Solid State Analysis of Drug Substance

Solid State Analysis of Drug Substance

Introduction• Pharmaceuticals are comprised of active pharmaceutical

ingredient (API), inactive ingredient as carrier or diluents system and a package for market performance and appeal.

• Majority of APIs exist as solid form.• An understanding of the solid-state properties of the API might

be utilized for optimizing operational and formulation strategies and in designing suitable stability protocols to avoid later problems in drug development

• Each solid form displays unique physicochemical properties that can profoundly influence the bioavailability, manufacturability, purification, stability and other performance characteristics of the drugs

Physicochemical properties• Packing : Molar volume and density, Refractive index,

Conductivity - electrical and thermal, Hygroscopicity• Thermodynamic : Melting and sublimation temperatures,

Internal energy, Enthalpy and Entropy, Heat capacity, Free energy and chemical potential, Thermodynamic activity, Vapor pressure, Solubility

• Spectroscopic : Electronic transitions - ultraviolet-visible spectra, Vibrational transitions - infrared and Raman spectra, Rotational transitions - Nuclear magnetic resonance chemical shifts

• Kinetic : Dissolution rate, Rates of solid-state reactions, Stability• Surface : Surface free energy, Interfacial tensions, Habit• Mechanical : Hardness, Tensile strength, Compactibility,

tabletability, flowability and blending

• Solid state analysis is part of pre-formulation studies• Physical properties of drug substances, excipients and

blends of them drastically affects the manufacturability of solid dosage forms.

• E.g. particle size – affects flowabilitycrystalline or amorphous – solubility

• Study of Polymorphism – Requires physical characterization of solid substances

Regulatory Impact• Regulatory bodies has always focused on concerns of safety and

efficacy, which led to an overwhelming emphasis on aspects of chemical purity.

• This situation has changed drastically over the past decade, with an ever-increasing degree of attention being given to the physical properties of the solids that compromise a dosage form

• It is now accepted that an evaluation of the polymorphism available to a drug substance must be thoroughly investigated early during the stages of development. The results of these studies must be included in the chemistry, manufacturing, and control section of NDA, and such information is required to demonstrate control over the manufacturing process.

Solid state analysis are done at the three level

At the molecular level

At the particulate level

At the bulk level

Properties associated with the molecular level

UV/Visible Diffuse Reflectance

SpectroscopyVibrational spectroscopy

Magnetic Resonance

Spectroscopy

Solid state analysis

Properties associated with the particulate level

Microscopy X- Ray diffractionXRD

Thermal method of analysis

Properties associated with the bulk level

Particle Size Distribution Micromeritics Powder

Characterization

PROPERTIES ASSOCIATED WITH MOLECULAR LEVEL

Definition: Properties associated with molecular level may be defined as

those material characteristics that can be measured for individual molecule.

(A) ULTRAVIOLET / VISIBLE DIFFUSE – REFLECTANCE SPECTROSCOPY

Diffuse reflectance spectroscopy is effective way of obtaining spectra directly on

powder sample with minimum sample preparation .

UV/Vis DRS is used to study reaction pathways of various solid-state reaction.

drug-excipient interactions

drug degradation pathways

An Example

Connors used diffuse reflectance spectroscopy to study the adsorption of

spiropyran on to pharmaceutically relevant solid .

The particular adsorbents studied were interesting in that spectral

characteristics of binary system depend strongly on the amt of material bound.

At low conc, the pyran sorbent exhibit its main absorption band around 550

nm , but as degree of coverage increase the 550 nm band still observed , but

much more intense absorption band at 470 nm became prominent .

This secondary effect was attributed to the presence of pyran- pyran interaction,

which became more prominent as conc of sorbent increase.

Another Application

Other applications - in the fields of color measurement and color matching,

applied to the coloring agents used in formulations.

For quantitative expression of color

In a recent application, the appearance testing of tablets through measurement

of color changes was automated using fiber optic probes and factor analysis of

the data.

Good correlation between measured chromaticity parameters and visual

subjective judgment was demonstrated, with samples of differing degrees of

whiteness being used to develop the correlation.

The methodology was complicated because surface defects on the analyzed

materials can compromise the quality of the correlation.

Some powder & rough surface solid change color as

function of temp, a phenomenon is known as

thermochromism.

Such phenomena effectively study by u.v visible

spectroscopy in combination with diffuse reflectance

accessory equipped with temp controlled reaction

chamber.

( B ) VIBRATIONAL SPECTROSCOPY

Two techniques : [1] FTIR and [2] Raman Spectroscopy

The energies associated with fundamental vibration mode of chemical compound

lie within the range of 400- 4000 cm-1 , that corresponds to mid –infrared

electromagnetic radiation.

Overtones & combination band of vibrational mode are observed in NIR region of

spectrum . ( 4000 – 13350 cm -1 )

FTIR is powerful technique for the physical characterization of pharmaceutical solid

.

In addition , this transition also can be observed using Raman spectroscopy , where

inelastic scattering of incident energy is used to obtain vibrational spectra.

FTIR spectra often used to evaluate

type of polymorphism that exist in drug substances &

to study water contained in hydrate species.

Solid state IR absorbtion spectra are obtained on powder solid through

combined use of FTIR & diffuse reflectance spectra and interpreted

through conventional group frequency compilation.

Example – Study of polymorphism by Diffuse Reflectance IR spectra

Glisentide has been obtained in a number of polymorphic and

solvatomorphic forms, with the anhydrous forms I and II exhibiting large

differences in infrared spectra.

GlisentideCharacteristic Form I Form II

Urea carbonyl group 1635 cm-1 and 1545 cm-1 1620 cm-1and 1545 cm-1, shoulder more intense

S=O stretching 1157 cm-1 1165 cm-1

Aromatic carbonyl group 1720 cm-1 Broadened, 1720 cm-1

Form I

Form II

Conclusion: polymorphism of glisentide probably is due to changes in crystal packing rather than conformational differences.

Raman Spectroscopy: Raman spectrum generally resembles the spectrum

obtained using the FTIR method

In , general symmetric vibration & non polar groups yield most intense

Raman scattering bands , whereas antisymmetric vibration & polar groups

yield the most intense infrared absorption bands.

Example

• Application of Raman spectroscopy in solid state analysis

• To study the effect of pressure on phase transition of Fluoranil crystals.

Raman spectra obtained at 300 K for crystalline fluoranil at pressures of (a) 1 atm,(b) 0.5 GPa, (c) 1.4 GPa, and (d) 2.4 GPa.

Near IR SpectrocopyNear-IR spectra consist of overtone transitions of fundamental vibrational modes and are not,

therefore, generally useful for identity purposes without the use of multicomponent analysis.

The spectral features are of greatest utility in determination & detection of functional groups

that contain unique hydrogen atoms.

For example, studies of water in solids can be easily performed through systematic

characterization of the characteristic OH band, usually observed around 5170 cm−1.

The determination of hydrate species in an anhydrous matrix can be performed easily using

near-IR analysis.

The near – IR technique has been used very successfully for moisture determination , whole

tablet assay and blend validation

It is possible to use the overtone and combination bands of water to develop near-IR

methods that have accuracy equivalent to that obtained using Karl–Fischer titration.

Advances in instrumentation and computer pulse sequences currently allow these studies to be carried out

routinely in the solid state - the Solid State NMR [SSNMR]

SSNMR mostly focused on C13 studies.

H-NMR remains an extremely difficult measurement in solid state , & data obtained only at medium resolution .

The main problem of H- NMR has peak broadening effect (smaller working range for chemical shift i.e. 12 ppm).

Solid state NMR spectra can be used to deduce the nature of polymorphic variation , especially when

polymorphism is conformational in nature .

Solid state NMR spectroscopy also can be used to study the molecular environment of nuclei because these

environment vary in the differing structure associated with solvates & hydrates .

( C ) MAGNETIC RESONANCE SPECTROSCOPY

Fosinopril sodium

For eg : solid state 13C – NMR spectra were obtained on the anhydrate &

monohydrate phase of androstanolone ( a known metabolite testosterone),

where many doublet were found in the anhydrate spectrum .

In the monohydrate phase , no such doubling was observed because the two

molecule present in the unit cell related by symmetry & consequently are

magnetically equivalent.

PROPERTIES ASSOCIATED WITH PARTICULATE LEVEL

DEFINITION: As those material characteristics that effectively can be determined by the

analysis of a relatively small ensemble of particles.

(A) MICRROSCOPY

Evaluation of the morphology of a pharmaceutical solid is of extreme importance,

because this property exerts a significant influence over the bulk powder properties of

the material.

Both optical & electron microscopy are widely used to characterize pharmaceutical

solid.

The two microscopy methods are complementary in that each can provide information

inaccessible to the other.

Optical and Electron Microscopy

• Light microscopy – gives information on the internal properties for small particles, fibers, and films.

• Polarizing optics – can be used to investigate optical properties of the crystals.

• Electron microscopy – topographic and shape information

Optical Microscopy• OPTICAL MICROSCOPY can be performed at magnification limit 600×.

• Optical microscope fall into two classes, (a) reflected light microscope and (b)

transmitted light microscope.

• Reflected light microscopes reveal details on the surface of small, relatively, thick,

opaque objects such as agglomerated crystals, tablets, capsules, packaging materials,

etc.

• Transmitted light microscopes, especially when equipped with polarizing attachments,

are suited for observations on a still smaller scale, i.e., individual crystals.

• 1) Light Microscopy

• 2) Polarizing Microscopy

• 3) Thermal Microscopy

• 4) Chemical Microscopy

1) Light Microscopy

• Light Microscope: • Imp. Parameters –

magnification, resolving power• Particle morphology can be

examined.

2) Polarizing Microscopy

• Polarizing microscope is essentially a light microscope equipped with a linear polarizer located below the condenser, and an additional polarizer mounted on top of the eyepiece.

• This method yield several directly measured parameters, such as the sign and magnitude of any observed birefringence, knowledge of RIs associated with each crystal direction, what the axis angles are and what the relations among the optical axes are.

• The crystal is built up through the repetition of a fundamental building block, known as UNIT CELL.

• The molecules in the solid form 3-D basic pattern, known as SPACE LATTICE.• 14 kinds of space lattices are possible.

• The refractive index of light passing through an isotropic crystal will be identical along each of the crystal axes and such crystals, therefore, possess single refraction.

• Anisotropic substances will exhibit different refractive indices for light polarized with respect to the crystal axes, thus exhibiting double refraction.

• Crystals within the hexagonal and tetragonal systems possess one isotropic direction and are termed uniaxial.

• Anisotropic crystals that possess two isotropic axes are termed biaxial and include all crystals that belong to the orthorhombic, monoclinic, or triclinic systems. Biaxial crystals will exhibit different indices of refraction along each of the crystal axes.

3) Thermal Microscopy• The ability to observe optical properties of crystals during

heating and cooling processes is termed thermal microscopy• Thermal microscopic work is conducted by mounting the

sample in a system whose temperature can be accurately controlled and monitored.

• Depending on the type of thermal control employed, it is usually termed as Hot Stage Microscopy [HSM] or Cold Stage Microscopy [CSM].

• CSM – RT to -50 °C• HSM – RT to 300-350 °C

• Thermal Microscopy can be a profoundly useful technique during the study of polymorphs and solvatomorphs.

• Crystal polymorphs ordinarily exhibit different melting points, and the order of the melting points is indicative of the order of stability at the elevated temperature condition.

• The interconversion of such crystal forms is classified as either enantiotropic or monotropic, according to whether the transformation of one modification into the other is reversible.

• Enantiotropic modifications interchange reversibly at the ordinary transition point, and each form is characterized by its own stability range of temperature.

• Monotropic substances are characterized by the existence of a purely hypothetical transition point, because this point is predicted to be higher in temperature than the melting point of one of the polymorphic forms.

• Monotropic polymorphs are characterized by the fact that one form is stable at all temperatures below its melting point, whereas the second form is metastable at all temperatures.

• The dehydration, desolvation, or decomposition temperature of a compound can also be evaluated by thermal microscopy.

• Most imp. use of thermal microscopy is accurate determination of melting points and melting point ranges. Such measurements can be used to deduce the relative purities of different lots of the same compounds.

• Microscopic determination of mole. Wt. can be done on the basis of lowering of freezing point of suitable solvent system.

4) Chemical Microscopy• In this microscopic technique, derivatives of the analyte

species are prepared, crystallized, and identified through the morphological characteristics of these derivatives.

Electron Microscopy

• In Electron microscopy electron beam is used instead of light, free electron travel in wave & the resolution power of electron microscope is far greater than other microscope.

• SCANNING ELECTRON MICROSCOPY is type of electron microscopy, it is used – to obtain the information at high magnification level or – when three dimensional view of particle surface is required.

• A conventional SEM is similar to an inverted light microscopy in that the source lies above the specimen, the interrogating electron beam is focused by a series of lenses, and the image is constructed on the basis of scattered electromagnetic radiation.

• Samples are usually coated with conductive materials to reduce the deleterious effects of surface charging, although newer systems are not necessarily limited in this regard.

• SEM analysis is often combined with x-ray analysis, whereby maps of the elemental distribution within a heterogeneous sample may be obtained.

• The morphology of excipient materials plays an important role is

their physical properties, which in turn affects their application as

formulation ingredients.

• SEM was successfully used for comprehensive study relating

morphology and functionality of 14 direct compression excipients.

• For instance, croscarmellose (Ac-Di-Sol) is a polymeric substance

that is commonly used in solid dosage forms as a disintegrant.

• When the substance is produced as an ensemble of short fibers,

improved flowability characteristics and good blending ability are

obtained without adversely affecting the disintegrant properties.

• The surface characteristics of excipients can also be studied and related to the dispersion and dissolution of poorly soluble drugs.

• Excipients with rough surfaces (e.g. Emcompress, with a porous surface) trap and drug particles in the indentations, which can then be blocked by fine excipient particles and decrease dissolution.

• However, smooth surfaces (such as spherical sugar beads) produced high dissolution efficiency of the poorly soluble drugs.

• SEM analysis was used to study the growth of carbamazepine crystal on surface of tablets that had been stored at elevated temp.

• This crystal growth found to take place only when stearic acid

was used as the tablet lubricant & it was shown that

carbamazepine drug substance could dissolve in the stearic

acid .

• The lubricant provided a mechanism to transport the drug to

the tablet surface , where it could crystallize.

• Compression of pharmaceutical materials can also be investigated with SEM.

• Simple powder mixtures have been used to illustrate the processes that occur during compression.

• The excipients chosen exhibited plastic and elastic deformation, as well as brittleness.

• Examination of dimetrally fractured compacts exhibited recrystallization in crystal interfaces within the compact as well.

• SEM can also be used for the study of film coatings and surface morphology of microcapsules and beads.

• Continuity and imperfections of the film surface were evaluated, and cross sections of the pellets were also examined to determine the presence of a distinct boundary between the film coating and the core.

• Anonther study correlated the film thickness and dissolution of acetaminophen beads.

• Using SEM it was found that a low coating level of 4 % resulted in discontinuous film over the beads with visible holes providing channels for drug release. High coating levels of 16 % resulted in a continuous film, which correlated to the drug release being controlled by diffusion through the film barrier and zero-order kinetics.

• Size measurements have also been collected for film thicknesses and bead sizes.

• These are a few of the many examples of the uses of SEM.

• The use of this technique with other physical characterization methods results in powerful pharmaceutical tool.

Crystalline materials

• A solid substance can be classified as being crystalline, noncrystalline, or a mixture of the two forms.

• In crystalline materials, the molecular or atomic species are ordered in 3-D array, called lattice, within the solid particles.

• This ordering of molecular components is lacking in noncrystalline material.

• Noncrystalline solids sometimes are referred to as glasses or amorphous solids.

Fundamentals of crystal structure

• Crystals consist of minimal building blocks, termed unit cells, each of which contain all the structural features and symmetry elements and is repeated regularly in three-dimensional space.

• The dimensions of the unit cell are characterized by six quantities; three axial lengths (a, b, c) and three interaxial angles (α, β, γ).

• Each unit cell contains at least one molecule and can be classified by one of the seven three-dimensional coordinate systems, which are the seven primitive crystal systems.

• Each of these crystal systems has one or more symmetry elements that describe the internal symmetry of the unit cell.

• The different symmetry elements comprise rotation, mirror, screw, glide, and rotation-inversion operations.

• There are 32 possible unique combinations of the different crystallographic symmetry elements.

• In total, there are 14 Bravais lattices consisting of seven primitive and seven nonprimitive lattices.

• The combination of 32 point groups with 14 Bravais lattices leads to 230 unique arrangements of points in space, termed space groups.

N

NH2O

(B ) X – RAY DIFFRACTION

• Primary method to obtain fundamental structural information on

crystalline substance.

• Every crystal form of a compound produces its own characteristic X-ray

diffraction pattern.

• Typical applications of XRPD:– Determination of crystal structure

– Evaluation of polymorphism & Solvate structure

– Evaluation degree of crystallinity

– Study of phase transition .

Principle - XRD• X-ray are EMR – wavelength range in angstrom (Å), 1 Å = 10-8cm.• Diffraction is a scattering phenomenon, bending of light around the edge of an

object.• When x-rays are incident on crystalline solids, they are scattered in all direction.

In some of these directions, the scattered beams are completely in phase and reinforce one another to form the diffracted beams.

Bragg’s equation

• Bragg’s law describes the conditions under which this (constructive inerference) would occur.

• When a perfectly parallel and monochromatic x-ray beam of wavelength λ, is incident on a crystalline sample at an angle θ, diffraction will occur if

• nλ = 2d sin θ, where d = distance between the planes in the crystal (Å), n = order of reflection (an integer).

• XRD techniques[1] Single Crystal X-ray Diffraction (SCXRD)[2] X-ray Powder Diffraction (XRPD)

• SINGLE CRYSTAL X-RAY DIFFRACTION is non destructive analytical technique which provides detailed information about the internal lattice of crystalline substance including cell dimension , bond length & bond angle .

• This information is extremely useful in the study of polymorphism and solvatomorphism.

• Crystals diffract X-rays in a pattern that is unique to the respective crystals and depends on their internal structure, and so X-ray diffraction can be used to determine crystal structure.

• Crystal Structure determination by SCXRD– It requires crystal of suitable size and quality.– minimum dimension along each axis of the crystal should

exceed 0.05 mm– Crystal should possess uniform internal structure– Special procedures are used to prepare satisfactory

crystals.– Crystallization from different solvents at different

temperatures, crystallization from supercritical fluids, addition of nonsolvents, pH adjustment, sublimation and crystallization from the melt.

The analysis of single crystal x-ray diffraction data is divided into three parts,

- The first of this is geometrical analysis , where the exact spatial distribution of x-ray

reflection is measured & used to compute the size & shape of unit cell.

- The second phase entails a study of intensities of various reflection , using this

information to determine the atomic distribution within the cell.

-Finally ,the x-ray diagram is examined the deduce qualitative information abt the

quality of crystal.

SCXRD is most powerful technique for the study of polymorphs and solvates but it

can not be used for routine evaluation of crystalline state of powdered solids.

This effect can be explained by invoking one of the two possibilities.

If the molecule constrained to exist as rigid grouping of atom , this atom may be

stacked in different motifs to occupy the points of different lattices .This type of

polymorphism attributed to packing phenomena & so termed as packing

polymorphism.

If is not rigidly constructed & can exist as in distinct conformational states , then each

of this conformationally distinct modification may crystallize in own lattice structure .

This behavior is termed as conformational polymorphism.

Packing polymorphism Conformational polymorphism

XRPD

XRPD method is used for routine evaluation of crystalline state of the solid drugs.

The powder methods provide an advantage over other means of analysis as it is

nondestructive in nature.

A powdered sample will present all possible crystal faces at a given interface and the

diffraction off this powdered surface will, therefore, provide information on all possible

atomic spacings (i.e., defined by the crystal lattice).

The powder pattern consists of a series of peaks of varying intensities detected at various

scattering angles.

These angles and their relative intensities are correlated with computed d spacings to

provide a full crystallographic characterization of the powdered sample.

After indexing all the scattered bands, it is possible to derive unit cell dimensions and other

crystallographic information from a high-resolution powder pattern of the substance

Application of XRPD method• To measure a powder pattern, a randomly oriented powdered

sample is prepared so as to expose all the planes of a sample. • The scattering angle is determined by slowly rotating the sample and

measuring the angle of diffracted x-rays (typically using a scintillation detector) with respect to the angle of the incident beam.

• Alternatively, the angle between the sample and the source can be kept fixed, while moving the detector to determine the angles of the scattered radiation.

• Because the wavelength of the incident beam is known, the spacing between the planes (identified as the d spacings) is calculated usingBragg’s law.

APPLICATIONS• QUALITATIVE ANALYSIS

• DEGREE OF CRYSTALLINITY

• PHASE QUANTIFICATION (QUANTITATIVE ANALYSIS)

• KINETICS OF SOLID-STATE REACTIONS

• DRUG-EXCIPIENT INTERACTION

61

QUALITATIVE ANALYSIS

Used for the identification and characterization of solid phases.1. Used to identify different polymorphic

forms of a compound. 2. Used to identify the solvated and

unsolvated forms of a compound.3. Used to distinguish amorphous and

crystalline phases of drugs. 62

Typical Powder Patterns Obtained for Four Solid Phases of Ampicillin

(The united states pharmacopeia; 24th Rev.; U.S. Pharmacopoieal Convention:Rockville, MD, 1999)

XRD – Distinguishing different crystalline forms

63

XRD patterns of (a) crystalline and (b) amorphous sucrose

(Surana R et al Quantitation of crystallinity in substantially amorphous pharmaceuticals and study of crystallization kinetics by X-ray powder diffractometry. Powder Diffr., 2000; 15: 2-6.)

XRD – Distinguishing crystalline and amorphous forms

64

Polymorphism: Applicable to polymorphs or to multi-

component formulations. The detection and quantification of

polymorphic contamination is used to improve production efficiency and cost.

65

X-ray powder diffraction patterns for the two polymorphs of paracetamol

(Nichols G et al Physicochemical characterization of the orthorhombic polymorph of paracetamol crystallize from solution, Indian J Pharm Sci, 87: 684-693.)

XRD – Distinguishing polymorphs

66

Phase Transitions Induced During Processing Investigation of excipient and processing on solid

phase transformation and dissolution of ciprofloxacin

Structure of Ciprofloxacin

67

Powder X-ray diffraction patterns of crystal forms of ciprofloxacin (a) anhydrate (b) hydrate

(Xianwen Li et al Investigation of excipient and processing on solid phase transformation and dissolution of ciprofloxacin, Int J Pharm, 2007; 328: 177-182.)

68

Powder X-ray diffraction patterns of anhydrate and monohydrate solid forms of baclofen

(Mirza S et al Indian J Pharm Sci, 2007; 96: 2399 – 2408.)

Phase transformation occur during wet granulation process for tabletting

69

DEGREE OF CRYSTALLINITY Refers to the degree of structural order in a solid.

It has a big influence on hardness, transparency, density and diffusion.

XRD patterns of the physical mixtures of crystalline and amorphous sucrose

(Surana R et al Quantitation of crystallinity in substantially amorphous pharmaceuticals and study of crystallization kinetics by X-ray powder diffractometry. Powder Diffr., 2000; 15: 2-6.)

70

PHASE QUANTIFICATION (QUANTITATIVE ANALYSIS) The Direct Method (No Internal Standard)

Internal Standard Method

Whole Powder Pattern Analysis

71

The Direct Method (No Internal Standard) Analysis of anhydrous α and β forms of Carbamezapine by

XRD pattern

72

Internal Standard Method

Analysis of S (+) enantiomer by internal standard method• Internal standard is added

Whole Powder Pattern Analysis Analysis of anhydrous α and β forms of

Carbamezapine and carbamezapine dihydrate from mixtures by whole powder patterns

73

KINETICS OF SOLID-STATE REACTIONS

Investigation of the Multi-Step Dehydration Reaction of Theophylline Monohydrate Using 2-Dimensional Powder X-ray Diffractometry • Dehydration kinetic study of Theophylline

Monohydrate were carried out at different temperature ( 35 °-130 ° C)

M A* A 74

DRUG-EXCIPIENT INTERACTION

Captopril and its interaction study with excipients • Captopril as ACE inhibitor used in

hypertension is analyzed using XRPD investigate interaction between captopril and excipients in tablet formulation

75

(C) THERMAL METHOD OF ANALYSIS

Thermal method of analysis is defined as those technique in which

property of analyte is determined as function of applied temp.

This technology is used to characterize compound purity , polymorphism ,

solvation , degradation & excipient compatibility .

Thermal analysis are used to monitor

endothermic process ( melting , boiling , sublimation , vaporization , desolvation , solid –

solid phase transition , chemical degradation ) as well as

exothermic process ( crystallization & oxidative decomposition ) .

Thermal methods are extremely useful at pre-formulation stage to study

the existence for possible drug-excipient interaction.

com Commonly used thermoanalytical technique is that of

THERMOGRAVIMTERY , where thermally induced weight loss of

material is measured as function of applied temp.

TG analysis is restricted to studies that involve either a mass gain

or loss, & is most commonly used to study desolvation process &

compound decomposition .

The major used of TG analysis is quantitative determination of

total volatile content of solid .

TG analysis of compound decomposition also can be used to

compare the stability of similar compound .

Differential thermal analysis ( DTA ) represents an improvement to the melting

point determination in that temp difference in sample & reference is monitored

as function of temp.

As long as no thermal transition take place , temp of sample & reference will be

same becoz the heat capacities of the two are roughly equivalent .

However , differences in temp between sample & reference are manifested

when change occur that require finite heat of reaction .

If, H for transition is +ve ( endothermic reaction ) , the temp of sample lag

behind that of the reference & this event record by thermogram as –ve going

peak.

If , H is –ve ( exothermic reaction ) , temp of sample exceed that of the

reference , event record in thermogram as +ve going peak .

Differential scanning calorimetry ( DSC ) represents an improvement to DTA

method .

IN DSC method sample & reference are kept at the same temp & heat flow

required to maintain the equality in temp between two is measured .

This equality can be achieved by placing separate heating element in sample &

reference cell , where rate of heating by these element is controlled &

measured .This method is termed as power compensated DSC.

It yield +ve going peak for endothermic reaction , -ve going peak for

exothermic reaction .

Another method is HEAT FLUX DSC , where sample & reference are heat from

same heating element .

It yield + ve going peak for exothermic reaction , -ve going peak for endothermic

reaction.

It is more preferable than power compensated method

DSC plot are obtained as the rate of heating against temp & thus they

represent direct measure of heat capacity of sample .

The area under a DSC peak is directly proportional to heat absorbed or evolved

by the thermal event & integration of peak area yield the heat of reaction .

DSC analysis used to determined absolute purity , When compound is melt

without decomposition .

This method can , therefore be used to evaluate the absolute purity of given

compd , without reference to standard , with purity being obtained in term of

mole percent .

Properties associated with the bulk level

Definition : As those characteristics of solid that can be measured only for

large ensemble of particles .

Bulk physical properties are of highest degree of importance once the solid formulation has reached the bulk mfg. stage.

For checking lot-to-lot consistency of the raw materials (API and excipients), they are subjected to bulk characterization.

Evaluation of bulk properties of a material depends critically on the samplingplan used.

Miligram to gram level samples taken from kilogram level bulk material must be representative of the bulk properties.

(A) PARTICLE SIZE DISTRIBUTION

PSD expressed as the number or weight of the particle lying within certain size range in given weight of powder.

PSD of drugs and excipients exerts profound effects on mixing phenomena and on possible segregation in mixed materials.

Homogenous mixture of powders can be easily produce if individual components to be mixed are of equivalent particle size.

All pharmaceutical dosage forms must be produced in uniform units, and good content uniformity is only possible when the particle size of the active component is carefully controlled.

The distribution of particle sizes in a powdered material can affect the bioavailability of certain active drugs, and certainly exerts a major effect on powder flowability.

METHODS FOR DETERMINATION OF PARTICLE SIZE DISTRIBUTION

PSD

SEDIMENTATION

OPTICLE MICROSCOPY

SIEVE ANALYSIS

ELETRCAL ZONE SENSING

LASER LIGHT SCATTERING

The choice of method is depend upon the type of the sample to be analyzed & nature of information required.

Light scattering & electrical zone sensing are normally carried out on solid dispersed in inert solvent medium, they are suited for particle size distribution in suspension.

Whereas microscopy & sieving are normally carried out on dry powder samples & therefore more useful as indicator of actual particle size of powder solid.

OPTICAL MICROSCOPY:

• Microscopy is the most absolute method for particle size determination.

• particle size in the range of 0.2 -100 µm can be measured by optical microscopy.

• Eye piece of microscope fitted with micrometer & this eye piece micrometer calibrated using

standard stage micrometer .

• In the automated methodology, microscope parameters are adjusted so as to optimize the contrast

between the background and the particles to be sized.

• A video image of powder is transmitted to a computer system , which then counts the no pixels that

make up a particle .

• The size of each pixels converted to micrometer & the data are analyzed.

• ADV :

– Direct and absolute information on the particles.

– Allow the observer to view the particle, agglomeration of particles & contamination in powder can be detected.

• Disadv. :

– it can provide data of particle on slide & therefore can be biased by slide preparation method .

– Diameter is obtained from only two dimension .i.e., length & breadth . Depth of particle is not measureable.

• SIEVE ANALYSIS : particle size range 50 – 1500 µm estimated by sieving method

• Sieve are in nest with coarset at the top, sample is placed on top sieve & allow to

distribute among the series of sieve .

• A proper size determination requires the use of five to six sieves, whose sizes are

selected to obtain approximately equal amounts of powder on each screen and past

the smallest sieve.

• A variety of facilitation methods can be provided during the sieving process; vibration,

ultrasound, or air suspension are used to assist the passage of particles through the

various screens.

• Smaller particle that pass through the screen are term as fines & lager particle that

retain on screen are term as coarse . Powder retained on the sieve is weighed.

• The data are most commonly displayed as the percent of material retained on each

sieve, the cumulative percent of sample retained, and the percent of sample passing

each sieve.

• ELETRICAL ZONE SENSING : ( METHOD BASE ON COULTER COUNTER ) :

• The particular instrument operates on principle that when a particle suspend in

conducting liquid pass through small orifice on either side of which are

electrode , a change in electrical resistance occurs.

• ADV :

• 4000 particle per second can be measured . Short time required & accurate

result.

• DISADV:

• Calibration using monodispersed particle of known diameter is required to

assign the particle size of unknown species.

(B) MICROMERITICS

• Micromeritics involve study of small particle & order of few

microns size.

• That include the field that relate to nature of surface that make

up the solid.• Important micromeritic properties1) surface area, 2) porosity, and 3) density of a material

• Surface area provides the information on the void space available on the surface of powdered solid.

• In addition, dissolution rate of a solid is largely affected by surface area.

• ADSORPTION METHOD:

• Most reproducible method for measurement of surface area

• Surface area of solid obtained by adsorbing a monolayer of inert gas onto the solid surface at

reduced temp and subsequently desorbing this gas at room temperature.

• In determining the surface area of the of adsorbent, the volume in cubic centimeter of gas adsorbed

per gram of adsorbent may be plotted against the pressure of gas at constant temp to give isotherm

• The sorption isotherms obtained are interpreted using the equations developed by Brunauer,

Emmett, and Teller. Therefore it is also known as BET method.

• The surface area obtained in unit square meter of surface per gram of material.

• Any condensable, inert gas can be used. E.g. Nitrogen and Krypton.

• Nitrogen is use for sample that exhibit surface area 2 m2/gm or greater but material with smaller

surface area should be measured using krypton..

An Example• Relationships between the internal surface area and tablet properties have been drawn

through the characterization of a variety of lactose compacts.

• For example, a given bulk sample of anhydrous α-lactose was sieved into selected size

fractions, and compacts of these fractions were prepared through compression at 37.5

mPa.

• Nitrogen gas adsorption was used to evaluate the surface area of the compacts and the

tablet crushing strengths of each were determined.

• The crushing strength of the compacts was found to be directly proportional to (and

almost linearly dependent on) the surface area of the compacted material.

• It also was found that compacts prepared from the coarser size fractions contained

significantly lower surface areas than compacts prepared from the fine fractions.

Porosity

• Although a variety of methods are available to characterize the interstitial voids of a

solid, the most useful of these is that of mercury intrusion porosimetry.

• This method is widely used to determine the pore size distribution of porous materials

and the void size of tablets and compacts.

• This method is based on the capillary rise phenomenon in which excess pressure is

required to force a non-wetting liquid (mercury) into a narrow volume.

• The mercury is forced into the pores of the sample using an externally applied pressure:

the smallest pores require the highest pressures to effect filling.

• The Washburn equation, as applied to circular pore openings, is used to relate the

applied pressure and the pore size opening.

• Measurements of particle porosity are a valuable supplement to studies of specific

surface area, and such data are particularly useful in the evaluation of materials used in

direct compression processes.

Another imp parameter of micromeritics is POWDER DENSITY which defined as the ratio of

mass to volume.

Three types of density, which differ in their determination of volume occupied by the powder,

are normally differentiated.

Bulk Density: obtained by measuring the volume of a known mass of powder sample (that has

been passed through a mesh screen) into a suitable volume-measuring apparatus. The Bulk

density is then obtained by dividing the mass of solid by the unsettled apparent volume.

Tapped Density: the volume of the solid is measured after subjecting the system to a number of

controlled shocks (tapping).

True Density: average mass per unit volume, exclusive of all voids that are not a fundamental

part of the molecular packing arrangement

• This density parameter is normally measured by helium pycnometry, where the volume

occupied by a known mass of powder is determined by measuring the volume of gas displaced

by the powder.

• The true density of a solid is an intrinsic property characteristic of the analyte and is determined

by the composition of the unit cell.

( C ) POWDER CHARACTERIZATION• One of the imp parameter of formulator is flowability of powder solids.

• The processiblity of this material greatly affected by flowability concerns.

• Irregular flow of powder from hopper produce tablet with nonuniform weight , &

content uniformity – dose precision can not achieve .

• So, Flowability of powder is evaluated by no. of parameter described by carr ,

(1) Angle of repose : defined as max. angle between surface of a pile of powder &

horizontal plane .

- bulk solid with angle of repose between 25 to 35 consider as free flowing.

(2) Angle of spatula : defined as angle formed when material is raised on flat surface out

of the bulk pile .

- it provide indication internal friction between the particle .

- bulk solid with angle of spatula less than appx 40 consider as free flowing .

(3) compressibility : obtained from bulk & tap density.

- bulk solid with compressibility less than 18 consider as free flowing .

(4) cohesion : related to attractive force between the particle .

when powder flow , they do so either in steady controlled fashion ( as in case of dry send ) or

in uncontrolled manner ( as in case of damp sand for which entire bulk tries to move in solid

mass.)

This latter condition is known as floodable flow & is most characteristics of the flow of cohesive

, sticky powder .

(5) Angle of fall : it is obtained as new angle of repose , when supporting surface of the pile

experience vibration, impact & other movement , the material on the slope side of pile

dislodge & flow down the slope.

(7) Angle of difference : it is obtained by subtracting the angle of fall from angle of repose. It

indicate internal cohesion of particle.

- larger the angle of difference ,more flowable the material .

(6) Dispersibility : ability of powder to flow or to form dust , loss of mass to surrounding in air .

Properties of compacted materials

• Quality of compacted materials may be evaluated by tablet hardness and friability.

• The bonding index is an estimation of the survival of tablet strength following the decompression that takes place after the tablet is ejected from the press.

• The brittle fracture index is a measure of the brittleness of a material, and it provides a measure of the ability of a compact to relieve stress through plastic deformation.

• The strain index is an indicator of the relative strain that forms in a compact following its decompression.