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PARTICLE SIZE, PARTICLE SIZE
DISTRIBUTION
&
COMPACTION AND COMPRESSION
[PREFORMULATION STUDY]
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 SIZE
Monodisperse powder:- all particles are of same size
Polydisperse 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] Microscopy
2] Sieving Method
3] Sedimentation
4] Elutration
5] Coulter counter
6] Permeability Method
7] Surface Method
8] Fluid Classification Method
9] Laser light scattering Method
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METHODS FOR PARTICLE SIZE ANALYSIS
1] MICROSCOPY
Range of analysis:TEM :– 0.001 – 0.1 micron
SEM :– 0.01 – 1000 micron
Light 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
(8-32)
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.
(9-32)
4] ELUTRATION
In this method fluid move opposite to gravitational force & particle moves
down ward side
If velocity of fluid is more then particle are carried upwards and vice versa
Separation 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.
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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 METHOD
In 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
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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)
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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 pile
IMPORTANCE: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 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 &
CONSOLIDATION
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 compaction
1. 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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REFERENCES
1. 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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