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Pharmaceutics II – Micrometrics 1.Definition 2.Particle Size 2.1Overview 2.2 Statistical Diameters 3.Particle Size Distribution 4.Comparing Different Distributions 5.Particle Shape and Surface Area 6.Particle Size Analysis 6.1Microscopy 6.2Sieving 6.3Sedimentation 6.4Coulter Counter 1 Dr M. Skinner

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Pharmaceutics II – Micrometrics 1DEFINITION Micrometrics is the science and technology of small particles. Examples of Particle Size in Pharmaceutical Disperse Systems μmmm 0.5 – – 0.010Suspensions, fine emulsions 10 – – 0.050Coarse emul., flocculated, suspensions 50 – – 0.100Fine powder range 150 – – 1.000Coarse powder range 1000 – – 3.360Average granule size Knowledge and control of the size and size range of particles is of profound importance in pharmacy. Size and surface area can be related in a significant way to the physical, chemical and pharmacologic properties of a drug. Dr M. Skinner 2

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Pharmaceutics II – Micrometrics 2IMPORTANCE IN FORMULATION AND PRODUCTION Suspensions - stability and rheological properties depend on particle size. Mixtures of powders - individual components should be roughly same size for ease of mixing otherwise de-mixing or segregation will occur. Powders of different sizes have different flows and packing properties which alter the volume of powder during each encapsulation or tablet compression event resulting in fluctuation in content of product. Direct Compression. Granule size - used in tables and capsules must be controlled - for good flow properties & inter-batch uniformity. Granulation to reduce settling etc. Filtration during manufacture - if a solid is to be separated from a fluid, it is essential to know the size of particle to be removed. Selection of filter. Mass Transfer – efficiency dependent on size and area. Dissolution. Dr M. Skinner 3

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Pharmaceutics II – Micrometrics 2PARTICLE SIZE 2.1Overview In a collection of particles of more than one size (polydisperse samples) 2 aspects are important, viz: shape of individual particles; size range and number of particles and therefore the total surface area – dependent on size distribution. When a large solid is milled -smaller fragments fine particles irregular different numbers of faces difficult to determine more than one dimension. 4 Dr M. Skinner

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Pharmaceutics II – Micrometrics The size of a sphere readily expressed in terms of its diameter but As the degree of asymmetry increases expressing size in terms of a meaningful diameter is difficult. Under these conditions there is no one unique diameter for a particle. Resort to the equivalent spherical diameter Relates the size of the particle to the diameter of a sphere which has the same length (diameter), surface area or volume. Measurement based on a hypothetical sphere Represents only an approximation of the true shape of the particle. Dr M. Skinner 5

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Pharmaceutics II – Micrometrics 2.2Statistical Diameters Theoretical diameters which represent asymmetric particles as symmetric particles. d ln - length mean diameter (length number) d sn - surface mean diameter (surface number) d vn – volume mean diameter (volume number) d st – Stokes diameter Median Diameter Dr M. Skinner 6

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Pharmaceutics II – Micrometrics d ln - length mean diameter (length number) - The usual way to express a mean. (measure the length of the particle). - Acceptable if the size range is narrow and distribution is normal. - However these conditions are rarely found in pharmaceutical powders. d sn – surface mean diameter (surface number) -Diameter of a sphere having the same surface area as the particle in question. - This is a function of the surface area of the particles. -Size is expressed as the mean surface diameter. Dr M. Skinner 7

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Pharmaceutics II – Micrometrics d vn – volume mean diameter (volume number)- -Diameter of a sphere having the same volume as the particle in question. - The packing and flow of a powder or granule depends on its volume. - If packing / filling etc is a prime consideration this is useful. d st – Stokes diameter. -Describes an equivalent sphere undergoing sedimentation at the same rate as the asymmetric particle. - Important in referring to the size of particles in suspensions. Median diameter. -The diameter for which 50% of the particles measured are less than the stated size 8Dr M. Skinner

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Pharmaceutics II – Micrometrics Dr M. Skinner 9

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Pharmaceutics II – Micrometrics 3PARTICLE SIZE DISTRIBUTION The frequency of distribution of particle sizes. As important as the size itself. Presented graphically. Concise and allows easy visualization of the results. Size distribution is broken down into different size ranges. Present data in a histogram. Plot the number (or weight) of particles lying within a certain size range vs. the size range or mean particle size. A frequency distribution curve is obtained Can compare the characteristics of 2 or more powders. Dr M. Skinner 10

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Pharmaceutics II – Micrometrics Dr M. Skinner 11

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Pharmaceutics II – Micrometrics Provides a visible representation of data that an average diameter calculation cannot achieve. Immediately apparent what particle size occurs most frequently. e.g. Comparison of 2 samples with the same average diameter but different distributions. This is the mode and it separates a normal curve into 2 identical halves. Normal distribution i.e. distribution is symmetric about the mean. The standard deviation, σ, is an indication of distribution about the mean. In a normal population:68% lie ±1 σ from the mean 95.5 lie ±2 σ from the mean 99.7 lie ±3 σ from the mean Dr M. Skinner 12

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Pharmaceutics II – Micrometrics In pharmaceutical powders, a normal distribution is not commonly found. These systems tend to have an un-symmetric or skewed distribution. When data are plotted as frequency versus the logarithm of the particle diameter, a typical bell-shaped curve is frequently obtained. A log-normal distribution. Dr M. Skinner 13

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Pharmaceutics II – Micrometrics 4COMPARING DIFFERENT DISTRIBUTIONS (a)Normal distribution where mean = mode. (b)This frequency distribution curve has an elongated tail towards higher size ranges - positively skewed. (c)More than 1 mode can occur - bimodial frequency distribution. - Milled powders - Coarser particles from the unmilled remain. Dr M. Skinner 14

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Pharmaceutics II – Micrometrics 5PARTICLE SHAPE AND SURFACE AREA A knowledge of the shape and surface area of a particle is desirable. Shape affects flow packing properties surface area. Area is significant in mass transfer processes. Equation expressing mass transfer. W = D A ( C 1 - C 2 ) t A = Surface Area L Operations such as dissolution, evaporation, extraction and drying will be influenced directly by particle size and area. Dr M. Skinner 15

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Pharmaceutics II – Micrometrics 6PARTICLE SIZE ANALYSIS Various methods attempt to express the “size” of an irregular, 3D particle. Measurements must be carried out on a sample representative of the whole. Generally, it is not sufficient to remove a small amount from the top of a container: -Segregation may have occurred during transport. -Preliminary mixing of contents. -One container may not be representative of the entire batch. Statistical sampling methods must be used to ensure a good representation. Dr M. Skinner 16

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Pharmaceutics II – Micrometrics 6.1MICROSCOPY An effective procedure Only direct measurement method. 0.2 to 100 μmordinary microscope 0.01 μm and above electron microscope The technique involves: - calibration of the microscope - visual measurement of particle size - sample as an emulsion or suspension, diluted or undiluted, - mounted slide or ruled cell - mechanical stage - eyepiece is fitted with a micrometer - by which the size of the particles may be estimated. - also projected onto a screen, or a photograph can taken - size determined therefrom. Dr M. Skinner 17

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Pharmaceutics II – Micrometrics Advantages and disadvantages The only method which enables direct visualization of the particle. Tedious and time-consuming method - A large number of measurements must be made. - Number of measurements must be large enough so that the result will not change on continued measuring - Recommended number is at least 625 -If the size distribution is large, this number may have to be increased. Shape - Particles measured along an arbitrarily chosen, fixed line, generally made horizontally across the center of the particle. - It is necessary to decide on one linear dimension to represent the particle. - e.g. consider a cylindrical particle. Which measurement should be used? Dr M. Skinner 18

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Pharmaceutics II – Micrometrics Particle Position - Using a microscope, we see a 2-D representation of a 3D object. - A particle will assume the position of maximum stability on the microscopic slide. - A laminar particle will appear to be much larger than if it was measured by a different method. Aggregation - Aggregation on the slide will produce anomalous results as the aggregate will be indistinguishable from a single particle. Sampling - special sampling techniques must be used as only a relatively small number of particles is measured. Like the counting and measuring procedures, sampling techniques must be rigidly standardised. Dr M. Skinner 19

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Pharmaceutics II – Micrometrics 6.2 SIEVING Most simple method. Inexpensive Rapid Dr M. Skinner 20

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Pharmaceutics II – Micrometrics Dr M. Skinner 21

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Pharmaceutics II – Micrometrics Dr M. Skinner The powder is passed over a perforated screen: - Particles sufficiently small will pass through - Oversize particles will be retained on the sieve - Sieving is a “go/no go” test which divides the powder into 2 fractions above and below a specified size. USP method for testing powder fineness – USP 32 pg 307: - Definite mass of sample is placed on the proper sieve in a mechanical shaker. - The powder is shaken for a definite period of time. - Material that passes through one side and is retained on the next finer sieve is collected and weighed. 22

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Pharmaceutics II – Micrometrics When a detailed analysis is desired: - Sieves may be arranged in a nest of about 5 - Coarsest sieve at the top. - A weighed sample of the powder is placed on the top sieve. - After the sieves are shaken for a predetermined period of time, the powder retained on each sieve is weighed. Results of sieve analysis: -Best presented in the form of a cumulative oversize curve. - A log-normal distribution is assumed. - Cumulative % by weight of powder retained on the sieves is plotted against the logarithm of the arithmetic mean size of 2 successive screens. - This will be plotted on semi-log paper. Dr M. Skinner 23

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Pharmaceutics II – Micrometrics BP APPENDIX XV11 A. Particle Size of Powders The degree of coarseness or fineness of a medicinal or pharmaceutical substance in powder form is differentiated and expressed by reference to the nominal mesh aperture size of the sieves used, or, where the use of the sieves is inappropriate, it is expressed in terms of the particle size as determined by suitable microscopic examination. The following terms are used in the description of powders: e.g. Coarse powder. A powder all the particles of which pass through a sieve with a nominal mesh aperture of 1700 μm and not more than 40.0% by weight pass through a sieve with a nominal mesh aperture of 355 μm. Dr M. Skinner 24

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Pharmaceutics II – Micrometrics To summarise the results (changes in current BP): Sieve (μm) through which Sieve (μm) through which not Grade of powderall particles must passmore than 40% of particles pass Coarse Moderately coarse Moderately fine Fine Very fine12545 Microfine:Not less than 90% by weight of the particles pass through a sieve of 45 μm Superfine:Not less than 90% by number of the particles are less than 10 μm in size Dr M. Skinner 25

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Pharmaceutics II – Micrometrics When the fineness of a powder is described by a number, it is intended that all particles of the powder shall pass through a sieve of which the nominal mesh aperture, in μm, is equal to that number. The limit for the 2 nd sieve is to place a limit on “fines” in the coarser grade of powders. The ideal, of course, is that none of the powder should pass through the lower sieve. No lower limit is placed on the microfine powder. Superfine powders will be determined by microscopy. Dr M. Skinner 26

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Pharmaceutics II – Micrometrics Standards for sieves -As powders are standardized by sieves, the sieves themselves must meet stringent specifications – ISO specificiations. -Wire mesh sieves are identified by numbers indicating the nominal mesh aperture in micrometers. -This is the distance between the wires. -The sieves should be made of suitable materials with square meshes. -There must be no reaction between the material of the sieve and the substance being sifted. REFERENCE: Table in Appendix XVII of the BP Dr M. Skinner 27

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Pharmaceutics II – Micrometrics Problems using sieving -Although a simple technique, it is difficult to obtain accurate results for a number of reasons. - Particle shape - Only spheres can pass through the sieve without having to assume a specific orientation. - Therefore the further the particle departs from the spherical shape, the greater the difficulty it will have in passing through the aperture. -Consider a cylindrical particle, lying lengthways will not pass through the sieve, but if it was end on, it would be able to pass through. Dr M. Skinner 28

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Pharmaceutics II – Micrometrics From this we can conclude that a sieve will classify a particle as less than the dimension of the mesh, provided that the particle is less than the mesh size in one plane and that the sifting process is carried on for sufficient time for the particle to become suitably orientated to the mesh opening. Humidity - Can affect particles of hygroscopic materials and lead to aggregation. Aggregates - Due to electrostatic charges, fine particles tend to form aggregates which do not pass through the sieve. Particle size distribution -Particles that are well below mesh size will pass through early. -Those that are ≥ 0.75 of mesh opening tend to form aggregates which block the sieve. -Similarly, particles up to 1.5 times the mesh size tend to block the sieve. Dr M. Skinner 29

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Pharmaceutics II – Micrometrics Technique and completion of sieving -Disturbance of the bed of particles by shaking or vibration is necessary for sieving to occur. -Standardisation is necessary, especially with regard to the end-point, since it is virtually impossible to sieve to completion. -Some sort of end-pt must therefore be set such as a specified time. Fines -Prolonged sieving can lead to fines formation by attrition of the coarser particles between each other and against the sieve. Number of data points obtained -Usually only a few data points are obtained i.e. depending on the number of sieves used. -The average size of particles held on any one sieve must be assumed to be the average of the aperture sizes of the sieves on either side of the sample. -This may be inaccurate. Dr M. Skinner 30

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Pharmaceutics II – Micrometrics 6.3 SEDIMENTATION The sedimentation rate of various particles within the sample is measured. The sedimentation rate may be expressed using Stokes’Equation: V = d 2 ( ρ S - ρ L ) g- V = velocity (m/s), 18 η- d = diameter - g is gravitational acceleration (m/s 2 ), - ρ S is the mass density of the particles (kg/m 3 ), - ρ L is the mass density of the fluid (kg/m 3 ). - η is viscosity of the fluid. This applies to:- an ideal situation - with spherical particles - in a dilute suspension - falling freely without hindrance - at a constant rate. It is important to note that [ V α d 2 ] since all other parameters remain constant for a given situation. Dr M. Skinner 31

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Pharmaceutics II – Micrometrics Andreasen Pipette Method -This method combines ease of analysis, accuracy and economy of equipment. -Apparatus consists of a 550 ml vessel containing a 10 ml pipette sealed into a ground-glass stopper. -When the pipette is in place in the cylinder, its lower tip is 20 cm below the surface of the suspension. Dr M. Skinner 32

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Pharmaceutics II – Micrometrics -A 1% suspension of particles in a medium containing a suitable deflocculating agent is introduced into the vessel and brought to the 550 ml mark. -The vessel is shaken to distribute particles uniformly. -At various time intervals, 10 ml samples are withdrawn and discharged by means of the 2-way stopcock. -The samples are evaporated and weighed or analyzed by other means. Dr M. Skinner 33

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Pharmaceutics II – Micrometrics -Use a modification of Stoke’s Law: d = SQRT. 18 η h. ( ρ S - ρ L ) g t -‘h’ is the height of the liquid above the lower end of the pipette at the time each sample is removed -From the data obtained a size VS less than stated size graph can be plotted. -Using the semi-log arithmetic plot (log size vs %) the geometric mean diameter and SD can be calculated. Dr M. Skinner 34

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Pharmaceutics II – Micrometrics 6.4COULTER COUNTER Dr M. Skinner 35

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Pharmaceutics II – Micrometrics Measures the volume of particles rather than particle size. -The CC works on the principle that a change in electrical resistance occurs when a particle suspended in a conducting liquid passes through a small orifice, on either side of which are electrodes. -A known volume of a dilute suspension is pumped through the orifice, and if it is sufficiently dilute, the particles pass through one at a time. -A constant voltage is applied across the electrodes so as to produce a current. -As the particle travels through the orifice, it displaces its own volume of electrolyte and this results in a change in resistance between the 2 electrodes. -This change in resistance causes a voltage pulse that is amplified and fed to a pulse height analyser calibrated in terms of particle size. Dr M. Skinner 36

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Pharmaceutics II – Micrometrics -In practice, the electronic counter is set within 2 threshold values, such that it will not count the particles which pass through the aperture that cause an impulse that does not fall within the threshold i.e. those particles that are either larger or smaller than a given size. -By repeating the process at various threshold values, data can be obtained as to the number and distribution of the particle sizes. -The instrument is capable of counting particles at the rate of approximately 4000 per second -Both gross counts and particle size distributions are obtained fairly rapidly. Useful over the range 0.5 – 100 μm. -The main disadvantage is with aqueous soluble particles, however, there are non-aqueous electrolytes that can be used to suspend the particles. Dr M. Skinner 37

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