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