PARTICLE SIZE, PARTICLE SIZE DISTRIBUTION

&COMPACTION AND COMPRESSION

[PREFORMULATION STUDY]

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INTRODUCTION OF PREFORMULATION

DEFINITION Preformulation involves the application of biopharmaceutical

principles to the physico – chemical parameters of a drug with the goal of designing an optimum drug delivery system. Characterization of drug molecule is a very important step at the preformulation phase of product development.

PARTICLE SIZE & PARTICLE SIZE DISTRIBUTION

DEFINITION Particle size is quieted as the diameter of the sphere equivalent to

the particle in the wt, vol, surface area, projected surface area or sedimentation velocity.

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TYPE OF POWDER ACCORDING TO PARTICLE SIZEMonodisperse powder:- all particles are of same sizePolydisperse powder:- particles of different size Generally powder sample contains no. of irregular shape three dimensional particles so generally we consider Avg. Ps. Average particle size: Average size of the particles which are

distributed in system. dmean = (ndp+f / ndf)1/p

p=1 - particle length, p=2 - surface p=3 -expression of volume, p= +ve -arithmetic mean p= -ve – harmonic mean, p= zero – geometric mean f = degree of freedom

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METHODS FOR PARTICLE SIZE ANALYSIS

1] Microscopy2] Sieving Method3] Sedimentation4] Elutration5] Coulter counter6] Permeability Method7] Surface Method8] Fluid Classification Method9] Laser light scattering Method

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METHODS FOR PARTICLE SIZE ANALYSIS

1] MICROSCOPYRange of analysis:-TEM :– 0.001 – 0.1 micronSEM :– 0.01 – 1000 micronLight microscope :- 1 – 1000 micron

•Light microscope :- Two dimensional image•No of particle count for draw size distribution curve(particle size v/s freq )

Alternative technique•Two Technique (1) Scanning Electron Microscopy (SEM) (2) Transmission Electron Microscopy

(TEM)•SEM give three dimensional image. It has more resolution

power then Light microscopy•Both SEM & TEM analysis use for lower particle size.

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2] SIEVING METHOD Range of analysis• Standardized by ISO • Lowest sieve diameter – 45 micron & Maximum sieve diameter 1000 micron• This method obtain particle range 5 – 12000 micron

Sample preparation and analysis condition

Sieve analysis is usually carried out using dry powders, although for powder in liquid suspension or which agglomerate during dry sieving a process of wet sieving can be used.

Alternative technique• Air jet sieving• uses individual sieves rather than complete nest of sieve

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3] SEDIMENTATION A number of classical techniques based on sedimentation methods, utilizing devices such as the Andersen pipette or recording balances that continually collect a settling suspension, are known however, these method are in general disfavor because of their tedious nature.

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4] ELUTRATIONIn this method fluid move opposite to gravitational force & particle moves down ward sideIf velocity of fluid is more then particle are carried upwards and vice versaSeparation of particles are depend upon their size and their position. It is affected by diameter of vessel also.

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5] ELECTRONIC SCANNING ZONE (COULTER COUNTER)

Main advantage are 1.Fastest counting.2.1000 Particle count in one second.3.More reliable since no. of particles are counted. (11-32)

6] PERMEABILITY METHOD Fluid caused to flow through a packed bed of particulate solids, the rate of flow will be described by Darcy’s law. Rate of flow that is permeability of fluid depends on particle size. Measurement of rate of fluid enables mean particle size to be calculated.

7] SURFACE METHOD Take powder and add air and liquid. Powder is absorb a liquid & air’s mono-molecular layer on their surface. This absorb volume can be give mean of powder’s particle size.

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8] LASER LIGHT SCATTERING METHODIn this method particle can be presented either in liquid or in air suspension.Both the large particle and small particle analyzers are based on the interaction

of laser light with particles.

Franhofer Diffraction:-For particles that are much larger than the wave length of light, any interaction with particles causes light to scattered in a forward direction with only a small change in angle. This phenomenon is known as Fraunhofer diffraction, and produces light intensity pattern that occur at regular angular intervals and are proportional to the particle diameter

Photon – Correlation Spectroscopy:-In this case Brownian motion is used to measure particle size. Brownian motion is independent of the suspending medium so increasing viscosity dose slow down the motion, the amplitude of the movements is unaltered. Because the suspended small particles are always in a state of motion they undergo diffusion.

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DIAGRAM

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Nano 25

• For measuring particle size, zeta potential and molecular weight• it measures particle size from 0.6nm to 6 micrometer• highly diluted to suspension and emulsion small sample – 0.75 ml• used in protein conformation study, crystallization study base of instrument is phase analysis light scattering (PASL) combined with• mixed mode measurement technology

X-ray diffraction method(15-32)

PROPERTIES OF DRUG THAT ARE AFFECTED BY PARTICLE SIZE AND PARTICLE SIZE DISTRIBUTION

Surface area Density, Porosity and Compressibility Angle of repose and Flow property Bulkiness and Packaging Criteria Hygroscopicity Electrostatic charge

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SURFACE AREA:-The particle size and surface area of drug exposed to medium can affect actual solubility

Log (S / S0) = [2γ V / 2.303 + RT r ] S = Solubity of small particle S0 = Solubity of large particle γ = Surface tension V = Molar volume R = Gas volume T = Absolute temperature r = Radius of small particle

The equation use to estimate the decrease in particle size required to increase solubility.

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DENSITY, POROSITY AND COMPRESSIBILITY:-

DENSITY:- The ratio of mass to volume is known as the density of the material, three types of density. TRUE DENSITY:- GRANULE DENSITY:- BULK DENSITY:-

POROSITY:- Is define as ratio of void volume to bulk volume of Packing.

%COMPRESSIBILITY FLOW

5 – 15 Excellent (free flowing granules)

12 – 16 Good (free flowing pwd granules)

17 – 21 Fair (pwd granules)

23 – 28 Poor (very fluid pwd)

28 -35 Poor (fluid cohesive pwd)

35 – 38 Very poor (fluid cohesive pwd)

More than 40 Extremely poor (cohesive pwd) (18-32)

FLOW PROPERTY AND ANGLE OF REPOSE

Cohesion and adhesion are phenomena occur at surface of particle that will affect flowability of powder.

Particles greater then 250 micron are free flowing. As PS decreases below 100 micron particle becomes more cohesive.

ANGLE OF REPOSE:- It is most imp tool for estimation of flow property of

powder. Determination done by “fixed height funnel method”Tan θ = h / r

h = ht of heap of pile r = radius of base of pileIMPORTANCE:- Particle size decreases angle of repose decreases due to cohesive forces flow property increases. If PS is increases, angle of repose decreases & flowability increases.

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BULKINESS AND PACKAGING

As particle size increase bulkiness decreases. It is a reciprocal of bulk density.

If more than smaller particle takes place in space between larger particles that decreases bulkiness.

HYGROSCOPICITY

Decrease in particles size give larger surface that will give high susceptibility for moisture absorption.

It is important for selection of production criteria. It also affects compressibility of drug.

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ELECTROSTATIC CHARGES

•That is most affects dispersed system like suspension, emulsion.•Particle size, PSD, cohesion, adhesion and electrical double layer property is most affected by it.

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IMPORTANCE OF PS AND PSDIMPORTANCE OF PS AND PSD

1. Particle size affect many physical properties of drug like surface area, density, porosity, compressibility, moisture absorption, surface properties like solubility, absorption, dissolution and bioavailability.

2. Tablet:- PS and PSD is important for selecting granulation process it also affect average tablet weight variation, granules properties like uniformity of color, size uniformity, also uniformity of dose, absorption, dissolution and finally bioavailability.

3. Suspension:- Sedimentation rate, suspendibility, redispersibility, coalescence and agglomeration.

4. Aerosol:- affects site of absorption in the bronchopulmonary tract.

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5. Bioavailability:- Drug whose BA is increase by PS reduction are Sulphadiazine, Phenothiazen, Tolbutamide, Spironolactone, Aspirin, Nitrofurantoin.

But in case of Nitrofurantoin increase in bioavailability may resulted in increase in its side effects.

Penicillin-G and Erythromycin if PS decreases, surface area increases if remains more time in contact with GIF so increases degradation.

Griseofulvin :- If micronized than increases rate of absorption and finally the dissolution.

Poorly soluble hydrophobic drug:- If PS is decreases then increases chance of formation of agglomerates.

PS & PSD also affects the porosity and bulkiness so affects packing.

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COMPACTION, COMPRESSION & COMPACTION, COMPRESSION & CONSOLIDATIONCONSOLIDATION

DEFINITION:-

COMPACTION:- Compaction of powder is term used to describe the situation in which material are subjected to some level of mechanical force.

COMPRESSION:- Compression is reduction in the bulk volume of the material particle displacement of gaseous phase.

CONSOLIDATION:- Consolidation is to increase in mechanical strength of material resulting form particle – particle interactions.

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DIFFERENT STAGES OF POWDER COMPACTION

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Initially, the powder is filled into the die with the excess of being swept off.

When appear punch first press down upon the powder bed, the particles rearrange themselves to achieve closer packing.

As the upper punch continues to advance upon the powder bed, the rearrangement become more difficult & deformation of particles will undergo elastic deformation. Which is a reversible process, but as continual presser applied, the particle begins to deform irreversibly.

Irreversible deformation can be due either to plastic deformation – which is a major factor attributing to the tablet’s mechanical strength or to brittle fraction which produces poor quality GMP act that causes crumbling of tablet during ejection.

Now concentrate on surface area change during powder compaction. Initially, - in S. A. noticed due to the fracture of particles as force increases. Eventually surface area decrease due to bonding & consolidation of particle at higher compression forces.

If we continue to force of upper punch on powder bed, - additional rise in surface area may cause lamination due to extensive rebound at decompression.

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Evaluation of compaction1. Strain index (SI) :- Measures internal strain associated with a powder when

compacted.2. Bonding index (BI) :-Ability of material to bonds.3. Brittle fracture index (BFI) :- Measures brittleness of material.

Higher is the BI index, stronger is the tablet.Higher is the SI index, softer is the tablet.

MCC, Erythromycin, etc have high BI and high SI. So compressibility is moderate.

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Effect of compaction on different factors:-

Compression force affects surface area, granule density, porosity and hardness and disintegration time of pharmaceutical tablets

Surface area increased to a maximum and then decreased.

Porosity decrease and density increased as a linear function of the logarithm of the compression force.

As the compression increase the tablet hardness and fracture resistance also rise.

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MOISTURE AND COMPRESSION Moisture is essential for the formation of the tablet. Moisture increase the tensile strength of the tablet by

increasing contact area for bonding Moisture decreases particle surface energy & thus decreases

adhesion of the tablet to the die wall. In case of MCC, moisture present within the pores facilitated

the flow during the compaction. Lack of moisture lids to lamination because of elastic

recovery. Excessive moisture produces capillary state of powder

aggregation and thus surface tension effects are insignificant to have better compaction.

Reported e.g. is that of Naproxen tablet which help of lactose. When moisture as more then 2% hardness of tablet decreased (at both low & high pressures.).

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REFERENCESREFERENCES1. Pharmaceutics by M. E. Aultion, 2nd edition Page 156 – 165.2. Physical pharmacy by Martin, 3rd edition Page 446.3. Remington “Pharmaceutical sciences”, 19th edition, vol-2; Page 894, 895, 1447

– 1462, 1620.4. The theory and Practice of industrial Pharmacy by Lehman, 3rd edition, Page

67, 71, 181.5. Encyclopedia of Pharmaceutical technology Dekker, vol-11; Page 237 – 258.6. Ansel’s Pharmaceutical Dosage forms and Drug Delivery Systems, 8th edition,

Page 101,190,191,150.7. Cooper and Gunn’s Tutorial Pharmacy, 6th edition, Pages 174 – 199.

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STUDY QUESTIONS

1. Discuss types of powders according to particle size and enlist methods for method of particle size analysis which properties of drug are affected by particle size and particle size distribution? (1st test 5th April 2006).

2. Explain different phases of powder compaction and its evaluation. . (1st test 30th March 2005).

3. Differentiate consolidation and compaction of powders. (1st test 30th March

2005).

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