 Drug product formulator approximately uniform

Micromeritics size > batch of latex particles as small as 0.06 µm in

 The science and technology of small particles . diameter with STD of ±0.012 µm and particles as
 Particles – is any unit of matter having defined large as 920 µm with STD of ±32.5
physical dimension  Uniform size – use in science, medicine,
 Pharmacy importance technology and diagnostic test – particle size
 Size and surface area of a particle > physical, standard for particle size analyzer
chemical and pharmacologic properties of drugs.
 Clinically, the particle size of a drug can affect its Average particle size
release from dosage forms that are administered  Statistical diameters pls refer to book
orally, parenterally, rectally and topically.
Particle size distribution and Number and
Origin weights distribution
 JM Dalla Valle > book > greek word small and  N and W – sieving or sedimentation technique
part  PSD – graphic (mode)

Application METHOD OF DETERMINING PARTICLE

 Release and dissolution - Higher surface area SIZE
brings about intimate contact of the drug with the Optical microscopy
dissolution fluids in vivo and increases the drug  Particle size measurement – 0.2µm to about 100
solubility and dissolution. µm
 Absorption and drug action - Higher the  Mechanical stage – eyepiece (micrometer)
dissolution, faster the absorption and hence quicker  Popular measurements: Feret diameter, Martin
and greater the drug action. (Therapeutic effect) diameter, and the projected area diameter
 Physical stability – suspension and emulsion
- Smaller the size of the particle, better the Martin diameter
physical stability of the dosage form owing to  Measure the length of a line that bisects the
the Brownian motion of the particles in the particle image .
dispersion.  The line may be drawn in any direction but must
- Dose uniformity - Good flow properties of be in same direction for all particles
granules and powders are important in the
manufacturing of tablets and capsules. The Feret diameter
distribution of particles should be uniform in terms  Distance between two tangent on opposite side s
of number and weight. of the particles parallel to some fixed direction

Particle size distribution Projected area diameter

 Important:  Is the diameter of a circle with the same area as
 Shape and the surface area of individual that of the particles perpendicular to the surface on
particles which the particles rest
 The size range and number or weight of
particles presence > surface are Note:
 Electronic scanner – use to remove the necessity
Particle dimension in Pharm’l Dispersed system of measuring the particles by visual observation
Micrometer Appropriate Examples  Video recording equipment – observe, record,
sieve size store and retrieve particle size data > tablet
0.5-10 - Susp, fine excipients > microcrytalline cellulose, SCMC,
emulsion sodium starch glycolate and methyl cellulose
10-50 - Upper limit of
subsieve range, Disadvantage
coarse  Diameter is obtained from only two dimensions
emulsion, of particles : length and the breadth. No estimation
flocculated of the depth (thickness)
susp.  Number of particles must be counted (300-500)
50-100 325-140 Lower limit of to obtain good estimation of distribution – tedious
sieve range fine  Microscopic examination (photomicrographs) –
powder range presence of agglomerates and particle of more tan
150-1000 100-18 Coarse powder one component may be detected
1000-3360 18-6 Average
granule Sieving
 Calibrated by National Bureau of Standards
Particle dimension in Pharm’l Dispersed system
 Grading coarser particles > extreme care > fine as  Embolism > with particles larger than 5µm
44µm (No. 325 sieve)
 Sieves are produced by photoetching and Italian pharmacopeia
electroforming techniques > 90µm down to 5µm  Parenteral preparation > greater than 100 ml
 USP powder fineness (definite mass) proper sieve NMT 100 particles 5µm and larger > NMT 4
(mechanical shaker) > definite time period and the particles 20µm in diameter and larger may be
material that passes thru one sieve and is retained on present in each mL of solution.
the next finer sieve is collected and weigh  Contaminants are found in > Filters, clothing and
 Nest five which has coarsest at the top container seals
 Sieve error – sieve loading and duration and
intensity of agitation USP standard sieve nos.
 12  20
Sedimentation  14  25
 Application of ultracentrifugation to the  16  35
determination of the MW of high polymer.  18  Indomethacin sustained release
 The equation holds exactly only for spheres
falling freely without hindrance and at constant rate Light energy diffraction
 Irregular shape – diameter is relative particle size  Reducing in light reaching the sensor as the
equivalent to that of sphere falling particles, dispersed in a liquid or gas, passes thru
 Note that particles must not be aggregated or sensing zone range (0.2-500 micrometer)
clumped together in susp. Clumps > fall mor rapidly
> erroneous result. Laser halography
 In short, sedimentation rate in which particle size  Laser is fired thru an aerosolized particles spray
is determined by measuring the terminal settling and photograph in three dimension with a
velocity of particles thru a liquid medium in a holographic camera
gravitational or centrifugal environment (range 0.8-  Individual image and sized (1.4-100 mcrometer)
300mm)
 Methods of sedimentation: Cascade impact
 Pipette method  Particles are driven into airstream will impact on
 Balance method a surface in its path, provided that its inertia is
 Hydrometer method Pipette method – Andreasen sufficient to overcome the drag force that tend to
apparatus – 550ml vessel containing 10 ml pipette keep in the air stream
sealed with a glass stoppered Pipette > cylinder
lower tip 20cm below surface of susp Other method of particle size determination
 Elutriation method
Pipette method  Centrifugal method
 1-2% medium > 550ml > stoppered and shake >  Permeation method
pipette place > clamp securely constant temp bath >  Adsorption method
time interval 10ml withdrawn and discharge by  Light obstruction method
means of two way stopcock > evaporated weigh and
analyzed Note: average particle size by weight
 Note : particle for submicron range (0.015 –  Sieve method
1.1µm)  Light scattering
 Sedimentation method
Particle volume measurement
 Coulter counter – (electronic sensing zone) Note: Average particle size by volume
instrument operates on particles that when  Light scattering
suspended in conducting liquid passes thru a small  Electronic sensing zone
orifice on either side of which are electrode, a  Light obstruction
change in electric resistance occurs  Air permeation
 Advantage: Particle growth and dissolution and  Optical microscope
effect of antibacterial agents on the growth of MO

HIAC/Royco instrument DISADVANTAGE OF POWDERS AS

 Instrument use to measure particulate DOSAGE FORM
contamination in parenteral solution  Potential misunderstanding of the correct method
Contaminants of use
 Vascular occlusion  Bitter and unpleasant tasting
 Inflammatory  Difficulty of protecting from decomposition >
 Neoplastic hygroscopic, deliquescent or aromatic material
 Allergic rxn
 Manufacturing expenses > individually wrapped  Shape affects the flow and packing properties of
dose of powder powder > surface area
 Surface area / unit weight or volume is an
Powders of vegetable and animal drugs important characteristic of powder – surface
Characteristics Description adsorption and dissolution rate
Very course (No. 8) All particles pass thru
No. 8 NMT 20% thru METHODS OF DETERMINING SURFACE
no. 60 AREA
Coarse (No. 20) All particles pass thru Adsorption method
No. 20 sieve and NMT  The amount of gas or liquid solute is adsorbed
40% thru no. 60 onto the sample of powder monolayer is a direct
Moderately course All particles pass thru function of surface area of sample
(No. 40) No. 40 NMT 40% thru  Particles with a large SSA are good adsorbent for
no. 80 the adsorption of gases and of solutes from solution
Fine (No. 60) All particles pass thru
No. 60 NMT 40% thru Air permeability method
no. 100  Depends on the fact that the rate at which gas or
Very fine (No. 80) All particles pass thru liquid permeates a bed of powder is related among
No. 80. there is no limit other factor. The surface are exposed to permeant
as to greater fineness  The principle resistance to the flow of a fluid
such as air thru a plug of compacted powder is the
Chemical surface area of powder
Classification Description  Note : the greater the SA the greater the
Course (No. 20) All particles pass thru resistance flow
No. 20 NMT 60% thru  Permeability of a pressure drop across the plug
no. 40 inversely to SA
Moderately coarse All particles pass thru  This is affected by:
(No.40) No. 40 NMT 6 0% thru  Degree of compression of particles
no. 60  Irregularity of the capillaries
Fine (No. 80) All particles pass thru
80. there is no limit as  Note the more compact the plug the lower the
to greater fineness porosity (ratio of the total space between particle to
Very fine (No. 120) All particles pass thru the total volume of the plug
120. there is no limit as
to greater fineness Pore size
 High specific area may have crack and pores that
PARTICLE SIZE INFLUENCE THE adsorb gases and vapor such as water into their
FOLLOWING FACTORS interstices
Dissolution rate  Insoluble powdered drugs may dissolve more or
 Higher SA faster dissolution rate faster drug less rapidly in aqueous medium depending upon
absorption their adsorption of moisture adsorption of moisture
or air
Suspendability  Dissolution rate of drug from tablet
 Particles intended to remained undissolved but  Adsorption characteristic of drug powders
uniformly dispersed in a liquid vehicle
 Coarse dispersion – 0.5 to 10 micrometer DERIVED PROPERTIES OF POWDER
Porosity
Uniform distribution  Zinc oxide > graduated cylinder and the total
 UD of drug substance in a powder mixture or volume
solid dosage form  Bulk volume (Vb) – volume occupied
 True volume (Vp) – non porous no internal pores
Penetrability
or capillary spaces
 Involve the powder intended to be inhaled to
 Void volume – space between particles
reach a desired location within the respiratory tract
 Porosity or void ( ) ratio of the void volume to
1-5 micrometer
the bulk volume of the packing
Nongrittiness
Packing arrangement
 Dermal ointments, cream, opthalmic prep
 Closest (rhombohedral) 26%
 Fine powders 50-100 micrometer
 Most open, loosest or cubic packing 48%
PARTICLE SIZE AND SURFACE AREA
Particle size and shape  Real powders – spherical in shape nor uniform
size > porosities of 30-50%
 Not uniform size > 26%  50cm³ powder > USP sieve No. 20 100ml
 Powder with flocculates or aggregates > 48% graduated cylinder > dropped 2 sec interval (hard
 Crystalline material compressed under force of wood surface 3 x height of 1 inch)
100,000 lb/in² porosity less than 1%  Dividing wt sx/final volume
 500 times
Densities of particles  Light – low bulk density or large bulk volume
 Density – weight / volume  Heavy – high bulk density or small volume
 Three density:  Interspace or void porosity – powder of porous
 True density – material itself exclusive of void granules is the relative volume of interspace voids
and intraparticles pores larger than molecular or to the bulk volume of the powder exclusive of
atomic dimensions in the crystal lattice intraparticle pores
 Granule density – determined by displacement of  Total porosity – of a porous powder is made up
Hg which does not penetrate at ordinary pressure of void between the particles as well as pores within
into pores smaller than about 10 µm the particles
 Bulk density – determined by from the bulk
volume and weight of a dry powder in a graduated Summary
cylinder  Specific true volume – is the volume of solid
material itself per unit mass of powder
Note:  Liquid > measure it does not penetrate
 Solid is nonporous – True and granule density are completely into the pores (vol/unit wt of the solid
identical material and small part of the pore volume within
 Helium or a liquid such as Hg, benzene, or water the granules > not penetrate
 Porous having internal surface – the true density  Specific granule volume – vol of solid and
– displacement of He which penetrates into smallest essentially all the pores within the particle
pores and is not adsorbed by the material  Specific bulk volume – vol/unit wt of solid, the
 Displacement in liquid = true density but may vol intraparticle pore and the void volume or the
differ if liquid does not penetrate into the pores volume of interparticulate space

True density Bulkiness

 Is the density of the actual solid material  Specific bulk volume – reciprocal to bulk density
 Methods (nonporous) displaced in liquid in which called as bulkiness or bulk.
insol  Packaging or powders
 Method (porous)  Calcium carbonate 0.1 to 1.3
 Helium densitometer – volume of empty  Note that lightness or bulkinest 13 x larger than
apparatus (dead space) > known quantity of He > that needed for the heaviest variety
sample tube weight amount of powder. Absorbed  Bulkiness increase with decrease in particle size
gases are removed  Mixture of material of different size smaller
 Hg manometer - pressure particle sift betweeb the larger ones and tend to
reduce te bulkiness
Apparent density
 Apparent density granular or bulk density Flow Properties
sometimes true density obtained by liquid  Bulk powder non Newtonian liquid (plastic flow
displacement and sometimes dilatancy
 (no more apparent density)  Powders may be free flowing or cohesive (sticky)
 Hausner ratio – or packed bulk density versus
Granule density loose bulk density, the rate of tamping, the flow rate
 Determined by liquid displacement method and free flow thru orifice
 Hg is used since it fills the void space but fails to  Elongated or flat particles tend to pack albeit
penetrate into the internal pores of the particles loosely > high porosity
 Tablet granulation – Hg displacement method >  High density and low porosity > free flowing
pcynometer (surface roughness) > poor flow character due to
 Compressed 100,000lb/sq inch friction and cohesiveness
 Intraparticles porosity of the granules may be  Dustibility – free flowing powder – signify the
computed from a knowledge of True and granule opposite of stickiness
density  Lycopodium – show greatest degree of
dustibility100%
Bulk density  Talcum powder – 57%
 Defined as the mass of a powder divided by the  Potato starch – 27%
bulk volume  Fine charcoal – 23%
 Finely powdered calomel – 0.7%
 Increase lubricant also raised the flow rate >
combination of lubricant and fine appeared to have
synergistic axn
 Angle of repose – maximum angle possible
between the surface of a pile of powder and the
horizontal plane
 Glidant – improve flow characteristic, added to
granular powder
 Mg stearate, starch and talc
 1% or less optimum glidant conc
 Optimum glidant concentration for lactose and
calcium hydrogen phosphate powders
 Sulfathiazole granulation as a function of average
particle size > presence of lubricant and admixture
of fines
 Angle increase with decrease particle size
 Addition of talc in low conc decrease angle of
repose but in high conc it increase angle
 Addition of fines – particles smaller than 100
mesh – to coarse granules resulted in marked
increase of the angle of repose
 Mixing – and prevention of unmixing is an
important > tab and cap
 Factor affecting the mixing process:
 Particle aggregation
 Size, shape
 Density differences
 Static charge

Compaction: compressed tablet

 Powders are compacted – 5kg/cm² the porosity of
the powder composed rigid particles (sodium
carbonate)
 Higher than the porosity of powder in closest
packing > tapping experiment
 Dilatant – unexpected expansion rather than
contraction under influence of stress
 Kaolin – soft and spongy particle – deformed on
compression porosity lower than after tapping the
powder down to its condition of closest packing

Influence of compression force

 SSA
 Granule density
 Porosity
 Tablet hardness
 Disintegration time
 Sulfathiazole tablet granulation – BET method
increased in maximum and then decrease
 New surface compression force 2500 lbs
 Porosity decrease and density increase
 Compression increase so tablet hardness and
fraction resistance also rise
 Tablet machine and tablet lubricant