PARTICLE SIZE ANALYSIS AND

DISTRIBUTION
Ahmed A. El-Shenawy
Department of Pharmaceutics and Pharmaceutical Technology
Particle and size distribution
• In a collection of particles of more than one size, two properties are
important:
1. The particle shape and the surface area.
2. The size range and number of particles weight.

Dimensions
• Particles would be irregular with different numbers of faces and it would be
difficult or impractical to determine more than one a single dimension.
• For this reason, a solid particle is often considered to approximate to a
sphere which can the be characterized by determining its diameter.
• The size of a sphere is readily expressed in terms of its diameter.
Particle and size distribution

 As the degree of asymmetry of particles increases, there is a

difficulty to express the size in terms of a meaningful diameter
and there is no one diameter for a particle.
 Because measurement is then based on a hypothetical, which
represents only an approximation to the true sphere of the
particle, the dimension is referred as the equivalent diameter of
the particle.
 Equivalent spherical diameter is used to relates the size of the
particle to the diameter of sphere having the same surface area,
volume or sedimentation rate.
Kinds of diameters
a) Surface diameter: It is the diameter of sphere having the
same surface area as the particle under investigation.
b) Volume diameter: It is the diameter of a sphere having the
same volume as the particle under investigation.
c) Stoke's diameter or sedimentation diameter: It describes
the diameter of a sphere having the same sedimentation rate
as the particle under investigation.
d) Projected diameter: It is the diameter of the sphere having
the same perimeter (circular boundary) as the particle under
investigation.
Equivalent diameters
The projected area diameter: is based on a circle of equivalent
area to that of the projected image of a solid particle.
The projected perimeter diameter: is based on a circle having
the same perimeter as the particle.
The type of the expressed diameter used depends on:
1. The method used to determine the diameter.
2. The purpose for which the powder is used.

Example:
 Powder used for suspension, the sedimentation rate must be
determined and so one uses Stoke's diameter.
 Powder used as adsorbent one uses surface diameter.
 Powders used for pharmacological action after dissolution and
absorption, one uses volume diameter.
Lifetime of the drug and effect of particle size
1. Drug synthesis. (physicochemical properties)
2. Development of the formulated drug. (physical properties)
3. Production of the formulated drug. (volumetric filling, flow,
packing properties')
4. Administration of the drug. (Release and dissolution rate)
5. Drug in body.
6. Drug removal from the body.
 Importance of drugs particle size determination
1. Respiratory tract drugs: The distance to which the particles
travel in the respiratory tract depends upon their particle size.
 Bigger particles do not travel long distances thus doing the action
in the upper respiratory tract and the smaller particles which do
their action in the lower respiratory tract.
2. Parenterally administered drugs with different routes of
injection their action depend on the particle size.
 Smaller particles dissolve faster and exert faster action.
 Bigger particles when injected may dissolve very slowly and may
act as a sustained release (depot).
 Importance of drugs particle size determination
3. Rectal absorption of drugs depends on the particle size, their
dissolution, and absorption.
4. Tablets, capsules and orally administered powders: Tablet will
not be absorbed unless it undergoes disintegration and dissolution,
and this depends on the particle size.
 The smaller and finer the particles; the higher is the solubility.
Dissolution of capsules and powders depend mainly on particle
size.
5. Pharmacokinetic aspects: Absorption, distribution, metabolism,
and excretion depend mainly on the particle size.
Parameters which are important in particle size determination:
1. Average particle size (mean).
2. Particle size distribution around the mean.
 Steps for particle size analysis
1. Sampling: It means taking the sample from the material to be analyzed.
This sample must be representative of the entire batch of the material.
Coning and quartering method
 It involve through premixing of the entire sample and then careful pouring
of the sample into a pile (cone).
 The cone is then divided into four approximately equal quarters. Two
opposite quarters are combined and mixed well while the remaining two
quarters are returned to the original container.
 The procedure is repeated four times until the desired size sample is
obtained.
 If four repeats cannot be made because of a small sample size, the
procedure is repeated using the material returned to the original container.
2. Generating the data
 In generating the data, individual particles or groups of
particles from each sample are sized and counted.
 The sizing and counting follow a particular pattern in order to
put the data into an orderly, meaningful form that can be
statistically analyzed for interpretive and comparative purposes.
3. Presentation of the data
1. Table form.
2. Graph form:
a. Histogram (Bar graph).
b. Frequency- distribution curves: Normal distribution curve (symmetrical
particle size distribution), skewed-distribution curve (asymmetrical particle
size distri­bution curve), and cumulative-distribution curve.
Size range Mean Frequency (ni) % Frequency Over size
(µm) No. of particles % of particles Cumulative %
0-5 2.5 96 6.5 6.5
5-10 7.5 105 7.1 13.6 (6.5+7.1)
10-15 12.5 116 7.8 21.4 (6.5+7.1+7.8)
15-20 17.5 129 8.7
20-25 150
25-30 27.5 212
30-35 148
35-40 127
40-45 114
45-50 101
50-55 92
55-60 57.5 88 99.4
Total = 1478,
∑ni
4. Treatment of data
a- Arithmetic mean (or average particle size)

Where: d= Arithmetic mean, ni = Frequency or number of particle in each size

range, di = Mid-point of the size range, ∑ni = Total number of particles.

b- Standard deviation
It is the deviation of sizes of individual particles from the average. It describes
the scatter or dispersion around the mean. It may be narrow or wide (the
narrow is better)

N= Total number of particles

4. Treatment of data
c- Median
• It is the diameter (particle size) that divides the distribution curve into 2
equal parts.

d- Mode
• It is the most frequent size.
• In normal distribution:
Mean = Mode = Median
Methods of measuring the particle size
1. Microscopy
Particle size range:
 Optical microscope: 0.5 - 100 µm.
 Electronic microscope: 0.01 - 1.0 µm.
Procedures
Preparing slurry of several milligrams of powder in a liquid dispersion
medium in which the sample is insoluble. One or two drops are placed on a
clean microscope slide, and a cover slip is applied. Several random fields are
selected for counting.
1. A calibrated graticule
Which is placed on the eye piece and it consists of a series of graded black and
open circles. The field is scanned from one side to the other using a
mechanical microscope stage and particles are sized according to the nearest
equivalent circle area.
Methods of measuring the particle size
2. A calibrated micrometer
The sample is placed over a calibrated micrometer and examined
under the optical microscope.
Advantages
1. Low cost.
2. Simple and direct method.
3. Preparing the sample is simple.
4. Give information about the shape of particles.

Disadvantages
1. Tedious.
2. Time consuming.
3. Aggregation of two or more particles together can be counted and
measured as one particle so give wrong results.
4. Air bubbles may be entrapped and may be considered wrongly as
particles.
2- Sieve analysis
Particle size range: 50 to 10000 µm.
Method: The simplest and the most frequently used method.
 The technique involves size classification followed by the determination of
weight of each fraction.
 This is carried out by passing the powder in specific sieves with different
mesh – size; the wider is placed on the top.
 The screens are attached to mechanical shaker.
 The particles of a powder mass are placed on the first screen and apply
shaking for certain time.
 The particles which smaller in size than the mesh openings are pass through it
to the next screen, and so on.
 Each fraction retained on each sieve is then taken and weighed.
Advantages
1. Very simple.
2. Fast.
3. Used in most pharmaceutical preparations.

Disadvantages
1. Development of electrostatic charges and so the particles may aggregate
together and do not pass through the sieves.
2. Humidity present in the atmosphere causes the particles to stick together.
3. The shape of the particles: e.g., particle present as needle shape, if it is in
vertical position it will pass but if it is in the horizontal position, it will not
pass.
4. The procedures should be standardized, i.e., shaking should be carried out
by the same shaker with the same rate and for certain fixed time.
3. Sedimentation (Gravitational sedimentation)
Range of particle size determination: 5-500 µm.
Method:
 Weight distribution is obtained by allowing a dispersed powder to settle in
air or in a liquid, in which it is insoluble and weighing the particles sediment
in each time interval, thus find a relation between the cumulative weights
and time.
By using Stock’s equation:

Where,
d = particle diameter (cm). η = Viscosity of fluid (poise = g/cm. sec). h =
distance of fall in cm. t = time of fall. ρ = density of the particles (g/ cm3). ρ0
= density of fluid (g/ cm3). g = Acceleration due to gravity 981 (cm / sec 2)
(gravity acceleration constant).

• Using either the micromeroghraph (where the powder particles settle in air) or
the chan sedimentation balance (where the powder particles settle in a liquid).
• The sample is dispersed in its settling medium and the powder particle settles
onto an ultrasensitive balance.
• Weight is recorded cumulatively against time. The time being the only variable
in Stoke's equation creating the change in diameter.
• Sedimentation methods are used for measuring the suspension stability.
Disadvantages of sedimentation methods
1. There are certain requirements for Stoke's law to be applied.
2. The particles must be spherical .If the particles are not
spherical, Stoke's law cannot be applied.
3. Deflocculating agent is added to allow separation and prevent
aggregation of particles.
4. Electronic determination of particle size

Range of particle size determination: 0.5-500 microns.

Average diameter determined: volume diameter.
Method:
 The apparatus used is the coulter counter.
 The principle of this apparatus depends on, when a particle suspended in a
conducting liquid passes through a small orifice, on either side of which are
electrodes, a change in electrical resistance occurs.
 The coulter counter determines the number and size of particles suspended
in an electrically conducted liquid in which the sample is not soluble.
 This is accomplished by forcing a thoroughly dispersed suspension of
particles through a small orifice on either side of which is an electrode.
 A constant voltage is applied across the electrodes so as to produce a
current.
 As the particle travel through the orifice, it displaces its own volume of
electrolyte and this result in an increased resistance between the two
electrodes.
 This, in turn, produces a short-duration voltage pulse of a magnitude
proportional to the volume of the particle (Increase in resistance).
 These pulses are sized and counted electronically.
Precautions that should be noted in using coulter counter

1. The selection of the proper size orifice for counting the sample
size range.
2. Adjusting the particle concentration such that only single
particle pass through the orifice thus preventing counting of two
or more particles at one time.
Advantages
1. This equipment can count large number of particles (500/min) very
rapidly.
2. The apparatus yields highly reproducible results.
3. Because of the large number of particles, statistics will be easy and
yield high level of confidence in the distribution of a sample.

Disadvantages
1. High cost.
2. The possibility of orifice blockage by the particles especially in
heavy suspensions.
3. The electrolyte used must be specific and selective in which the
material to be counted is insoluble and is suitable in terms of electrical
resistance to the counted particles.