GPAT ONLINE CLASSES

Physical PharmacyPresented by

Dr. T.E.Gopala Krishna MurthyProfessor & Principal

Bapatla College of PharmacyBapatla, Andhra Pradesh.

GPAT ONLINE CLASSES

In collaboration with A.P govt.

Topics to be covered in this session

1. Matter, properties of matter

2. Micrometrics and powder rheology

3. Surface and interfacial phenomenon

4. Viscosity and rheology

5. Complexation

6. Buffers

7. Solutions

1. Matter, properties of matter

– Change in the state of matter

– Latent heat and vapour pressure

– Sublimation

– Eutectic mixtures

– Relative humidity

– Liquid complexes

– Liquid crystals

– Glassy state

– Crystalline and amorphous solids

– Polymorphism

• The enthalpy and entropy increases as the material

go from solid to liquid to gas

• Balance of enthalpy, entropy and temperature

determines the spontaneous process changes

• Latent heat in change of state. Heat of fusion and

heat of vaporization

Change in the state of matter

Latent heat and vapour pressure

• Its depends on temperature not on the

amount of liquid

Sublimation

• Transformation of a solid to vapour without passage

through liquid state

• Solid sublimes only when the pressure of the vapour

is below the triple point of that substance

• Camphor, naphthalene, P-dichlorobenzene and

iodine have triple point pressure below 1 atm.

Eutectic mixtures

• Thymol- salol, salol and camphor, camphor. Chloral

hydrate, menthol- betanaphthol aspirin and

acetaminophen.

Relative humidity

• Water of hydration, crystallization, adsorption,

drying , production of effervescent products

Liquid complexes

• Creation of a solute structure with in a solvent

• Reduced rate of hydrolysis of benzocaine solution

containing caffeine

• Improved light stability of chlorpromazine in

solutions containing saccharin

Liquid crystals

• The molecules in liquid are mobile in three directions and

rotate about three axes

• In solids, the molecules are immobile and rotations are

not possible

• Heating of lipids results intermediate liquid crystal

phases

• Biological systems lyotropic mesomorphism takes place

in presence of water

• Freedom to move, take many shapes and maintaining a

high degree of order

Liquid crystals

• Prepared by heat treatment (thermo tropic), by

adding controlled amount of water

• Molecules that form liquid crystals are

✓ Organic

✓ Elongated

✓ Rectilinear in shape

rigid and posses strong dipoles and easily

polarisable groups

• Nematic phase

– Parallel arrangements with restricted rotation about

at least one axis

– Might be to be thread or cable like

• Smectic phase or two dimensional crystal

– Molecular arrangement as layers

– Mobile in two directions, rotate about one axis

• Cholesteric phase

– Combination of smectic and nematic

– Thicker than smectic

Properties and significance

• Mobile and possess the property of birefringence

• Change in colour with temperature

• Nematic crystals are sensitive to electric field

• Smectic for solubilisation of hydrophobic materials

• Similar structure like cell membranes

• Gall stones and atherosclerosis

Glassy state

• Highly disordered or short range order

• Do not have specific melting points

• No decrease in volume at the crystallisation

temperature

Crystalline and amorphous solids

• Metallic, ionic, valence and molecular bonds are

involved in solids

• Arrangement in a regularly repeating pattern in

crystalline solids

• The units can be atoms, ions or molecules.

Covalent, electrostatic attractions, van der Walls

forces and hydrogen bonding are involved.

• Cubic (sodium chloride), tetragonal (urea),

hexagonal (urea) , rhombic (iodine), monoclinic

(sucrose) and triclinic (boric acid)

• Amorphous solids are super cooled liquids with

random arrangement

• Amorphous and cubic crystals are isotropic

Crystalline and amorphous solids

Polymorphism

• Exist in more than one crystalline form of chemically

identical components

• Differences in melting point, IR spectra solubility

and X-ray diffraction

• Depending on factors such as storage temperature,

recrystallization solvent, rate of cooling and rate of

recrystallization

2. Micromeritics and powder rheology

– Particle size and distribution

– Number and weight distribution

– Particle number

– Methods of determination of particle size

– Methods of determination of particle volume

– Methods of determination of particle surface area

Particle size and distribution

• Shape and surface area of individual particles and

size range & number or weight of particles present

are important in poly disperse sample

• Equivalent spherical diameter, volume diameter,

projected diameter and stokes diameter

General equation for average particle size

• P=1, 2, 3 corresponding to length, surface or volume

• P is positive for arithmetic and negative for harmonic

• Frequency distribution curve, cumulative percentage

frequency over size or under size

• The distribution may follow log normal distribution

• Log probability plot is employed for geometric mean and s.d

p

f

fp

meannd

ndd

/1

=

+

Number and weight distribution

• Number distribution from microscopy and weight

distribution from sieving and sedimentation

• Inter conversion by using the Hatch-Choate

equation

gg

in dd 2'

log757.5loglog −=

Particle number

• The number of particles per unit weight. It’s

determined as follows.

3

6

cnd

N =

Methods of determination of particle size

• Optical microscopy

– Range of 0.2 -100 µm

– Length and breadth are only possible

– Slow and tedious

– 300- 500 particles are counted

– Aggregates can be detected

• Sieving

– As fine as 44 µ

– Sieve loading, duration and intensity of agitation and attrition

of granular materials

Sedimentation

• The mean particle size is calculated with the

following equation

• Applicable to spherical shaped particles

• Free from aggregates, deflocculating agent is

required

• Flow of dispersion medium around particles is

laminar or streamline

( )gt

hd

os

ost

−=

18

Sedimentation

• Pipette method, balance method and hydrometer

method are available

• Specifications of Andreasen apparatus are 550

ml vessel, 10 ml pipette 2o cm below the

suspension surface and 1- 2% suspension at

constant temperature

Methods of determination of particle volume

• Coulter counter is employed

• Capable of counting 4000 per second

• Particle growth and dissolution

• Effect of antibacterial agent on growth of

microorganisms

Methods of determination of particle surface area

• Adsorption method

– Amount of a gas/liquid solute that is adsorbed on

to the sample of powder to form a monolayer

– Type II isotherm may be constructed

– Based on BET equation

( )

( )

om

p

mo bpV

b

bVppV

p 11 −+=

−

Methods of determination of particle surface area

• Adsorption method

– Nitrogen gas is commonly employed and the

apparatus is quantasorb

– A plot of p/V (p-p0) against p/p0 is a straight line

with a slope and intercepts b and Vm

• Air permeability method

– The rate of penetration of a gas or liquid on to the

powder is related to resistance to the flow of a

liquid through a compact of powder

– Based on Kozeny- Carman equation

( )23

21

..

−

=

KI

Pt

S

AV

w

1-1 Constant Pressure Regulator

1-2 Pressure Control

1-3 Air Filter

1-4 Air Pump

1-5 Dryer

1-6 Packed Powder Sample

1-7 Sample Tube

1-8 Range Control

1-9 Manometer

1-10 Calculator Chart

1-11 Manometer Level ControlFisher-sub-sieve-sizer-principle-

picture-1/HMK-22 Fisher Sub Sieve

Sizer

Fisher sub sieve sizer

• Derived properties of powders

• Based on two fundamental properties size

distribution and surface area

– Porosity

– Packing arrangements

• The porosity of spherical uniform size particles

in closest and loosest packing is 26 and 48%

• Derived Properties of Powders

• Densities of particles

– Bulk density,

– granule density and

– true density

• In non porous solids, true and granule densities are

equal

• For nonporous solids, displacement of helium or

mercury, benzene or water is used

g

raparticle −=1int

• Densities of particles

• For porous solids and for true density helium is used

• Mercury is used for granule density

• Intra particle, inter particle and total porosity

g

berspace

−=1int

• Bulkiness

• Reciprocal of bulk density and influenced by

particle size and size distribution

• Flow properties

– High density, low internal porosity offers free

flowing

• Dustibility and stickiness

3. Surface and interfacial phenomenon

• Contents:

– Liquid interface

– Surface and interfacial tensions

– Surface free energy

– Measurement of surface and interfacial tensions

– Spreading coefficient

– Adsorption and liquid interface

– HLB classification

– Surface active agents

– Adsorption at solid interface

– Electrical properties of films

• Liquid interface

– Cohesive forces in bulk and adhesive forces at

surface

• Surface and interfacial tensions

– The force per unit length applied parallel to the

surface/ interface

– Expressed in dyne/cm

• Surface free energy

– W=γ∆A

– Expressed in ergs

• Measurement of surface and interfacial tensions

– Capillary rise, DuNouy ring , drop weight, bubble pressure,

sessile drop, and Wilhelmy plate methods are used

– Choice of method depends on the parameter to be determined,

desired accuracy and convenience, available sample size and

the effect of time on surface tension

– Temperature control is necessary

– Capillary rise method is not suitable for surface tension

– γ=1/2 rhрg

– Force required detaching a platinum- iridium ring immersed at

the surface/ interface

• Spreading coefficient

– S=γ S –γ L-γ LS

• Adsorption and liquid interface

– Positive adsorption

– Negative adsorption

• Surface active agents

– Ions and molecules adsorbed at the interface

– Amphiphilic

• HLB classification

– 0-3 anti foaming agents, 3-8 W/O emulsifying agents, 7-9

wetting and spreading agents, 8-16 O/W emulsifying

agents, 13-16 detergents >16 solubiling agents

• Adsorption at solid interface

– Adsorption of gas on solid surface to remove

odour , gas masks

– Adsorption of liquid on solid in decolourisation,

chromatography, detergency and wetting

– Solid-gas interface

– Solid- liquid interface

• Solid-gas interface

– Physical adsorption is associated with van der Waals forces

and chemisorption's with irreversible chemical bonds

– Depends on chemical nature of the adsorbent, material used

to adsorb the gas, surface area of the adsorbent,

temperature and partial pressure of the adsorbed gas

Freundlich isotherm Langmuir isotherm

• Solid- liquid interface

✓Adsorption of drugs from solution

✓Wetting WS/L=γ L (1+cos ∅)

• Electrical properties of films

– Dispersed particles may have charge due to

– Selective adsorption of particular species of ions at

interface

– Ionization of groups situated at the surface of the particle

– Difference in dielectric constant between particle and

dispersion medium

– The potential at the solid surface due to potential

determining ions is called Nernst potential

– The difference in potential between the surface of the

tightly bound layer and electro neutral region of solution is

known as zeta potential.

4. Viscosity

and Rheology

– Newtonian systems

– Kinematic viscosity

– Effect of temperature

– Non- Newtonian systems

– Thixotropy in formulations

– Determination of viscosity

• Newtonian systems– Law of flow

– Velocity gradient or rate of shear is directly proportional to shearing stress

– Unit in CGS system is dynes/cm2.scc-1 or gm/cm. s=poise

– In SI system, Newton/m2.s-1 or Pascal.sec=10 poise

• Kinematic viscosity– The unit is stoke

• Effect of temperature– Arrhenius equation

=ityisKinematicv cos

r

v

d

d

A

F=

'

RTEvAe /=

• Non- Newtonian systems

– Flocculated suspensions exhibit plastic flow and polymer

dispersions exhibit pseudo plastic

– Viscosity of pseudo plastic systems decreases with

increasing rate of shear

– Increased volume with shear is noticed with dilatants

systems (>50% solid content)

– Pseudo plastic is shear thinning and dilatants are shear

thickening

– Time dependent and time independent non Newtonian

fluids

– Lower Newtonian or zero shear viscosity

dy

dukV += 0

'

'

n

vdy

duK

=

K’= Flow consistency index

n’= Flow behavior index

n’<1 = For pseudo plastic

n’>1 = For dilatant systems

Upper Newtonian viscosity

• Thixotropy in formulations

– Isothermal, comparatively slow recovery of a consistency

of a material lost through shearing

– Observed in plastic and pseudo plastic systems that are

shear thinning

– Measurement of thixotropy

• Determination of viscosity

– Single point and multi point instruments

– Capillary viscometer

– Based on Poiseuille's law

lV

Ptr

8

4 =

• Falling sphere viscometer

• Rotational viscometer

• MacMichael type, the torque is measured against

the rotating outer cup

• Storner type, cup is stationary and the bob or rotor

is driven

• Coaxial- cylinder viscometer

• Infinite gap viscometer

• Cone and plate viscometer

• Parallel plate viscometer

• Viscosity is calculated by means of Margules equation

• Applications of rheology in pharmacy

( )tB LK −=

Capillary

Falling ball

Rotational viscometer

5. Complexation

5.1. Classification of complexes

✓ Metal ion complexes

✓ Organic molecular complexes (charge transfer

complexes)

✓ Inclusion or occlusion complexes

5.2. Methods of preparation

5.3. Analysis

5.4. Applications

• Metal ion complexes– Inorganic type

– Chelates

– Olefin type

– Aromatic type pi, sigma and sandwich

– Coordination complex contains a central metal surrounded

by electron pair donor

– 4 and 6 is the commonly observed coordination number

– Uni dental and multi dental ligands

5.1. Classification of complexes

• Metal ion complexes– Chlorophyll and hemoglobin are naturally occurring

chelates

– Platinum and silver are commonly used in metal-

olefin complexes

– The red solution of iodine in benzene is due to pi bond

– Sigma complex is noticed in Friedel- Crafts reaction

– Sandwich complex is observed between d orbital of

metal and molecular orbital of aromatic ring

• Organic molecular complexes (charge transfer

complexes)

– Quinhydrone type, picric acid type, caffeine and

other drug complexes and polymer type

– Electro static interactions and hydrogen bonding is

involved

– The bond distance is greater than 3A and the energy

is less than 5 kcal/mole

– Quinhydrone is formed by mixing eqimolar

concentrations of alcoholic benzoquinone and

htdroquinone , salicylic acid forms complex

– Picric acid forms complex with weak bases

– Polymers containing nucleophilic oxygen can

form complexes

• Inclusion or occlusion complexes

– Channel, layer, clathrates, monomolecular and

macromolecular type

5.2. Methods of preparation

– Physical mixing

– Kneading

– Co precipitation

– Solvent evaporation

5.3. Analysis

– Continuous variation

– pH titration method

– Distribution method

– Solubility method

– Spectroscopy

– NMR and IR spectroscopy

– Polarography

– Circular dichroism

– DSC

– XRD

5.4. Applications

– In drug delivery

– In analysis (affinity and chiral

chromatography)

– Protein binding

– In therapeutics

6. Buffers

• Buffer equations

• Buffer capacity, buffer efficiency, buffer index, buffer value

• Buffers in pharmaceutical systems

• Preparation and stability

• Buffered isotonic solutions

• Measurement of tonicity

• Calculations and Methods of adjusting tonicity

• Buffer equations– For weak acid and its salt

– For weak base and its salt

• Buffer capacity, buffer efficiency, buffer index, buffer value

– Maximum buffer capacity

salt

basepKpKpH bw log+−=

acid

saltpKpH a log+=

pH

B

=

( )23

33.2+

+

+=

OHK

OHKC

a

a

C576.0max =

Buffers in pharmaceutical systems

Composition pH range

HCl and KCl 1.2-2.2

HCl and C8H5KO4 2.2- 4.0

NaOH and C8H5KO4 4.2-5.8

NaOH and KH2PO4 5.8-8.0

H3BO3, NaOH and

KCl

8.0-10

• Preparation and stability

– Selection of a weak acid

– Selection of ratio

– Selection of individual concentration 0.05-0.5 M with buffer

capacity 0.01-0.1

– Availability, sterility, stability and freedom from toxicity

• Buffered isotonic solutions

– Hypertonic solutions causes crenated and hypotonic

solutions causes hemolysis

• Measurement of tonicity

– Hemolytic method

– Colligative properties

• Calculations and Methods of adjusting tonicity

– Class I methods

• Cryoscopic method

• %w/v NaCl required=0.52-a/0.576

• Sodium chloride equivalent method

• E=17 L/M

– Class II methods

• White- Vincent method

• V=WxEx111.1

– Sprowls method

CHAPTER-7

SOLUTIONS

Contents» Solubility

» Solubility curves

» Types of solutions

» Effect of co-solvency, pH & other factors on

solubility

» Solubility of gases in liquids

» Solubility liquids in liquids

» Solubility of solids in liquids

» Critical solution temperature

» Law of partitioning and its applications

» Solute- solvent interactions

» Expression of concentrations

Solubility• Concentration of a solute in a saturated solution at a certain

temperature

– Phase rule F=C-P+2

– Rate of solution=DA/l (C1-C2)

– Particle size, stirring, solubility and viscosity of solvent affect rate of

solution

• Descriptive terms for solubility

Descriptive termPart of solvent required per part of

solute

Very soluble Less than 1

Freely soluble From 1 to 10

Soluble From 10 to 30

Sparingly soluble From 30 to 100

Slightly soluble From 100 to 1000

Very slightly soluble From 1000 to 10,000

Practically insoluble 10,000 and over

Solubility curves

Types of solutions

• Solutions of solids in liquids

• Solutions of liquids in liquids

• Solutions of gases in liquids

• Solutions of solids in solids

O/W W/O W/O/W

Effect of co-solvency, PH & other factors on solubility

• Co-solvent increases the solubility of un ionized

species by adjusting the polarity of the solvent

• It may decrease the dissociation of a weak

electrolyte

• The solubility of week electrolyte is influenced by the pH

o

oap

S

SSpKpH

−+= log

o

obwp

SS

SpKpKpH

−+−= log

Solubility of gases in liquids

• Hcl, NH3, effervescent preparations and aerosols

• Depends on pressure ,temperature, salts and chemical

reaction

• Henrys law C2= σ р = product of solubility coefficient and

partial pressure of the gas

• Solubility decreases with temperature

• Salting out

• Henrys law not applicable in a chemical reaction

• Solubility of a gas in liquid is expressed by Henrys law

constant or Bunsen absorption coefficient α

Solubility liquids in liquids

• Divided in to complete and

partial miscibility systems

• Binary and ternary

systems

• Molecular connectivity (χ, zero, first and higher order). Sum of the

reciprocal of square root number

• Molecular surface area related properties like the total surface

area(TSA), hydrocarbon surface area(HYSA) and functional group

surface area(FGSA)

Solubility of solids in liquids

• With or without accompanying chemical reaction in the

solvent

• Effect of temperature

• Effect of salts salting in, salting out or no alteration

• Solubility of solutes containing two or more species

common ion effect

• Solubility following a chemical reaction

• In ideal solutions heat of solution is equal to heat of

fusion

Solubility of solids in liquids

• Solubility of a solid in ideal solution depends on

temperature, melting point and molar heat of fusion

• In ideal solutions, the slope of the line drawn between

log solubility (mole fraction) vs reciprocal of absolute

temperature is – ∆Hf/2,303R

• In non ideal solutions, the concentration is replaced with

activity, solubility parameter determined from heat of

vaporization, internal pressure and surface tension

• EHS Solubility approach

Critical solution temperature

Law of partitioning and its applications

K=c1/c2

• Effect of ionic dissociation and molecular

association on partition

• Extraction

• Solubility

• Preservative action

• Biological activity

Solute- solvent interactions

• Like dissolves like

• Dipole moment

• Hydrogen bond

• Difference in acidic and basic constituents

• Ratio of polar to non polar groups of the molecule

Expression of concentrations

• Volume of the solvent required to dissolve one gram of

solute (g/ml)

• Quantity of solute in grams dissolves in 100 ml

• Quantity of solute in grams dissolved in 100 gm

• Number of moles of solute in 1 liter of solvent

• 100 ml of saturated solution contains – gms of solute

• %w/w, %w/v, %v/v

• Molarity, molality and mole fraction