Solid State Analysis of Drug Substance

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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 4/27/12 and formulation strategies and in

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

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Solid state analysis is part of preformulation studies Physical properties of drug substances, excipients and blends of them drastically affects the manufacturability of solid dosage forms. E.g. particle size affects flowability
crystalline or amorphous solubility
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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 everincreasing degree of attention being given to the physical properties of the solids that compromise a dosage 4/27/12

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Solid state analysis

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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.
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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 pyran4/27/12

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
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color changes was automated using fiber

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
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combination with diffuse reflectance

( 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 4/27/12

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 4/27/12 solvatomorphic forms, with the anhydrous forms I and

Glisentide
Characteristic Urea carbonyl group Form I Form II 1635 cm-1 and 1545 1620 cm-1and 1545 cm-1 cm-1, shoulder more intense 1157 cm-1 1720 cm-1 1165 cm-1 Broadened, 1720 cm-1

S=O stretching Aromatic carbonyl group

Form II

For mI

Conclusion: polymorphism of glisentide probably is due to changes in crystal packing rather than conformational differences. 4/27/12

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
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groups yield the most intense

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. 4/27/12

Near IR Spectrocopy
Near-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.
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The spectral features are of

(C)

MAGNETIC RESONANCE SPECTROSCOPY

Advances in instrumentation
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Fosinopril sodium

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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.

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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.

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(A)

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
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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 4/27/12

1) Light Microscopy

Light Microscope: Imp. Parameters magnification, resolving power Particle morphology can be examined.

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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 4/27/12

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.

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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. 4/27/12

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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

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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 4/27/12 to whether the transformation of one

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. 4/27/12 can be done on the basis of

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4) Chemical Microscopy

In this microscopic technique, derivatives of the analyte species are prepared, crystallized, and identified through the morphological characteristics of these derivatives.

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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.
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SEM analysis is often combined with x-ray analysis, whereby

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

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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. 4/27/12

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
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shown that carbamazepine drug

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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.
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Examination of dimetrally fractured

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, 4/27/12

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.

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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 4/27/12 noncrystalline material.

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 threedimensional space. The dimensions of the unit cell are characterized by six quantities; three axial lengths (a, b, c) and three interaxial angles (, , ). Each unit cell contains at least one 4/27/12

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NH2

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(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 .

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Principle - XRD

X-ray are EMR wavelength range in angstrom (), 1 = 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 4/27/12 beams.

Braggs equation

Braggs law describes the conditions under which this (constructive inerference) would occur. When a perfectly parallel and monochromatic x-ray beam of wavelength , is incident on a crystalline sample at an angle , diffraction will occur if n = 2d sin , where d = distance 4/27/12 between the planes in the crystal (),

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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 4/27/12 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. 4/27/12

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

Packing polymorphism

Conformational polymorphism

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.
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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
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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 xrays (typically using a scintillation detector) with respect to the angle of the incident beam. 4/27/12

APPLICATIONS

QUALITATIVE ANALYSIS DEGREE OF CRYSTALLINITY PHASE QUANTIFICATION (QUANTITATIVE ANALYSIS) Kinetics of Solid-state reactions Drug-Excipient Interaction

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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.
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XRD Distinguishing different crystalline forms

Typical Powder Patterns Obtained for Four Solid Phases of Ampicillin 4/27/12 6363

XRD Distinguishing crystalline and amorphous forms

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

(Surana R et al Quantitation of crystallinity in substantially amorphous pharmaceuticals and of crystallization kinetics by X-ray 4/27/12 study 6464 powder diffractometry. Powder Diffr., 2000; 15: 2-6.)

Polymorphism: Applicable to polymorphs or to multicomponent formulations. The detection and quantification of polymorphic contamination is used to improve production efficiency and cost.

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XRD Distinguishing polymorphs

X-ray powder diffraction patterns for the two polymorphs of paracetamol 4/27/12
(Nichols G et al Physicochemical characterization of the orthorhombic polymorph of paracetamol crystallize from solution, Indian6666 Sci, 87: 684-693.) J Pharm

Phase Transitions Induced During Processing Investigation of excipient and processing on solid phase transformation and dissolution of ciprofloxacin

Structure of Ciprofloxacin

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

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(Xianwen Li et al Investigation of excipient and processing on solid phase transformation and

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Phase transformation occur during wet granulation process for tabletting

Powder X-ray diffraction patterns of anhydrate and monohydrate solid forms of baclofen 4/27/12 6969 (Mirza S et al Indian J Pharm Sci, 2007; 96: 2399 2408.)

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 4/27/12 7070

(Surana R et al Quantitation of crystallinity in substantially amorphous pharmaceuticals and

PHASE QUANTIFICATION (QUANTITATIVE ANALYSIS)

The Direct Method (No Internal Standard) Internal Standard Method Whole Powder Pattern Analysis

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The Direct Method (No Internal Standard) Analysis of anhydrous and forms of Carbamezapine by XRD pattern

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Internal Standard Method

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

Whole Powder Pattern Analysis Analysis of anhydrous and forms of Carbamezapine and carbamezapine dihydrate from mixtures by whole powder patterns 4/27/12 7373

Kinetics of Solid-state reactions

Investigation of the Multi-Step Dehydration Reaction of Theophylline Monohydrate Using 2Dimensional Powder X-ray Diffractometry Dehydration kinetic study of Theophylline Monohydrate were carried out at different temperature ( 35 -130 C)
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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

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(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

4/27/12 exothermic process ( crystallization & oxidative decomposition ) .

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 . 4/27/12

com

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

4/27/12 of sample lag behind that of the reference & this event record

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 .
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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 .
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Properties associated with the bulk levelthat can be Definition : As those characteristics of solid
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 sampling plan used. Miligram to gram level samples taken from kilogram level bulk material must be representative of the bulk properties.
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(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.
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METHODS FOR DETERMINATION OF PARTICLE SIZE DISTRIBUTION

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 4/27/12 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 m 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 . 4/27/12

SIEVE ANALYSIS : particle size range 50 1500 m 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.
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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.
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(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 properties surface area, porosity, and

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1)

2)

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.

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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

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anhydrous -lactose was sieved into

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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

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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 4/27/12

( C ) POWDER CHARACTERIZATION solids. One of the imp parameter of formulator is flowability of powder
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. 4/27/12

(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. 4/27/12 - larger the angle of difference ,more flowable the material .

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 4/27/12 measure of the brittleness of a