PREFORMULATION

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PARTICLE SIZE, PARTICLE SIZE DISTRIBUTION
COMPACTION AND COMPRESSIONPREFORMULATION
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
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 (?ndpf / ?ndf)1/p
p1 - particle length, p2 - surface
p3 -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

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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 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
• Fastest counting.
• 1000 Particle count in one second.
• 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 Darcys
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 airs
mono-molecular layer on their surface. This
absorb volume can be give mean of powders
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) 2? V / 2.303 RT r
S Solubity
of small particle
S0 Solubity of large particle
? 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 ? 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 DEFINITIO
N- 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 tablets 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
• Strain index (SI) - Measures internal strain
  associated with a powder when compacted.
• Bonding index (BI) -Ability of material to
  bonds.
• 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
• Pharmaceutics by M. E. Aultion, 2nd edition Page
  156 165.
• Physical pharmacy by Martin, 3rd edition Page
  446.
• Remington Pharmaceutical sciences, 19th
  edition, vol-2 Page 894, 895, 1447 1462, 1620.
• The theory and Practice of industrial Pharmacy by
  Lehman, 3rd edition, Page 67, 71, 181.
• Encyclopedia of Pharmaceutical technology Dekker,
  vol-11 Page 237 258.
• Ansels Pharmaceutical Dosage forms and Drug
  Delivery Systems, 8th edition, Page
  101,190,191,150.
• Cooper and Gunns Tutorial Pharmacy, 6th edition,
  Pages 174 199.

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STUDY QUESTIONS

• 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).
• Explain different phases of powder compaction and
  its evaluation.
  
  .
  
  (1st test 30th March 2005).
• Differentiate consolidation and compaction of
  powders.
• 
  (1st test 30th March
  2005).

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