Al2O3 ndash Cr2O3 system Components rarr Al2O3 Cr2O3

                                                                                                  Component the smallest number of constituent by which the composition of each phase in the system at equilibrium can be expressed in form of chemical formula or equation

                                                                                                  Phase Equilibria amp The Phase RuleComponents of a system

                                                                                                  The number of phases in a system is denoted P

                                                                                                  (a)A gas or a gaseous mixture is a single phase P=1

                                                                                                  (b) For a solid system an alloy of two metals is a two-phase system (P=2) if the metals are immiscible but a single-phase system (P=1) if they are miscible---a homogeneous mixture of the two substances---is uniform on a molecular scale

                                                                                                  (c) For a liquid system according to the solubility to decide whether a system consists of one phase or of two For example a solution of sodium chloride in water is a single phase A pair of liquids that are partially miscible or immiscible is a two-phase system(P=2)

                                                                                                  Oil in water

                                                                                                  Degrees of Freedom = What you can control What the system controls

                                                                                                  F = C + 2 P

                                                                                                  Can control the no of components added and P amp T

                                                                                                  System decided how many phases to produce given the

                                                                                                  conditions

                                                                                                  A way of understanding the Gibbs Phase RuleThe degrees of freedom can be thought of as the difference between what you (can) control and

                                                                                                  what the system controls

                                                                                                  F degree of freedom the least number of intensive variable that must be fixed (known) to describe the system completely

                                                                                                  Degree of freedom (or variance) F is the number of variables (T p andor composition) that can be changed independently without changing the phases of the system

                                                                                                  a) At the triple pointP = 3 (solid liquid and gas)

                                                                                                  C= 1 (water)P + F = C + 2

                                                                                                  F = 0 (no degree of freedom)

                                                                                                  b) liquid-solid curveP = 2

                                                                                                  2+F = 1 + 2F= 1

                                                                                                  One variable (T or P) can be changed

                                                                                                  c) LiquidP =1

                                                                                                  So F =2Two variables (T and P) can be varied independently

                                                                                                  and the system will remains a single phase

                                                                                                  One-component systemsPhase diagram of water

                                                                                                  P (

                                                                                                  atm

                                                                                                  )

                                                                                                  Critical point

                                                                                                  374

                                                                                                  1

                                                                                                  =100=0O--Triple point

                                                                                                  0006

                                                                                                  218

                                                                                                  Curve O -CSublimation

                                                                                                  Deposition

                                                                                                  Curve O-AVaporizationCondensation

                                                                                                  Curve O -BMelting

                                                                                                  Freezing

                                                                                                  F = C P + 2

                                                                                                  F = C P + 2

                                                                                                  Phase Diagram of Carbon Dioxide

                                                                                                  Condensed system System in which the vapor phase is ignored and only the solid andor liquid phases are considered

                                                                                                  Two component system For two component system F can be 3 (3D model is needed) eg T p

                                                                                                  and concentration usually we fix p = 1atm the vapor phase is neglected and F is reduced to 2

                                                                                                  For three component system the pressure and temperature are fixed

                                                                                                  Phenol water phase diagram

                                                                                                  eg for point d (24)

                                                                                                  Two component system containing liquid phase

                                                                                                  Tie Line bc line The line at which the system at equilibrium will separate into phases of constant composition termed lsquoconjugate phasesrsquo

                                                                                                  Lever Rule a way to calculate the proportions of each phase present on a phase diagram in a two phase field (at a given temperature and composition)

                                                                                                  eg for point d (24)

                                                                                                  For every 10 g of liquid system in equilibrium in point d

                                                                                                  75 g phase A25 g phase B

                                                                                                  ExampleMixed 24g phenol +76g water T 50degC

                                                                                                  equilibrium75 g phase A 25 g phase B

                                                                                                  11 phenol 63 phenol

                                                                                                  011 times75 g=825 g phenol

                                                                                                  063 times25 g=1575 g phenol

                                                                                                  water rich phasecontains water+ phenol(11)

                                                                                                  Phenol rich phasecontains Phenol (63)+ water

                                                                                                  The Critical Solution Temperature CST

                                                                                                  Is the maximum temperature at which the 2-phase region exists (or upper consolute temperature)

                                                                                                  In the case of the phenol-water system this is 668oC (point h)

                                                                                                  All combinations of phenol and water gt CST are completely miscible and yield 1-phase liquid systems

                                                                                                  Systems Showing a Decrease in Miscibility with Rise in Temperature

                                                                                                  A few mixtures exhibit a lower critical solution temperature (low CST) eg triethylamine plus water The miscibility with in temperature

                                                                                                  Systems Showing Upper and Lower CSTs

                                                                                                  The miscibility with temp

                                                                                                  a certain temperature miscibility starts to again with further in temperature

                                                                                                  Closed-phase diagram ie nicotine-water system

                                                                                                  A salol B thymol

                                                                                                  53

                                                                                                  Two component system containing solid and liquid phase (Eutectic Mixtures)

                                                                                                  A salol B thymol

                                                                                                  EMLAreg (lidocaine 25 and prilocaine 25) Cream

                                                                                                  EMLA Cream (lidocaine 25 and prilocaine 25) is an emulsion in which the oil phase is a eutectic mixture of lidocaine and prilocaine in a ratio of 11 by weight This eutectic mixture has a melting point below room temperature and therefore both local anesthetics exist as a liquid oil rather than as crystals

                                                                                                  Eutectic mixture Pharmaceutical Application

                                                                                                  Triangular Diagrams for three ndash component systems

                                                                                                  Three component system

                                                                                                  Birzeit University Physical Pharmacy PHAR 323 Dr Hani Shtaya

                                                                                                  1 Binding Forces Between Molecules2 Repulsive and Attractive Forces3 The Gaseous State The Ideal Gas Law Liquefaction of Gases Aerosols4 Solids and the Crystalline State Crystalline Solids Polymorphism Solvates Amorphous Solids5 Phase Equilibria and the Phase Rule Phase Rule Systems Containing One Component Condensed System Two-Component Systems Containing Liquid Phases Two-Component Systems Containing Solid and Liquid Phases Eutectic Mixtures Rules Relating to Triangular Diagrams

                                                                                                  Topics that we have covered

                                                                                                  • States of Matter
                                                                                                  • States of Matter (2)
                                                                                                  • Objectives of the lecture
                                                                                                  • Comparison of Gases Liquids and Solids
                                                                                                  • Slide 5
                                                                                                  • Repulsive and Attractive Forces
                                                                                                  • Ideal Gas Equation
                                                                                                  • Gaseous state
                                                                                                  • Slide 9
                                                                                                  • Gaseous state (2)
                                                                                                  • Liquefaction of Gases
                                                                                                  • Slide 12
                                                                                                  • SOLIDS amp CRYSTALLINE STATE Pharmaceutical Drugs more than 80
                                                                                                  • Solids and the crystalline state
                                                                                                  • Classification of Solids
                                                                                                  • Slide 16
                                                                                                  • Slide 17
                                                                                                  • Crystal forms
                                                                                                  • Types of Crystals
                                                                                                  • Slide 20
                                                                                                  • Slide 21
                                                                                                  • Polymorphism
                                                                                                  • Slide 23
                                                                                                  • Slide 24
                                                                                                  • Slide 25
                                                                                                  • Slide 26
                                                                                                  • Cocrystal
                                                                                                  • Principle of polymorphism
                                                                                                  • Solvates
                                                                                                  • Polymorphism (2)
                                                                                                  • Amorphous Solid
                                                                                                  • Amorphous or crystalline amp therapeutic activity
                                                                                                  • Slide 33
                                                                                                  • Slide 34
                                                                                                  • Polymorphism and Industry Pharmaceutical
                                                                                                  • Celecoxib
                                                                                                  • Furosemide
                                                                                                  • Bioavailability
                                                                                                  • Slide 39
                                                                                                  • Slide 40
                                                                                                  • Bioequivalence
                                                                                                  • Slide 42
                                                                                                  • Carbamazepine
                                                                                                  • Slide 44
                                                                                                  • AIDS drug ritonavir
                                                                                                  • Slide 46
                                                                                                  • Slide 47
                                                                                                  • Phase Equilibria amp The Phase Rule
                                                                                                  • Phase diagram ndash Water
                                                                                                  • Phase Equilibria amp The Phase Rule Definitions
                                                                                                  • Phase Definition
                                                                                                  • Examples
                                                                                                  • Components
                                                                                                  • Examples
                                                                                                  • Slide 55
                                                                                                  • Degrees of freedom (or variance)
                                                                                                  • Examples (2)
                                                                                                  • Phase Equilibria amp The Phase Rule
                                                                                                  • The phase rule
                                                                                                  • Slide 60
                                                                                                  • Phase Equilibria amp The Phase Rule (2)
                                                                                                  • The number of phases in a system is denoted P
                                                                                                  • Slide 63
                                                                                                  • Slide 64
                                                                                                  • One-component systems
                                                                                                  • Slide 66
                                                                                                  • Slide 67
                                                                                                  • Slide 68
                                                                                                  • Slide 69
                                                                                                  • Slide 70
                                                                                                  • Two component system containing liquid phase
                                                                                                  • Slide 72
                                                                                                  • The Critical Solution Temperature CST
                                                                                                  • Systems Showing a Decrease in Miscibility with Rise in Temperat
                                                                                                  • Systems Showing Upper and Lower CSTs
                                                                                                  • Two component system containing solid and liquid phase (Eutecti
                                                                                                  • Slide 77
                                                                                                  • Eutectic mixture Pharmaceutical Application
                                                                                                  • Three component system
                                                                                                  • Slide 80
                                                                                                  • Topics that we have covered

                                                                                                    The degrees of freedom or variance of a system is defined as the minimum number of variables such as

                                                                                                    temperaturepressureconcentrationwhich must be fixed in order to define the system completely

                                                                                                    Degrees of freedom (or variance)

                                                                                                    F = C P + 2

                                                                                                    1 A gaseous mixture of CO2 and N2 Three variables pressure temperature and composition are required to define this system This is hence a trivariant system

                                                                                                    2 A system having only liquid water has two degrees of freedom or is bivariant Both temperature and pressure need to be mentioned in order to define the system

                                                                                                    3 If to the system containing liquid water pieces of ice are added and this system with 2 phases is allowed to come to equilibrium then it is an univariant system

                                                                                                    Only one variable either temperature or pressure need to be specified in order to define the systemIf the pressure on the system is maintained at 1 atm then the temperature of the system gets automatically fixed at 0oC the normal melting point of ice

                                                                                                    bull Examples

                                                                                                    Phase Equilibria amp The Phase Rule

                                                                                                    A phase diagram (Equilibrium Phase Diagram) summarizes the conditions at which a substance exists as a solid liquid or gas

                                                                                                    OR It is a ldquomaprdquo of the information about the control of phase structure of a particular material system

                                                                                                    The relationships between temperature and the compositions and the quantities of phases present at equilibrium are represented

                                                                                                    F = C P + 2The phase rule

                                                                                                    The phase rule JW Gibbs formulated the phase rule which is a general relation

                                                                                                    between the variance F the number of component C and the number of phases P at equilibrium for a system of any composition

                                                                                                    For a system in equilibrium

                                                                                                    F degree of freedom the least number of intensive variable that must be fixed (known) to describe the system completely

                                                                                                    Phase Rule relation to determine the least number of intensive variable that can be changed without changing the equilibrium state of the system or alternately

                                                                                                    The least number required to define the state of the system which is called degree of freedom F

                                                                                                    Intensive variable independent variable that do not depend on the volume or the size egTemp pressure

                                                                                                    Independent chemical species which comprise the system These could be Elements Ions Compounds

                                                                                                    Eg Au-Cu system Components rarr Au Cu Ice-water system Component rarr H2O

                                                                                                    Al2O3 ndash Cr2O3 system Components rarr Al2O3 Cr2O3

                                                                                                    Component the smallest number of constituent by which the composition of each phase in the system at equilibrium can be expressed in form of chemical formula or equation

                                                                                                    Phase Equilibria amp The Phase RuleComponents of a system

                                                                                                    The number of phases in a system is denoted P

                                                                                                    (a)A gas or a gaseous mixture is a single phase P=1

                                                                                                    (b) For a solid system an alloy of two metals is a two-phase system (P=2) if the metals are immiscible but a single-phase system (P=1) if they are miscible---a homogeneous mixture of the two substances---is uniform on a molecular scale

                                                                                                    (c) For a liquid system according to the solubility to decide whether a system consists of one phase or of two For example a solution of sodium chloride in water is a single phase A pair of liquids that are partially miscible or immiscible is a two-phase system(P=2)

                                                                                                    Oil in water

                                                                                                    Degrees of Freedom = What you can control What the system controls

                                                                                                    F = C + 2 P

                                                                                                    Can control the no of components added and P amp T

                                                                                                    System decided how many phases to produce given the

                                                                                                    conditions

                                                                                                    A way of understanding the Gibbs Phase RuleThe degrees of freedom can be thought of as the difference between what you (can) control and

                                                                                                    what the system controls

                                                                                                    F degree of freedom the least number of intensive variable that must be fixed (known) to describe the system completely

                                                                                                    Degree of freedom (or variance) F is the number of variables (T p andor composition) that can be changed independently without changing the phases of the system

                                                                                                    a) At the triple pointP = 3 (solid liquid and gas)

                                                                                                    C= 1 (water)P + F = C + 2

                                                                                                    F = 0 (no degree of freedom)

                                                                                                    b) liquid-solid curveP = 2

                                                                                                    2+F = 1 + 2F= 1

                                                                                                    One variable (T or P) can be changed

                                                                                                    c) LiquidP =1

                                                                                                    So F =2Two variables (T and P) can be varied independently

                                                                                                    and the system will remains a single phase

                                                                                                    One-component systemsPhase diagram of water

                                                                                                    P (

                                                                                                    atm

                                                                                                    )

                                                                                                    Critical point

                                                                                                    374

                                                                                                    1

                                                                                                    =100=0O--Triple point

                                                                                                    0006

                                                                                                    218

                                                                                                    Curve O -CSublimation

                                                                                                    Deposition

                                                                                                    Curve O-AVaporizationCondensation

                                                                                                    Curve O -BMelting

                                                                                                    Freezing

                                                                                                    F = C P + 2

                                                                                                    F = C P + 2

                                                                                                    Phase Diagram of Carbon Dioxide

                                                                                                    Condensed system System in which the vapor phase is ignored and only the solid andor liquid phases are considered

                                                                                                    Two component system For two component system F can be 3 (3D model is needed) eg T p

                                                                                                    and concentration usually we fix p = 1atm the vapor phase is neglected and F is reduced to 2

                                                                                                    For three component system the pressure and temperature are fixed

                                                                                                    Phenol water phase diagram

                                                                                                    eg for point d (24)

                                                                                                    Two component system containing liquid phase

                                                                                                    Tie Line bc line The line at which the system at equilibrium will separate into phases of constant composition termed lsquoconjugate phasesrsquo

                                                                                                    Lever Rule a way to calculate the proportions of each phase present on a phase diagram in a two phase field (at a given temperature and composition)

                                                                                                    eg for point d (24)

                                                                                                    For every 10 g of liquid system in equilibrium in point d

                                                                                                    75 g phase A25 g phase B

                                                                                                    ExampleMixed 24g phenol +76g water T 50degC

                                                                                                    equilibrium75 g phase A 25 g phase B

                                                                                                    11 phenol 63 phenol

                                                                                                    011 times75 g=825 g phenol

                                                                                                    063 times25 g=1575 g phenol

                                                                                                    water rich phasecontains water+ phenol(11)

                                                                                                    Phenol rich phasecontains Phenol (63)+ water

                                                                                                    The Critical Solution Temperature CST

                                                                                                    Is the maximum temperature at which the 2-phase region exists (or upper consolute temperature)

                                                                                                    In the case of the phenol-water system this is 668oC (point h)

                                                                                                    All combinations of phenol and water gt CST are completely miscible and yield 1-phase liquid systems

                                                                                                    Systems Showing a Decrease in Miscibility with Rise in Temperature

                                                                                                    A few mixtures exhibit a lower critical solution temperature (low CST) eg triethylamine plus water The miscibility with in temperature

                                                                                                    Systems Showing Upper and Lower CSTs

                                                                                                    The miscibility with temp

                                                                                                    a certain temperature miscibility starts to again with further in temperature

                                                                                                    Closed-phase diagram ie nicotine-water system

                                                                                                    A salol B thymol

                                                                                                    53

                                                                                                    Two component system containing solid and liquid phase (Eutectic Mixtures)

                                                                                                    A salol B thymol

                                                                                                    EMLAreg (lidocaine 25 and prilocaine 25) Cream

                                                                                                    EMLA Cream (lidocaine 25 and prilocaine 25) is an emulsion in which the oil phase is a eutectic mixture of lidocaine and prilocaine in a ratio of 11 by weight This eutectic mixture has a melting point below room temperature and therefore both local anesthetics exist as a liquid oil rather than as crystals

                                                                                                    Eutectic mixture Pharmaceutical Application

                                                                                                    Triangular Diagrams for three ndash component systems

                                                                                                    Three component system

                                                                                                    Birzeit University Physical Pharmacy PHAR 323 Dr Hani Shtaya

                                                                                                    1 Binding Forces Between Molecules2 Repulsive and Attractive Forces3 The Gaseous State The Ideal Gas Law Liquefaction of Gases Aerosols4 Solids and the Crystalline State Crystalline Solids Polymorphism Solvates Amorphous Solids5 Phase Equilibria and the Phase Rule Phase Rule Systems Containing One Component Condensed System Two-Component Systems Containing Liquid Phases Two-Component Systems Containing Solid and Liquid Phases Eutectic Mixtures Rules Relating to Triangular Diagrams

                                                                                                    Topics that we have covered

                                                                                                    • States of Matter
                                                                                                    • States of Matter (2)
                                                                                                    • Objectives of the lecture
                                                                                                    • Comparison of Gases Liquids and Solids
                                                                                                    • Slide 5
                                                                                                    • Repulsive and Attractive Forces
                                                                                                    • Ideal Gas Equation
                                                                                                    • Gaseous state
                                                                                                    • Slide 9
                                                                                                    • Gaseous state (2)
                                                                                                    • Liquefaction of Gases
                                                                                                    • Slide 12
                                                                                                    • SOLIDS amp CRYSTALLINE STATE Pharmaceutical Drugs more than 80
                                                                                                    • Solids and the crystalline state
                                                                                                    • Classification of Solids
                                                                                                    • Slide 16
                                                                                                    • Slide 17
                                                                                                    • Crystal forms
                                                                                                    • Types of Crystals
                                                                                                    • Slide 20
                                                                                                    • Slide 21
                                                                                                    • Polymorphism
                                                                                                    • Slide 23
                                                                                                    • Slide 24
                                                                                                    • Slide 25
                                                                                                    • Slide 26
                                                                                                    • Cocrystal
                                                                                                    • Principle of polymorphism
                                                                                                    • Solvates
                                                                                                    • Polymorphism (2)
                                                                                                    • Amorphous Solid
                                                                                                    • Amorphous or crystalline amp therapeutic activity
                                                                                                    • Slide 33
                                                                                                    • Slide 34
                                                                                                    • Polymorphism and Industry Pharmaceutical
                                                                                                    • Celecoxib
                                                                                                    • Furosemide
                                                                                                    • Bioavailability
                                                                                                    • Slide 39
                                                                                                    • Slide 40
                                                                                                    • Bioequivalence
                                                                                                    • Slide 42
                                                                                                    • Carbamazepine
                                                                                                    • Slide 44
                                                                                                    • AIDS drug ritonavir
                                                                                                    • Slide 46
                                                                                                    • Slide 47
                                                                                                    • Phase Equilibria amp The Phase Rule
                                                                                                    • Phase diagram ndash Water
                                                                                                    • Phase Equilibria amp The Phase Rule Definitions
                                                                                                    • Phase Definition
                                                                                                    • Examples
                                                                                                    • Components
                                                                                                    • Examples
                                                                                                    • Slide 55
                                                                                                    • Degrees of freedom (or variance)
                                                                                                    • Examples (2)
                                                                                                    • Phase Equilibria amp The Phase Rule
                                                                                                    • The phase rule
                                                                                                    • Slide 60
                                                                                                    • Phase Equilibria amp The Phase Rule (2)
                                                                                                    • The number of phases in a system is denoted P
                                                                                                    • Slide 63
                                                                                                    • Slide 64
                                                                                                    • One-component systems
                                                                                                    • Slide 66
                                                                                                    • Slide 67
                                                                                                    • Slide 68
                                                                                                    • Slide 69
                                                                                                    • Slide 70
                                                                                                    • Two component system containing liquid phase
                                                                                                    • Slide 72
                                                                                                    • The Critical Solution Temperature CST
                                                                                                    • Systems Showing a Decrease in Miscibility with Rise in Temperat
                                                                                                    • Systems Showing Upper and Lower CSTs
                                                                                                    • Two component system containing solid and liquid phase (Eutecti
                                                                                                    • Slide 77
                                                                                                    • Eutectic mixture Pharmaceutical Application
                                                                                                    • Three component system
                                                                                                    • Slide 80
                                                                                                    • Topics that we have covered

                                                                                                      1 A gaseous mixture of CO2 and N2 Three variables pressure temperature and composition are required to define this system This is hence a trivariant system

                                                                                                      2 A system having only liquid water has two degrees of freedom or is bivariant Both temperature and pressure need to be mentioned in order to define the system

                                                                                                      3 If to the system containing liquid water pieces of ice are added and this system with 2 phases is allowed to come to equilibrium then it is an univariant system

                                                                                                      Only one variable either temperature or pressure need to be specified in order to define the systemIf the pressure on the system is maintained at 1 atm then the temperature of the system gets automatically fixed at 0oC the normal melting point of ice

                                                                                                      bull Examples

                                                                                                      Phase Equilibria amp The Phase Rule

                                                                                                      A phase diagram (Equilibrium Phase Diagram) summarizes the conditions at which a substance exists as a solid liquid or gas

                                                                                                      OR It is a ldquomaprdquo of the information about the control of phase structure of a particular material system

                                                                                                      The relationships between temperature and the compositions and the quantities of phases present at equilibrium are represented

                                                                                                      F = C P + 2The phase rule

                                                                                                      The phase rule JW Gibbs formulated the phase rule which is a general relation

                                                                                                      between the variance F the number of component C and the number of phases P at equilibrium for a system of any composition

                                                                                                      For a system in equilibrium

                                                                                                      F degree of freedom the least number of intensive variable that must be fixed (known) to describe the system completely

                                                                                                      Phase Rule relation to determine the least number of intensive variable that can be changed without changing the equilibrium state of the system or alternately

                                                                                                      The least number required to define the state of the system which is called degree of freedom F

                                                                                                      Intensive variable independent variable that do not depend on the volume or the size egTemp pressure

                                                                                                      Independent chemical species which comprise the system These could be Elements Ions Compounds

                                                                                                      Eg Au-Cu system Components rarr Au Cu Ice-water system Component rarr H2O

                                                                                                      Al2O3 ndash Cr2O3 system Components rarr Al2O3 Cr2O3

                                                                                                      Component the smallest number of constituent by which the composition of each phase in the system at equilibrium can be expressed in form of chemical formula or equation

                                                                                                      Phase Equilibria amp The Phase RuleComponents of a system

                                                                                                      The number of phases in a system is denoted P

                                                                                                      (a)A gas or a gaseous mixture is a single phase P=1

                                                                                                      (b) For a solid system an alloy of two metals is a two-phase system (P=2) if the metals are immiscible but a single-phase system (P=1) if they are miscible---a homogeneous mixture of the two substances---is uniform on a molecular scale

                                                                                                      (c) For a liquid system according to the solubility to decide whether a system consists of one phase or of two For example a solution of sodium chloride in water is a single phase A pair of liquids that are partially miscible or immiscible is a two-phase system(P=2)

                                                                                                      Oil in water

                                                                                                      Degrees of Freedom = What you can control What the system controls

                                                                                                      F = C + 2 P

                                                                                                      Can control the no of components added and P amp T

                                                                                                      System decided how many phases to produce given the

                                                                                                      conditions

                                                                                                      A way of understanding the Gibbs Phase RuleThe degrees of freedom can be thought of as the difference between what you (can) control and

                                                                                                      what the system controls

                                                                                                      F degree of freedom the least number of intensive variable that must be fixed (known) to describe the system completely

                                                                                                      Degree of freedom (or variance) F is the number of variables (T p andor composition) that can be changed independently without changing the phases of the system

                                                                                                      a) At the triple pointP = 3 (solid liquid and gas)

                                                                                                      C= 1 (water)P + F = C + 2

                                                                                                      F = 0 (no degree of freedom)

                                                                                                      b) liquid-solid curveP = 2

                                                                                                      2+F = 1 + 2F= 1

                                                                                                      One variable (T or P) can be changed

                                                                                                      c) LiquidP =1

                                                                                                      So F =2Two variables (T and P) can be varied independently

                                                                                                      and the system will remains a single phase

                                                                                                      One-component systemsPhase diagram of water

                                                                                                      P (

                                                                                                      atm

                                                                                                      )

                                                                                                      Critical point

                                                                                                      374

                                                                                                      1

                                                                                                      =100=0O--Triple point

                                                                                                      0006

                                                                                                      218

                                                                                                      Curve O -CSublimation

                                                                                                      Deposition

                                                                                                      Curve O-AVaporizationCondensation

                                                                                                      Curve O -BMelting

                                                                                                      Freezing

                                                                                                      F = C P + 2

                                                                                                      F = C P + 2

                                                                                                      Phase Diagram of Carbon Dioxide

                                                                                                      Condensed system System in which the vapor phase is ignored and only the solid andor liquid phases are considered

                                                                                                      Two component system For two component system F can be 3 (3D model is needed) eg T p

                                                                                                      and concentration usually we fix p = 1atm the vapor phase is neglected and F is reduced to 2

                                                                                                      For three component system the pressure and temperature are fixed

                                                                                                      Phenol water phase diagram

                                                                                                      eg for point d (24)

                                                                                                      Two component system containing liquid phase

                                                                                                      Tie Line bc line The line at which the system at equilibrium will separate into phases of constant composition termed lsquoconjugate phasesrsquo

                                                                                                      Lever Rule a way to calculate the proportions of each phase present on a phase diagram in a two phase field (at a given temperature and composition)

                                                                                                      eg for point d (24)

                                                                                                      For every 10 g of liquid system in equilibrium in point d

                                                                                                      75 g phase A25 g phase B

                                                                                                      ExampleMixed 24g phenol +76g water T 50degC

                                                                                                      equilibrium75 g phase A 25 g phase B

                                                                                                      11 phenol 63 phenol

                                                                                                      011 times75 g=825 g phenol

                                                                                                      063 times25 g=1575 g phenol

                                                                                                      water rich phasecontains water+ phenol(11)

                                                                                                      Phenol rich phasecontains Phenol (63)+ water

                                                                                                      The Critical Solution Temperature CST

                                                                                                      Is the maximum temperature at which the 2-phase region exists (or upper consolute temperature)

                                                                                                      In the case of the phenol-water system this is 668oC (point h)

                                                                                                      All combinations of phenol and water gt CST are completely miscible and yield 1-phase liquid systems

                                                                                                      Systems Showing a Decrease in Miscibility with Rise in Temperature

                                                                                                      A few mixtures exhibit a lower critical solution temperature (low CST) eg triethylamine plus water The miscibility with in temperature

                                                                                                      Systems Showing Upper and Lower CSTs

                                                                                                      The miscibility with temp

                                                                                                      a certain temperature miscibility starts to again with further in temperature

                                                                                                      Closed-phase diagram ie nicotine-water system

                                                                                                      A salol B thymol

                                                                                                      53

                                                                                                      Two component system containing solid and liquid phase (Eutectic Mixtures)

                                                                                                      A salol B thymol

                                                                                                      EMLAreg (lidocaine 25 and prilocaine 25) Cream

                                                                                                      EMLA Cream (lidocaine 25 and prilocaine 25) is an emulsion in which the oil phase is a eutectic mixture of lidocaine and prilocaine in a ratio of 11 by weight This eutectic mixture has a melting point below room temperature and therefore both local anesthetics exist as a liquid oil rather than as crystals

                                                                                                      Eutectic mixture Pharmaceutical Application

                                                                                                      Triangular Diagrams for three ndash component systems

                                                                                                      Three component system

                                                                                                      Birzeit University Physical Pharmacy PHAR 323 Dr Hani Shtaya

                                                                                                      1 Binding Forces Between Molecules2 Repulsive and Attractive Forces3 The Gaseous State The Ideal Gas Law Liquefaction of Gases Aerosols4 Solids and the Crystalline State Crystalline Solids Polymorphism Solvates Amorphous Solids5 Phase Equilibria and the Phase Rule Phase Rule Systems Containing One Component Condensed System Two-Component Systems Containing Liquid Phases Two-Component Systems Containing Solid and Liquid Phases Eutectic Mixtures Rules Relating to Triangular Diagrams

                                                                                                      Topics that we have covered

                                                                                                      • States of Matter
                                                                                                      • States of Matter (2)
                                                                                                      • Objectives of the lecture
                                                                                                      • Comparison of Gases Liquids and Solids
                                                                                                      • Slide 5
                                                                                                      • Repulsive and Attractive Forces
                                                                                                      • Ideal Gas Equation
                                                                                                      • Gaseous state
                                                                                                      • Slide 9
                                                                                                      • Gaseous state (2)
                                                                                                      • Liquefaction of Gases
                                                                                                      • Slide 12
                                                                                                      • SOLIDS amp CRYSTALLINE STATE Pharmaceutical Drugs more than 80
                                                                                                      • Solids and the crystalline state
                                                                                                      • Classification of Solids
                                                                                                      • Slide 16
                                                                                                      • Slide 17
                                                                                                      • Crystal forms
                                                                                                      • Types of Crystals
                                                                                                      • Slide 20
                                                                                                      • Slide 21
                                                                                                      • Polymorphism
                                                                                                      • Slide 23
                                                                                                      • Slide 24
                                                                                                      • Slide 25
                                                                                                      • Slide 26
                                                                                                      • Cocrystal
                                                                                                      • Principle of polymorphism
                                                                                                      • Solvates
                                                                                                      • Polymorphism (2)
                                                                                                      • Amorphous Solid
                                                                                                      • Amorphous or crystalline amp therapeutic activity
                                                                                                      • Slide 33
                                                                                                      • Slide 34
                                                                                                      • Polymorphism and Industry Pharmaceutical
                                                                                                      • Celecoxib
                                                                                                      • Furosemide
                                                                                                      • Bioavailability
                                                                                                      • Slide 39
                                                                                                      • Slide 40
                                                                                                      • Bioequivalence
                                                                                                      • Slide 42
                                                                                                      • Carbamazepine
                                                                                                      • Slide 44
                                                                                                      • AIDS drug ritonavir
                                                                                                      • Slide 46
                                                                                                      • Slide 47
                                                                                                      • Phase Equilibria amp The Phase Rule
                                                                                                      • Phase diagram ndash Water
                                                                                                      • Phase Equilibria amp The Phase Rule Definitions
                                                                                                      • Phase Definition
                                                                                                      • Examples
                                                                                                      • Components
                                                                                                      • Examples
                                                                                                      • Slide 55
                                                                                                      • Degrees of freedom (or variance)
                                                                                                      • Examples (2)
                                                                                                      • Phase Equilibria amp The Phase Rule
                                                                                                      • The phase rule
                                                                                                      • Slide 60
                                                                                                      • Phase Equilibria amp The Phase Rule (2)
                                                                                                      • The number of phases in a system is denoted P
                                                                                                      • Slide 63
                                                                                                      • Slide 64
                                                                                                      • One-component systems
                                                                                                      • Slide 66
                                                                                                      • Slide 67
                                                                                                      • Slide 68
                                                                                                      • Slide 69
                                                                                                      • Slide 70
                                                                                                      • Two component system containing liquid phase
                                                                                                      • Slide 72
                                                                                                      • The Critical Solution Temperature CST
                                                                                                      • Systems Showing a Decrease in Miscibility with Rise in Temperat
                                                                                                      • Systems Showing Upper and Lower CSTs
                                                                                                      • Two component system containing solid and liquid phase (Eutecti
                                                                                                      • Slide 77
                                                                                                      • Eutectic mixture Pharmaceutical Application
                                                                                                      • Three component system
                                                                                                      • Slide 80
                                                                                                      • Topics that we have covered

                                                                                                        Phase Equilibria amp The Phase Rule

                                                                                                        A phase diagram (Equilibrium Phase Diagram) summarizes the conditions at which a substance exists as a solid liquid or gas

                                                                                                        OR It is a ldquomaprdquo of the information about the control of phase structure of a particular material system

                                                                                                        The relationships between temperature and the compositions and the quantities of phases present at equilibrium are represented

                                                                                                        F = C P + 2The phase rule

                                                                                                        The phase rule JW Gibbs formulated the phase rule which is a general relation

                                                                                                        between the variance F the number of component C and the number of phases P at equilibrium for a system of any composition

                                                                                                        For a system in equilibrium

                                                                                                        F degree of freedom the least number of intensive variable that must be fixed (known) to describe the system completely

                                                                                                        Phase Rule relation to determine the least number of intensive variable that can be changed without changing the equilibrium state of the system or alternately

                                                                                                        The least number required to define the state of the system which is called degree of freedom F

                                                                                                        Intensive variable independent variable that do not depend on the volume or the size egTemp pressure

                                                                                                        Independent chemical species which comprise the system These could be Elements Ions Compounds

                                                                                                        Eg Au-Cu system Components rarr Au Cu Ice-water system Component rarr H2O

                                                                                                        Al2O3 ndash Cr2O3 system Components rarr Al2O3 Cr2O3

                                                                                                        Component the smallest number of constituent by which the composition of each phase in the system at equilibrium can be expressed in form of chemical formula or equation

                                                                                                        Phase Equilibria amp The Phase RuleComponents of a system

                                                                                                        The number of phases in a system is denoted P

                                                                                                        (a)A gas or a gaseous mixture is a single phase P=1

                                                                                                        (b) For a solid system an alloy of two metals is a two-phase system (P=2) if the metals are immiscible but a single-phase system (P=1) if they are miscible---a homogeneous mixture of the two substances---is uniform on a molecular scale

                                                                                                        (c) For a liquid system according to the solubility to decide whether a system consists of one phase or of two For example a solution of sodium chloride in water is a single phase A pair of liquids that are partially miscible or immiscible is a two-phase system(P=2)

                                                                                                        Oil in water

                                                                                                        Degrees of Freedom = What you can control What the system controls

                                                                                                        F = C + 2 P

                                                                                                        Can control the no of components added and P amp T

                                                                                                        System decided how many phases to produce given the

                                                                                                        conditions

                                                                                                        A way of understanding the Gibbs Phase RuleThe degrees of freedom can be thought of as the difference between what you (can) control and

                                                                                                        what the system controls

                                                                                                        F degree of freedom the least number of intensive variable that must be fixed (known) to describe the system completely

                                                                                                        Degree of freedom (or variance) F is the number of variables (T p andor composition) that can be changed independently without changing the phases of the system

                                                                                                        a) At the triple pointP = 3 (solid liquid and gas)

                                                                                                        C= 1 (water)P + F = C + 2

                                                                                                        F = 0 (no degree of freedom)

                                                                                                        b) liquid-solid curveP = 2

                                                                                                        2+F = 1 + 2F= 1

                                                                                                        One variable (T or P) can be changed

                                                                                                        c) LiquidP =1

                                                                                                        So F =2Two variables (T and P) can be varied independently

                                                                                                        and the system will remains a single phase

                                                                                                        One-component systemsPhase diagram of water

                                                                                                        P (

                                                                                                        atm

                                                                                                        )

                                                                                                        Critical point

                                                                                                        374

                                                                                                        1

                                                                                                        =100=0O--Triple point

                                                                                                        0006

                                                                                                        218

                                                                                                        Curve O -CSublimation

                                                                                                        Deposition

                                                                                                        Curve O-AVaporizationCondensation

                                                                                                        Curve O -BMelting

                                                                                                        Freezing

                                                                                                        F = C P + 2

                                                                                                        F = C P + 2

                                                                                                        Phase Diagram of Carbon Dioxide

                                                                                                        Condensed system System in which the vapor phase is ignored and only the solid andor liquid phases are considered

                                                                                                        Two component system For two component system F can be 3 (3D model is needed) eg T p

                                                                                                        and concentration usually we fix p = 1atm the vapor phase is neglected and F is reduced to 2

                                                                                                        For three component system the pressure and temperature are fixed

                                                                                                        Phenol water phase diagram

                                                                                                        eg for point d (24)

                                                                                                        Two component system containing liquid phase

                                                                                                        Tie Line bc line The line at which the system at equilibrium will separate into phases of constant composition termed lsquoconjugate phasesrsquo

                                                                                                        Lever Rule a way to calculate the proportions of each phase present on a phase diagram in a two phase field (at a given temperature and composition)

                                                                                                        eg for point d (24)

                                                                                                        For every 10 g of liquid system in equilibrium in point d

                                                                                                        75 g phase A25 g phase B

                                                                                                        ExampleMixed 24g phenol +76g water T 50degC

                                                                                                        equilibrium75 g phase A 25 g phase B

                                                                                                        11 phenol 63 phenol

                                                                                                        011 times75 g=825 g phenol

                                                                                                        063 times25 g=1575 g phenol

                                                                                                        water rich phasecontains water+ phenol(11)

                                                                                                        Phenol rich phasecontains Phenol (63)+ water

                                                                                                        The Critical Solution Temperature CST

                                                                                                        Is the maximum temperature at which the 2-phase region exists (or upper consolute temperature)

                                                                                                        In the case of the phenol-water system this is 668oC (point h)

                                                                                                        All combinations of phenol and water gt CST are completely miscible and yield 1-phase liquid systems

                                                                                                        Systems Showing a Decrease in Miscibility with Rise in Temperature

                                                                                                        A few mixtures exhibit a lower critical solution temperature (low CST) eg triethylamine plus water The miscibility with in temperature

                                                                                                        Systems Showing Upper and Lower CSTs

                                                                                                        The miscibility with temp

                                                                                                        a certain temperature miscibility starts to again with further in temperature

                                                                                                        Closed-phase diagram ie nicotine-water system

                                                                                                        A salol B thymol

                                                                                                        53

                                                                                                        Two component system containing solid and liquid phase (Eutectic Mixtures)

                                                                                                        A salol B thymol

                                                                                                        EMLAreg (lidocaine 25 and prilocaine 25) Cream

                                                                                                        EMLA Cream (lidocaine 25 and prilocaine 25) is an emulsion in which the oil phase is a eutectic mixture of lidocaine and prilocaine in a ratio of 11 by weight This eutectic mixture has a melting point below room temperature and therefore both local anesthetics exist as a liquid oil rather than as crystals

                                                                                                        Eutectic mixture Pharmaceutical Application

                                                                                                        Triangular Diagrams for three ndash component systems

                                                                                                        Three component system

                                                                                                        Birzeit University Physical Pharmacy PHAR 323 Dr Hani Shtaya

                                                                                                        1 Binding Forces Between Molecules2 Repulsive and Attractive Forces3 The Gaseous State The Ideal Gas Law Liquefaction of Gases Aerosols4 Solids and the Crystalline State Crystalline Solids Polymorphism Solvates Amorphous Solids5 Phase Equilibria and the Phase Rule Phase Rule Systems Containing One Component Condensed System Two-Component Systems Containing Liquid Phases Two-Component Systems Containing Solid and Liquid Phases Eutectic Mixtures Rules Relating to Triangular Diagrams

                                                                                                        Topics that we have covered

                                                                                                        • States of Matter
                                                                                                        • States of Matter (2)
                                                                                                        • Objectives of the lecture
                                                                                                        • Comparison of Gases Liquids and Solids
                                                                                                        • Slide 5
                                                                                                        • Repulsive and Attractive Forces
                                                                                                        • Ideal Gas Equation
                                                                                                        • Gaseous state
                                                                                                        • Slide 9
                                                                                                        • Gaseous state (2)
                                                                                                        • Liquefaction of Gases
                                                                                                        • Slide 12
                                                                                                        • SOLIDS amp CRYSTALLINE STATE Pharmaceutical Drugs more than 80
                                                                                                        • Solids and the crystalline state
                                                                                                        • Classification of Solids
                                                                                                        • Slide 16
                                                                                                        • Slide 17
                                                                                                        • Crystal forms
                                                                                                        • Types of Crystals
                                                                                                        • Slide 20
                                                                                                        • Slide 21
                                                                                                        • Polymorphism
                                                                                                        • Slide 23
                                                                                                        • Slide 24
                                                                                                        • Slide 25
                                                                                                        • Slide 26
                                                                                                        • Cocrystal
                                                                                                        • Principle of polymorphism
                                                                                                        • Solvates
                                                                                                        • Polymorphism (2)
                                                                                                        • Amorphous Solid
                                                                                                        • Amorphous or crystalline amp therapeutic activity
                                                                                                        • Slide 33
                                                                                                        • Slide 34
                                                                                                        • Polymorphism and Industry Pharmaceutical
                                                                                                        • Celecoxib
                                                                                                        • Furosemide
                                                                                                        • Bioavailability
                                                                                                        • Slide 39
                                                                                                        • Slide 40
                                                                                                        • Bioequivalence
                                                                                                        • Slide 42
                                                                                                        • Carbamazepine
                                                                                                        • Slide 44
                                                                                                        • AIDS drug ritonavir
                                                                                                        • Slide 46
                                                                                                        • Slide 47
                                                                                                        • Phase Equilibria amp The Phase Rule
                                                                                                        • Phase diagram ndash Water
                                                                                                        • Phase Equilibria amp The Phase Rule Definitions
                                                                                                        • Phase Definition
                                                                                                        • Examples
                                                                                                        • Components
                                                                                                        • Examples
                                                                                                        • Slide 55
                                                                                                        • Degrees of freedom (or variance)
                                                                                                        • Examples (2)
                                                                                                        • Phase Equilibria amp The Phase Rule
                                                                                                        • The phase rule
                                                                                                        • Slide 60
                                                                                                        • Phase Equilibria amp The Phase Rule (2)
                                                                                                        • The number of phases in a system is denoted P
                                                                                                        • Slide 63
                                                                                                        • Slide 64
                                                                                                        • One-component systems
                                                                                                        • Slide 66
                                                                                                        • Slide 67
                                                                                                        • Slide 68
                                                                                                        • Slide 69
                                                                                                        • Slide 70
                                                                                                        • Two component system containing liquid phase
                                                                                                        • Slide 72
                                                                                                        • The Critical Solution Temperature CST
                                                                                                        • Systems Showing a Decrease in Miscibility with Rise in Temperat
                                                                                                        • Systems Showing Upper and Lower CSTs
                                                                                                        • Two component system containing solid and liquid phase (Eutecti
                                                                                                        • Slide 77
                                                                                                        • Eutectic mixture Pharmaceutical Application
                                                                                                        • Three component system
                                                                                                        • Slide 80
                                                                                                        • Topics that we have covered

                                                                                                          F = C P + 2The phase rule

                                                                                                          The phase rule JW Gibbs formulated the phase rule which is a general relation

                                                                                                          between the variance F the number of component C and the number of phases P at equilibrium for a system of any composition

                                                                                                          For a system in equilibrium

                                                                                                          F degree of freedom the least number of intensive variable that must be fixed (known) to describe the system completely

                                                                                                          Phase Rule relation to determine the least number of intensive variable that can be changed without changing the equilibrium state of the system or alternately

                                                                                                          The least number required to define the state of the system which is called degree of freedom F

                                                                                                          Intensive variable independent variable that do not depend on the volume or the size egTemp pressure

                                                                                                          Independent chemical species which comprise the system These could be Elements Ions Compounds

                                                                                                          Eg Au-Cu system Components rarr Au Cu Ice-water system Component rarr H2O

                                                                                                          Al2O3 ndash Cr2O3 system Components rarr Al2O3 Cr2O3

                                                                                                          Component the smallest number of constituent by which the composition of each phase in the system at equilibrium can be expressed in form of chemical formula or equation

                                                                                                          Phase Equilibria amp The Phase RuleComponents of a system

                                                                                                          The number of phases in a system is denoted P

                                                                                                          (a)A gas or a gaseous mixture is a single phase P=1

                                                                                                          (b) For a solid system an alloy of two metals is a two-phase system (P=2) if the metals are immiscible but a single-phase system (P=1) if they are miscible---a homogeneous mixture of the two substances---is uniform on a molecular scale

                                                                                                          (c) For a liquid system according to the solubility to decide whether a system consists of one phase or of two For example a solution of sodium chloride in water is a single phase A pair of liquids that are partially miscible or immiscible is a two-phase system(P=2)

                                                                                                          Oil in water

                                                                                                          Degrees of Freedom = What you can control What the system controls

                                                                                                          F = C + 2 P

                                                                                                          Can control the no of components added and P amp T

                                                                                                          System decided how many phases to produce given the

                                                                                                          conditions

                                                                                                          A way of understanding the Gibbs Phase RuleThe degrees of freedom can be thought of as the difference between what you (can) control and

                                                                                                          what the system controls

                                                                                                          F degree of freedom the least number of intensive variable that must be fixed (known) to describe the system completely

                                                                                                          Degree of freedom (or variance) F is the number of variables (T p andor composition) that can be changed independently without changing the phases of the system

                                                                                                          a) At the triple pointP = 3 (solid liquid and gas)

                                                                                                          C= 1 (water)P + F = C + 2

                                                                                                          F = 0 (no degree of freedom)

                                                                                                          b) liquid-solid curveP = 2

                                                                                                          2+F = 1 + 2F= 1

                                                                                                          One variable (T or P) can be changed

                                                                                                          c) LiquidP =1

                                                                                                          So F =2Two variables (T and P) can be varied independently

                                                                                                          and the system will remains a single phase

                                                                                                          One-component systemsPhase diagram of water

                                                                                                          P (

                                                                                                          atm

                                                                                                          )

                                                                                                          Critical point

                                                                                                          374

                                                                                                          1

                                                                                                          =100=0O--Triple point

                                                                                                          0006

                                                                                                          218

                                                                                                          Curve O -CSublimation

                                                                                                          Deposition

                                                                                                          Curve O-AVaporizationCondensation

                                                                                                          Curve O -BMelting

                                                                                                          Freezing

                                                                                                          F = C P + 2

                                                                                                          F = C P + 2

                                                                                                          Phase Diagram of Carbon Dioxide

                                                                                                          Condensed system System in which the vapor phase is ignored and only the solid andor liquid phases are considered

                                                                                                          Two component system For two component system F can be 3 (3D model is needed) eg T p

                                                                                                          and concentration usually we fix p = 1atm the vapor phase is neglected and F is reduced to 2

                                                                                                          For three component system the pressure and temperature are fixed

                                                                                                          Phenol water phase diagram

                                                                                                          eg for point d (24)

                                                                                                          Two component system containing liquid phase

                                                                                                          Tie Line bc line The line at which the system at equilibrium will separate into phases of constant composition termed lsquoconjugate phasesrsquo

                                                                                                          Lever Rule a way to calculate the proportions of each phase present on a phase diagram in a two phase field (at a given temperature and composition)

                                                                                                          eg for point d (24)

                                                                                                          For every 10 g of liquid system in equilibrium in point d

                                                                                                          75 g phase A25 g phase B

                                                                                                          ExampleMixed 24g phenol +76g water T 50degC

                                                                                                          equilibrium75 g phase A 25 g phase B

                                                                                                          11 phenol 63 phenol

                                                                                                          011 times75 g=825 g phenol

                                                                                                          063 times25 g=1575 g phenol

                                                                                                          water rich phasecontains water+ phenol(11)

                                                                                                          Phenol rich phasecontains Phenol (63)+ water

                                                                                                          The Critical Solution Temperature CST

                                                                                                          Is the maximum temperature at which the 2-phase region exists (or upper consolute temperature)

                                                                                                          In the case of the phenol-water system this is 668oC (point h)

                                                                                                          All combinations of phenol and water gt CST are completely miscible and yield 1-phase liquid systems

                                                                                                          Systems Showing a Decrease in Miscibility with Rise in Temperature

                                                                                                          A few mixtures exhibit a lower critical solution temperature (low CST) eg triethylamine plus water The miscibility with in temperature

                                                                                                          Systems Showing Upper and Lower CSTs

                                                                                                          The miscibility with temp

                                                                                                          a certain temperature miscibility starts to again with further in temperature

                                                                                                          Closed-phase diagram ie nicotine-water system

                                                                                                          A salol B thymol

                                                                                                          53

                                                                                                          Two component system containing solid and liquid phase (Eutectic Mixtures)

                                                                                                          A salol B thymol

                                                                                                          EMLAreg (lidocaine 25 and prilocaine 25) Cream

                                                                                                          EMLA Cream (lidocaine 25 and prilocaine 25) is an emulsion in which the oil phase is a eutectic mixture of lidocaine and prilocaine in a ratio of 11 by weight This eutectic mixture has a melting point below room temperature and therefore both local anesthetics exist as a liquid oil rather than as crystals

                                                                                                          Eutectic mixture Pharmaceutical Application

                                                                                                          Triangular Diagrams for three ndash component systems

                                                                                                          Three component system

                                                                                                          Birzeit University Physical Pharmacy PHAR 323 Dr Hani Shtaya

                                                                                                          1 Binding Forces Between Molecules2 Repulsive and Attractive Forces3 The Gaseous State The Ideal Gas Law Liquefaction of Gases Aerosols4 Solids and the Crystalline State Crystalline Solids Polymorphism Solvates Amorphous Solids5 Phase Equilibria and the Phase Rule Phase Rule Systems Containing One Component Condensed System Two-Component Systems Containing Liquid Phases Two-Component Systems Containing Solid and Liquid Phases Eutectic Mixtures Rules Relating to Triangular Diagrams

                                                                                                          Topics that we have covered

                                                                                                          • States of Matter
                                                                                                          • States of Matter (2)
                                                                                                          • Objectives of the lecture
                                                                                                          • Comparison of Gases Liquids and Solids
                                                                                                          • Slide 5
                                                                                                          • Repulsive and Attractive Forces
                                                                                                          • Ideal Gas Equation
                                                                                                          • Gaseous state
                                                                                                          • Slide 9
                                                                                                          • Gaseous state (2)
                                                                                                          • Liquefaction of Gases
                                                                                                          • Slide 12
                                                                                                          • SOLIDS amp CRYSTALLINE STATE Pharmaceutical Drugs more than 80
                                                                                                          • Solids and the crystalline state
                                                                                                          • Classification of Solids
                                                                                                          • Slide 16
                                                                                                          • Slide 17
                                                                                                          • Crystal forms
                                                                                                          • Types of Crystals
                                                                                                          • Slide 20
                                                                                                          • Slide 21
                                                                                                          • Polymorphism
                                                                                                          • Slide 23
                                                                                                          • Slide 24
                                                                                                          • Slide 25
                                                                                                          • Slide 26
                                                                                                          • Cocrystal
                                                                                                          • Principle of polymorphism
                                                                                                          • Solvates
                                                                                                          • Polymorphism (2)
                                                                                                          • Amorphous Solid
                                                                                                          • Amorphous or crystalline amp therapeutic activity
                                                                                                          • Slide 33
                                                                                                          • Slide 34
                                                                                                          • Polymorphism and Industry Pharmaceutical
                                                                                                          • Celecoxib
                                                                                                          • Furosemide
                                                                                                          • Bioavailability
                                                                                                          • Slide 39
                                                                                                          • Slide 40
                                                                                                          • Bioequivalence
                                                                                                          • Slide 42
                                                                                                          • Carbamazepine
                                                                                                          • Slide 44
                                                                                                          • AIDS drug ritonavir
                                                                                                          • Slide 46
                                                                                                          • Slide 47
                                                                                                          • Phase Equilibria amp The Phase Rule
                                                                                                          • Phase diagram ndash Water
                                                                                                          • Phase Equilibria amp The Phase Rule Definitions
                                                                                                          • Phase Definition
                                                                                                          • Examples
                                                                                                          • Components
                                                                                                          • Examples
                                                                                                          • Slide 55
                                                                                                          • Degrees of freedom (or variance)
                                                                                                          • Examples (2)
                                                                                                          • Phase Equilibria amp The Phase Rule
                                                                                                          • The phase rule
                                                                                                          • Slide 60
                                                                                                          • Phase Equilibria amp The Phase Rule (2)
                                                                                                          • The number of phases in a system is denoted P
                                                                                                          • Slide 63
                                                                                                          • Slide 64
                                                                                                          • One-component systems
                                                                                                          • Slide 66
                                                                                                          • Slide 67
                                                                                                          • Slide 68
                                                                                                          • Slide 69
                                                                                                          • Slide 70
                                                                                                          • Two component system containing liquid phase
                                                                                                          • Slide 72
                                                                                                          • The Critical Solution Temperature CST
                                                                                                          • Systems Showing a Decrease in Miscibility with Rise in Temperat
                                                                                                          • Systems Showing Upper and Lower CSTs
                                                                                                          • Two component system containing solid and liquid phase (Eutecti
                                                                                                          • Slide 77
                                                                                                          • Eutectic mixture Pharmaceutical Application
                                                                                                          • Three component system
                                                                                                          • Slide 80
                                                                                                          • Topics that we have covered

                                                                                                            Phase Rule relation to determine the least number of intensive variable that can be changed without changing the equilibrium state of the system or alternately

                                                                                                            The least number required to define the state of the system which is called degree of freedom F

                                                                                                            Intensive variable independent variable that do not depend on the volume or the size egTemp pressure

                                                                                                            Independent chemical species which comprise the system These could be Elements Ions Compounds

                                                                                                            Eg Au-Cu system Components rarr Au Cu Ice-water system Component rarr H2O

                                                                                                            Al2O3 ndash Cr2O3 system Components rarr Al2O3 Cr2O3

                                                                                                            Component the smallest number of constituent by which the composition of each phase in the system at equilibrium can be expressed in form of chemical formula or equation

                                                                                                            Phase Equilibria amp The Phase RuleComponents of a system

                                                                                                            The number of phases in a system is denoted P

                                                                                                            (a)A gas or a gaseous mixture is a single phase P=1

                                                                                                            (b) For a solid system an alloy of two metals is a two-phase system (P=2) if the metals are immiscible but a single-phase system (P=1) if they are miscible---a homogeneous mixture of the two substances---is uniform on a molecular scale

                                                                                                            (c) For a liquid system according to the solubility to decide whether a system consists of one phase or of two For example a solution of sodium chloride in water is a single phase A pair of liquids that are partially miscible or immiscible is a two-phase system(P=2)

                                                                                                            Oil in water

                                                                                                            Degrees of Freedom = What you can control What the system controls

                                                                                                            F = C + 2 P

                                                                                                            Can control the no of components added and P amp T

                                                                                                            System decided how many phases to produce given the

                                                                                                            conditions

                                                                                                            A way of understanding the Gibbs Phase RuleThe degrees of freedom can be thought of as the difference between what you (can) control and

                                                                                                            what the system controls

                                                                                                            F degree of freedom the least number of intensive variable that must be fixed (known) to describe the system completely

                                                                                                            Degree of freedom (or variance) F is the number of variables (T p andor composition) that can be changed independently without changing the phases of the system

                                                                                                            a) At the triple pointP = 3 (solid liquid and gas)

                                                                                                            C= 1 (water)P + F = C + 2

                                                                                                            F = 0 (no degree of freedom)

                                                                                                            b) liquid-solid curveP = 2

                                                                                                            2+F = 1 + 2F= 1

                                                                                                            One variable (T or P) can be changed

                                                                                                            c) LiquidP =1

                                                                                                            So F =2Two variables (T and P) can be varied independently

                                                                                                            and the system will remains a single phase

                                                                                                            One-component systemsPhase diagram of water

                                                                                                            P (

                                                                                                            atm

                                                                                                            )

                                                                                                            Critical point

                                                                                                            374

                                                                                                            1

                                                                                                            =100=0O--Triple point

                                                                                                            0006

                                                                                                            218

                                                                                                            Curve O -CSublimation

                                                                                                            Deposition

                                                                                                            Curve O-AVaporizationCondensation

                                                                                                            Curve O -BMelting

                                                                                                            Freezing

                                                                                                            F = C P + 2

                                                                                                            F = C P + 2

                                                                                                            Phase Diagram of Carbon Dioxide

                                                                                                            Condensed system System in which the vapor phase is ignored and only the solid andor liquid phases are considered

                                                                                                            Two component system For two component system F can be 3 (3D model is needed) eg T p

                                                                                                            and concentration usually we fix p = 1atm the vapor phase is neglected and F is reduced to 2

                                                                                                            For three component system the pressure and temperature are fixed

                                                                                                            Phenol water phase diagram

                                                                                                            eg for point d (24)

                                                                                                            Two component system containing liquid phase

                                                                                                            Tie Line bc line The line at which the system at equilibrium will separate into phases of constant composition termed lsquoconjugate phasesrsquo

                                                                                                            Lever Rule a way to calculate the proportions of each phase present on a phase diagram in a two phase field (at a given temperature and composition)

                                                                                                            eg for point d (24)

                                                                                                            For every 10 g of liquid system in equilibrium in point d

                                                                                                            75 g phase A25 g phase B

                                                                                                            ExampleMixed 24g phenol +76g water T 50degC

                                                                                                            equilibrium75 g phase A 25 g phase B

                                                                                                            11 phenol 63 phenol

                                                                                                            011 times75 g=825 g phenol

                                                                                                            063 times25 g=1575 g phenol

                                                                                                            water rich phasecontains water+ phenol(11)

                                                                                                            Phenol rich phasecontains Phenol (63)+ water

                                                                                                            The Critical Solution Temperature CST

                                                                                                            Is the maximum temperature at which the 2-phase region exists (or upper consolute temperature)

                                                                                                            In the case of the phenol-water system this is 668oC (point h)

                                                                                                            All combinations of phenol and water gt CST are completely miscible and yield 1-phase liquid systems

                                                                                                            Systems Showing a Decrease in Miscibility with Rise in Temperature

                                                                                                            A few mixtures exhibit a lower critical solution temperature (low CST) eg triethylamine plus water The miscibility with in temperature

                                                                                                            Systems Showing Upper and Lower CSTs

                                                                                                            The miscibility with temp

                                                                                                            a certain temperature miscibility starts to again with further in temperature

                                                                                                            Closed-phase diagram ie nicotine-water system

                                                                                                            A salol B thymol

                                                                                                            53

                                                                                                            Two component system containing solid and liquid phase (Eutectic Mixtures)

                                                                                                            A salol B thymol

                                                                                                            EMLAreg (lidocaine 25 and prilocaine 25) Cream

                                                                                                            EMLA Cream (lidocaine 25 and prilocaine 25) is an emulsion in which the oil phase is a eutectic mixture of lidocaine and prilocaine in a ratio of 11 by weight This eutectic mixture has a melting point below room temperature and therefore both local anesthetics exist as a liquid oil rather than as crystals

                                                                                                            Eutectic mixture Pharmaceutical Application

                                                                                                            Triangular Diagrams for three ndash component systems

                                                                                                            Three component system

                                                                                                            Birzeit University Physical Pharmacy PHAR 323 Dr Hani Shtaya

                                                                                                            1 Binding Forces Between Molecules2 Repulsive and Attractive Forces3 The Gaseous State The Ideal Gas Law Liquefaction of Gases Aerosols4 Solids and the Crystalline State Crystalline Solids Polymorphism Solvates Amorphous Solids5 Phase Equilibria and the Phase Rule Phase Rule Systems Containing One Component Condensed System Two-Component Systems Containing Liquid Phases Two-Component Systems Containing Solid and Liquid Phases Eutectic Mixtures Rules Relating to Triangular Diagrams

                                                                                                            Topics that we have covered

                                                                                                            • States of Matter
                                                                                                            • States of Matter (2)
                                                                                                            • Objectives of the lecture
                                                                                                            • Comparison of Gases Liquids and Solids
                                                                                                            • Slide 5
                                                                                                            • Repulsive and Attractive Forces
                                                                                                            • Ideal Gas Equation
                                                                                                            • Gaseous state
                                                                                                            • Slide 9
                                                                                                            • Gaseous state (2)
                                                                                                            • Liquefaction of Gases
                                                                                                            • Slide 12
                                                                                                            • SOLIDS amp CRYSTALLINE STATE Pharmaceutical Drugs more than 80
                                                                                                            • Solids and the crystalline state
                                                                                                            • Classification of Solids
                                                                                                            • Slide 16
                                                                                                            • Slide 17
                                                                                                            • Crystal forms
                                                                                                            • Types of Crystals
                                                                                                            • Slide 20
                                                                                                            • Slide 21
                                                                                                            • Polymorphism
                                                                                                            • Slide 23
                                                                                                            • Slide 24
                                                                                                            • Slide 25
                                                                                                            • Slide 26
                                                                                                            • Cocrystal
                                                                                                            • Principle of polymorphism
                                                                                                            • Solvates
                                                                                                            • Polymorphism (2)
                                                                                                            • Amorphous Solid
                                                                                                            • Amorphous or crystalline amp therapeutic activity
                                                                                                            • Slide 33
                                                                                                            • Slide 34
                                                                                                            • Polymorphism and Industry Pharmaceutical
                                                                                                            • Celecoxib
                                                                                                            • Furosemide
                                                                                                            • Bioavailability
                                                                                                            • Slide 39
                                                                                                            • Slide 40
                                                                                                            • Bioequivalence
                                                                                                            • Slide 42
                                                                                                            • Carbamazepine
                                                                                                            • Slide 44
                                                                                                            • AIDS drug ritonavir
                                                                                                            • Slide 46
                                                                                                            • Slide 47
                                                                                                            • Phase Equilibria amp The Phase Rule
                                                                                                            • Phase diagram ndash Water
                                                                                                            • Phase Equilibria amp The Phase Rule Definitions
                                                                                                            • Phase Definition
                                                                                                            • Examples
                                                                                                            • Components
                                                                                                            • Examples
                                                                                                            • Slide 55
                                                                                                            • Degrees of freedom (or variance)
                                                                                                            • Examples (2)
                                                                                                            • Phase Equilibria amp The Phase Rule
                                                                                                            • The phase rule
                                                                                                            • Slide 60
                                                                                                            • Phase Equilibria amp The Phase Rule (2)
                                                                                                            • The number of phases in a system is denoted P
                                                                                                            • Slide 63
                                                                                                            • Slide 64
                                                                                                            • One-component systems
                                                                                                            • Slide 66
                                                                                                            • Slide 67
                                                                                                            • Slide 68
                                                                                                            • Slide 69
                                                                                                            • Slide 70
                                                                                                            • Two component system containing liquid phase
                                                                                                            • Slide 72
                                                                                                            • The Critical Solution Temperature CST
                                                                                                            • Systems Showing a Decrease in Miscibility with Rise in Temperat
                                                                                                            • Systems Showing Upper and Lower CSTs
                                                                                                            • Two component system containing solid and liquid phase (Eutecti
                                                                                                            • Slide 77
                                                                                                            • Eutectic mixture Pharmaceutical Application
                                                                                                            • Three component system
                                                                                                            • Slide 80
                                                                                                            • Topics that we have covered

                                                                                                              Independent chemical species which comprise the system These could be Elements Ions Compounds

                                                                                                              Eg Au-Cu system Components rarr Au Cu Ice-water system Component rarr H2O

                                                                                                              Al2O3 ndash Cr2O3 system Components rarr Al2O3 Cr2O3

                                                                                                              Component the smallest number of constituent by which the composition of each phase in the system at equilibrium can be expressed in form of chemical formula or equation

                                                                                                              Phase Equilibria amp The Phase RuleComponents of a system

                                                                                                              The number of phases in a system is denoted P

                                                                                                              (a)A gas or a gaseous mixture is a single phase P=1

                                                                                                              (b) For a solid system an alloy of two metals is a two-phase system (P=2) if the metals are immiscible but a single-phase system (P=1) if they are miscible---a homogeneous mixture of the two substances---is uniform on a molecular scale

                                                                                                              (c) For a liquid system according to the solubility to decide whether a system consists of one phase or of two For example a solution of sodium chloride in water is a single phase A pair of liquids that are partially miscible or immiscible is a two-phase system(P=2)

                                                                                                              Oil in water

                                                                                                              Degrees of Freedom = What you can control What the system controls

                                                                                                              F = C + 2 P

                                                                                                              Can control the no of components added and P amp T

                                                                                                              System decided how many phases to produce given the

                                                                                                              conditions

                                                                                                              A way of understanding the Gibbs Phase RuleThe degrees of freedom can be thought of as the difference between what you (can) control and

                                                                                                              what the system controls

                                                                                                              F degree of freedom the least number of intensive variable that must be fixed (known) to describe the system completely

                                                                                                              Degree of freedom (or variance) F is the number of variables (T p andor composition) that can be changed independently without changing the phases of the system

                                                                                                              a) At the triple pointP = 3 (solid liquid and gas)

                                                                                                              C= 1 (water)P + F = C + 2

                                                                                                              F = 0 (no degree of freedom)

                                                                                                              b) liquid-solid curveP = 2

                                                                                                              2+F = 1 + 2F= 1

                                                                                                              One variable (T or P) can be changed

                                                                                                              c) LiquidP =1

                                                                                                              So F =2Two variables (T and P) can be varied independently

                                                                                                              and the system will remains a single phase

                                                                                                              One-component systemsPhase diagram of water

                                                                                                              P (

                                                                                                              atm

                                                                                                              )

                                                                                                              Critical point

                                                                                                              374

                                                                                                              1

                                                                                                              =100=0O--Triple point

                                                                                                              0006

                                                                                                              218

                                                                                                              Curve O -CSublimation

                                                                                                              Deposition

                                                                                                              Curve O-AVaporizationCondensation

                                                                                                              Curve O -BMelting

                                                                                                              Freezing

                                                                                                              F = C P + 2

                                                                                                              F = C P + 2

                                                                                                              Phase Diagram of Carbon Dioxide

                                                                                                              Condensed system System in which the vapor phase is ignored and only the solid andor liquid phases are considered

                                                                                                              Two component system For two component system F can be 3 (3D model is needed) eg T p

                                                                                                              and concentration usually we fix p = 1atm the vapor phase is neglected and F is reduced to 2

                                                                                                              For three component system the pressure and temperature are fixed

                                                                                                              Phenol water phase diagram

                                                                                                              eg for point d (24)

                                                                                                              Two component system containing liquid phase

                                                                                                              Tie Line bc line The line at which the system at equilibrium will separate into phases of constant composition termed lsquoconjugate phasesrsquo

                                                                                                              Lever Rule a way to calculate the proportions of each phase present on a phase diagram in a two phase field (at a given temperature and composition)

                                                                                                              eg for point d (24)

                                                                                                              For every 10 g of liquid system in equilibrium in point d

                                                                                                              75 g phase A25 g phase B

                                                                                                              ExampleMixed 24g phenol +76g water T 50degC

                                                                                                              equilibrium75 g phase A 25 g phase B

                                                                                                              11 phenol 63 phenol

                                                                                                              011 times75 g=825 g phenol

                                                                                                              063 times25 g=1575 g phenol

                                                                                                              water rich phasecontains water+ phenol(11)

                                                                                                              Phenol rich phasecontains Phenol (63)+ water

                                                                                                              The Critical Solution Temperature CST

                                                                                                              Is the maximum temperature at which the 2-phase region exists (or upper consolute temperature)

                                                                                                              In the case of the phenol-water system this is 668oC (point h)

                                                                                                              All combinations of phenol and water gt CST are completely miscible and yield 1-phase liquid systems

                                                                                                              Systems Showing a Decrease in Miscibility with Rise in Temperature

                                                                                                              A few mixtures exhibit a lower critical solution temperature (low CST) eg triethylamine plus water The miscibility with in temperature

                                                                                                              Systems Showing Upper and Lower CSTs

                                                                                                              The miscibility with temp

                                                                                                              a certain temperature miscibility starts to again with further in temperature

                                                                                                              Closed-phase diagram ie nicotine-water system

                                                                                                              A salol B thymol

                                                                                                              53

                                                                                                              Two component system containing solid and liquid phase (Eutectic Mixtures)

                                                                                                              A salol B thymol

                                                                                                              EMLAreg (lidocaine 25 and prilocaine 25) Cream

                                                                                                              EMLA Cream (lidocaine 25 and prilocaine 25) is an emulsion in which the oil phase is a eutectic mixture of lidocaine and prilocaine in a ratio of 11 by weight This eutectic mixture has a melting point below room temperature and therefore both local anesthetics exist as a liquid oil rather than as crystals

                                                                                                              Eutectic mixture Pharmaceutical Application

                                                                                                              Triangular Diagrams for three ndash component systems

                                                                                                              Three component system

                                                                                                              Birzeit University Physical Pharmacy PHAR 323 Dr Hani Shtaya

                                                                                                              1 Binding Forces Between Molecules2 Repulsive and Attractive Forces3 The Gaseous State The Ideal Gas Law Liquefaction of Gases Aerosols4 Solids and the Crystalline State Crystalline Solids Polymorphism Solvates Amorphous Solids5 Phase Equilibria and the Phase Rule Phase Rule Systems Containing One Component Condensed System Two-Component Systems Containing Liquid Phases Two-Component Systems Containing Solid and Liquid Phases Eutectic Mixtures Rules Relating to Triangular Diagrams

                                                                                                              Topics that we have covered

                                                                                                              • States of Matter
                                                                                                              • States of Matter (2)
                                                                                                              • Objectives of the lecture
                                                                                                              • Comparison of Gases Liquids and Solids
                                                                                                              • Slide 5
                                                                                                              • Repulsive and Attractive Forces
                                                                                                              • Ideal Gas Equation
                                                                                                              • Gaseous state
                                                                                                              • Slide 9
                                                                                                              • Gaseous state (2)
                                                                                                              • Liquefaction of Gases
                                                                                                              • Slide 12
                                                                                                              • SOLIDS amp CRYSTALLINE STATE Pharmaceutical Drugs more than 80
                                                                                                              • Solids and the crystalline state
                                                                                                              • Classification of Solids
                                                                                                              • Slide 16
                                                                                                              • Slide 17
                                                                                                              • Crystal forms
                                                                                                              • Types of Crystals
                                                                                                              • Slide 20
                                                                                                              • Slide 21
                                                                                                              • Polymorphism
                                                                                                              • Slide 23
                                                                                                              • Slide 24
                                                                                                              • Slide 25
                                                                                                              • Slide 26
                                                                                                              • Cocrystal
                                                                                                              • Principle of polymorphism
                                                                                                              • Solvates
                                                                                                              • Polymorphism (2)
                                                                                                              • Amorphous Solid
                                                                                                              • Amorphous or crystalline amp therapeutic activity
                                                                                                              • Slide 33
                                                                                                              • Slide 34
                                                                                                              • Polymorphism and Industry Pharmaceutical
                                                                                                              • Celecoxib
                                                                                                              • Furosemide
                                                                                                              • Bioavailability
                                                                                                              • Slide 39
                                                                                                              • Slide 40
                                                                                                              • Bioequivalence
                                                                                                              • Slide 42
                                                                                                              • Carbamazepine
                                                                                                              • Slide 44
                                                                                                              • AIDS drug ritonavir
                                                                                                              • Slide 46
                                                                                                              • Slide 47
                                                                                                              • Phase Equilibria amp The Phase Rule
                                                                                                              • Phase diagram ndash Water
                                                                                                              • Phase Equilibria amp The Phase Rule Definitions
                                                                                                              • Phase Definition
                                                                                                              • Examples
                                                                                                              • Components
                                                                                                              • Examples
                                                                                                              • Slide 55
                                                                                                              • Degrees of freedom (or variance)
                                                                                                              • Examples (2)
                                                                                                              • Phase Equilibria amp The Phase Rule
                                                                                                              • The phase rule
                                                                                                              • Slide 60
                                                                                                              • Phase Equilibria amp The Phase Rule (2)
                                                                                                              • The number of phases in a system is denoted P
                                                                                                              • Slide 63
                                                                                                              • Slide 64
                                                                                                              • One-component systems
                                                                                                              • Slide 66
                                                                                                              • Slide 67
                                                                                                              • Slide 68
                                                                                                              • Slide 69
                                                                                                              • Slide 70
                                                                                                              • Two component system containing liquid phase
                                                                                                              • Slide 72
                                                                                                              • The Critical Solution Temperature CST
                                                                                                              • Systems Showing a Decrease in Miscibility with Rise in Temperat
                                                                                                              • Systems Showing Upper and Lower CSTs
                                                                                                              • Two component system containing solid and liquid phase (Eutecti
                                                                                                              • Slide 77
                                                                                                              • Eutectic mixture Pharmaceutical Application
                                                                                                              • Three component system
                                                                                                              • Slide 80
                                                                                                              • Topics that we have covered

                                                                                                                The number of phases in a system is denoted P

                                                                                                                (a)A gas or a gaseous mixture is a single phase P=1

                                                                                                                (b) For a solid system an alloy of two metals is a two-phase system (P=2) if the metals are immiscible but a single-phase system (P=1) if they are miscible---a homogeneous mixture of the two substances---is uniform on a molecular scale

                                                                                                                (c) For a liquid system according to the solubility to decide whether a system consists of one phase or of two For example a solution of sodium chloride in water is a single phase A pair of liquids that are partially miscible or immiscible is a two-phase system(P=2)

                                                                                                                Oil in water

                                                                                                                Degrees of Freedom = What you can control What the system controls

                                                                                                                F = C + 2 P

                                                                                                                Can control the no of components added and P amp T

                                                                                                                System decided how many phases to produce given the

                                                                                                                conditions

                                                                                                                A way of understanding the Gibbs Phase RuleThe degrees of freedom can be thought of as the difference between what you (can) control and

                                                                                                                what the system controls

                                                                                                                F degree of freedom the least number of intensive variable that must be fixed (known) to describe the system completely

                                                                                                                Degree of freedom (or variance) F is the number of variables (T p andor composition) that can be changed independently without changing the phases of the system

                                                                                                                a) At the triple pointP = 3 (solid liquid and gas)

                                                                                                                C= 1 (water)P + F = C + 2

                                                                                                                F = 0 (no degree of freedom)

                                                                                                                b) liquid-solid curveP = 2

                                                                                                                2+F = 1 + 2F= 1

                                                                                                                One variable (T or P) can be changed

                                                                                                                c) LiquidP =1

                                                                                                                So F =2Two variables (T and P) can be varied independently

                                                                                                                and the system will remains a single phase

                                                                                                                One-component systemsPhase diagram of water

                                                                                                                P (

                                                                                                                atm

                                                                                                                )

                                                                                                                Critical point

                                                                                                                374

                                                                                                                1

                                                                                                                =100=0O--Triple point

                                                                                                                0006

                                                                                                                218

                                                                                                                Curve O -CSublimation

                                                                                                                Deposition

                                                                                                                Curve O-AVaporizationCondensation

                                                                                                                Curve O -BMelting

                                                                                                                Freezing

                                                                                                                F = C P + 2

                                                                                                                F = C P + 2

                                                                                                                Phase Diagram of Carbon Dioxide

                                                                                                                Condensed system System in which the vapor phase is ignored and only the solid andor liquid phases are considered

                                                                                                                Two component system For two component system F can be 3 (3D model is needed) eg T p

                                                                                                                and concentration usually we fix p = 1atm the vapor phase is neglected and F is reduced to 2

                                                                                                                For three component system the pressure and temperature are fixed

                                                                                                                Phenol water phase diagram

                                                                                                                eg for point d (24)

                                                                                                                Two component system containing liquid phase

                                                                                                                Tie Line bc line The line at which the system at equilibrium will separate into phases of constant composition termed lsquoconjugate phasesrsquo

                                                                                                                Lever Rule a way to calculate the proportions of each phase present on a phase diagram in a two phase field (at a given temperature and composition)

                                                                                                                eg for point d (24)

                                                                                                                For every 10 g of liquid system in equilibrium in point d

                                                                                                                75 g phase A25 g phase B

                                                                                                                ExampleMixed 24g phenol +76g water T 50degC

                                                                                                                equilibrium75 g phase A 25 g phase B

                                                                                                                11 phenol 63 phenol

                                                                                                                011 times75 g=825 g phenol

                                                                                                                063 times25 g=1575 g phenol

                                                                                                                water rich phasecontains water+ phenol(11)

                                                                                                                Phenol rich phasecontains Phenol (63)+ water

                                                                                                                The Critical Solution Temperature CST

                                                                                                                Is the maximum temperature at which the 2-phase region exists (or upper consolute temperature)

                                                                                                                In the case of the phenol-water system this is 668oC (point h)

                                                                                                                All combinations of phenol and water gt CST are completely miscible and yield 1-phase liquid systems

                                                                                                                Systems Showing a Decrease in Miscibility with Rise in Temperature

                                                                                                                A few mixtures exhibit a lower critical solution temperature (low CST) eg triethylamine plus water The miscibility with in temperature

                                                                                                                Systems Showing Upper and Lower CSTs

                                                                                                                The miscibility with temp

                                                                                                                a certain temperature miscibility starts to again with further in temperature

                                                                                                                Closed-phase diagram ie nicotine-water system

                                                                                                                A salol B thymol

                                                                                                                53

                                                                                                                Two component system containing solid and liquid phase (Eutectic Mixtures)

                                                                                                                A salol B thymol

                                                                                                                EMLAreg (lidocaine 25 and prilocaine 25) Cream

                                                                                                                EMLA Cream (lidocaine 25 and prilocaine 25) is an emulsion in which the oil phase is a eutectic mixture of lidocaine and prilocaine in a ratio of 11 by weight This eutectic mixture has a melting point below room temperature and therefore both local anesthetics exist as a liquid oil rather than as crystals

                                                                                                                Eutectic mixture Pharmaceutical Application

                                                                                                                Triangular Diagrams for three ndash component systems

                                                                                                                Three component system

                                                                                                                Birzeit University Physical Pharmacy PHAR 323 Dr Hani Shtaya

                                                                                                                1 Binding Forces Between Molecules2 Repulsive and Attractive Forces3 The Gaseous State The Ideal Gas Law Liquefaction of Gases Aerosols4 Solids and the Crystalline State Crystalline Solids Polymorphism Solvates Amorphous Solids5 Phase Equilibria and the Phase Rule Phase Rule Systems Containing One Component Condensed System Two-Component Systems Containing Liquid Phases Two-Component Systems Containing Solid and Liquid Phases Eutectic Mixtures Rules Relating to Triangular Diagrams

                                                                                                                Topics that we have covered

                                                                                                                • States of Matter
                                                                                                                • States of Matter (2)
                                                                                                                • Objectives of the lecture
                                                                                                                • Comparison of Gases Liquids and Solids
                                                                                                                • Slide 5
                                                                                                                • Repulsive and Attractive Forces
                                                                                                                • Ideal Gas Equation
                                                                                                                • Gaseous state
                                                                                                                • Slide 9
                                                                                                                • Gaseous state (2)
                                                                                                                • Liquefaction of Gases
                                                                                                                • Slide 12
                                                                                                                • SOLIDS amp CRYSTALLINE STATE Pharmaceutical Drugs more than 80
                                                                                                                • Solids and the crystalline state
                                                                                                                • Classification of Solids
                                                                                                                • Slide 16
                                                                                                                • Slide 17
                                                                                                                • Crystal forms
                                                                                                                • Types of Crystals
                                                                                                                • Slide 20
                                                                                                                • Slide 21
                                                                                                                • Polymorphism
                                                                                                                • Slide 23
                                                                                                                • Slide 24
                                                                                                                • Slide 25
                                                                                                                • Slide 26
                                                                                                                • Cocrystal
                                                                                                                • Principle of polymorphism
                                                                                                                • Solvates
                                                                                                                • Polymorphism (2)
                                                                                                                • Amorphous Solid
                                                                                                                • Amorphous or crystalline amp therapeutic activity
                                                                                                                • Slide 33
                                                                                                                • Slide 34
                                                                                                                • Polymorphism and Industry Pharmaceutical
                                                                                                                • Celecoxib
                                                                                                                • Furosemide
                                                                                                                • Bioavailability
                                                                                                                • Slide 39
                                                                                                                • Slide 40
                                                                                                                • Bioequivalence
                                                                                                                • Slide 42
                                                                                                                • Carbamazepine
                                                                                                                • Slide 44
                                                                                                                • AIDS drug ritonavir
                                                                                                                • Slide 46
                                                                                                                • Slide 47
                                                                                                                • Phase Equilibria amp The Phase Rule
                                                                                                                • Phase diagram ndash Water
                                                                                                                • Phase Equilibria amp The Phase Rule Definitions
                                                                                                                • Phase Definition
                                                                                                                • Examples
                                                                                                                • Components
                                                                                                                • Examples
                                                                                                                • Slide 55
                                                                                                                • Degrees of freedom (or variance)
                                                                                                                • Examples (2)
                                                                                                                • Phase Equilibria amp The Phase Rule
                                                                                                                • The phase rule
                                                                                                                • Slide 60
                                                                                                                • Phase Equilibria amp The Phase Rule (2)
                                                                                                                • The number of phases in a system is denoted P
                                                                                                                • Slide 63
                                                                                                                • Slide 64
                                                                                                                • One-component systems
                                                                                                                • Slide 66
                                                                                                                • Slide 67
                                                                                                                • Slide 68
                                                                                                                • Slide 69
                                                                                                                • Slide 70
                                                                                                                • Two component system containing liquid phase
                                                                                                                • Slide 72
                                                                                                                • The Critical Solution Temperature CST
                                                                                                                • Systems Showing a Decrease in Miscibility with Rise in Temperat
                                                                                                                • Systems Showing Upper and Lower CSTs
                                                                                                                • Two component system containing solid and liquid phase (Eutecti
                                                                                                                • Slide 77
                                                                                                                • Eutectic mixture Pharmaceutical Application
                                                                                                                • Three component system
                                                                                                                • Slide 80
                                                                                                                • Topics that we have covered

                                                                                                                  Degrees of Freedom = What you can control What the system controls

                                                                                                                  F = C + 2 P

                                                                                                                  Can control the no of components added and P amp T

                                                                                                                  System decided how many phases to produce given the

                                                                                                                  conditions

                                                                                                                  A way of understanding the Gibbs Phase RuleThe degrees of freedom can be thought of as the difference between what you (can) control and

                                                                                                                  what the system controls

                                                                                                                  F degree of freedom the least number of intensive variable that must be fixed (known) to describe the system completely

                                                                                                                  Degree of freedom (or variance) F is the number of variables (T p andor composition) that can be changed independently without changing the phases of the system

                                                                                                                  a) At the triple pointP = 3 (solid liquid and gas)

                                                                                                                  C= 1 (water)P + F = C + 2

                                                                                                                  F = 0 (no degree of freedom)

                                                                                                                  b) liquid-solid curveP = 2

                                                                                                                  2+F = 1 + 2F= 1

                                                                                                                  One variable (T or P) can be changed

                                                                                                                  c) LiquidP =1

                                                                                                                  So F =2Two variables (T and P) can be varied independently

                                                                                                                  and the system will remains a single phase

                                                                                                                  One-component systemsPhase diagram of water

                                                                                                                  P (

                                                                                                                  atm

                                                                                                                  )

                                                                                                                  Critical point

                                                                                                                  374

                                                                                                                  1

                                                                                                                  =100=0O--Triple point

                                                                                                                  0006

                                                                                                                  218

                                                                                                                  Curve O -CSublimation

                                                                                                                  Deposition

                                                                                                                  Curve O-AVaporizationCondensation

                                                                                                                  Curve O -BMelting

                                                                                                                  Freezing

                                                                                                                  F = C P + 2

                                                                                                                  F = C P + 2

                                                                                                                  Phase Diagram of Carbon Dioxide

                                                                                                                  Condensed system System in which the vapor phase is ignored and only the solid andor liquid phases are considered

                                                                                                                  Two component system For two component system F can be 3 (3D model is needed) eg T p

                                                                                                                  and concentration usually we fix p = 1atm the vapor phase is neglected and F is reduced to 2

                                                                                                                  For three component system the pressure and temperature are fixed

                                                                                                                  Phenol water phase diagram

                                                                                                                  eg for point d (24)

                                                                                                                  Two component system containing liquid phase

                                                                                                                  Tie Line bc line The line at which the system at equilibrium will separate into phases of constant composition termed lsquoconjugate phasesrsquo

                                                                                                                  Lever Rule a way to calculate the proportions of each phase present on a phase diagram in a two phase field (at a given temperature and composition)

                                                                                                                  eg for point d (24)

                                                                                                                  For every 10 g of liquid system in equilibrium in point d

                                                                                                                  75 g phase A25 g phase B

                                                                                                                  ExampleMixed 24g phenol +76g water T 50degC

                                                                                                                  equilibrium75 g phase A 25 g phase B

                                                                                                                  11 phenol 63 phenol

                                                                                                                  011 times75 g=825 g phenol

                                                                                                                  063 times25 g=1575 g phenol

                                                                                                                  water rich phasecontains water+ phenol(11)

                                                                                                                  Phenol rich phasecontains Phenol (63)+ water

                                                                                                                  The Critical Solution Temperature CST

                                                                                                                  Is the maximum temperature at which the 2-phase region exists (or upper consolute temperature)

                                                                                                                  In the case of the phenol-water system this is 668oC (point h)

                                                                                                                  All combinations of phenol and water gt CST are completely miscible and yield 1-phase liquid systems

                                                                                                                  Systems Showing a Decrease in Miscibility with Rise in Temperature

                                                                                                                  A few mixtures exhibit a lower critical solution temperature (low CST) eg triethylamine plus water The miscibility with in temperature

                                                                                                                  Systems Showing Upper and Lower CSTs

                                                                                                                  The miscibility with temp

                                                                                                                  a certain temperature miscibility starts to again with further in temperature

                                                                                                                  Closed-phase diagram ie nicotine-water system

                                                                                                                  A salol B thymol

                                                                                                                  53

                                                                                                                  Two component system containing solid and liquid phase (Eutectic Mixtures)

                                                                                                                  A salol B thymol

                                                                                                                  EMLAreg (lidocaine 25 and prilocaine 25) Cream

                                                                                                                  EMLA Cream (lidocaine 25 and prilocaine 25) is an emulsion in which the oil phase is a eutectic mixture of lidocaine and prilocaine in a ratio of 11 by weight This eutectic mixture has a melting point below room temperature and therefore both local anesthetics exist as a liquid oil rather than as crystals

                                                                                                                  Eutectic mixture Pharmaceutical Application

                                                                                                                  Triangular Diagrams for three ndash component systems

                                                                                                                  Three component system

                                                                                                                  Birzeit University Physical Pharmacy PHAR 323 Dr Hani Shtaya

                                                                                                                  1 Binding Forces Between Molecules2 Repulsive and Attractive Forces3 The Gaseous State The Ideal Gas Law Liquefaction of Gases Aerosols4 Solids and the Crystalline State Crystalline Solids Polymorphism Solvates Amorphous Solids5 Phase Equilibria and the Phase Rule Phase Rule Systems Containing One Component Condensed System Two-Component Systems Containing Liquid Phases Two-Component Systems Containing Solid and Liquid Phases Eutectic Mixtures Rules Relating to Triangular Diagrams

                                                                                                                  Topics that we have covered

                                                                                                                  • States of Matter
                                                                                                                  • States of Matter (2)
                                                                                                                  • Objectives of the lecture
                                                                                                                  • Comparison of Gases Liquids and Solids
                                                                                                                  • Slide 5
                                                                                                                  • Repulsive and Attractive Forces
                                                                                                                  • Ideal Gas Equation
                                                                                                                  • Gaseous state
                                                                                                                  • Slide 9
                                                                                                                  • Gaseous state (2)
                                                                                                                  • Liquefaction of Gases
                                                                                                                  • Slide 12
                                                                                                                  • SOLIDS amp CRYSTALLINE STATE Pharmaceutical Drugs more than 80
                                                                                                                  • Solids and the crystalline state
                                                                                                                  • Classification of Solids
                                                                                                                  • Slide 16
                                                                                                                  • Slide 17
                                                                                                                  • Crystal forms
                                                                                                                  • Types of Crystals
                                                                                                                  • Slide 20
                                                                                                                  • Slide 21
                                                                                                                  • Polymorphism
                                                                                                                  • Slide 23
                                                                                                                  • Slide 24
                                                                                                                  • Slide 25
                                                                                                                  • Slide 26
                                                                                                                  • Cocrystal
                                                                                                                  • Principle of polymorphism
                                                                                                                  • Solvates
                                                                                                                  • Polymorphism (2)
                                                                                                                  • Amorphous Solid
                                                                                                                  • Amorphous or crystalline amp therapeutic activity
                                                                                                                  • Slide 33
                                                                                                                  • Slide 34
                                                                                                                  • Polymorphism and Industry Pharmaceutical
                                                                                                                  • Celecoxib
                                                                                                                  • Furosemide
                                                                                                                  • Bioavailability
                                                                                                                  • Slide 39
                                                                                                                  • Slide 40
                                                                                                                  • Bioequivalence
                                                                                                                  • Slide 42
                                                                                                                  • Carbamazepine
                                                                                                                  • Slide 44
                                                                                                                  • AIDS drug ritonavir
                                                                                                                  • Slide 46
                                                                                                                  • Slide 47
                                                                                                                  • Phase Equilibria amp The Phase Rule
                                                                                                                  • Phase diagram ndash Water
                                                                                                                  • Phase Equilibria amp The Phase Rule Definitions
                                                                                                                  • Phase Definition
                                                                                                                  • Examples
                                                                                                                  • Components
                                                                                                                  • Examples
                                                                                                                  • Slide 55
                                                                                                                  • Degrees of freedom (or variance)
                                                                                                                  • Examples (2)
                                                                                                                  • Phase Equilibria amp The Phase Rule
                                                                                                                  • The phase rule
                                                                                                                  • Slide 60
                                                                                                                  • Phase Equilibria amp The Phase Rule (2)
                                                                                                                  • The number of phases in a system is denoted P
                                                                                                                  • Slide 63
                                                                                                                  • Slide 64
                                                                                                                  • One-component systems
                                                                                                                  • Slide 66
                                                                                                                  • Slide 67
                                                                                                                  • Slide 68
                                                                                                                  • Slide 69
                                                                                                                  • Slide 70
                                                                                                                  • Two component system containing liquid phase
                                                                                                                  • Slide 72
                                                                                                                  • The Critical Solution Temperature CST
                                                                                                                  • Systems Showing a Decrease in Miscibility with Rise in Temperat
                                                                                                                  • Systems Showing Upper and Lower CSTs
                                                                                                                  • Two component system containing solid and liquid phase (Eutecti
                                                                                                                  • Slide 77
                                                                                                                  • Eutectic mixture Pharmaceutical Application
                                                                                                                  • Three component system
                                                                                                                  • Slide 80
                                                                                                                  • Topics that we have covered

                                                                                                                    F degree of freedom the least number of intensive variable that must be fixed (known) to describe the system completely

                                                                                                                    Degree of freedom (or variance) F is the number of variables (T p andor composition) that can be changed independently without changing the phases of the system

                                                                                                                    a) At the triple pointP = 3 (solid liquid and gas)

                                                                                                                    C= 1 (water)P + F = C + 2

                                                                                                                    F = 0 (no degree of freedom)

                                                                                                                    b) liquid-solid curveP = 2

                                                                                                                    2+F = 1 + 2F= 1

                                                                                                                    One variable (T or P) can be changed

                                                                                                                    c) LiquidP =1

                                                                                                                    So F =2Two variables (T and P) can be varied independently

                                                                                                                    and the system will remains a single phase

                                                                                                                    One-component systemsPhase diagram of water

                                                                                                                    P (

                                                                                                                    atm

                                                                                                                    )

                                                                                                                    Critical point

                                                                                                                    374

                                                                                                                    1

                                                                                                                    =100=0O--Triple point

                                                                                                                    0006

                                                                                                                    218

                                                                                                                    Curve O -CSublimation

                                                                                                                    Deposition

                                                                                                                    Curve O-AVaporizationCondensation

                                                                                                                    Curve O -BMelting

                                                                                                                    Freezing

                                                                                                                    F = C P + 2

                                                                                                                    F = C P + 2

                                                                                                                    Phase Diagram of Carbon Dioxide

                                                                                                                    Condensed system System in which the vapor phase is ignored and only the solid andor liquid phases are considered

                                                                                                                    Two component system For two component system F can be 3 (3D model is needed) eg T p

                                                                                                                    and concentration usually we fix p = 1atm the vapor phase is neglected and F is reduced to 2

                                                                                                                    For three component system the pressure and temperature are fixed

                                                                                                                    Phenol water phase diagram

                                                                                                                    eg for point d (24)

                                                                                                                    Two component system containing liquid phase

                                                                                                                    Tie Line bc line The line at which the system at equilibrium will separate into phases of constant composition termed lsquoconjugate phasesrsquo

                                                                                                                    Lever Rule a way to calculate the proportions of each phase present on a phase diagram in a two phase field (at a given temperature and composition)

                                                                                                                    eg for point d (24)

                                                                                                                    For every 10 g of liquid system in equilibrium in point d

                                                                                                                    75 g phase A25 g phase B

                                                                                                                    ExampleMixed 24g phenol +76g water T 50degC

                                                                                                                    equilibrium75 g phase A 25 g phase B

                                                                                                                    11 phenol 63 phenol

                                                                                                                    011 times75 g=825 g phenol

                                                                                                                    063 times25 g=1575 g phenol

                                                                                                                    water rich phasecontains water+ phenol(11)

                                                                                                                    Phenol rich phasecontains Phenol (63)+ water

                                                                                                                    The Critical Solution Temperature CST

                                                                                                                    Is the maximum temperature at which the 2-phase region exists (or upper consolute temperature)

                                                                                                                    In the case of the phenol-water system this is 668oC (point h)

                                                                                                                    All combinations of phenol and water gt CST are completely miscible and yield 1-phase liquid systems

                                                                                                                    Systems Showing a Decrease in Miscibility with Rise in Temperature

                                                                                                                    A few mixtures exhibit a lower critical solution temperature (low CST) eg triethylamine plus water The miscibility with in temperature

                                                                                                                    Systems Showing Upper and Lower CSTs

                                                                                                                    The miscibility with temp

                                                                                                                    a certain temperature miscibility starts to again with further in temperature

                                                                                                                    Closed-phase diagram ie nicotine-water system

                                                                                                                    A salol B thymol

                                                                                                                    53

                                                                                                                    Two component system containing solid and liquid phase (Eutectic Mixtures)

                                                                                                                    A salol B thymol

                                                                                                                    EMLAreg (lidocaine 25 and prilocaine 25) Cream

                                                                                                                    EMLA Cream (lidocaine 25 and prilocaine 25) is an emulsion in which the oil phase is a eutectic mixture of lidocaine and prilocaine in a ratio of 11 by weight This eutectic mixture has a melting point below room temperature and therefore both local anesthetics exist as a liquid oil rather than as crystals

                                                                                                                    Eutectic mixture Pharmaceutical Application

                                                                                                                    Triangular Diagrams for three ndash component systems

                                                                                                                    Three component system

                                                                                                                    Birzeit University Physical Pharmacy PHAR 323 Dr Hani Shtaya

                                                                                                                    1 Binding Forces Between Molecules2 Repulsive and Attractive Forces3 The Gaseous State The Ideal Gas Law Liquefaction of Gases Aerosols4 Solids and the Crystalline State Crystalline Solids Polymorphism Solvates Amorphous Solids5 Phase Equilibria and the Phase Rule Phase Rule Systems Containing One Component Condensed System Two-Component Systems Containing Liquid Phases Two-Component Systems Containing Solid and Liquid Phases Eutectic Mixtures Rules Relating to Triangular Diagrams

                                                                                                                    Topics that we have covered

                                                                                                                    • States of Matter
                                                                                                                    • States of Matter (2)
                                                                                                                    • Objectives of the lecture
                                                                                                                    • Comparison of Gases Liquids and Solids
                                                                                                                    • Slide 5
                                                                                                                    • Repulsive and Attractive Forces
                                                                                                                    • Ideal Gas Equation
                                                                                                                    • Gaseous state
                                                                                                                    • Slide 9
                                                                                                                    • Gaseous state (2)
                                                                                                                    • Liquefaction of Gases
                                                                                                                    • Slide 12
                                                                                                                    • SOLIDS amp CRYSTALLINE STATE Pharmaceutical Drugs more than 80
                                                                                                                    • Solids and the crystalline state
                                                                                                                    • Classification of Solids
                                                                                                                    • Slide 16
                                                                                                                    • Slide 17
                                                                                                                    • Crystal forms
                                                                                                                    • Types of Crystals
                                                                                                                    • Slide 20
                                                                                                                    • Slide 21
                                                                                                                    • Polymorphism
                                                                                                                    • Slide 23
                                                                                                                    • Slide 24
                                                                                                                    • Slide 25
                                                                                                                    • Slide 26
                                                                                                                    • Cocrystal
                                                                                                                    • Principle of polymorphism
                                                                                                                    • Solvates
                                                                                                                    • Polymorphism (2)
                                                                                                                    • Amorphous Solid
                                                                                                                    • Amorphous or crystalline amp therapeutic activity
                                                                                                                    • Slide 33
                                                                                                                    • Slide 34
                                                                                                                    • Polymorphism and Industry Pharmaceutical
                                                                                                                    • Celecoxib
                                                                                                                    • Furosemide
                                                                                                                    • Bioavailability
                                                                                                                    • Slide 39
                                                                                                                    • Slide 40
                                                                                                                    • Bioequivalence
                                                                                                                    • Slide 42
                                                                                                                    • Carbamazepine
                                                                                                                    • Slide 44
                                                                                                                    • AIDS drug ritonavir
                                                                                                                    • Slide 46
                                                                                                                    • Slide 47
                                                                                                                    • Phase Equilibria amp The Phase Rule
                                                                                                                    • Phase diagram ndash Water
                                                                                                                    • Phase Equilibria amp The Phase Rule Definitions
                                                                                                                    • Phase Definition
                                                                                                                    • Examples
                                                                                                                    • Components
                                                                                                                    • Examples
                                                                                                                    • Slide 55
                                                                                                                    • Degrees of freedom (or variance)
                                                                                                                    • Examples (2)
                                                                                                                    • Phase Equilibria amp The Phase Rule
                                                                                                                    • The phase rule
                                                                                                                    • Slide 60
                                                                                                                    • Phase Equilibria amp The Phase Rule (2)
                                                                                                                    • The number of phases in a system is denoted P
                                                                                                                    • Slide 63
                                                                                                                    • Slide 64
                                                                                                                    • One-component systems
                                                                                                                    • Slide 66
                                                                                                                    • Slide 67
                                                                                                                    • Slide 68
                                                                                                                    • Slide 69
                                                                                                                    • Slide 70
                                                                                                                    • Two component system containing liquid phase
                                                                                                                    • Slide 72
                                                                                                                    • The Critical Solution Temperature CST
                                                                                                                    • Systems Showing a Decrease in Miscibility with Rise in Temperat
                                                                                                                    • Systems Showing Upper and Lower CSTs
                                                                                                                    • Two component system containing solid and liquid phase (Eutecti
                                                                                                                    • Slide 77
                                                                                                                    • Eutectic mixture Pharmaceutical Application
                                                                                                                    • Three component system
                                                                                                                    • Slide 80
                                                                                                                    • Topics that we have covered

                                                                                                                      One-component systemsPhase diagram of water

                                                                                                                      P (

                                                                                                                      atm

                                                                                                                      )

                                                                                                                      Critical point

                                                                                                                      374

                                                                                                                      1

                                                                                                                      =100=0O--Triple point

                                                                                                                      0006

                                                                                                                      218

                                                                                                                      Curve O -CSublimation

                                                                                                                      Deposition

                                                                                                                      Curve O-AVaporizationCondensation

                                                                                                                      Curve O -BMelting

                                                                                                                      Freezing

                                                                                                                      F = C P + 2

                                                                                                                      F = C P + 2

                                                                                                                      Phase Diagram of Carbon Dioxide

                                                                                                                      Condensed system System in which the vapor phase is ignored and only the solid andor liquid phases are considered

                                                                                                                      Two component system For two component system F can be 3 (3D model is needed) eg T p

                                                                                                                      and concentration usually we fix p = 1atm the vapor phase is neglected and F is reduced to 2

                                                                                                                      For three component system the pressure and temperature are fixed

                                                                                                                      Phenol water phase diagram

                                                                                                                      eg for point d (24)

                                                                                                                      Two component system containing liquid phase

                                                                                                                      Tie Line bc line The line at which the system at equilibrium will separate into phases of constant composition termed lsquoconjugate phasesrsquo

                                                                                                                      Lever Rule a way to calculate the proportions of each phase present on a phase diagram in a two phase field (at a given temperature and composition)

                                                                                                                      eg for point d (24)

                                                                                                                      For every 10 g of liquid system in equilibrium in point d

                                                                                                                      75 g phase A25 g phase B

                                                                                                                      ExampleMixed 24g phenol +76g water T 50degC

                                                                                                                      equilibrium75 g phase A 25 g phase B

                                                                                                                      11 phenol 63 phenol

                                                                                                                      011 times75 g=825 g phenol

                                                                                                                      063 times25 g=1575 g phenol

                                                                                                                      water rich phasecontains water+ phenol(11)

                                                                                                                      Phenol rich phasecontains Phenol (63)+ water

                                                                                                                      The Critical Solution Temperature CST

                                                                                                                      Is the maximum temperature at which the 2-phase region exists (or upper consolute temperature)

                                                                                                                      In the case of the phenol-water system this is 668oC (point h)

                                                                                                                      All combinations of phenol and water gt CST are completely miscible and yield 1-phase liquid systems

                                                                                                                      Systems Showing a Decrease in Miscibility with Rise in Temperature

                                                                                                                      A few mixtures exhibit a lower critical solution temperature (low CST) eg triethylamine plus water The miscibility with in temperature

                                                                                                                      Systems Showing Upper and Lower CSTs

                                                                                                                      The miscibility with temp

                                                                                                                      a certain temperature miscibility starts to again with further in temperature

                                                                                                                      Closed-phase diagram ie nicotine-water system

                                                                                                                      A salol B thymol

                                                                                                                      53

                                                                                                                      Two component system containing solid and liquid phase (Eutectic Mixtures)

                                                                                                                      A salol B thymol

                                                                                                                      EMLAreg (lidocaine 25 and prilocaine 25) Cream

                                                                                                                      EMLA Cream (lidocaine 25 and prilocaine 25) is an emulsion in which the oil phase is a eutectic mixture of lidocaine and prilocaine in a ratio of 11 by weight This eutectic mixture has a melting point below room temperature and therefore both local anesthetics exist as a liquid oil rather than as crystals

                                                                                                                      Eutectic mixture Pharmaceutical Application

                                                                                                                      Triangular Diagrams for three ndash component systems

                                                                                                                      Three component system

                                                                                                                      Birzeit University Physical Pharmacy PHAR 323 Dr Hani Shtaya

                                                                                                                      1 Binding Forces Between Molecules2 Repulsive and Attractive Forces3 The Gaseous State The Ideal Gas Law Liquefaction of Gases Aerosols4 Solids and the Crystalline State Crystalline Solids Polymorphism Solvates Amorphous Solids5 Phase Equilibria and the Phase Rule Phase Rule Systems Containing One Component Condensed System Two-Component Systems Containing Liquid Phases Two-Component Systems Containing Solid and Liquid Phases Eutectic Mixtures Rules Relating to Triangular Diagrams

                                                                                                                      Topics that we have covered

                                                                                                                      • States of Matter
                                                                                                                      • States of Matter (2)
                                                                                                                      • Objectives of the lecture
                                                                                                                      • Comparison of Gases Liquids and Solids
                                                                                                                      • Slide 5
                                                                                                                      • Repulsive and Attractive Forces
                                                                                                                      • Ideal Gas Equation
                                                                                                                      • Gaseous state
                                                                                                                      • Slide 9
                                                                                                                      • Gaseous state (2)
                                                                                                                      • Liquefaction of Gases
                                                                                                                      • Slide 12
                                                                                                                      • SOLIDS amp CRYSTALLINE STATE Pharmaceutical Drugs more than 80
                                                                                                                      • Solids and the crystalline state
                                                                                                                      • Classification of Solids
                                                                                                                      • Slide 16
                                                                                                                      • Slide 17
                                                                                                                      • Crystal forms
                                                                                                                      • Types of Crystals
                                                                                                                      • Slide 20
                                                                                                                      • Slide 21
                                                                                                                      • Polymorphism
                                                                                                                      • Slide 23
                                                                                                                      • Slide 24
                                                                                                                      • Slide 25
                                                                                                                      • Slide 26
                                                                                                                      • Cocrystal
                                                                                                                      • Principle of polymorphism
                                                                                                                      • Solvates
                                                                                                                      • Polymorphism (2)
                                                                                                                      • Amorphous Solid
                                                                                                                      • Amorphous or crystalline amp therapeutic activity
                                                                                                                      • Slide 33
                                                                                                                      • Slide 34
                                                                                                                      • Polymorphism and Industry Pharmaceutical
                                                                                                                      • Celecoxib
                                                                                                                      • Furosemide
                                                                                                                      • Bioavailability
                                                                                                                      • Slide 39
                                                                                                                      • Slide 40
                                                                                                                      • Bioequivalence
                                                                                                                      • Slide 42
                                                                                                                      • Carbamazepine
                                                                                                                      • Slide 44
                                                                                                                      • AIDS drug ritonavir
                                                                                                                      • Slide 46
                                                                                                                      • Slide 47
                                                                                                                      • Phase Equilibria amp The Phase Rule
                                                                                                                      • Phase diagram ndash Water
                                                                                                                      • Phase Equilibria amp The Phase Rule Definitions
                                                                                                                      • Phase Definition
                                                                                                                      • Examples
                                                                                                                      • Components
                                                                                                                      • Examples
                                                                                                                      • Slide 55
                                                                                                                      • Degrees of freedom (or variance)
                                                                                                                      • Examples (2)
                                                                                                                      • Phase Equilibria amp The Phase Rule
                                                                                                                      • The phase rule
                                                                                                                      • Slide 60
                                                                                                                      • Phase Equilibria amp The Phase Rule (2)
                                                                                                                      • The number of phases in a system is denoted P
                                                                                                                      • Slide 63
                                                                                                                      • Slide 64
                                                                                                                      • One-component systems
                                                                                                                      • Slide 66
                                                                                                                      • Slide 67
                                                                                                                      • Slide 68
                                                                                                                      • Slide 69
                                                                                                                      • Slide 70
                                                                                                                      • Two component system containing liquid phase
                                                                                                                      • Slide 72
                                                                                                                      • The Critical Solution Temperature CST
                                                                                                                      • Systems Showing a Decrease in Miscibility with Rise in Temperat
                                                                                                                      • Systems Showing Upper and Lower CSTs
                                                                                                                      • Two component system containing solid and liquid phase (Eutecti
                                                                                                                      • Slide 77
                                                                                                                      • Eutectic mixture Pharmaceutical Application
                                                                                                                      • Three component system
                                                                                                                      • Slide 80
                                                                                                                      • Topics that we have covered

                                                                                                                        F = C P + 2

                                                                                                                        Phase Diagram of Carbon Dioxide

                                                                                                                        Condensed system System in which the vapor phase is ignored and only the solid andor liquid phases are considered

                                                                                                                        Two component system For two component system F can be 3 (3D model is needed) eg T p

                                                                                                                        and concentration usually we fix p = 1atm the vapor phase is neglected and F is reduced to 2

                                                                                                                        For three component system the pressure and temperature are fixed

                                                                                                                        Phenol water phase diagram

                                                                                                                        eg for point d (24)

                                                                                                                        Two component system containing liquid phase

                                                                                                                        Tie Line bc line The line at which the system at equilibrium will separate into phases of constant composition termed lsquoconjugate phasesrsquo

                                                                                                                        Lever Rule a way to calculate the proportions of each phase present on a phase diagram in a two phase field (at a given temperature and composition)

                                                                                                                        eg for point d (24)

                                                                                                                        For every 10 g of liquid system in equilibrium in point d

                                                                                                                        75 g phase A25 g phase B

                                                                                                                        ExampleMixed 24g phenol +76g water T 50degC

                                                                                                                        equilibrium75 g phase A 25 g phase B

                                                                                                                        11 phenol 63 phenol

                                                                                                                        011 times75 g=825 g phenol

                                                                                                                        063 times25 g=1575 g phenol

                                                                                                                        water rich phasecontains water+ phenol(11)

                                                                                                                        Phenol rich phasecontains Phenol (63)+ water

                                                                                                                        The Critical Solution Temperature CST

                                                                                                                        Is the maximum temperature at which the 2-phase region exists (or upper consolute temperature)

                                                                                                                        In the case of the phenol-water system this is 668oC (point h)

                                                                                                                        All combinations of phenol and water gt CST are completely miscible and yield 1-phase liquid systems

                                                                                                                        Systems Showing a Decrease in Miscibility with Rise in Temperature

                                                                                                                        A few mixtures exhibit a lower critical solution temperature (low CST) eg triethylamine plus water The miscibility with in temperature

                                                                                                                        Systems Showing Upper and Lower CSTs

                                                                                                                        The miscibility with temp

                                                                                                                        a certain temperature miscibility starts to again with further in temperature

                                                                                                                        Closed-phase diagram ie nicotine-water system

                                                                                                                        A salol B thymol

                                                                                                                        53

                                                                                                                        Two component system containing solid and liquid phase (Eutectic Mixtures)

                                                                                                                        A salol B thymol

                                                                                                                        EMLAreg (lidocaine 25 and prilocaine 25) Cream

                                                                                                                        EMLA Cream (lidocaine 25 and prilocaine 25) is an emulsion in which the oil phase is a eutectic mixture of lidocaine and prilocaine in a ratio of 11 by weight This eutectic mixture has a melting point below room temperature and therefore both local anesthetics exist as a liquid oil rather than as crystals

                                                                                                                        Eutectic mixture Pharmaceutical Application

                                                                                                                        Triangular Diagrams for three ndash component systems

                                                                                                                        Three component system

                                                                                                                        Birzeit University Physical Pharmacy PHAR 323 Dr Hani Shtaya

                                                                                                                        1 Binding Forces Between Molecules2 Repulsive and Attractive Forces3 The Gaseous State The Ideal Gas Law Liquefaction of Gases Aerosols4 Solids and the Crystalline State Crystalline Solids Polymorphism Solvates Amorphous Solids5 Phase Equilibria and the Phase Rule Phase Rule Systems Containing One Component Condensed System Two-Component Systems Containing Liquid Phases Two-Component Systems Containing Solid and Liquid Phases Eutectic Mixtures Rules Relating to Triangular Diagrams

                                                                                                                        Topics that we have covered

                                                                                                                        • States of Matter
                                                                                                                        • States of Matter (2)
                                                                                                                        • Objectives of the lecture
                                                                                                                        • Comparison of Gases Liquids and Solids
                                                                                                                        • Slide 5
                                                                                                                        • Repulsive and Attractive Forces
                                                                                                                        • Ideal Gas Equation
                                                                                                                        • Gaseous state
                                                                                                                        • Slide 9
                                                                                                                        • Gaseous state (2)
                                                                                                                        • Liquefaction of Gases
                                                                                                                        • Slide 12
                                                                                                                        • SOLIDS amp CRYSTALLINE STATE Pharmaceutical Drugs more than 80
                                                                                                                        • Solids and the crystalline state
                                                                                                                        • Classification of Solids
                                                                                                                        • Slide 16
                                                                                                                        • Slide 17
                                                                                                                        • Crystal forms
                                                                                                                        • Types of Crystals
                                                                                                                        • Slide 20
                                                                                                                        • Slide 21
                                                                                                                        • Polymorphism
                                                                                                                        • Slide 23
                                                                                                                        • Slide 24
                                                                                                                        • Slide 25
                                                                                                                        • Slide 26
                                                                                                                        • Cocrystal
                                                                                                                        • Principle of polymorphism
                                                                                                                        • Solvates
                                                                                                                        • Polymorphism (2)
                                                                                                                        • Amorphous Solid
                                                                                                                        • Amorphous or crystalline amp therapeutic activity
                                                                                                                        • Slide 33
                                                                                                                        • Slide 34
                                                                                                                        • Polymorphism and Industry Pharmaceutical
                                                                                                                        • Celecoxib
                                                                                                                        • Furosemide
                                                                                                                        • Bioavailability
                                                                                                                        • Slide 39
                                                                                                                        • Slide 40
                                                                                                                        • Bioequivalence
                                                                                                                        • Slide 42
                                                                                                                        • Carbamazepine
                                                                                                                        • Slide 44
                                                                                                                        • AIDS drug ritonavir
                                                                                                                        • Slide 46
                                                                                                                        • Slide 47
                                                                                                                        • Phase Equilibria amp The Phase Rule
                                                                                                                        • Phase diagram ndash Water
                                                                                                                        • Phase Equilibria amp The Phase Rule Definitions
                                                                                                                        • Phase Definition
                                                                                                                        • Examples
                                                                                                                        • Components
                                                                                                                        • Examples
                                                                                                                        • Slide 55
                                                                                                                        • Degrees of freedom (or variance)
                                                                                                                        • Examples (2)
                                                                                                                        • Phase Equilibria amp The Phase Rule
                                                                                                                        • The phase rule
                                                                                                                        • Slide 60
                                                                                                                        • Phase Equilibria amp The Phase Rule (2)
                                                                                                                        • The number of phases in a system is denoted P
                                                                                                                        • Slide 63
                                                                                                                        • Slide 64
                                                                                                                        • One-component systems
                                                                                                                        • Slide 66
                                                                                                                        • Slide 67
                                                                                                                        • Slide 68
                                                                                                                        • Slide 69
                                                                                                                        • Slide 70
                                                                                                                        • Two component system containing liquid phase
                                                                                                                        • Slide 72
                                                                                                                        • The Critical Solution Temperature CST
                                                                                                                        • Systems Showing a Decrease in Miscibility with Rise in Temperat
                                                                                                                        • Systems Showing Upper and Lower CSTs
                                                                                                                        • Two component system containing solid and liquid phase (Eutecti
                                                                                                                        • Slide 77
                                                                                                                        • Eutectic mixture Pharmaceutical Application
                                                                                                                        • Three component system
                                                                                                                        • Slide 80
                                                                                                                        • Topics that we have covered

                                                                                                                          Phase Diagram of Carbon Dioxide

                                                                                                                          Condensed system System in which the vapor phase is ignored and only the solid andor liquid phases are considered

                                                                                                                          Two component system For two component system F can be 3 (3D model is needed) eg T p

                                                                                                                          and concentration usually we fix p = 1atm the vapor phase is neglected and F is reduced to 2

                                                                                                                          For three component system the pressure and temperature are fixed

                                                                                                                          Phenol water phase diagram

                                                                                                                          eg for point d (24)

                                                                                                                          Two component system containing liquid phase

                                                                                                                          Tie Line bc line The line at which the system at equilibrium will separate into phases of constant composition termed lsquoconjugate phasesrsquo

                                                                                                                          Lever Rule a way to calculate the proportions of each phase present on a phase diagram in a two phase field (at a given temperature and composition)

                                                                                                                          eg for point d (24)

                                                                                                                          For every 10 g of liquid system in equilibrium in point d

                                                                                                                          75 g phase A25 g phase B

                                                                                                                          ExampleMixed 24g phenol +76g water T 50degC

                                                                                                                          equilibrium75 g phase A 25 g phase B

                                                                                                                          11 phenol 63 phenol

                                                                                                                          011 times75 g=825 g phenol

                                                                                                                          063 times25 g=1575 g phenol

                                                                                                                          water rich phasecontains water+ phenol(11)

                                                                                                                          Phenol rich phasecontains Phenol (63)+ water

                                                                                                                          The Critical Solution Temperature CST

                                                                                                                          Is the maximum temperature at which the 2-phase region exists (or upper consolute temperature)

                                                                                                                          In the case of the phenol-water system this is 668oC (point h)

                                                                                                                          All combinations of phenol and water gt CST are completely miscible and yield 1-phase liquid systems

                                                                                                                          Systems Showing a Decrease in Miscibility with Rise in Temperature

                                                                                                                          A few mixtures exhibit a lower critical solution temperature (low CST) eg triethylamine plus water The miscibility with in temperature

                                                                                                                          Systems Showing Upper and Lower CSTs

                                                                                                                          The miscibility with temp

                                                                                                                          a certain temperature miscibility starts to again with further in temperature

                                                                                                                          Closed-phase diagram ie nicotine-water system

                                                                                                                          A salol B thymol

                                                                                                                          53

                                                                                                                          Two component system containing solid and liquid phase (Eutectic Mixtures)

                                                                                                                          A salol B thymol

                                                                                                                          EMLAreg (lidocaine 25 and prilocaine 25) Cream

                                                                                                                          EMLA Cream (lidocaine 25 and prilocaine 25) is an emulsion in which the oil phase is a eutectic mixture of lidocaine and prilocaine in a ratio of 11 by weight This eutectic mixture has a melting point below room temperature and therefore both local anesthetics exist as a liquid oil rather than as crystals

                                                                                                                          Eutectic mixture Pharmaceutical Application

                                                                                                                          Triangular Diagrams for three ndash component systems

                                                                                                                          Three component system

                                                                                                                          Birzeit University Physical Pharmacy PHAR 323 Dr Hani Shtaya

                                                                                                                          1 Binding Forces Between Molecules2 Repulsive and Attractive Forces3 The Gaseous State The Ideal Gas Law Liquefaction of Gases Aerosols4 Solids and the Crystalline State Crystalline Solids Polymorphism Solvates Amorphous Solids5 Phase Equilibria and the Phase Rule Phase Rule Systems Containing One Component Condensed System Two-Component Systems Containing Liquid Phases Two-Component Systems Containing Solid and Liquid Phases Eutectic Mixtures Rules Relating to Triangular Diagrams

                                                                                                                          Topics that we have covered

                                                                                                                          • States of Matter
                                                                                                                          • States of Matter (2)
                                                                                                                          • Objectives of the lecture
                                                                                                                          • Comparison of Gases Liquids and Solids
                                                                                                                          • Slide 5
                                                                                                                          • Repulsive and Attractive Forces
                                                                                                                          • Ideal Gas Equation
                                                                                                                          • Gaseous state
                                                                                                                          • Slide 9
                                                                                                                          • Gaseous state (2)
                                                                                                                          • Liquefaction of Gases
                                                                                                                          • Slide 12
                                                                                                                          • SOLIDS amp CRYSTALLINE STATE Pharmaceutical Drugs more than 80
                                                                                                                          • Solids and the crystalline state
                                                                                                                          • Classification of Solids
                                                                                                                          • Slide 16
                                                                                                                          • Slide 17
                                                                                                                          • Crystal forms
                                                                                                                          • Types of Crystals
                                                                                                                          • Slide 20
                                                                                                                          • Slide 21
                                                                                                                          • Polymorphism
                                                                                                                          • Slide 23
                                                                                                                          • Slide 24
                                                                                                                          • Slide 25
                                                                                                                          • Slide 26
                                                                                                                          • Cocrystal
                                                                                                                          • Principle of polymorphism
                                                                                                                          • Solvates
                                                                                                                          • Polymorphism (2)
                                                                                                                          • Amorphous Solid
                                                                                                                          • Amorphous or crystalline amp therapeutic activity
                                                                                                                          • Slide 33
                                                                                                                          • Slide 34
                                                                                                                          • Polymorphism and Industry Pharmaceutical
                                                                                                                          • Celecoxib
                                                                                                                          • Furosemide
                                                                                                                          • Bioavailability
                                                                                                                          • Slide 39
                                                                                                                          • Slide 40
                                                                                                                          • Bioequivalence
                                                                                                                          • Slide 42
                                                                                                                          • Carbamazepine
                                                                                                                          • Slide 44
                                                                                                                          • AIDS drug ritonavir
                                                                                                                          • Slide 46
                                                                                                                          • Slide 47
                                                                                                                          • Phase Equilibria amp The Phase Rule
                                                                                                                          • Phase diagram ndash Water
                                                                                                                          • Phase Equilibria amp The Phase Rule Definitions
                                                                                                                          • Phase Definition
                                                                                                                          • Examples
                                                                                                                          • Components
                                                                                                                          • Examples
                                                                                                                          • Slide 55
                                                                                                                          • Degrees of freedom (or variance)
                                                                                                                          • Examples (2)
                                                                                                                          • Phase Equilibria amp The Phase Rule
                                                                                                                          • The phase rule
                                                                                                                          • Slide 60
                                                                                                                          • Phase Equilibria amp The Phase Rule (2)
                                                                                                                          • The number of phases in a system is denoted P
                                                                                                                          • Slide 63
                                                                                                                          • Slide 64
                                                                                                                          • One-component systems
                                                                                                                          • Slide 66
                                                                                                                          • Slide 67
                                                                                                                          • Slide 68
                                                                                                                          • Slide 69
                                                                                                                          • Slide 70
                                                                                                                          • Two component system containing liquid phase
                                                                                                                          • Slide 72
                                                                                                                          • The Critical Solution Temperature CST
                                                                                                                          • Systems Showing a Decrease in Miscibility with Rise in Temperat
                                                                                                                          • Systems Showing Upper and Lower CSTs
                                                                                                                          • Two component system containing solid and liquid phase (Eutecti
                                                                                                                          • Slide 77
                                                                                                                          • Eutectic mixture Pharmaceutical Application
                                                                                                                          • Three component system
                                                                                                                          • Slide 80
                                                                                                                          • Topics that we have covered

                                                                                                                            Condensed system System in which the vapor phase is ignored and only the solid andor liquid phases are considered

                                                                                                                            Two component system For two component system F can be 3 (3D model is needed) eg T p

                                                                                                                            and concentration usually we fix p = 1atm the vapor phase is neglected and F is reduced to 2

                                                                                                                            For three component system the pressure and temperature are fixed

                                                                                                                            Phenol water phase diagram

                                                                                                                            eg for point d (24)

                                                                                                                            Two component system containing liquid phase

                                                                                                                            Tie Line bc line The line at which the system at equilibrium will separate into phases of constant composition termed lsquoconjugate phasesrsquo

                                                                                                                            Lever Rule a way to calculate the proportions of each phase present on a phase diagram in a two phase field (at a given temperature and composition)

                                                                                                                            eg for point d (24)

                                                                                                                            For every 10 g of liquid system in equilibrium in point d

                                                                                                                            75 g phase A25 g phase B

                                                                                                                            ExampleMixed 24g phenol +76g water T 50degC

                                                                                                                            equilibrium75 g phase A 25 g phase B

                                                                                                                            11 phenol 63 phenol

                                                                                                                            011 times75 g=825 g phenol

                                                                                                                            063 times25 g=1575 g phenol

                                                                                                                            water rich phasecontains water+ phenol(11)

                                                                                                                            Phenol rich phasecontains Phenol (63)+ water

                                                                                                                            The Critical Solution Temperature CST

                                                                                                                            Is the maximum temperature at which the 2-phase region exists (or upper consolute temperature)

                                                                                                                            In the case of the phenol-water system this is 668oC (point h)

                                                                                                                            All combinations of phenol and water gt CST are completely miscible and yield 1-phase liquid systems

                                                                                                                            Systems Showing a Decrease in Miscibility with Rise in Temperature

                                                                                                                            A few mixtures exhibit a lower critical solution temperature (low CST) eg triethylamine plus water The miscibility with in temperature

                                                                                                                            Systems Showing Upper and Lower CSTs

                                                                                                                            The miscibility with temp

                                                                                                                            a certain temperature miscibility starts to again with further in temperature

                                                                                                                            Closed-phase diagram ie nicotine-water system

                                                                                                                            A salol B thymol

                                                                                                                            53

                                                                                                                            Two component system containing solid and liquid phase (Eutectic Mixtures)

                                                                                                                            A salol B thymol

                                                                                                                            EMLAreg (lidocaine 25 and prilocaine 25) Cream

                                                                                                                            EMLA Cream (lidocaine 25 and prilocaine 25) is an emulsion in which the oil phase is a eutectic mixture of lidocaine and prilocaine in a ratio of 11 by weight This eutectic mixture has a melting point below room temperature and therefore both local anesthetics exist as a liquid oil rather than as crystals

                                                                                                                            Eutectic mixture Pharmaceutical Application

                                                                                                                            Triangular Diagrams for three ndash component systems

                                                                                                                            Three component system

                                                                                                                            Birzeit University Physical Pharmacy PHAR 323 Dr Hani Shtaya

                                                                                                                            1 Binding Forces Between Molecules2 Repulsive and Attractive Forces3 The Gaseous State The Ideal Gas Law Liquefaction of Gases Aerosols4 Solids and the Crystalline State Crystalline Solids Polymorphism Solvates Amorphous Solids5 Phase Equilibria and the Phase Rule Phase Rule Systems Containing One Component Condensed System Two-Component Systems Containing Liquid Phases Two-Component Systems Containing Solid and Liquid Phases Eutectic Mixtures Rules Relating to Triangular Diagrams

                                                                                                                            Topics that we have covered

                                                                                                                            • States of Matter
                                                                                                                            • States of Matter (2)
                                                                                                                            • Objectives of the lecture
                                                                                                                            • Comparison of Gases Liquids and Solids
                                                                                                                            • Slide 5
                                                                                                                            • Repulsive and Attractive Forces
                                                                                                                            • Ideal Gas Equation
                                                                                                                            • Gaseous state
                                                                                                                            • Slide 9
                                                                                                                            • Gaseous state (2)
                                                                                                                            • Liquefaction of Gases
                                                                                                                            • Slide 12
                                                                                                                            • SOLIDS amp CRYSTALLINE STATE Pharmaceutical Drugs more than 80
                                                                                                                            • Solids and the crystalline state
                                                                                                                            • Classification of Solids
                                                                                                                            • Slide 16
                                                                                                                            • Slide 17
                                                                                                                            • Crystal forms
                                                                                                                            • Types of Crystals
                                                                                                                            • Slide 20
                                                                                                                            • Slide 21
                                                                                                                            • Polymorphism
                                                                                                                            • Slide 23
                                                                                                                            • Slide 24
                                                                                                                            • Slide 25
                                                                                                                            • Slide 26
                                                                                                                            • Cocrystal
                                                                                                                            • Principle of polymorphism
                                                                                                                            • Solvates
                                                                                                                            • Polymorphism (2)
                                                                                                                            • Amorphous Solid
                                                                                                                            • Amorphous or crystalline amp therapeutic activity
                                                                                                                            • Slide 33
                                                                                                                            • Slide 34
                                                                                                                            • Polymorphism and Industry Pharmaceutical
                                                                                                                            • Celecoxib
                                                                                                                            • Furosemide
                                                                                                                            • Bioavailability
                                                                                                                            • Slide 39
                                                                                                                            • Slide 40
                                                                                                                            • Bioequivalence
                                                                                                                            • Slide 42
                                                                                                                            • Carbamazepine
                                                                                                                            • Slide 44
                                                                                                                            • AIDS drug ritonavir
                                                                                                                            • Slide 46
                                                                                                                            • Slide 47
                                                                                                                            • Phase Equilibria amp The Phase Rule
                                                                                                                            • Phase diagram ndash Water
                                                                                                                            • Phase Equilibria amp The Phase Rule Definitions
                                                                                                                            • Phase Definition
                                                                                                                            • Examples
                                                                                                                            • Components
                                                                                                                            • Examples
                                                                                                                            • Slide 55
                                                                                                                            • Degrees of freedom (or variance)
                                                                                                                            • Examples (2)
                                                                                                                            • Phase Equilibria amp The Phase Rule
                                                                                                                            • The phase rule
                                                                                                                            • Slide 60
                                                                                                                            • Phase Equilibria amp The Phase Rule (2)
                                                                                                                            • The number of phases in a system is denoted P
                                                                                                                            • Slide 63
                                                                                                                            • Slide 64
                                                                                                                            • One-component systems
                                                                                                                            • Slide 66
                                                                                                                            • Slide 67
                                                                                                                            • Slide 68
                                                                                                                            • Slide 69
                                                                                                                            • Slide 70
                                                                                                                            • Two component system containing liquid phase
                                                                                                                            • Slide 72
                                                                                                                            • The Critical Solution Temperature CST
                                                                                                                            • Systems Showing a Decrease in Miscibility with Rise in Temperat
                                                                                                                            • Systems Showing Upper and Lower CSTs
                                                                                                                            • Two component system containing solid and liquid phase (Eutecti
                                                                                                                            • Slide 77
                                                                                                                            • Eutectic mixture Pharmaceutical Application
                                                                                                                            • Three component system
                                                                                                                            • Slide 80
                                                                                                                            • Topics that we have covered

                                                                                                                              Phenol water phase diagram

                                                                                                                              eg for point d (24)

                                                                                                                              Two component system containing liquid phase

                                                                                                                              Tie Line bc line The line at which the system at equilibrium will separate into phases of constant composition termed lsquoconjugate phasesrsquo

                                                                                                                              Lever Rule a way to calculate the proportions of each phase present on a phase diagram in a two phase field (at a given temperature and composition)

                                                                                                                              eg for point d (24)

                                                                                                                              For every 10 g of liquid system in equilibrium in point d

                                                                                                                              75 g phase A25 g phase B

                                                                                                                              ExampleMixed 24g phenol +76g water T 50degC

                                                                                                                              equilibrium75 g phase A 25 g phase B

                                                                                                                              11 phenol 63 phenol

                                                                                                                              011 times75 g=825 g phenol

                                                                                                                              063 times25 g=1575 g phenol

                                                                                                                              water rich phasecontains water+ phenol(11)

                                                                                                                              Phenol rich phasecontains Phenol (63)+ water

                                                                                                                              The Critical Solution Temperature CST

                                                                                                                              Is the maximum temperature at which the 2-phase region exists (or upper consolute temperature)

                                                                                                                              In the case of the phenol-water system this is 668oC (point h)

                                                                                                                              All combinations of phenol and water gt CST are completely miscible and yield 1-phase liquid systems

                                                                                                                              Systems Showing a Decrease in Miscibility with Rise in Temperature

                                                                                                                              A few mixtures exhibit a lower critical solution temperature (low CST) eg triethylamine plus water The miscibility with in temperature

                                                                                                                              Systems Showing Upper and Lower CSTs

                                                                                                                              The miscibility with temp

                                                                                                                              a certain temperature miscibility starts to again with further in temperature

                                                                                                                              Closed-phase diagram ie nicotine-water system

                                                                                                                              A salol B thymol

                                                                                                                              53

                                                                                                                              Two component system containing solid and liquid phase (Eutectic Mixtures)

                                                                                                                              A salol B thymol

                                                                                                                              EMLAreg (lidocaine 25 and prilocaine 25) Cream

                                                                                                                              EMLA Cream (lidocaine 25 and prilocaine 25) is an emulsion in which the oil phase is a eutectic mixture of lidocaine and prilocaine in a ratio of 11 by weight This eutectic mixture has a melting point below room temperature and therefore both local anesthetics exist as a liquid oil rather than as crystals

                                                                                                                              Eutectic mixture Pharmaceutical Application

                                                                                                                              Triangular Diagrams for three ndash component systems

                                                                                                                              Three component system

                                                                                                                              Birzeit University Physical Pharmacy PHAR 323 Dr Hani Shtaya

                                                                                                                              1 Binding Forces Between Molecules2 Repulsive and Attractive Forces3 The Gaseous State The Ideal Gas Law Liquefaction of Gases Aerosols4 Solids and the Crystalline State Crystalline Solids Polymorphism Solvates Amorphous Solids5 Phase Equilibria and the Phase Rule Phase Rule Systems Containing One Component Condensed System Two-Component Systems Containing Liquid Phases Two-Component Systems Containing Solid and Liquid Phases Eutectic Mixtures Rules Relating to Triangular Diagrams

                                                                                                                              Topics that we have covered

                                                                                                                              • States of Matter
                                                                                                                              • States of Matter (2)
                                                                                                                              • Objectives of the lecture
                                                                                                                              • Comparison of Gases Liquids and Solids
                                                                                                                              • Slide 5
                                                                                                                              • Repulsive and Attractive Forces
                                                                                                                              • Ideal Gas Equation
                                                                                                                              • Gaseous state
                                                                                                                              • Slide 9
                                                                                                                              • Gaseous state (2)
                                                                                                                              • Liquefaction of Gases
                                                                                                                              • Slide 12
                                                                                                                              • SOLIDS amp CRYSTALLINE STATE Pharmaceutical Drugs more than 80
                                                                                                                              • Solids and the crystalline state
                                                                                                                              • Classification of Solids
                                                                                                                              • Slide 16
                                                                                                                              • Slide 17
                                                                                                                              • Crystal forms
                                                                                                                              • Types of Crystals
                                                                                                                              • Slide 20
                                                                                                                              • Slide 21
                                                                                                                              • Polymorphism
                                                                                                                              • Slide 23
                                                                                                                              • Slide 24
                                                                                                                              • Slide 25
                                                                                                                              • Slide 26
                                                                                                                              • Cocrystal
                                                                                                                              • Principle of polymorphism
                                                                                                                              • Solvates
                                                                                                                              • Polymorphism (2)
                                                                                                                              • Amorphous Solid
                                                                                                                              • Amorphous or crystalline amp therapeutic activity
                                                                                                                              • Slide 33
                                                                                                                              • Slide 34
                                                                                                                              • Polymorphism and Industry Pharmaceutical
                                                                                                                              • Celecoxib
                                                                                                                              • Furosemide
                                                                                                                              • Bioavailability
                                                                                                                              • Slide 39
                                                                                                                              • Slide 40
                                                                                                                              • Bioequivalence
                                                                                                                              • Slide 42
                                                                                                                              • Carbamazepine
                                                                                                                              • Slide 44
                                                                                                                              • AIDS drug ritonavir
                                                                                                                              • Slide 46
                                                                                                                              • Slide 47
                                                                                                                              • Phase Equilibria amp The Phase Rule
                                                                                                                              • Phase diagram ndash Water
                                                                                                                              • Phase Equilibria amp The Phase Rule Definitions
                                                                                                                              • Phase Definition
                                                                                                                              • Examples
                                                                                                                              • Components
                                                                                                                              • Examples
                                                                                                                              • Slide 55
                                                                                                                              • Degrees of freedom (or variance)
                                                                                                                              • Examples (2)
                                                                                                                              • Phase Equilibria amp The Phase Rule
                                                                                                                              • The phase rule
                                                                                                                              • Slide 60
                                                                                                                              • Phase Equilibria amp The Phase Rule (2)
                                                                                                                              • The number of phases in a system is denoted P
                                                                                                                              • Slide 63
                                                                                                                              • Slide 64
                                                                                                                              • One-component systems
                                                                                                                              • Slide 66
                                                                                                                              • Slide 67
                                                                                                                              • Slide 68
                                                                                                                              • Slide 69
                                                                                                                              • Slide 70
                                                                                                                              • Two component system containing liquid phase
                                                                                                                              • Slide 72
                                                                                                                              • The Critical Solution Temperature CST
                                                                                                                              • Systems Showing a Decrease in Miscibility with Rise in Temperat
                                                                                                                              • Systems Showing Upper and Lower CSTs
                                                                                                                              • Two component system containing solid and liquid phase (Eutecti
                                                                                                                              • Slide 77
                                                                                                                              • Eutectic mixture Pharmaceutical Application
                                                                                                                              • Three component system
                                                                                                                              • Slide 80
                                                                                                                              • Topics that we have covered

                                                                                                                                eg for point d (24)

                                                                                                                                Two component system containing liquid phase

                                                                                                                                Tie Line bc line The line at which the system at equilibrium will separate into phases of constant composition termed lsquoconjugate phasesrsquo

                                                                                                                                Lever Rule a way to calculate the proportions of each phase present on a phase diagram in a two phase field (at a given temperature and composition)

                                                                                                                                eg for point d (24)

                                                                                                                                For every 10 g of liquid system in equilibrium in point d

                                                                                                                                75 g phase A25 g phase B

                                                                                                                                ExampleMixed 24g phenol +76g water T 50degC

                                                                                                                                equilibrium75 g phase A 25 g phase B

                                                                                                                                11 phenol 63 phenol

                                                                                                                                011 times75 g=825 g phenol

                                                                                                                                063 times25 g=1575 g phenol

                                                                                                                                water rich phasecontains water+ phenol(11)

                                                                                                                                Phenol rich phasecontains Phenol (63)+ water

                                                                                                                                The Critical Solution Temperature CST

                                                                                                                                Is the maximum temperature at which the 2-phase region exists (or upper consolute temperature)

                                                                                                                                In the case of the phenol-water system this is 668oC (point h)

                                                                                                                                All combinations of phenol and water gt CST are completely miscible and yield 1-phase liquid systems

                                                                                                                                Systems Showing a Decrease in Miscibility with Rise in Temperature

                                                                                                                                A few mixtures exhibit a lower critical solution temperature (low CST) eg triethylamine plus water The miscibility with in temperature

                                                                                                                                Systems Showing Upper and Lower CSTs

                                                                                                                                The miscibility with temp

                                                                                                                                a certain temperature miscibility starts to again with further in temperature

                                                                                                                                Closed-phase diagram ie nicotine-water system

                                                                                                                                A salol B thymol

                                                                                                                                53

                                                                                                                                Two component system containing solid and liquid phase (Eutectic Mixtures)

                                                                                                                                A salol B thymol

                                                                                                                                EMLAreg (lidocaine 25 and prilocaine 25) Cream

                                                                                                                                EMLA Cream (lidocaine 25 and prilocaine 25) is an emulsion in which the oil phase is a eutectic mixture of lidocaine and prilocaine in a ratio of 11 by weight This eutectic mixture has a melting point below room temperature and therefore both local anesthetics exist as a liquid oil rather than as crystals

                                                                                                                                Eutectic mixture Pharmaceutical Application

                                                                                                                                Triangular Diagrams for three ndash component systems

                                                                                                                                Three component system

                                                                                                                                Birzeit University Physical Pharmacy PHAR 323 Dr Hani Shtaya

                                                                                                                                1 Binding Forces Between Molecules2 Repulsive and Attractive Forces3 The Gaseous State The Ideal Gas Law Liquefaction of Gases Aerosols4 Solids and the Crystalline State Crystalline Solids Polymorphism Solvates Amorphous Solids5 Phase Equilibria and the Phase Rule Phase Rule Systems Containing One Component Condensed System Two-Component Systems Containing Liquid Phases Two-Component Systems Containing Solid and Liquid Phases Eutectic Mixtures Rules Relating to Triangular Diagrams

                                                                                                                                Topics that we have covered

                                                                                                                                • States of Matter
                                                                                                                                • States of Matter (2)
                                                                                                                                • Objectives of the lecture
                                                                                                                                • Comparison of Gases Liquids and Solids
                                                                                                                                • Slide 5
                                                                                                                                • Repulsive and Attractive Forces
                                                                                                                                • Ideal Gas Equation
                                                                                                                                • Gaseous state
                                                                                                                                • Slide 9
                                                                                                                                • Gaseous state (2)
                                                                                                                                • Liquefaction of Gases
                                                                                                                                • Slide 12
                                                                                                                                • SOLIDS amp CRYSTALLINE STATE Pharmaceutical Drugs more than 80
                                                                                                                                • Solids and the crystalline state
                                                                                                                                • Classification of Solids
                                                                                                                                • Slide 16
                                                                                                                                • Slide 17
                                                                                                                                • Crystal forms
                                                                                                                                • Types of Crystals
                                                                                                                                • Slide 20
                                                                                                                                • Slide 21
                                                                                                                                • Polymorphism
                                                                                                                                • Slide 23
                                                                                                                                • Slide 24
                                                                                                                                • Slide 25
                                                                                                                                • Slide 26
                                                                                                                                • Cocrystal
                                                                                                                                • Principle of polymorphism
                                                                                                                                • Solvates
                                                                                                                                • Polymorphism (2)
                                                                                                                                • Amorphous Solid
                                                                                                                                • Amorphous or crystalline amp therapeutic activity
                                                                                                                                • Slide 33
                                                                                                                                • Slide 34
                                                                                                                                • Polymorphism and Industry Pharmaceutical
                                                                                                                                • Celecoxib
                                                                                                                                • Furosemide
                                                                                                                                • Bioavailability
                                                                                                                                • Slide 39
                                                                                                                                • Slide 40
                                                                                                                                • Bioequivalence
                                                                                                                                • Slide 42
                                                                                                                                • Carbamazepine
                                                                                                                                • Slide 44
                                                                                                                                • AIDS drug ritonavir
                                                                                                                                • Slide 46
                                                                                                                                • Slide 47
                                                                                                                                • Phase Equilibria amp The Phase Rule
                                                                                                                                • Phase diagram ndash Water
                                                                                                                                • Phase Equilibria amp The Phase Rule Definitions
                                                                                                                                • Phase Definition
                                                                                                                                • Examples
                                                                                                                                • Components
                                                                                                                                • Examples
                                                                                                                                • Slide 55
                                                                                                                                • Degrees of freedom (or variance)
                                                                                                                                • Examples (2)
                                                                                                                                • Phase Equilibria amp The Phase Rule
                                                                                                                                • The phase rule
                                                                                                                                • Slide 60
                                                                                                                                • Phase Equilibria amp The Phase Rule (2)
                                                                                                                                • The number of phases in a system is denoted P
                                                                                                                                • Slide 63
                                                                                                                                • Slide 64
                                                                                                                                • One-component systems
                                                                                                                                • Slide 66
                                                                                                                                • Slide 67
                                                                                                                                • Slide 68
                                                                                                                                • Slide 69
                                                                                                                                • Slide 70
                                                                                                                                • Two component system containing liquid phase
                                                                                                                                • Slide 72
                                                                                                                                • The Critical Solution Temperature CST
                                                                                                                                • Systems Showing a Decrease in Miscibility with Rise in Temperat
                                                                                                                                • Systems Showing Upper and Lower CSTs
                                                                                                                                • Two component system containing solid and liquid phase (Eutecti
                                                                                                                                • Slide 77
                                                                                                                                • Eutectic mixture Pharmaceutical Application
                                                                                                                                • Three component system
                                                                                                                                • Slide 80
                                                                                                                                • Topics that we have covered

                                                                                                                                  eg for point d (24)

                                                                                                                                  For every 10 g of liquid system in equilibrium in point d

                                                                                                                                  75 g phase A25 g phase B

                                                                                                                                  ExampleMixed 24g phenol +76g water T 50degC

                                                                                                                                  equilibrium75 g phase A 25 g phase B

                                                                                                                                  11 phenol 63 phenol

                                                                                                                                  011 times75 g=825 g phenol

                                                                                                                                  063 times25 g=1575 g phenol

                                                                                                                                  water rich phasecontains water+ phenol(11)

                                                                                                                                  Phenol rich phasecontains Phenol (63)+ water

                                                                                                                                  The Critical Solution Temperature CST

                                                                                                                                  Is the maximum temperature at which the 2-phase region exists (or upper consolute temperature)

                                                                                                                                  In the case of the phenol-water system this is 668oC (point h)

                                                                                                                                  All combinations of phenol and water gt CST are completely miscible and yield 1-phase liquid systems

                                                                                                                                  Systems Showing a Decrease in Miscibility with Rise in Temperature

                                                                                                                                  A few mixtures exhibit a lower critical solution temperature (low CST) eg triethylamine plus water The miscibility with in temperature

                                                                                                                                  Systems Showing Upper and Lower CSTs

                                                                                                                                  The miscibility with temp

                                                                                                                                  a certain temperature miscibility starts to again with further in temperature

                                                                                                                                  Closed-phase diagram ie nicotine-water system

                                                                                                                                  A salol B thymol

                                                                                                                                  53

                                                                                                                                  Two component system containing solid and liquid phase (Eutectic Mixtures)

                                                                                                                                  A salol B thymol

                                                                                                                                  EMLAreg (lidocaine 25 and prilocaine 25) Cream

                                                                                                                                  EMLA Cream (lidocaine 25 and prilocaine 25) is an emulsion in which the oil phase is a eutectic mixture of lidocaine and prilocaine in a ratio of 11 by weight This eutectic mixture has a melting point below room temperature and therefore both local anesthetics exist as a liquid oil rather than as crystals

                                                                                                                                  Eutectic mixture Pharmaceutical Application

                                                                                                                                  Triangular Diagrams for three ndash component systems

                                                                                                                                  Three component system

                                                                                                                                  Birzeit University Physical Pharmacy PHAR 323 Dr Hani Shtaya

                                                                                                                                  1 Binding Forces Between Molecules2 Repulsive and Attractive Forces3 The Gaseous State The Ideal Gas Law Liquefaction of Gases Aerosols4 Solids and the Crystalline State Crystalline Solids Polymorphism Solvates Amorphous Solids5 Phase Equilibria and the Phase Rule Phase Rule Systems Containing One Component Condensed System Two-Component Systems Containing Liquid Phases Two-Component Systems Containing Solid and Liquid Phases Eutectic Mixtures Rules Relating to Triangular Diagrams

                                                                                                                                  Topics that we have covered

                                                                                                                                  • States of Matter
                                                                                                                                  • States of Matter (2)
                                                                                                                                  • Objectives of the lecture
                                                                                                                                  • Comparison of Gases Liquids and Solids
                                                                                                                                  • Slide 5
                                                                                                                                  • Repulsive and Attractive Forces
                                                                                                                                  • Ideal Gas Equation
                                                                                                                                  • Gaseous state
                                                                                                                                  • Slide 9
                                                                                                                                  • Gaseous state (2)
                                                                                                                                  • Liquefaction of Gases
                                                                                                                                  • Slide 12
                                                                                                                                  • SOLIDS amp CRYSTALLINE STATE Pharmaceutical Drugs more than 80
                                                                                                                                  • Solids and the crystalline state
                                                                                                                                  • Classification of Solids
                                                                                                                                  • Slide 16
                                                                                                                                  • Slide 17
                                                                                                                                  • Crystal forms
                                                                                                                                  • Types of Crystals
                                                                                                                                  • Slide 20
                                                                                                                                  • Slide 21
                                                                                                                                  • Polymorphism
                                                                                                                                  • Slide 23
                                                                                                                                  • Slide 24
                                                                                                                                  • Slide 25
                                                                                                                                  • Slide 26
                                                                                                                                  • Cocrystal
                                                                                                                                  • Principle of polymorphism
                                                                                                                                  • Solvates
                                                                                                                                  • Polymorphism (2)
                                                                                                                                  • Amorphous Solid
                                                                                                                                  • Amorphous or crystalline amp therapeutic activity
                                                                                                                                  • Slide 33
                                                                                                                                  • Slide 34
                                                                                                                                  • Polymorphism and Industry Pharmaceutical
                                                                                                                                  • Celecoxib
                                                                                                                                  • Furosemide
                                                                                                                                  • Bioavailability
                                                                                                                                  • Slide 39
                                                                                                                                  • Slide 40
                                                                                                                                  • Bioequivalence
                                                                                                                                  • Slide 42
                                                                                                                                  • Carbamazepine
                                                                                                                                  • Slide 44
                                                                                                                                  • AIDS drug ritonavir
                                                                                                                                  • Slide 46
                                                                                                                                  • Slide 47
                                                                                                                                  • Phase Equilibria amp The Phase Rule
                                                                                                                                  • Phase diagram ndash Water
                                                                                                                                  • Phase Equilibria amp The Phase Rule Definitions
                                                                                                                                  • Phase Definition
                                                                                                                                  • Examples
                                                                                                                                  • Components
                                                                                                                                  • Examples
                                                                                                                                  • Slide 55
                                                                                                                                  • Degrees of freedom (or variance)
                                                                                                                                  • Examples (2)
                                                                                                                                  • Phase Equilibria amp The Phase Rule
                                                                                                                                  • The phase rule
                                                                                                                                  • Slide 60
                                                                                                                                  • Phase Equilibria amp The Phase Rule (2)
                                                                                                                                  • The number of phases in a system is denoted P
                                                                                                                                  • Slide 63
                                                                                                                                  • Slide 64
                                                                                                                                  • One-component systems
                                                                                                                                  • Slide 66
                                                                                                                                  • Slide 67
                                                                                                                                  • Slide 68
                                                                                                                                  • Slide 69
                                                                                                                                  • Slide 70
                                                                                                                                  • Two component system containing liquid phase
                                                                                                                                  • Slide 72
                                                                                                                                  • The Critical Solution Temperature CST
                                                                                                                                  • Systems Showing a Decrease in Miscibility with Rise in Temperat
                                                                                                                                  • Systems Showing Upper and Lower CSTs
                                                                                                                                  • Two component system containing solid and liquid phase (Eutecti
                                                                                                                                  • Slide 77
                                                                                                                                  • Eutectic mixture Pharmaceutical Application
                                                                                                                                  • Three component system
                                                                                                                                  • Slide 80
                                                                                                                                  • Topics that we have covered

                                                                                                                                    The Critical Solution Temperature CST

                                                                                                                                    Is the maximum temperature at which the 2-phase region exists (or upper consolute temperature)

                                                                                                                                    In the case of the phenol-water system this is 668oC (point h)

                                                                                                                                    All combinations of phenol and water gt CST are completely miscible and yield 1-phase liquid systems

                                                                                                                                    Systems Showing a Decrease in Miscibility with Rise in Temperature

                                                                                                                                    A few mixtures exhibit a lower critical solution temperature (low CST) eg triethylamine plus water The miscibility with in temperature

                                                                                                                                    Systems Showing Upper and Lower CSTs

                                                                                                                                    The miscibility with temp

                                                                                                                                    a certain temperature miscibility starts to again with further in temperature

                                                                                                                                    Closed-phase diagram ie nicotine-water system

                                                                                                                                    A salol B thymol

                                                                                                                                    53

                                                                                                                                    Two component system containing solid and liquid phase (Eutectic Mixtures)

                                                                                                                                    A salol B thymol

                                                                                                                                    EMLAreg (lidocaine 25 and prilocaine 25) Cream

                                                                                                                                    EMLA Cream (lidocaine 25 and prilocaine 25) is an emulsion in which the oil phase is a eutectic mixture of lidocaine and prilocaine in a ratio of 11 by weight This eutectic mixture has a melting point below room temperature and therefore both local anesthetics exist as a liquid oil rather than as crystals

                                                                                                                                    Eutectic mixture Pharmaceutical Application

                                                                                                                                    Triangular Diagrams for three ndash component systems

                                                                                                                                    Three component system

                                                                                                                                    Birzeit University Physical Pharmacy PHAR 323 Dr Hani Shtaya

                                                                                                                                    1 Binding Forces Between Molecules2 Repulsive and Attractive Forces3 The Gaseous State The Ideal Gas Law Liquefaction of Gases Aerosols4 Solids and the Crystalline State Crystalline Solids Polymorphism Solvates Amorphous Solids5 Phase Equilibria and the Phase Rule Phase Rule Systems Containing One Component Condensed System Two-Component Systems Containing Liquid Phases Two-Component Systems Containing Solid and Liquid Phases Eutectic Mixtures Rules Relating to Triangular Diagrams

                                                                                                                                    Topics that we have covered

                                                                                                                                    • States of Matter
                                                                                                                                    • States of Matter (2)
                                                                                                                                    • Objectives of the lecture
                                                                                                                                    • Comparison of Gases Liquids and Solids
                                                                                                                                    • Slide 5
                                                                                                                                    • Repulsive and Attractive Forces
                                                                                                                                    • Ideal Gas Equation
                                                                                                                                    • Gaseous state
                                                                                                                                    • Slide 9
                                                                                                                                    • Gaseous state (2)
                                                                                                                                    • Liquefaction of Gases
                                                                                                                                    • Slide 12
                                                                                                                                    • SOLIDS amp CRYSTALLINE STATE Pharmaceutical Drugs more than 80
                                                                                                                                    • Solids and the crystalline state
                                                                                                                                    • Classification of Solids
                                                                                                                                    • Slide 16
                                                                                                                                    • Slide 17
                                                                                                                                    • Crystal forms
                                                                                                                                    • Types of Crystals
                                                                                                                                    • Slide 20
                                                                                                                                    • Slide 21
                                                                                                                                    • Polymorphism
                                                                                                                                    • Slide 23
                                                                                                                                    • Slide 24
                                                                                                                                    • Slide 25
                                                                                                                                    • Slide 26
                                                                                                                                    • Cocrystal
                                                                                                                                    • Principle of polymorphism
                                                                                                                                    • Solvates
                                                                                                                                    • Polymorphism (2)
                                                                                                                                    • Amorphous Solid
                                                                                                                                    • Amorphous or crystalline amp therapeutic activity
                                                                                                                                    • Slide 33
                                                                                                                                    • Slide 34
                                                                                                                                    • Polymorphism and Industry Pharmaceutical
                                                                                                                                    • Celecoxib
                                                                                                                                    • Furosemide
                                                                                                                                    • Bioavailability
                                                                                                                                    • Slide 39
                                                                                                                                    • Slide 40
                                                                                                                                    • Bioequivalence
                                                                                                                                    • Slide 42
                                                                                                                                    • Carbamazepine
                                                                                                                                    • Slide 44
                                                                                                                                    • AIDS drug ritonavir
                                                                                                                                    • Slide 46
                                                                                                                                    • Slide 47
                                                                                                                                    • Phase Equilibria amp The Phase Rule
                                                                                                                                    • Phase diagram ndash Water
                                                                                                                                    • Phase Equilibria amp The Phase Rule Definitions
                                                                                                                                    • Phase Definition
                                                                                                                                    • Examples
                                                                                                                                    • Components
                                                                                                                                    • Examples
                                                                                                                                    • Slide 55
                                                                                                                                    • Degrees of freedom (or variance)
                                                                                                                                    • Examples (2)
                                                                                                                                    • Phase Equilibria amp The Phase Rule
                                                                                                                                    • The phase rule
                                                                                                                                    • Slide 60
                                                                                                                                    • Phase Equilibria amp The Phase Rule (2)
                                                                                                                                    • The number of phases in a system is denoted P
                                                                                                                                    • Slide 63
                                                                                                                                    • Slide 64
                                                                                                                                    • One-component systems
                                                                                                                                    • Slide 66
                                                                                                                                    • Slide 67
                                                                                                                                    • Slide 68
                                                                                                                                    • Slide 69
                                                                                                                                    • Slide 70
                                                                                                                                    • Two component system containing liquid phase
                                                                                                                                    • Slide 72
                                                                                                                                    • The Critical Solution Temperature CST
                                                                                                                                    • Systems Showing a Decrease in Miscibility with Rise in Temperat
                                                                                                                                    • Systems Showing Upper and Lower CSTs
                                                                                                                                    • Two component system containing solid and liquid phase (Eutecti
                                                                                                                                    • Slide 77
                                                                                                                                    • Eutectic mixture Pharmaceutical Application
                                                                                                                                    • Three component system
                                                                                                                                    • Slide 80
                                                                                                                                    • Topics that we have covered

                                                                                                                                      Systems Showing a Decrease in Miscibility with Rise in Temperature

                                                                                                                                      A few mixtures exhibit a lower critical solution temperature (low CST) eg triethylamine plus water The miscibility with in temperature

                                                                                                                                      Systems Showing Upper and Lower CSTs

                                                                                                                                      The miscibility with temp

                                                                                                                                      a certain temperature miscibility starts to again with further in temperature

                                                                                                                                      Closed-phase diagram ie nicotine-water system

                                                                                                                                      A salol B thymol

                                                                                                                                      53

                                                                                                                                      Two component system containing solid and liquid phase (Eutectic Mixtures)

                                                                                                                                      A salol B thymol

                                                                                                                                      EMLAreg (lidocaine 25 and prilocaine 25) Cream

                                                                                                                                      EMLA Cream (lidocaine 25 and prilocaine 25) is an emulsion in which the oil phase is a eutectic mixture of lidocaine and prilocaine in a ratio of 11 by weight This eutectic mixture has a melting point below room temperature and therefore both local anesthetics exist as a liquid oil rather than as crystals

                                                                                                                                      Eutectic mixture Pharmaceutical Application

                                                                                                                                      Triangular Diagrams for three ndash component systems

                                                                                                                                      Three component system

                                                                                                                                      Birzeit University Physical Pharmacy PHAR 323 Dr Hani Shtaya

                                                                                                                                      1 Binding Forces Between Molecules2 Repulsive and Attractive Forces3 The Gaseous State The Ideal Gas Law Liquefaction of Gases Aerosols4 Solids and the Crystalline State Crystalline Solids Polymorphism Solvates Amorphous Solids5 Phase Equilibria and the Phase Rule Phase Rule Systems Containing One Component Condensed System Two-Component Systems Containing Liquid Phases Two-Component Systems Containing Solid and Liquid Phases Eutectic Mixtures Rules Relating to Triangular Diagrams

                                                                                                                                      Topics that we have covered

                                                                                                                                      • States of Matter
                                                                                                                                      • States of Matter (2)
                                                                                                                                      • Objectives of the lecture
                                                                                                                                      • Comparison of Gases Liquids and Solids
                                                                                                                                      • Slide 5
                                                                                                                                      • Repulsive and Attractive Forces
                                                                                                                                      • Ideal Gas Equation
                                                                                                                                      • Gaseous state
                                                                                                                                      • Slide 9
                                                                                                                                      • Gaseous state (2)
                                                                                                                                      • Liquefaction of Gases
                                                                                                                                      • Slide 12
                                                                                                                                      • SOLIDS amp CRYSTALLINE STATE Pharmaceutical Drugs more than 80
                                                                                                                                      • Solids and the crystalline state
                                                                                                                                      • Classification of Solids
                                                                                                                                      • Slide 16
                                                                                                                                      • Slide 17
                                                                                                                                      • Crystal forms
                                                                                                                                      • Types of Crystals
                                                                                                                                      • Slide 20
                                                                                                                                      • Slide 21
                                                                                                                                      • Polymorphism
                                                                                                                                      • Slide 23
                                                                                                                                      • Slide 24
                                                                                                                                      • Slide 25
                                                                                                                                      • Slide 26
                                                                                                                                      • Cocrystal
                                                                                                                                      • Principle of polymorphism
                                                                                                                                      • Solvates
                                                                                                                                      • Polymorphism (2)
                                                                                                                                      • Amorphous Solid
                                                                                                                                      • Amorphous or crystalline amp therapeutic activity
                                                                                                                                      • Slide 33
                                                                                                                                      • Slide 34
                                                                                                                                      • Polymorphism and Industry Pharmaceutical
                                                                                                                                      • Celecoxib
                                                                                                                                      • Furosemide
                                                                                                                                      • Bioavailability
                                                                                                                                      • Slide 39
                                                                                                                                      • Slide 40
                                                                                                                                      • Bioequivalence
                                                                                                                                      • Slide 42
                                                                                                                                      • Carbamazepine
                                                                                                                                      • Slide 44
                                                                                                                                      • AIDS drug ritonavir
                                                                                                                                      • Slide 46
                                                                                                                                      • Slide 47
                                                                                                                                      • Phase Equilibria amp The Phase Rule
                                                                                                                                      • Phase diagram ndash Water
                                                                                                                                      • Phase Equilibria amp The Phase Rule Definitions
                                                                                                                                      • Phase Definition
                                                                                                                                      • Examples
                                                                                                                                      • Components
                                                                                                                                      • Examples
                                                                                                                                      • Slide 55
                                                                                                                                      • Degrees of freedom (or variance)
                                                                                                                                      • Examples (2)
                                                                                                                                      • Phase Equilibria amp The Phase Rule
                                                                                                                                      • The phase rule
                                                                                                                                      • Slide 60
                                                                                                                                      • Phase Equilibria amp The Phase Rule (2)
                                                                                                                                      • The number of phases in a system is denoted P
                                                                                                                                      • Slide 63
                                                                                                                                      • Slide 64
                                                                                                                                      • One-component systems
                                                                                                                                      • Slide 66
                                                                                                                                      • Slide 67
                                                                                                                                      • Slide 68
                                                                                                                                      • Slide 69
                                                                                                                                      • Slide 70
                                                                                                                                      • Two component system containing liquid phase
                                                                                                                                      • Slide 72
                                                                                                                                      • The Critical Solution Temperature CST
                                                                                                                                      • Systems Showing a Decrease in Miscibility with Rise in Temperat
                                                                                                                                      • Systems Showing Upper and Lower CSTs
                                                                                                                                      • Two component system containing solid and liquid phase (Eutecti
                                                                                                                                      • Slide 77
                                                                                                                                      • Eutectic mixture Pharmaceutical Application
                                                                                                                                      • Three component system
                                                                                                                                      • Slide 80
                                                                                                                                      • Topics that we have covered

                                                                                                                                        Systems Showing Upper and Lower CSTs

                                                                                                                                        The miscibility with temp

                                                                                                                                        a certain temperature miscibility starts to again with further in temperature

                                                                                                                                        Closed-phase diagram ie nicotine-water system

                                                                                                                                        A salol B thymol

                                                                                                                                        53

                                                                                                                                        Two component system containing solid and liquid phase (Eutectic Mixtures)

                                                                                                                                        A salol B thymol

                                                                                                                                        EMLAreg (lidocaine 25 and prilocaine 25) Cream

                                                                                                                                        EMLA Cream (lidocaine 25 and prilocaine 25) is an emulsion in which the oil phase is a eutectic mixture of lidocaine and prilocaine in a ratio of 11 by weight This eutectic mixture has a melting point below room temperature and therefore both local anesthetics exist as a liquid oil rather than as crystals

                                                                                                                                        Eutectic mixture Pharmaceutical Application

                                                                                                                                        Triangular Diagrams for three ndash component systems

                                                                                                                                        Three component system

                                                                                                                                        Birzeit University Physical Pharmacy PHAR 323 Dr Hani Shtaya

                                                                                                                                        1 Binding Forces Between Molecules2 Repulsive and Attractive Forces3 The Gaseous State The Ideal Gas Law Liquefaction of Gases Aerosols4 Solids and the Crystalline State Crystalline Solids Polymorphism Solvates Amorphous Solids5 Phase Equilibria and the Phase Rule Phase Rule Systems Containing One Component Condensed System Two-Component Systems Containing Liquid Phases Two-Component Systems Containing Solid and Liquid Phases Eutectic Mixtures Rules Relating to Triangular Diagrams

                                                                                                                                        Topics that we have covered

                                                                                                                                        • States of Matter
                                                                                                                                        • States of Matter (2)
                                                                                                                                        • Objectives of the lecture
                                                                                                                                        • Comparison of Gases Liquids and Solids
                                                                                                                                        • Slide 5
                                                                                                                                        • Repulsive and Attractive Forces
                                                                                                                                        • Ideal Gas Equation
                                                                                                                                        • Gaseous state
                                                                                                                                        • Slide 9
                                                                                                                                        • Gaseous state (2)
                                                                                                                                        • Liquefaction of Gases
                                                                                                                                        • Slide 12
                                                                                                                                        • SOLIDS amp CRYSTALLINE STATE Pharmaceutical Drugs more than 80
                                                                                                                                        • Solids and the crystalline state
                                                                                                                                        • Classification of Solids
                                                                                                                                        • Slide 16
                                                                                                                                        • Slide 17
                                                                                                                                        • Crystal forms
                                                                                                                                        • Types of Crystals
                                                                                                                                        • Slide 20
                                                                                                                                        • Slide 21
                                                                                                                                        • Polymorphism
                                                                                                                                        • Slide 23
                                                                                                                                        • Slide 24
                                                                                                                                        • Slide 25
                                                                                                                                        • Slide 26
                                                                                                                                        • Cocrystal
                                                                                                                                        • Principle of polymorphism
                                                                                                                                        • Solvates
                                                                                                                                        • Polymorphism (2)
                                                                                                                                        • Amorphous Solid
                                                                                                                                        • Amorphous or crystalline amp therapeutic activity
                                                                                                                                        • Slide 33
                                                                                                                                        • Slide 34
                                                                                                                                        • Polymorphism and Industry Pharmaceutical
                                                                                                                                        • Celecoxib
                                                                                                                                        • Furosemide
                                                                                                                                        • Bioavailability
                                                                                                                                        • Slide 39
                                                                                                                                        • Slide 40
                                                                                                                                        • Bioequivalence
                                                                                                                                        • Slide 42
                                                                                                                                        • Carbamazepine
                                                                                                                                        • Slide 44
                                                                                                                                        • AIDS drug ritonavir
                                                                                                                                        • Slide 46
                                                                                                                                        • Slide 47
                                                                                                                                        • Phase Equilibria amp The Phase Rule
                                                                                                                                        • Phase diagram ndash Water
                                                                                                                                        • Phase Equilibria amp The Phase Rule Definitions
                                                                                                                                        • Phase Definition
                                                                                                                                        • Examples
                                                                                                                                        • Components
                                                                                                                                        • Examples
                                                                                                                                        • Slide 55
                                                                                                                                        • Degrees of freedom (or variance)
                                                                                                                                        • Examples (2)
                                                                                                                                        • Phase Equilibria amp The Phase Rule
                                                                                                                                        • The phase rule
                                                                                                                                        • Slide 60
                                                                                                                                        • Phase Equilibria amp The Phase Rule (2)
                                                                                                                                        • The number of phases in a system is denoted P
                                                                                                                                        • Slide 63
                                                                                                                                        • Slide 64
                                                                                                                                        • One-component systems
                                                                                                                                        • Slide 66
                                                                                                                                        • Slide 67
                                                                                                                                        • Slide 68
                                                                                                                                        • Slide 69
                                                                                                                                        • Slide 70
                                                                                                                                        • Two component system containing liquid phase
                                                                                                                                        • Slide 72
                                                                                                                                        • The Critical Solution Temperature CST
                                                                                                                                        • Systems Showing a Decrease in Miscibility with Rise in Temperat
                                                                                                                                        • Systems Showing Upper and Lower CSTs
                                                                                                                                        • Two component system containing solid and liquid phase (Eutecti
                                                                                                                                        • Slide 77
                                                                                                                                        • Eutectic mixture Pharmaceutical Application
                                                                                                                                        • Three component system
                                                                                                                                        • Slide 80
                                                                                                                                        • Topics that we have covered

                                                                                                                                          A salol B thymol

                                                                                                                                          53

                                                                                                                                          Two component system containing solid and liquid phase (Eutectic Mixtures)

                                                                                                                                          A salol B thymol

                                                                                                                                          EMLAreg (lidocaine 25 and prilocaine 25) Cream

                                                                                                                                          EMLA Cream (lidocaine 25 and prilocaine 25) is an emulsion in which the oil phase is a eutectic mixture of lidocaine and prilocaine in a ratio of 11 by weight This eutectic mixture has a melting point below room temperature and therefore both local anesthetics exist as a liquid oil rather than as crystals

                                                                                                                                          Eutectic mixture Pharmaceutical Application

                                                                                                                                          Triangular Diagrams for three ndash component systems

                                                                                                                                          Three component system

                                                                                                                                          Birzeit University Physical Pharmacy PHAR 323 Dr Hani Shtaya

                                                                                                                                          1 Binding Forces Between Molecules2 Repulsive and Attractive Forces3 The Gaseous State The Ideal Gas Law Liquefaction of Gases Aerosols4 Solids and the Crystalline State Crystalline Solids Polymorphism Solvates Amorphous Solids5 Phase Equilibria and the Phase Rule Phase Rule Systems Containing One Component Condensed System Two-Component Systems Containing Liquid Phases Two-Component Systems Containing Solid and Liquid Phases Eutectic Mixtures Rules Relating to Triangular Diagrams

                                                                                                                                          Topics that we have covered

                                                                                                                                          • States of Matter
                                                                                                                                          • States of Matter (2)
                                                                                                                                          • Objectives of the lecture
                                                                                                                                          • Comparison of Gases Liquids and Solids
                                                                                                                                          • Slide 5
                                                                                                                                          • Repulsive and Attractive Forces
                                                                                                                                          • Ideal Gas Equation
                                                                                                                                          • Gaseous state
                                                                                                                                          • Slide 9
                                                                                                                                          • Gaseous state (2)
                                                                                                                                          • Liquefaction of Gases
                                                                                                                                          • Slide 12
                                                                                                                                          • SOLIDS amp CRYSTALLINE STATE Pharmaceutical Drugs more than 80
                                                                                                                                          • Solids and the crystalline state
                                                                                                                                          • Classification of Solids
                                                                                                                                          • Slide 16
                                                                                                                                          • Slide 17
                                                                                                                                          • Crystal forms
                                                                                                                                          • Types of Crystals
                                                                                                                                          • Slide 20
                                                                                                                                          • Slide 21
                                                                                                                                          • Polymorphism
                                                                                                                                          • Slide 23
                                                                                                                                          • Slide 24
                                                                                                                                          • Slide 25
                                                                                                                                          • Slide 26
                                                                                                                                          • Cocrystal
                                                                                                                                          • Principle of polymorphism
                                                                                                                                          • Solvates
                                                                                                                                          • Polymorphism (2)
                                                                                                                                          • Amorphous Solid
                                                                                                                                          • Amorphous or crystalline amp therapeutic activity
                                                                                                                                          • Slide 33
                                                                                                                                          • Slide 34
                                                                                                                                          • Polymorphism and Industry Pharmaceutical
                                                                                                                                          • Celecoxib
                                                                                                                                          • Furosemide
                                                                                                                                          • Bioavailability
                                                                                                                                          • Slide 39
                                                                                                                                          • Slide 40
                                                                                                                                          • Bioequivalence
                                                                                                                                          • Slide 42
                                                                                                                                          • Carbamazepine
                                                                                                                                          • Slide 44
                                                                                                                                          • AIDS drug ritonavir
                                                                                                                                          • Slide 46
                                                                                                                                          • Slide 47
                                                                                                                                          • Phase Equilibria amp The Phase Rule
                                                                                                                                          • Phase diagram ndash Water
                                                                                                                                          • Phase Equilibria amp The Phase Rule Definitions
                                                                                                                                          • Phase Definition
                                                                                                                                          • Examples
                                                                                                                                          • Components
                                                                                                                                          • Examples
                                                                                                                                          • Slide 55
                                                                                                                                          • Degrees of freedom (or variance)
                                                                                                                                          • Examples (2)
                                                                                                                                          • Phase Equilibria amp The Phase Rule
                                                                                                                                          • The phase rule
                                                                                                                                          • Slide 60
                                                                                                                                          • Phase Equilibria amp The Phase Rule (2)
                                                                                                                                          • The number of phases in a system is denoted P
                                                                                                                                          • Slide 63
                                                                                                                                          • Slide 64
                                                                                                                                          • One-component systems
                                                                                                                                          • Slide 66
                                                                                                                                          • Slide 67
                                                                                                                                          • Slide 68
                                                                                                                                          • Slide 69
                                                                                                                                          • Slide 70
                                                                                                                                          • Two component system containing liquid phase
                                                                                                                                          • Slide 72
                                                                                                                                          • The Critical Solution Temperature CST
                                                                                                                                          • Systems Showing a Decrease in Miscibility with Rise in Temperat
                                                                                                                                          • Systems Showing Upper and Lower CSTs
                                                                                                                                          • Two component system containing solid and liquid phase (Eutecti
                                                                                                                                          • Slide 77
                                                                                                                                          • Eutectic mixture Pharmaceutical Application
                                                                                                                                          • Three component system
                                                                                                                                          • Slide 80
                                                                                                                                          • Topics that we have covered

                                                                                                                                            A salol B thymol

                                                                                                                                            EMLAreg (lidocaine 25 and prilocaine 25) Cream

                                                                                                                                            EMLA Cream (lidocaine 25 and prilocaine 25) is an emulsion in which the oil phase is a eutectic mixture of lidocaine and prilocaine in a ratio of 11 by weight This eutectic mixture has a melting point below room temperature and therefore both local anesthetics exist as a liquid oil rather than as crystals

                                                                                                                                            Eutectic mixture Pharmaceutical Application

                                                                                                                                            Triangular Diagrams for three ndash component systems

                                                                                                                                            Three component system

                                                                                                                                            Birzeit University Physical Pharmacy PHAR 323 Dr Hani Shtaya

                                                                                                                                            1 Binding Forces Between Molecules2 Repulsive and Attractive Forces3 The Gaseous State The Ideal Gas Law Liquefaction of Gases Aerosols4 Solids and the Crystalline State Crystalline Solids Polymorphism Solvates Amorphous Solids5 Phase Equilibria and the Phase Rule Phase Rule Systems Containing One Component Condensed System Two-Component Systems Containing Liquid Phases Two-Component Systems Containing Solid and Liquid Phases Eutectic Mixtures Rules Relating to Triangular Diagrams

                                                                                                                                            Topics that we have covered

                                                                                                                                            • States of Matter
                                                                                                                                            • States of Matter (2)
                                                                                                                                            • Objectives of the lecture
                                                                                                                                            • Comparison of Gases Liquids and Solids
                                                                                                                                            • Slide 5
                                                                                                                                            • Repulsive and Attractive Forces
                                                                                                                                            • Ideal Gas Equation
                                                                                                                                            • Gaseous state
                                                                                                                                            • Slide 9
                                                                                                                                            • Gaseous state (2)
                                                                                                                                            • Liquefaction of Gases
                                                                                                                                            • Slide 12
                                                                                                                                            • SOLIDS amp CRYSTALLINE STATE Pharmaceutical Drugs more than 80
                                                                                                                                            • Solids and the crystalline state
                                                                                                                                            • Classification of Solids
                                                                                                                                            • Slide 16
                                                                                                                                            • Slide 17
                                                                                                                                            • Crystal forms
                                                                                                                                            • Types of Crystals
                                                                                                                                            • Slide 20
                                                                                                                                            • Slide 21
                                                                                                                                            • Polymorphism
                                                                                                                                            • Slide 23
                                                                                                                                            • Slide 24
                                                                                                                                            • Slide 25
                                                                                                                                            • Slide 26
                                                                                                                                            • Cocrystal
                                                                                                                                            • Principle of polymorphism
                                                                                                                                            • Solvates
                                                                                                                                            • Polymorphism (2)
                                                                                                                                            • Amorphous Solid
                                                                                                                                            • Amorphous or crystalline amp therapeutic activity
                                                                                                                                            • Slide 33
                                                                                                                                            • Slide 34
                                                                                                                                            • Polymorphism and Industry Pharmaceutical
                                                                                                                                            • Celecoxib
                                                                                                                                            • Furosemide
                                                                                                                                            • Bioavailability
                                                                                                                                            • Slide 39
                                                                                                                                            • Slide 40
                                                                                                                                            • Bioequivalence
                                                                                                                                            • Slide 42
                                                                                                                                            • Carbamazepine
                                                                                                                                            • Slide 44
                                                                                                                                            • AIDS drug ritonavir
                                                                                                                                            • Slide 46
                                                                                                                                            • Slide 47
                                                                                                                                            • Phase Equilibria amp The Phase Rule
                                                                                                                                            • Phase diagram ndash Water
                                                                                                                                            • Phase Equilibria amp The Phase Rule Definitions
                                                                                                                                            • Phase Definition
                                                                                                                                            • Examples
                                                                                                                                            • Components
                                                                                                                                            • Examples
                                                                                                                                            • Slide 55
                                                                                                                                            • Degrees of freedom (or variance)
                                                                                                                                            • Examples (2)
                                                                                                                                            • Phase Equilibria amp The Phase Rule
                                                                                                                                            • The phase rule
                                                                                                                                            • Slide 60
                                                                                                                                            • Phase Equilibria amp The Phase Rule (2)
                                                                                                                                            • The number of phases in a system is denoted P
                                                                                                                                            • Slide 63
                                                                                                                                            • Slide 64
                                                                                                                                            • One-component systems
                                                                                                                                            • Slide 66
                                                                                                                                            • Slide 67
                                                                                                                                            • Slide 68
                                                                                                                                            • Slide 69
                                                                                                                                            • Slide 70
                                                                                                                                            • Two component system containing liquid phase
                                                                                                                                            • Slide 72
                                                                                                                                            • The Critical Solution Temperature CST
                                                                                                                                            • Systems Showing a Decrease in Miscibility with Rise in Temperat
                                                                                                                                            • Systems Showing Upper and Lower CSTs
                                                                                                                                            • Two component system containing solid and liquid phase (Eutecti
                                                                                                                                            • Slide 77
                                                                                                                                            • Eutectic mixture Pharmaceutical Application
                                                                                                                                            • Three component system
                                                                                                                                            • Slide 80
                                                                                                                                            • Topics that we have covered

                                                                                                                                              EMLAreg (lidocaine 25 and prilocaine 25) Cream

                                                                                                                                              EMLA Cream (lidocaine 25 and prilocaine 25) is an emulsion in which the oil phase is a eutectic mixture of lidocaine and prilocaine in a ratio of 11 by weight This eutectic mixture has a melting point below room temperature and therefore both local anesthetics exist as a liquid oil rather than as crystals

                                                                                                                                              Eutectic mixture Pharmaceutical Application

                                                                                                                                              Triangular Diagrams for three ndash component systems

                                                                                                                                              Three component system

                                                                                                                                              Birzeit University Physical Pharmacy PHAR 323 Dr Hani Shtaya

                                                                                                                                              1 Binding Forces Between Molecules2 Repulsive and Attractive Forces3 The Gaseous State The Ideal Gas Law Liquefaction of Gases Aerosols4 Solids and the Crystalline State Crystalline Solids Polymorphism Solvates Amorphous Solids5 Phase Equilibria and the Phase Rule Phase Rule Systems Containing One Component Condensed System Two-Component Systems Containing Liquid Phases Two-Component Systems Containing Solid and Liquid Phases Eutectic Mixtures Rules Relating to Triangular Diagrams

                                                                                                                                              Topics that we have covered

                                                                                                                                              • States of Matter
                                                                                                                                              • States of Matter (2)
                                                                                                                                              • Objectives of the lecture
                                                                                                                                              • Comparison of Gases Liquids and Solids
                                                                                                                                              • Slide 5
                                                                                                                                              • Repulsive and Attractive Forces
                                                                                                                                              • Ideal Gas Equation
                                                                                                                                              • Gaseous state
                                                                                                                                              • Slide 9
                                                                                                                                              • Gaseous state (2)
                                                                                                                                              • Liquefaction of Gases
                                                                                                                                              • Slide 12
                                                                                                                                              • SOLIDS amp CRYSTALLINE STATE Pharmaceutical Drugs more than 80
                                                                                                                                              • Solids and the crystalline state
                                                                                                                                              • Classification of Solids
                                                                                                                                              • Slide 16
                                                                                                                                              • Slide 17
                                                                                                                                              • Crystal forms
                                                                                                                                              • Types of Crystals
                                                                                                                                              • Slide 20
                                                                                                                                              • Slide 21
                                                                                                                                              • Polymorphism
                                                                                                                                              • Slide 23
                                                                                                                                              • Slide 24
                                                                                                                                              • Slide 25
                                                                                                                                              • Slide 26
                                                                                                                                              • Cocrystal
                                                                                                                                              • Principle of polymorphism
                                                                                                                                              • Solvates
                                                                                                                                              • Polymorphism (2)
                                                                                                                                              • Amorphous Solid
                                                                                                                                              • Amorphous or crystalline amp therapeutic activity
                                                                                                                                              • Slide 33
                                                                                                                                              • Slide 34
                                                                                                                                              • Polymorphism and Industry Pharmaceutical
                                                                                                                                              • Celecoxib
                                                                                                                                              • Furosemide
                                                                                                                                              • Bioavailability
                                                                                                                                              • Slide 39
                                                                                                                                              • Slide 40
                                                                                                                                              • Bioequivalence
                                                                                                                                              • Slide 42
                                                                                                                                              • Carbamazepine
                                                                                                                                              • Slide 44
                                                                                                                                              • AIDS drug ritonavir
                                                                                                                                              • Slide 46
                                                                                                                                              • Slide 47
                                                                                                                                              • Phase Equilibria amp The Phase Rule
                                                                                                                                              • Phase diagram ndash Water
                                                                                                                                              • Phase Equilibria amp The Phase Rule Definitions
                                                                                                                                              • Phase Definition
                                                                                                                                              • Examples
                                                                                                                                              • Components
                                                                                                                                              • Examples
                                                                                                                                              • Slide 55
                                                                                                                                              • Degrees of freedom (or variance)
                                                                                                                                              • Examples (2)
                                                                                                                                              • Phase Equilibria amp The Phase Rule
                                                                                                                                              • The phase rule
                                                                                                                                              • Slide 60
                                                                                                                                              • Phase Equilibria amp The Phase Rule (2)
                                                                                                                                              • The number of phases in a system is denoted P
                                                                                                                                              • Slide 63
                                                                                                                                              • Slide 64
                                                                                                                                              • One-component systems
                                                                                                                                              • Slide 66
                                                                                                                                              • Slide 67
                                                                                                                                              • Slide 68
                                                                                                                                              • Slide 69
                                                                                                                                              • Slide 70
                                                                                                                                              • Two component system containing liquid phase
                                                                                                                                              • Slide 72
                                                                                                                                              • The Critical Solution Temperature CST
                                                                                                                                              • Systems Showing a Decrease in Miscibility with Rise in Temperat
                                                                                                                                              • Systems Showing Upper and Lower CSTs
                                                                                                                                              • Two component system containing solid and liquid phase (Eutecti
                                                                                                                                              • Slide 77
                                                                                                                                              • Eutectic mixture Pharmaceutical Application
                                                                                                                                              • Three component system
                                                                                                                                              • Slide 80
                                                                                                                                              • Topics that we have covered

                                                                                                                                                Triangular Diagrams for three ndash component systems

                                                                                                                                                Three component system

                                                                                                                                                Birzeit University Physical Pharmacy PHAR 323 Dr Hani Shtaya

                                                                                                                                                1 Binding Forces Between Molecules2 Repulsive and Attractive Forces3 The Gaseous State The Ideal Gas Law Liquefaction of Gases Aerosols4 Solids and the Crystalline State Crystalline Solids Polymorphism Solvates Amorphous Solids5 Phase Equilibria and the Phase Rule Phase Rule Systems Containing One Component Condensed System Two-Component Systems Containing Liquid Phases Two-Component Systems Containing Solid and Liquid Phases Eutectic Mixtures Rules Relating to Triangular Diagrams

                                                                                                                                                Topics that we have covered

                                                                                                                                                • States of Matter
                                                                                                                                                • States of Matter (2)
                                                                                                                                                • Objectives of the lecture
                                                                                                                                                • Comparison of Gases Liquids and Solids
                                                                                                                                                • Slide 5
                                                                                                                                                • Repulsive and Attractive Forces
                                                                                                                                                • Ideal Gas Equation
                                                                                                                                                • Gaseous state
                                                                                                                                                • Slide 9
                                                                                                                                                • Gaseous state (2)
                                                                                                                                                • Liquefaction of Gases
                                                                                                                                                • Slide 12
                                                                                                                                                • SOLIDS amp CRYSTALLINE STATE Pharmaceutical Drugs more than 80
                                                                                                                                                • Solids and the crystalline state
                                                                                                                                                • Classification of Solids
                                                                                                                                                • Slide 16
                                                                                                                                                • Slide 17
                                                                                                                                                • Crystal forms
                                                                                                                                                • Types of Crystals
                                                                                                                                                • Slide 20
                                                                                                                                                • Slide 21
                                                                                                                                                • Polymorphism
                                                                                                                                                • Slide 23
                                                                                                                                                • Slide 24
                                                                                                                                                • Slide 25
                                                                                                                                                • Slide 26
                                                                                                                                                • Cocrystal
                                                                                                                                                • Principle of polymorphism
                                                                                                                                                • Solvates
                                                                                                                                                • Polymorphism (2)
                                                                                                                                                • Amorphous Solid
                                                                                                                                                • Amorphous or crystalline amp therapeutic activity
                                                                                                                                                • Slide 33
                                                                                                                                                • Slide 34
                                                                                                                                                • Polymorphism and Industry Pharmaceutical
                                                                                                                                                • Celecoxib
                                                                                                                                                • Furosemide
                                                                                                                                                • Bioavailability
                                                                                                                                                • Slide 39
                                                                                                                                                • Slide 40
                                                                                                                                                • Bioequivalence
                                                                                                                                                • Slide 42
                                                                                                                                                • Carbamazepine
                                                                                                                                                • Slide 44
                                                                                                                                                • AIDS drug ritonavir
                                                                                                                                                • Slide 46
                                                                                                                                                • Slide 47
                                                                                                                                                • Phase Equilibria amp The Phase Rule
                                                                                                                                                • Phase diagram ndash Water
                                                                                                                                                • Phase Equilibria amp The Phase Rule Definitions
                                                                                                                                                • Phase Definition
                                                                                                                                                • Examples
                                                                                                                                                • Components
                                                                                                                                                • Examples
                                                                                                                                                • Slide 55
                                                                                                                                                • Degrees of freedom (or variance)
                                                                                                                                                • Examples (2)
                                                                                                                                                • Phase Equilibria amp The Phase Rule
                                                                                                                                                • The phase rule
                                                                                                                                                • Slide 60
                                                                                                                                                • Phase Equilibria amp The Phase Rule (2)
                                                                                                                                                • The number of phases in a system is denoted P
                                                                                                                                                • Slide 63
                                                                                                                                                • Slide 64
                                                                                                                                                • One-component systems
                                                                                                                                                • Slide 66
                                                                                                                                                • Slide 67
                                                                                                                                                • Slide 68
                                                                                                                                                • Slide 69
                                                                                                                                                • Slide 70
                                                                                                                                                • Two component system containing liquid phase
                                                                                                                                                • Slide 72
                                                                                                                                                • The Critical Solution Temperature CST
                                                                                                                                                • Systems Showing a Decrease in Miscibility with Rise in Temperat
                                                                                                                                                • Systems Showing Upper and Lower CSTs
                                                                                                                                                • Two component system containing solid and liquid phase (Eutecti
                                                                                                                                                • Slide 77
                                                                                                                                                • Eutectic mixture Pharmaceutical Application
                                                                                                                                                • Three component system
                                                                                                                                                • Slide 80
                                                                                                                                                • Topics that we have covered

                                                                                                                                                  Birzeit University Physical Pharmacy PHAR 323 Dr Hani Shtaya

                                                                                                                                                  1 Binding Forces Between Molecules2 Repulsive and Attractive Forces3 The Gaseous State The Ideal Gas Law Liquefaction of Gases Aerosols4 Solids and the Crystalline State Crystalline Solids Polymorphism Solvates Amorphous Solids5 Phase Equilibria and the Phase Rule Phase Rule Systems Containing One Component Condensed System Two-Component Systems Containing Liquid Phases Two-Component Systems Containing Solid and Liquid Phases Eutectic Mixtures Rules Relating to Triangular Diagrams

                                                                                                                                                  Topics that we have covered

                                                                                                                                                  • States of Matter
                                                                                                                                                  • States of Matter (2)
                                                                                                                                                  • Objectives of the lecture
                                                                                                                                                  • Comparison of Gases Liquids and Solids
                                                                                                                                                  • Slide 5
                                                                                                                                                  • Repulsive and Attractive Forces
                                                                                                                                                  • Ideal Gas Equation
                                                                                                                                                  • Gaseous state
                                                                                                                                                  • Slide 9
                                                                                                                                                  • Gaseous state (2)
                                                                                                                                                  • Liquefaction of Gases
                                                                                                                                                  • Slide 12
                                                                                                                                                  • SOLIDS amp CRYSTALLINE STATE Pharmaceutical Drugs more than 80
                                                                                                                                                  • Solids and the crystalline state
                                                                                                                                                  • Classification of Solids
                                                                                                                                                  • Slide 16
                                                                                                                                                  • Slide 17
                                                                                                                                                  • Crystal forms
                                                                                                                                                  • Types of Crystals
                                                                                                                                                  • Slide 20
                                                                                                                                                  • Slide 21
                                                                                                                                                  • Polymorphism
                                                                                                                                                  • Slide 23
                                                                                                                                                  • Slide 24
                                                                                                                                                  • Slide 25
                                                                                                                                                  • Slide 26
                                                                                                                                                  • Cocrystal
                                                                                                                                                  • Principle of polymorphism
                                                                                                                                                  • Solvates
                                                                                                                                                  • Polymorphism (2)
                                                                                                                                                  • Amorphous Solid
                                                                                                                                                  • Amorphous or crystalline amp therapeutic activity
                                                                                                                                                  • Slide 33
                                                                                                                                                  • Slide 34
                                                                                                                                                  • Polymorphism and Industry Pharmaceutical
                                                                                                                                                  • Celecoxib
                                                                                                                                                  • Furosemide
                                                                                                                                                  • Bioavailability
                                                                                                                                                  • Slide 39
                                                                                                                                                  • Slide 40
                                                                                                                                                  • Bioequivalence
                                                                                                                                                  • Slide 42
                                                                                                                                                  • Carbamazepine
                                                                                                                                                  • Slide 44
                                                                                                                                                  • AIDS drug ritonavir
                                                                                                                                                  • Slide 46
                                                                                                                                                  • Slide 47
                                                                                                                                                  • Phase Equilibria amp The Phase Rule
                                                                                                                                                  • Phase diagram ndash Water
                                                                                                                                                  • Phase Equilibria amp The Phase Rule Definitions
                                                                                                                                                  • Phase Definition
                                                                                                                                                  • Examples
                                                                                                                                                  • Components
                                                                                                                                                  • Examples
                                                                                                                                                  • Slide 55
                                                                                                                                                  • Degrees of freedom (or variance)
                                                                                                                                                  • Examples (2)
                                                                                                                                                  • Phase Equilibria amp The Phase Rule
                                                                                                                                                  • The phase rule
                                                                                                                                                  • Slide 60
                                                                                                                                                  • Phase Equilibria amp The Phase Rule (2)
                                                                                                                                                  • The number of phases in a system is denoted P
                                                                                                                                                  • Slide 63
                                                                                                                                                  • Slide 64
                                                                                                                                                  • One-component systems
                                                                                                                                                  • Slide 66
                                                                                                                                                  • Slide 67
                                                                                                                                                  • Slide 68
                                                                                                                                                  • Slide 69
                                                                                                                                                  • Slide 70
                                                                                                                                                  • Two component system containing liquid phase
                                                                                                                                                  • Slide 72
                                                                                                                                                  • The Critical Solution Temperature CST
                                                                                                                                                  • Systems Showing a Decrease in Miscibility with Rise in Temperat
                                                                                                                                                  • Systems Showing Upper and Lower CSTs
                                                                                                                                                  • Two component system containing solid and liquid phase (Eutecti
                                                                                                                                                  • Slide 77
                                                                                                                                                  • Eutectic mixture Pharmaceutical Application
                                                                                                                                                  • Three component system
                                                                                                                                                  • Slide 80
                                                                                                                                                  • Topics that we have covered

                                                                                                                                                    1 Binding Forces Between Molecules2 Repulsive and Attractive Forces3 The Gaseous State The Ideal Gas Law Liquefaction of Gases Aerosols4 Solids and the Crystalline State Crystalline Solids Polymorphism Solvates Amorphous Solids5 Phase Equilibria and the Phase Rule Phase Rule Systems Containing One Component Condensed System Two-Component Systems Containing Liquid Phases Two-Component Systems Containing Solid and Liquid Phases Eutectic Mixtures Rules Relating to Triangular Diagrams

                                                                                                                                                    Topics that we have covered

                                                                                                                                                    • States of Matter
                                                                                                                                                    • States of Matter (2)
                                                                                                                                                    • Objectives of the lecture
                                                                                                                                                    • Comparison of Gases Liquids and Solids
                                                                                                                                                    • Slide 5
                                                                                                                                                    • Repulsive and Attractive Forces
                                                                                                                                                    • Ideal Gas Equation
                                                                                                                                                    • Gaseous state
                                                                                                                                                    • Slide 9
                                                                                                                                                    • Gaseous state (2)
                                                                                                                                                    • Liquefaction of Gases
                                                                                                                                                    • Slide 12
                                                                                                                                                    • SOLIDS amp CRYSTALLINE STATE Pharmaceutical Drugs more than 80
                                                                                                                                                    • Solids and the crystalline state
                                                                                                                                                    • Classification of Solids
                                                                                                                                                    • Slide 16
                                                                                                                                                    • Slide 17
                                                                                                                                                    • Crystal forms
                                                                                                                                                    • Types of Crystals
                                                                                                                                                    • Slide 20
                                                                                                                                                    • Slide 21
                                                                                                                                                    • Polymorphism
                                                                                                                                                    • Slide 23
                                                                                                                                                    • Slide 24
                                                                                                                                                    • Slide 25
                                                                                                                                                    • Slide 26
                                                                                                                                                    • Cocrystal
                                                                                                                                                    • Principle of polymorphism
                                                                                                                                                    • Solvates
                                                                                                                                                    • Polymorphism (2)
                                                                                                                                                    • Amorphous Solid
                                                                                                                                                    • Amorphous or crystalline amp therapeutic activity
                                                                                                                                                    • Slide 33
                                                                                                                                                    • Slide 34
                                                                                                                                                    • Polymorphism and Industry Pharmaceutical
                                                                                                                                                    • Celecoxib
                                                                                                                                                    • Furosemide
                                                                                                                                                    • Bioavailability
                                                                                                                                                    • Slide 39
                                                                                                                                                    • Slide 40
                                                                                                                                                    • Bioequivalence
                                                                                                                                                    • Slide 42
                                                                                                                                                    • Carbamazepine
                                                                                                                                                    • Slide 44
                                                                                                                                                    • AIDS drug ritonavir
                                                                                                                                                    • Slide 46
                                                                                                                                                    • Slide 47
                                                                                                                                                    • Phase Equilibria amp The Phase Rule
                                                                                                                                                    • Phase diagram ndash Water
                                                                                                                                                    • Phase Equilibria amp The Phase Rule Definitions
                                                                                                                                                    • Phase Definition
                                                                                                                                                    • Examples
                                                                                                                                                    • Components
                                                                                                                                                    • Examples
                                                                                                                                                    • Slide 55
                                                                                                                                                    • Degrees of freedom (or variance)
                                                                                                                                                    • Examples (2)
                                                                                                                                                    • Phase Equilibria amp The Phase Rule
                                                                                                                                                    • The phase rule
                                                                                                                                                    • Slide 60
                                                                                                                                                    • Phase Equilibria amp The Phase Rule (2)
                                                                                                                                                    • The number of phases in a system is denoted P
                                                                                                                                                    • Slide 63
                                                                                                                                                    • Slide 64
                                                                                                                                                    • One-component systems
                                                                                                                                                    • Slide 66
                                                                                                                                                    • Slide 67
                                                                                                                                                    • Slide 68
                                                                                                                                                    • Slide 69
                                                                                                                                                    • Slide 70
                                                                                                                                                    • Two component system containing liquid phase
                                                                                                                                                    • Slide 72
                                                                                                                                                    • The Critical Solution Temperature CST
                                                                                                                                                    • Systems Showing a Decrease in Miscibility with Rise in Temperat
                                                                                                                                                    • Systems Showing Upper and Lower CSTs
                                                                                                                                                    • Two component system containing solid and liquid phase (Eutecti
                                                                                                                                                    • Slide 77
                                                                                                                                                    • Eutectic mixture Pharmaceutical Application
                                                                                                                                                    • Three component system
                                                                                                                                                    • Slide 80
                                                                                                                                                    • Topics that we have covered

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