Introduction

Micromeretics is the science and technology of small particles Micromeretics is thus the study of the fundamental and derived properties of individual as well as collection of particles

Importance in pharmacy
The study of particle size and particle size distribution has a number of application in the field of pharmacy including:
i. The physical properties of powders such as bulk density, porosity and compressibility are dependent on the particle size and size distribution. For example the bulk density of light and heavy magnesium carbonate differs because of the difference in their particle size. ii. The flow properties of powders are dependent upon the particle size, size distribution and particle

shape. Asymmetric particles have poor flow characteristics and hence granulation techniques are
used to convert blends of drug and other additives into particles of uniform size having good flow properties iii. The rate of dissolution of poorly soluble drugs are directly related to the size of the drug particles. In general a decrease in particle size of drug increase the dissolution rate iv. Chemical properties of particles such as surface oxidation also depend on the particle size

Smaller the particle size, more is the surface area for oxidation. v. Properties of drugs such as rate of absorption and hence the pharmacological activity depend on the particle size vi. Elegance of pharmaceutical preparations such as emulsions, suspensions, ointments often depend on the particle size of dispersed phase vii. Release characteristics of drugs from ointments, creams and suppositories are depend on the particle size of the dispersed drug viii. Particle size of the dispersed drug also influence the spredability and performance of some cosmetic preparations like dusting powders ix. Particle size and size distribution has a profound influence on the uniform mixing of solids x. The stability of systems such as colloid suspension and emulsions depend on the particle size. As the particle size increases, the stability of these systems decreases xi. Even the feel, texture and colour of certain drugs depends upon the particle size. For example the

difference in colour of yellow and red mercuric oxide is due to the deference in their particle size
xii. Process such as extraction and dying are accelerated following a reduction in the particle size of the material xiii. The absorption capacity of a material also increase by a decrease in its particle size

The following are the five fundamental properties of powders from which other properties can be derived.
Particle size and size distribution Particle shape

Particle volume
Particle number Particle surface area

Particle size
0.5 - 10.0 m 10.0 - 50.0 m

Disperse system
Suspension, fine emulsion Coarse emulsion, flocculated suspension

50.0 - 100.0 m
150.0 - 1000.0 m 1000.0 - 3360.0 m

Fine powder range

Coarse powder range Average granule size

The size of a spherical particle can be easily expressed in terms of its diameter, d. For a perfect sphere the surface area is given by : S = d2 and the volume is given by V =

d3/6

A non-spherical particle has a definite surface area and volume but being asymmetric it is not possible to express its size in diameter. Its size is therefore expressed in terms of equivalent spherical diameter by using some measurable property such as surface area, volume etc.

Surface diameter, ds is the diameter of a sphere having the same surface area as that of the asymmetric particle

Volume diameter, dv is the diameter of a sphere having the same volume as the asymmetric particle

 Stokes diameter, dst refers to the diameter of a sphere with the same density as the asymmetric particle which undergoes sedimentation at the same rate as the asymmetric particle in a given fluid within the range of Stokes law. Projected diameter, dp is the diameter of a sphere having the same observed area as the asymmetric particle. This diameter is usually determined by microscopic technique

Martin's diameter (M) The length of the line which bisects the particle image. The lines may be drawn in any direction which must be maintained constant for all image measurements. Feret's diameter (F) is the distance between two tangents on opposite sides of the particle, parallel to some fixed direction.

Average particle size

Average particle size (dmean) can be calculated from the following formula: dmean = nd / n , where n is the number of particles and d is the diameter of particles

Edmundson derived such a general equation for calculation of the average particle
size, dmean =

ndp+f ndf

1/p

Where n is the number of particle in each size range , d is the diameter of particles in

a given size range, p is an index related to the size of an individual particle and f is the
frequency index. d raised to the power p = 1 gives the particle length; p = 2 gives the particle surface and p = 3 gives the particle volume

The value of p also indicate the type of mean obtained. If the value of p is positive the

mean is arithmetic, if p is zero the mean is geometric and if p is negative then the
mean is harmonic

For a collection of particles the frequency with which a particle in a certain size range occurs is expressed as ndf

Some of the important arithmetic diameters:

Size index [p] Frequency index [f] Size parameter Frequency Mean diameter Edmundson equation
nd n nd2 n
3nd2

1 2

0 0

Length Surface

Number Number

Length number mean (dln) Surface number mean (dsn)

3
1

0
1

Volume
Length

Number
Length

Volume number mean (dvn)

Length weighted mean (dsl)

n nd2 nd nd3 nd2 nd4 nd3

1
1

2
3

Length
Length

Surface
Weight

Surface weighted mean (dvs)

Volume weighted mean (dwm)

Powder is polydisperse that is consists of a mixture of particles of varying size and shape. It is therefore necessary to know not only the size of a certain particle in the sample but also the number of particles of the same size present in the sample. Thus we need to know the size range present and number or weight fraction for each range which is called particle size distribution.

1.

The particle size distribution in a powder may be quantified by one of the following way: By determining the number of particles present in each size range (usually determined by microscopic technique)

2.

By determining the weight of particles present in each size range (usually determined by sedimentation and sieving methods)

When the number of particles is plotted against the mean particle size, the curve obtained is known as the number frequency distribution curve and when the weight of particles is plotted against the mean particle size, the curve obtained is known as the weight distribution frequency curve

Powder is monodisperse that is consist of a mixture of particles of similar size and shape

Monodisperse

Polydisperse

A polydisperse powder is said to have a normal distribution if a typically bell shaped frequency distribution curve is obtained, in such case one half of the curve is super imposable on the other half

Negatively skew indicates that the tail on the left side longer than the right side of the mass distribution and the bulk of the values lie to the right of the mean Positively skew indicates that the tail on the right side longer than the right side of the mass distribution and the bulk of the values lie to the left of the mean

Particle number

Particle number, N is defined as the number of particles per unit weight of a powder and can be obtained in the following manner. If the particles of the powder are spherical, the volume of single particle is dvn3/6 and the mass is dvn3/6 g per particle where dvn is the mean diameter based on volume and number and is density of the particle. The number of particles per gram can then obtained from the expression: N N = = 1 gm of the powder Mass of one particle 1 dvn3/6 6 dvn3

Or N

 The following methods are generally used for the determination of particle

size and particle size distribution:

1. Microscopic technique

2. Sieving technique
3. Sedimentation technique 4. Optical and electrical sensing zone method 5. Laser light scattering techniques

Selection of particle size analysis method

Particle size analysis method selection depends mainly on the properties of the powder particles and the type of size information required. Toxicity Solubility Cost effectiveness Density Specification requirement Cohesivity Speed of measurement Ease of handling

1. Microscopic technique:
Optical microscopy is generally used for particle size measurement in the range of 0.2 m to about 100.0 m. At least 300 to 500 particles must be counted in order to obtain a good size distribution analysis of data. Advantages Relatively inexpensive Each particle individually examined - detect aggregates, 2D shape, colour, Permanent record - photograph Small sample sizes required Disadvantages Time consuming - few particles examined Very low throughput No information on 3D shape Certain amount of subjectivity associated with sizing - operator bias For submicron particles it is necessary to use electron microscopy either

TEM (Transmission Electron Microscopy) or SEM (Scanning Electron Microscopy). TEM and SEM (0.001 5.0 m)

Advantages and disadvantages of electron microscopy are Advantages

Particles are individually examined

Visual means to see sub-micron specimens Particle shape can be measured

Disadvantages Very expensive Time consuming sample preparation

Materials such as emulsions difficult/impossible to prepare

Low throughput - Not for routine use

2. Sieving technique:
Sieving technique is generally useful for coarse particles since the technique is limited by the smallest size and hence measurement of sizes smaller than 50.0 m is difficult Sieve analysis is performed using a nest or stack of sieves where each lower sieve has a smaller aperture size than that of the sieve above it. Sieves can be referred to either by their aperture size or by their mesh size (or sieve number). The mesh size is the number of wires per linear inch. Approx. size range : 5m - ~3mm Standard woven wire sieves Electroformed micromesh sieves at the lower end or range (< 20m) Punch plate sieves at the upper range.

Sieving may be performed wet or dry; by machine or by hand, for a fixed time or until powder passes through the sieve at a constant low rate

Advantages:
This method is very simple, not expensive and easy to prepare

Disadvantages:
Particles may aggregate during sieving due to generation of electrostatic charge Moisture can also lead to aggregation of powders and the actual particle size may not be obtained Attrition of particles during sieving may lead to size reduction Sieve loading and duration of mechanical shaking can influence the results

British Pharmacopoeia Volume IV Appendix XVII A. Particle Size of PowdersParticle size classification of powders (Ph. Eur. method 2.9.12, Sieve test) The degree of fineness of a powder may be expressed by reference to sieves that comply with the specifications for non-analytical sieves (2.1.4). Where the degree of fineness of powders is determined by sieving, it is defined in relation to the sieve number(s) used either by means of the following terms or, where such terms cannot be used, by expressing the fineness of the powder as a percentage m/m passing the sieve(s) used. The following terms are used in the description of powders: Coarse powder: Not less than 95% by mass passes through a number 1400 sieve and not more than 40 % by mass passes through a number 355 sieve. Moderately fine powder: Not less than 95% by mass passes through a number 355 sieve and not more than 40% by mass passes through a number 180 sieve. Fine powder: Not less than 95% by mass passes through a number 180 sieve and not more than 40% by mass passes through a number 125 sieve.

United States Pharmacopeia

General Chapters: <811> POWDER FINENESS

Classification of Powders by Fineness Classification of Powder d50 Sieve Opening (m) Very Coarse Coarse Moderately Fine Fine Very Fine > 1000 3551000 180355 125180 90125

d50= smallest sieve opening through which 50% or more of the material passes

3. Sedimentation technique:
Andreason pipette is generally used for the determination of particle size distribution by the sedimentation technique. The residue of dried sample obtained at a particle time is the weight fraction having particles of sizes less than the size obtained by the Stokes law calculation for that time period of settling.

Size distribution is determined by allowing a homogeneous suspension to settle in a cylinder and taking samples from the settling suspension at a fixed horizontal level at intervals of time. Each sample will contain a representative sample of the suspension, with the exception of particles greater than a critical size, all of which will have settled below the level of the sampling point. The concentration of solid in a sample taken at time t is determined by centrifugation of the sample followed by drying and weighing or simply by drying and weighing. This concentration expressed as a percentage of the initial concentration gives the percentage (w/w) of particles whose falling velocities are equal to or less than x/t. Substitution in the equation above gives the corresponding Stokes' diameter.

Advantages:
The apparatus is inexpensive and the technique is simple The results is obtained are precise provided the technique is adequately standardised

Disadvantages:
The method is laborious since separate analyses are required for each experiment very small particle can not be determined accurately using this method

 Particles

pass through a laser beam and the light scattered by them is collected over a range of angles in the forward direction. simplest case inversely related to the particle size.

The angles of diffraction are, in the

The

particles pass through an expanded and collimated laser beam in front of a lens in whose focal plane is positioned a photosensitive detector consisting of a series of concentric rings.
analysed by computer to yield the particle size distribution.

Volume distribution

Distribution of scattered intensity is

Advantages:
Non-intrusive : uses a low power laser beam

Fast : typically <3minutes to take a measurement and analyse.

Precise and wide range - up to 64 size bands can be displayed covering a

range of up to 1000,000:1 in size. Absolute measurement, no calibration is required. The instrument is based on fundamental physical properties. Simple to use Highly versatile Disadvantages: expense volume measurement all other outputs are numerical transformations of this basic output form, assuming spherical particles must be a difference in refractive indices between particles and suspending medium

 Large particles move more slowly than small particles, so that the rate of

fluctuation of the light scattered from them is also slower.

PCS uses the rate of change of these light fluctuations to determine the size

distribution of the particles scattering light.

Comparison of a "snap-shot" of each speckle pattern with another taken at a

very short time later (microseconds).

The time dependent change in position of the speckles relates to the change

of position of the particles and hence particle size.

The dynamic light signal is sampled and correlated with itself at different time

intervals using a digital correlator and associated computer software.

The relationship of the auto-correlation function obtained to time intervals is

processed to provide estimates of the particle size distribution.

Particle shape affects the packing properties and flow of a powder and it also has some influence on the surface area Surface area per unit weight or volume is an important characteristics which determine surface adsorption and dissolution rate of particle A sphere has a minimum surface area per unit volume. The more asymmetric the particle becomes, the greater is the surface area per unit volume A sphere is characterised by its diameter, while an asymmetric particle is difficult to characterise in terms of surface diameter

Hence the asymmetric particles surface diameter is measured in terms of some equivalent spherical diameter
The specific surface area of a powder is defined as the surface area per unit volume (Sv) or per unit weight (Sw) The specific surface area per unit volume is given by:

Sv
Sw

Surface area of particles Volume of particles

S v /

Where is the density of particles

 Particle volume measurement

1.

Coulter counter method (Electrical stream sensing method) Methods of determining surface area Adsorption method Air permeability method

1. 2.

 The number and size of particles suspended in an electrolyte is determined by causing them to pass through an orifice an either side of which is immersed an electrode. The changes in electric impedance (resistance) as particles pass through the orifice generate voltage pulses

whose amplitude are proportional to the

volumes of the particles.
Advantages
It is precise and accurate method Analysis range is wide Disadvantages

It is a sophisticated method
It is expensive method


1.

Methods of determining surface area

Adsorption method

2.

Air permeability method

1. Adsorption method:
Particles with large specific surface area (small particle size) are good adsorbents for the adsorption of gases and solutes from solution. The amount of gas or solute adsorbed on the sample of powder to form a monolayer is found out and from this data, the surface area of the powder is determined.

2. Air permeability method

This method is based on the principle that the resistance offered to the flow of a fluid such as air through a plug of compacted powder is proportional to the surface area of the powder. The greater the surface area per gram of the powder, the greater is the resistance to flow. Surface area determination by air permeability method is generally carried out with Fisher subsieve sizer.

Particle size distribution and surface area are two fundamental properties of powders. From these properties of powders a number of derived properties can be obtained Porosity of powders Packing arrangement in powder beds Density of powders Bulkiness Flow properties of powders

Porosity of powders

Bulk volume is equal to the true volume for a non porous material. Most pharmaceutical solids are porous, they have internal pores or capillary space and hence the bulk volume is greater than the true volume. The volume of the spaces known as the void volume is given by
v = Vb - Vp

Where Vb is the bulk volume and Vp is the true volume of the particles

The porosity or voids is defined as the ratio of the void volume to the bulk volume of the powder packing Vb - Vp Vb

Thus, =

Porosity is expressed as percentage i.e., x 100

Packing arrangement in powder beds

A bed or heap of powder consists of a number of particles each in contact with its neighbours Theoretically two types of packing's are possible. These include the closest or rhombohedral packing and the most open or loosest or cubical packing The fraction of the total volume occupied by the free space between the particles is porosity. If the powder bed consists of spherical particles a theoretical porosity of 26% is possible in the closest packing and 48% in the loosest packing.

a) Closest packing

b) Loosest packing

When the particles of varying sizes are present porosity lower than the theoretical minimum of 26% is possible. On the other hand if the powder contains floccules or aggregates the porosity may go beyond the theoretical maximum of 48% due to large void space with entrapped air.

Density of Powder
Density is universally defined as the mass per unit volume

However difficulty in determining the true volume of powders arises because these
contain microscopic cracks, internal pores and capillary spaces. Based on the method of determination, three types of densities can be found1. True density density of materials exclusive of pores Mass of the powder True volume

True density =

2. Granule density - is the ratio of the mass of the granular powder and the volume

occupied by the granular material together with its intraparticular spaces.

Mass of the granular powder Granule volume

Granule density =

3. Bulk density bulk density of a powder is defined as the ratio of the mass of the powder and its bulk volume. Bulk Density = Mass of the powder Bulk volume

Bulkiness The reciprocal to bulk density is known as bulkiness. Bulkiness usually increases

with a decrease in particle size. It is useful property to be considered while choosing

a suitable container for packing of bulk powders or during filling of drug powders into capsules.

Flow properties of powders

The flow properties of powders is an important parameter to be considered in the production of pharmaceutical dosage forms since most of the processes such as uniform filling of dies during tabletting. Powders may be free flowing or may have poor flow. The poor flow of powders are generally attributed to one or more of the following reasons 1. Cohesiveness or stickiness between particles due to presence of Van der Waals, surface free energy and electrostatic force 2. Adhesion between the particles and the container walls due to the above forces 3. Friction between particles due to surface roughness or morphology 4. Physical interlocking of particles specially if these are of irregular shape and different sizes

 The cohesiveness of particles has been found to depend upon a number of factors

including particle size, shape, density or porosity of the powders and the presence of
absorbed moisture layer on the powder surface. Thus very fine particles less than < 10.0 m in size tend to be more cohesive due to their larger surface area and densed materials tend to be less cohesive than lighter

ones
Poor flow some times result from presence of moisture which increase the cohesiveness, drying of granules can easily remove this problem. Poorly flowing powders or granules exhibit many difficulties to the pharmaceutical

industry the production of uniform dosage forms such as tablets and capsule
depend upon several granular properties

Assessment of flow properties of powders

Flow properties of powders is generally assessed by determining the angle of repose of the powders. It is defined as the maximum angle possible between the surface of a pile of powder and the horizontal plane. The angle which the heap forms with the horizontal surface is the angle of repose and is determined by the formula : Tan = h/r Where, is the angle of repose, h is the height of the heap of the powder and r is the radius of the base of the heap of the powder.

Angle of repose <25 25-30 30-40 >40

Flow excellent good passable very poor

tapped bulk density initial bulk density Carrs Index (%) = tapped bulk density
Carrs index (%) 5-15 2-16 Flow Excellent good

100

18-21
23-25 33-38 >40

fair to passable
poor very poor extremely poor

Hausners ratio =

tapped bulk density Initial bulk density

Hausners ratio of less than 1.1 indicates excellent flow, between 1.2 fair flow

and 1.5 indicates very poor flow

Improvement of powder flow properties

Flow properties of powders can be improved by the following methods :
1. Altering the particle size increasing the average particle size of particles improve the flow properties due to the reduction in the cohesive forces. 2. Removal or addition of fines small amount of fines may improve flow, while large

amount of fines may reduce the flow property

3. Altering the particle shape and texture Spherical and smooth surface particles 4. Altering the surface forces reduction in electrostatic force by reduction in friction during processing

5. Removing extra moisture drying of powders can remove the moisture which
decreases cohesiveness and improve powder flow 6. Adding flow enhancer or glidants flow properties of powder may improve significantly by addition of materials known as glidant, e.g.- magnesium stearate .

These act by forming a thin film on the surface of powder decrease adhesion and
cohesion of powders.