Micromeritics: The study of small particles

The study of particle size and particle size distribution has a number of
applications in the field of pharmacy:

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 as well as the 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 is directly related to the
size of the drug particles. In general, a decrease in the particle size of the
drug increases the dissolution rate.
iv) The chemical properties of particles such as surface oxidation also
depend on the particle size. Smaller the particle size, more is the surface
area exposed 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 upon the particle size of the
dispersed phase.
vii) The release characteristics of drugs from ointments, creams and
suppositories are dependent on the particle size of the dispersed drug.
viii)Particle size of the dispersed drug also influences the spreadability 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 colloids, suspensions 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 differences in their particle size.
xii) Processes such as extraction and drying are accelerated following a
reduction in the particle size of the material.
(xiii) The adsorption capacity of a material also increases by a decrease in its
particle size.
FUNDAMENTAL PROPERTIES OF COLLECTION OF PARTICLES

The following are the five fundamental properties of powders from which
other properties can be derived.

i) Particle size and size distribution

ii) Particle shape
iii) Particle volume
iv) Particle number
(v) Particle surface area

Particle size and size distribution

The size of a spherical particle can be easily expressed in terms of
its diameter. Thus, 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 also has a definite surface area and volume but
being asymmetric, its apparent length varies with its orientation. Hence, it is not
possible to express its size in terms of its diameter, its size is therefore expressed
in terms of equivalent spherical diameters by using some measurable property
such as surface area, volume or diameter. Thus,
Surface diameter, ds is the diameter of a sphere having the same surface
area as that of the asymmetric particle in question.
Volume diameter, dv is the diameter of a sphere having the same volume as
the asymmetric particle in question.
Projected diameter, dp is the diameter of a sphere having the same observed
area as the asymmetric particle in question when viewed normal to its most
stable plain. This diameter is usually determined by microscopic technique.
Stokes diameter, dst refers to the diameter of a sphere with the same density
as the asymmetric particle in question and which undergoes sedimentation at
the same rate as the asymmetric particle in a given fluid within the range of
Stokes law. This diameter is usually measured by sedimentation method.
Any collection of particles (powder) is polydisperse, i.e., consists of a mixture
of particles of varying sizes and shape. It therefore becomes 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 an estimate of the
size range present and the number or weight fraction of each particle size. This
is called the particle size distribution and from this we can derive the average
particle size of the collection of particles.
 Average Particle Size
Suppose the particle size of a powder is analysed microscopically and the number
of particles in each size range is determined. Data similar to that shown in Table
2.1 is obtained. From the data, the average particle size of the powder may be
calculated as :

Particle Size =
 nd = 377 = 2.16 m
n 174

However, in the above calculation, only the total number and mean size of the
particles have been considered for expressing the average particle size. Certain
modifications in the calculation can be done in order to take into account the
surface and volume of the particle also.

Particle size Distribution

The particle size distribution in a powder may be quantified by one of the following
two ways:

1. 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 or sieving techniques)
When this number or weight of particles lying within a certain size range is
plotted against the size range or mean particle size, a. frequency distribution
curve is obtained. Such frequency plots (Fig. 2.1) can give a visual
representation of the distribution which an average diameter can not achieve.
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.
Two samples of powders may have the same average diameter but may not
have the same frequency distribution. The expression of the size in terms of
average diameter will therefore not give a clear expression of the particle size
distribution which will be easily obtained from the frequency distribution curve.
Also from the frequency distribution curve, one can readily obtain the particle
size which occurs most frequently and is referred to as mode. Alternatively one
can plot the cumulative percentage under (or over) a particular size versus the
particle size. This gives a sigmoidal curve (Fig. 2.2) with the mode being the
particle size of the greatest slope.

polydisperse powder is said to have a normal distribution if a typical

bell-shaped frequency distribution curve (Fig. 2.1) is obtained. In such a case
one half of the curve is superimposable on the other half. However, normal
distribution is not commonly found in pharmaceutical powders which are
frequently processed by milling or precipitation. More commonly, unsymmetric
or skewed distribution (Fig. 2.3) is obtained.
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. Assuming that the
particles of the powder are spherical, the volume of a single particle is dvn3/6
and the mass (volume x density) 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:
1 gm of the powder
N=
Mass of one particle

1
N=
d vn 3  / 6

Particle Size Conversion Table

Sieve Designation Nominal Sieve Opening
Standard Mesh inches mm Microns
25.4 mm 1 in. 1.00 25.4 25400
22.6 mm 7/8 in. 0.875 22.6 22600
19.0 mm 3/4 in. 0.750 19.0 19000
16.0 mm 5/8 in. 0.625 16.0 16000
13.5 mm 0.530 in. 0.530 13.5 13500
12.7 mm 1/2 in. 0.500 12.7 12700
11.2 mm 7/16 in. 0.438 11.2 11200
9.51 mm 3/8 in. 0.375 9.51 9510
8.00 mm 5/16 in. 0.312 8.00 8000
6.73 mm 0.265 in. 0.265 6.73 6730
6.35 mm 1/4 in. 0.250 6.35 6350
5.66 mm No.3 1/2 0.223 5.66 5660
4.76 mm No. 4 0.187 4.76 4760
4.00 mm No. 5 0.157 4.00 4000
3.36 mm No. 6 0.132 3.36 3360
2.83 mm No. 7 0.111 2.83 2830
2.38 mm No. 8 0.0937 2.38 2380
2.00 mm No. 10 0.0787 2.00 2000
1.68 mm No. 12 0.0661 1.68 1680
1.41 mm No. 14 0.0555 1.41 1410
1.19 mm No. 16 0.0469 1.19 1190
1.00 mm No. 18 0.0394 1.00 1000
0.841 mm No. 20 0.0331 0.841 841
 0.707 mm No. 25 0.0278 0.707 707
0.595 mm No. 30 0.0234 0.595 595
0.500 mm No. 35 0.0197 0.500 500
0.420 mm No. 40 0.0165 0.420 420
0.354 mm No. 45 0.0139 0.354 354
0.297 mm No. 50 0.0117 0.297 297
0.250 mm No. 60 0.0098 0.250 250
0.210 mm No. 70 0.0083 0.210 210
0.177 mm No. 80 0.0070 0.177 177
0.149 mm No. 100 0.0059 0.149 149
0.125 mm No. 120 0.0049 0.125 125
0.105 mm No. 140 0.0041 0.105 105
0.088 mm No. 170 0.0035 0.088 88
0.074 mm No. 200 0.0029 0.074 74
0.063 mm No. 230 0.0025 0.063 63
0.053 mm No. 270 0.0021 0.053 53
0.044 mm No. 325 0.0017 0.044 44
0.037 mm No. 400 0.0015 0.037 37

Larger sieve openings (1 in. to 1/4 in.) have been designated by a sieve "mesh" size that corresponds to the size of the opening
inches. Smaller sieve "mesh" sizes of 3 1/2 to 400 are designated by the number of openings per linear inch in the sieve.
The following convention is used to characterize particle size by mesh designation:

 a "+" before the sieve mesh indicates the particles are retained by the sieve;

 a "-" before the sieve mesh indicates the particles pass through the sieve;

 typically 90% or more of the particles will lie within the indicated range.
For example, if the particle size of a material is described as -4 +40 mesh, then 90% or more of the material will pass through a
4-mesh sieve (particles smaller than 4.76 mm) and be retained by a 40-mesh sieve (particles larger than 0.420 mm). If a material
described as -40 mesh, then 90% or more of the material will pass through a 40-mesh sieve (particles smaller than 0.420 mm).
This information is also provided on page T848 of the Aldrich 2003-2004 Catalog/Handbook of Fine Chemicals.
PARTICLE SIZE DETERMINATION
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

1. Microscopic Technique
Optical microscopy is generally used for particle size measurement in the range
of 0.2 m to about 100 m. At least 300 to 500 particles must be counted in
order to obtain a good size distribution analysis of data.
A dilute suspension of the powder particles whose sizes are to be determined is
prepared in a liquid vehicle in which it is insoluble. If it is slightly soluble, a
saturated solution of the powder can be used for the preparation of the
suspension. A drop of the suspension is mounted on a slide or ruled cell and
observed under the microscope. The eyepiece of the microscope is fitted with a
micrometer by which an estimate of the particle size can be obtained. All the
particles observed in a field are counted through the eye-piece. The data may
be scientifically represented as size-frequency distribution curve. From the
data, the average particle size as well as the size distribution is determined.
For ease in counting the particles, the field viewed through the microscope can
be projected on a screen or photographed for later measurement. Particles may
also be counted with electronic scanners to avoid the strain of visual
observation. For measuring very small particle size, an electron microscope or
a scanning electron microscope may be used. The latter is also capable of
proving an estimate of the particle depth.

Disadvantages of microscopic technique:

i) The measured diameter of the particles represents two dimensions only, i.e.,
length and breadth and an estimate of the depth is not obtained.

ii)The method tends to be slow and tedious since at least 300 to 500 particles
should be counted to get reliable data.

2. Sieving Technique:

In this technique the powder whose particle size is to be determined is

placed on a nest of standard sieves stacked over one another with the sieve
of largest aperture on top followed by sieves of gradually decreasing pore
sizes. The powder is shaken for a definite period of time using a mechanical
shaker and the material that passes through a particular sieve and is
retained on the next finer sieve is collected and weighed. The data obtained
is analysed and the particle size and size distribution is calculated.
 Sieving technique is generally useful for coarse particles since the technique
is limited by the smallest size of sieve that can be produced and hence
measurement of sizes smaller than 50 m are difficult.

Disadvantages of sieving technique:

i) Particles may aggregate during sieving due to generation of electrostatic

charge.
ii) Moisture can also lead to aggregation of powders and the actual particle size
may not be obtained.
iii) Attrition of particles during sieving may lead to size reduction.
iv) Sieve loading and duration of mechanical shaking can influence the results.

3. Sedimentation Technique
Andreason pipette is generally used for the determination of particle size
distribution by the sedimentation technique. The apparatus consists of a
550 ml stoppered cylindrical vessel of about 5.5 cm internal diameter with a
vertical scale graduated from 0 to 20 cm on it. The stopper has an integral
10 ml bulb pipette fitted with a two-way stopcock and a side tube for
discharging the sample. The stem of the pipette is made up of narrow bore
tubing in order to minimize the volume retained in the stem after each
sampling. When the pipette is fitted into its place in the cylinder, its lower
tip is 20 cm below the surface of the suspension.
For analysis of the particle size distribution, a 1 or 2% suspension of the
powder is prepared in a medium containing a suitable deflocculating agent
to break any powder aggregates. The suspension is introduced into the
vessel upto the 550 ml mark. The vessel is stoppered and shaken to
distribute the particles uniformly within the medium. The pipette is then
secured in its place and the whole assembly is kept undisturbed in a
constant temperature bath. At various time intervals, 10 ml samples of the
suspension are withdrawn through the two-way stopcock into previously
weighed china-dishes. The samples are evaporated and weighed and
necessary correction is made for the deflocculating agent added.
The particle diameter corresponding to the various time periods is
calculated by using the Stoke's equation:
The residue of dried sample obtained at a particular time is the weight
fraction having particles of sizes less than the size obtained by the Stoke's
law calculation for that time period of settling. The weight of each sample
residue is therefore called the weight undersize and the sum of the
successive weights is known as the cumulative weight undersize. The
cumulative weight undersize is then plotted on the probability scale against
the particle diameter on the log scale using a log-probability graph paper.
Various statistical diameters are then obtained from the plot.
Advantages
i) The apparatus is inexpensive and the technique is simple.
ii)The results obtained are precise provided the technique is adequately
standardised.
Disadvantages
i) The method is laborious since separate analyses are required for each
experimental point on the distribution curve.
ii) Very small particles cannot be determined accurately since their settling
is unduly prolonged and is subject to interference due to convection,
diffusion and brownian motion.
Centrifugal methods are sometimes used for accelerating the rate of
sedimentation and minimize the above effects.
PARTICLE VOLUME MEASUREMENT
Coulter Counter Method

The coulter counter is a popular instrument for measuring the particle

volume. It operates on the principle that when a particle suspended in a
conducting liquid passes through a small orifice (opening), on either side of
which are electrodes, a change in electric resistance occurs.
Fig. 2.7 shows the essential mechanical parts of the instrument. It consists
of two electrodes one of which is dipped into a beaker containing the particle
suspension in an electrolyte (such as 0.9% NaCI). The other electrode is
dipped into the electrolyte solution contained in a glass tube which in turn
is immersed into the beaker containing the particle suspension in the
electrolyte. The glass tube has a very small orifice at its lower end through
which the particles are sucked into the inner glass tube.
For the experiment, powder samples are dispersed in the electrolyte to form
a very dilute suspension. A known volume of the suspension is pumped
through the orifice so that only one particle passes at a time through the
orifice. 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 an increased resistance between the
two electrodes. The change in the electrical resistance between the
electrodes that is proportional to the volume of the particle is converted into
a voltage pulse that is amplified and processed electronically. The
instrument records all those particles producing pulses that are within two
threshold values of the analyser. By systematically varying the threshold
value and counting the number of particles in a constant sample size, a
particle size distribution is obtained.
Coulter counter method has been also used to study the particle growth and
dissolution in formulations and the effect of antimicrobial agents on the
growth of micro-organisms.

Advantages

i) The operation is very rapid with a single count taking less than 30
seconds.
ii) Since a large number of particles are counted, the results are more
reliable.
iii) Since the aperture is automatic, operator variability is avoided.
(iv) The instrument can operate with particles between 0.5 and 1000
micrometers.

Disadvantages

(i) The material has to be suspended in an electrolyte liquid before

measurement can be made.
ii) Aggregation of particles can give false results.

PARTICLE SHAPE AND SURFACE AREA

The particle shape is related to the geometric shape as well as the surface
irregularity (Fig. 2.8). 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 characteristic which determines
surface adsorption and dissolution rate of the particle.
Particle Shape: A sphere has a minimum surface area per unit volume.
Hence more asymmetric the particle becomes, the greater is the surface
area per unit volume. Hence, it may be necessary to determine the extent of
asymmetry in a particle.
A sphere is characterised by its diameter. An asymmetric particle is more
difficult to characterise in terms of surface diameter. Hence, the asymmetric
particle's surface diameter is measured in terms of some equivalent
spherical diameter.
 Surface area of a sphere is given by: S = d2

while its volume is given by : d3/6

where d is the diameter of the particle.

The surface area of a particle is determined by:

i) The adsorption method
ii) The air permeability method

DERIVED PROPERTIES OF POWDERS

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:

For a non-porous material, the bulk volume is equal to the true volume.
Most pharmaceutical solids are porous i.e. they have internal pores or
capillary space and hence the bulk volume is greater than true volume.
The volume of the spaces known as the void volume V 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.
Thus,
Vb  V p Vp
  1
Vb Vb

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

Example :
Calculate the percent porosity of Titanium dioxide having a true density of
4.26 g/cm3 and 100 g sample which was found to occupy a bulk volume of
80 ml.
Solution
Bulk volume of the powder Vb = 80 ml = 80 cm3
Weight of the powder =100 g
True density of powder (p) = 4.26 g/cm3
True volume of the powder sample (Vp) = Weight/True density
=100/4.26cm3
=23.47cm3
Vb  V p 80  23.47
% porosity e = x 100 = x 100 = 70.66%
Vb 80

DENSITY OF POWDERS : |

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 distinguished:
1. True Density i.e., density of the material exclusive of pores, etc.
2. Granule density as determined by the displacement of mercury which does not
penetrate at ordinary pressure into pores smaller than about 10 m.
3. Bulk density as determined from the bulk volume and the weight of a drug powder
in a graduated cylinder.

True Density (p)

It is the density of the actual solid material devoid of free spaces and is defined as the
ratio of the given mass of a powder and its true volume.
True Volume = Bulk Volume - Void Volume
The true density of a powder may be determined by the following methods:

Liquid displacement method :

In this method a liquid in which the solid is insoluble is generally used. The powder
whose density is to be determined is added into a standard flask of known volume
and the weight determined. An ordinary pycnometer is generally suitable for the
purpose. Now a liquid in which the powder is insoluble is introduced into the flask.
The liquid fills up the void spaces between the particles until the whole volume of the
flask is occupied. The flask is again weighed. The contents of the flask are emptied
and only the liquid is filled into it and weighed. The true density is obtained as the
ratio between the weight of the material and the weight of the liquid it displaces.

Gas displacement method

Granule Density (p )
Granule density is the ratio of the mass of the granular powder and the
volume occupied by the granular material together with its intraparticle
spaces.
Granule Density = Mass of the granular powder/Granule volume

The granule density is also determined in a manner similar to liquid

displacement method but mercury is used as the displacement liquid
since mercury does not enter the internal pores of the particles. The
volume of the material thus obtained is the true volume of the material
along with the volume occupied by the intraparticle spaces.

Bulk Density (pb)

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

For determination of the bulk density, a weighed quantity of the powder

material is introduced into a graduated measuring cylinder and is tapped
mechanically either manually or using a tapping device till a constant
volume is obtained. This volume, known as the bulk volume of the powder
is noted and includes the true volume of the powder as well as the volume
occupied by the interparticle and intraparticle spaces.
The bulk density of a powder depends mainly on the particle size
distribution, particle shape and the packing arrangement.

Bulkiness
The reciprocal of bulk density is known as the bulk or bulkiness or specific
bulk volume. Bulkiness usually increases with a decrease in particle size.
However, in a mixture of particles with different sizes, the bulkiness may
get reduced since the smaller particles may sift between the larger ones. It
is a useful property to be considered while choosing a suitable container
for packaging 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 and
proper filling of capsules during capsule filling directly depend on the flow
properties of the powder mass. Other processes such as gravity feeding of
powders or their pneumatic and hydraulic transfer from one place to
another also depend on the flow properties.
Powders may be free flowing or may have a poor flow. The poor flow in
powders is generally attributed to one or more of the following reasons:

i) Cohesiveness or stickiness between particles due to presence of

Van der Waals, surface tension and electrostatic forces.
ii) Adhesion between the particles and the container wall due to the
above forces,
iii) Friction between particles due to surface roughness,
iv) Physical interlocking of particles specially if these are of irregular
shape.
The cohesiveness of particles has been found to depend upon a number of
factors including particle size and shape, the density or porosity of the
powder and the presence of adsorbed materials on the powder surface.
Thus, very fine particles (less than 10 microns in size) tend to be more
cohesive due to their larger surface area and dense materials tend to be less
cohesive than lighter ones. Poor flow sometimes results from presence of
moisture which increases the cohesiveness. Drying of granules can easily
remove this problem.
Poorly flowing powders or granulations present many difficulties to the
pharmaceutical industry. The production of uniform dosage forms such as
tablets and capsules depends upon several granular properties. It is generally
seen that as the granule size is reduced, the problem of tablet weight variation
also gets reduced. The particle size and size distribution also affects the
internal flow and segregation of a granulation. During the flow of tablet
granulation through the hopper, granule demixing may take place and the
fines being heavier per unit volume may segregate from coarse granules. This
will cause a decrease in the tablet weight during the latter portion of the
compression process.
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 of repose is
determined by allowing a mass of powder to flow freely through an orifice from
a certain height and form a conical heap on the horizontal surface . As the heap
is formed, the particles slip and roll over each other until the mutual friction
between the particles just balances the gravitational force. 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 powder and
r is the radius of the base of the heap of powder.
Improvement of Flow Properties:

Flow properties of powders can be improved by one or more of the following

methods:
1. Altering the Particle Size : Increasing the average particle size of particles
improves the flow properties due to reduction of the cohesive forces.
During tabletting, fine powders are converted to coarse granules in order
to impart good flow properties to them.
2. Removal or Addition of Fines :Presence of a small proportion of fines in a
powder or granular mass may improve the flow properties by filling up
the pits and crevices on the surface of particles. On the other hand,
larger proportion of fines may retard the flow properties. 'Hence, an
optimum concentration of fines is desirable for best results.
3. Altering the particle shape and texture: Spherical particles tend to have
better flowability as compared to irregular partides. Hence, techniques
like spray drying may be used to give spherical particles with good flow
properties. Alteration of crystallization conditions may also produce
particles of the desired shape and texture.
4. Altering the surface forces : Reduction of electrostatic charges on particle
surface by reducing frictional contacts such as during transfer or during
processes such as sieving can improve the flow properties.
5. Removing extra moisture : Drying of powders in order to remove the
moisture from surfaces can improve the flow properties by decreasing
the cohesiveness.
6. Adding flow activators or Glidants : Flow properties of pharmaceutical
powders may be improved significantly by the of materials known as
glidants. These act by forming a thin uniform film on the surface of
particles to reduce the adhesion and cohesion between particles.
Examples of such materials include magnesium stearate, starch and talc. The
optimum concentration of glidants has been experimentally demonstrated to
be generally 1% or less and above this concentration usually there is a
decrease in flow rate. Colloidal silicon dioxide is another flow activator with a
very high specific surface area which acts by reducing the bulk density of
tightly packed powders.