Particle Size

Analysis
Prof. Sayed Mohamed Ahmed
◼ This lecture includes:
◼ Definition

◼ Importance of Particle Size Analysis in

pharmaceutical industry

◼ Particle size and size distribution

◼ Steps for particle size analysis

◼ Methods of measuring the particle size

Definition:
◼ Particle size analysis is a part of micromeritics
which is the science and technology of small
particles.
◼ The concerned pharmaceutical preparations
are:
❖ Colloids
❖ Emulsions and dispersions (suspensions)

❖ Tablet granulations and granular salts

The Units used to measure particle size

are the micrometer ,µm, also called the

micron, µ, and equal to 106 m. For finer size
ranges, the millimicron, mµ referred to as

nanometer, nm is frequently used,

nm = 10-9m.
Importance of particle size analysis:
1. Particle size, and hence surface area, of a
certain drug can affect its physical, chemical
and pharmacological properties.

2. Successful formulation of suspensions,

emulsions and tablets from view point of
physical stability and pharmacological response
also depends on the particle size.
3. In tablet and capsule manufacture control of
the particle size is essential in achieving the
required flow properties and proper mixing of
granules and powders.

4. The importance of particle size in extraction,

drying, chemical and physico-chemical drug-
excepient interactions, crystallization and other
pharmaceutical unit operations is well-known.
Particle size and size distribution:
The size of a sphere is readily expressed in terms
of diameter. As the degree of asymmetry of
particles increases (as in polydisperse samples),
it becomes difficult to express the size in
diameter.
Therefore the size can be expressed in terms of
the following:
a. Surface diameter, ds, which is the diameter of
a sphere having the same surface area as the
particle in question.
b. Volume diameter, dv, the diameter of sphere
having the same volume as the particle.
c. Stock’s diameter, dst, the diameter of a
sphere undergoing sedimentation at the
same rate as the particle.
d. Projected diameter, dp, is the diameter of
a sphere having the same observed area as
the particle when viewed normal to its most
stable plane.
Stock’s diameter is determined from
sedimentation technique.
Projected diameter from microscopic
technique.
Particle Size distribution
In a polydisperse system, it is necessary to know
(1) ranges of sizes, and (2) how many
(number or weight %) particles are present in
each range. This is the particle size
distribution from which we can calculate the
average particle size of the sample.
Steps for particle size analysis:
1- Sampling :
Which means taking the sample from the material to be
analyzed.
This sample must be representative of the entire lot or
batch of material .
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 form that can be
statistically analyzed for interpretive and comparative
purposes.
Methods of measuring the particle size
1– Microscopy:
Particle size range:
Optical microscope 0.5 - 100 mm
Electronic microscope 0.01 - 1.0 mm
Procedures
➢Preparing a slurry of several mg of powder in a liquid
dispersion medium in which the sample is insoluble.
➢One or two drops of the well - mixed slurry is placed
on a clean microscope slide, and a cover slip is applied.
➢Several random fields are selected for counting. The
particle sizing may be accomplished by using:
(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
Advantages:
1. Low cost
2. It is 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.
 Sieve Analysis
This is carried out by
▪Procedure and calculation:
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 smaller than the mesh pass
through 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:
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 sedimented in each time interval, thus find a relation
between the cumulative weights and time.
By using stock’s equation:
18..h
d=
(P-PO) gt

d = particle diameter (cm),µ= Viscosity of fluid (poise = g/cm.)

h = distance of fall in cm, t = time off all.
P = density of the particles (g/ cm3)
Po = density of fluid (g/ cm3)
g = Acceleration due to gravity 981 (cm / sec 2) (gravity acceleration constant)
◼ The particles must not be aggregated or
clumped together in the suspension since
such clumps would fall more rapidly than
the individual particle, and erroneous
results would be obtained. The proper
deflocculating agent must be found for each
sample that will keep the particles free and
separate as they fall through the medium.
◼ For Stock’s law to apply, a further requirement
is that the flow of dispersion medium around
the particle as it sediments is laminar or
streamline because any turbulence will affect
the sedimentation of the particle.
Andreasen pipette method :
◼ The easiest and most accurate method.

◼ This apparatus is designed for a settling liquid

that will not dissolve the sample and can be
easily and completely evaporated by heat
and/or vacuum.
Andreasen pipette
 It consists of a 550-ml vessel containing a 10-
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. A 1 or 2% suspension of the
particles is introduced into the vessel and
brought to the 550-ml mark. The Stoppard
vessel is shaken to distribute the particles
uniformly throughout the suspension, with the
pipette in place, in a constant temperature
water bath.
 - At various time intervals, 10-ml samples are
withdrawn and discharged by means of the two-
way stopcock. The samples are evaporated and
weighed or analyzed to determine its particles
content.
- The particle diameter corresponding to the
various time periods is calculated from Stock’s law,
with (h) in the equation being the height of the
liquid above the lower end of the pipette at the time
each sample is removed.
The residue or dried sample obtained at
particular time is the weight fraction, having
particles of sizes less than the size obtained by
the Stock’s law calculated for the 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 the
cumulative weight undersize.
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.
4: Particle volume measurement:
The coulter counter
The coulter counter has been used in the
pharmaceutical sciences to study particle growth
and dissolution and the effect of antibacterial
agents on the growth of microorganisms.

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 electric
resistance occurs.
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. Cost of equipment is high
2. The possibility of orifice blockage by the particles specially 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.
4. Wrong results may produced if there is electrolytic back
(B)
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.
 The coulter counter determines the number and
size of particles suspended in an electrically
conducted liquid in which the sample is not
soluble.
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.
As large number of particles, statistics will
be easy and yield high level of confidence
in the distribution of a sample.
Disadvantages:
1. Cost of equipment is high
2.The possibility of orifice blockage by the
particles specially 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.
4.Wrong results may produced if there is
electrolytic back ground.
Thank you