Lecture 1

Particle size
analysis

Dr. MUSA ALBATSH

Contents
• Introduction
• Optimal particle size ranges
• Equivalent sphere diameters
• Particle size distribution
• Statistical methods to summarize size
distribution data
• Particle size analysis methods
 Introduction Importance of
Particle size analysis
• The size of particulate solids is important in achieving
optimum formulation and production of efficacious medicine
• During stages 1 and 2, when a drug is synthesized and
formulated, the particle size of the drug and other powders in
the formulation is determined, and this influences the
physical performance of the medicine and the subsequent
pharmacological effects of the drug.
• Any interference with the uniformity of fill volumes may alter
the mass of drug incorporated into the tablet or capsule and
hence adversely affect the content uniformity of the Schematic representation of the
medicine. Powders with different particle sizes have different lifetime of a drug.
flow and packing properties, which alter the volumes of
powder during each encapsulation or tablet compression
event. In order to avoid such problems, the particle sizes of
drugs and other powders must be defined during formulation
so that problems during production are avoided.
 Importance of Particle size
analysis
• Following administration of the medicine (stage 4), the dosage form should release the
drug into solution at the optimum rate. This depends on several actors, one of which will
be the particle size of drug, which is inversely related to particle size.

• Thus, reducing the size of particles will generally increase the rate of dissolution, which
can have a direct impact on bioavailability and subsequent drug handling by the body
(stages 5 and 6).
• For example, the drug griseofulvin has a low solubility by oral administration but is
rapidly distributed following absorption; reducing the particle size increases the rate
of dissolution and consequently the amount of drug absorbed. However, a reduction in
particle size to improve dissolution rate and hence bioavailability is not always
beneficial.
• For example, reducing the particle size of nitrofurantoin increases its dissolution rate,
and may consequently produce adverse side-effects because of its more rapid
absorption.
 Optimal particle size ranges

• Coarse powder: majority of

particles > 350 µm
• Medium fine powder: 100–
350 µm
• Fine powder: 50–100 µm
• Very fine powder: 10–50 µm
• Micronized powder: < 10 µm
(majority < 5 µm).
 Equivalent sphere diameters
• Describing the size of irregularly shaped particles is difficult because they
do not have 3D. To overcome this problem, we employ the concept o
the equivalent sphere. Using this approach, a particle is considered to
approximate to a sphere: some property of the particle is measured and
related to a sphere, the diameter of which can be quoted. Because the
measurement is then based on a hypothetical sphere, which represents
only an approximation to the true size and shape of the particle, the
dimension is referred to as the equivalent sphere diameter or
equivalent diameter of the particle.

• The projected area diameter is based on a circle of equivalent area to

that of the projected image of a particle; the perimeter diameter is
based on a circle having the same perimeter as the particle. Unless the
particles are unsymmetrical in three dimensions then these two
diameters will be independent of particle orientation.
Equivalent sphere diameters
• It is also possible to determine the equivalent sphere diameters of
particles based on other actors such as volume, surface, sieve
aperture, sedimentation characteristics, etc
• In general, the method used to determine particle size dictates the
type of equivalent diameter that is measured.
• Inter-conversion of the various equivalent particle sizes may be
carried out and this can be done mathematically or automatically as
part of the size analysis
 Particle size distribution
Normal distribution
(symmetrical)
• A particle population which consists of spheres or equivalent
spheres of the same diameter is said to be monodispersed
or monosized, and its characteristics can be described by a
single diameter or equivalent sphere diameter. (RARE)
• Most powders contain particles with a range of different
equivalent diameters, i.e. they are polydispersed or
heterodispersed.
• In order to be able to define a size distribution or compare +ve skewed (tail
toward high sizes)
the characteristics of two or more powders consisting of
particles with many different diameters, the size distribution
can be broken down into different size ranges, which can be
presented in the form of a histogram plotted from data
Particle size distribution
• Such a histogram presents an interpretation of the particle size
distribution and enables the percentage of particles having a given
equivalent diameter to be determined. A histogram allows different
particle size distributions to be compared.

• In some size distributions more than one mode occurs, An alternative to

the histogram representation of particle size distribution is obtained by
sequentially adding the percent frequency values, as shown in Table next
page, to produce a cumulative percent frequency distribution
Statistical methods to
summarize size distribution data
• Although it is possible to describe particle size distributions qualitatively, it is always more
satisfactory to compare particle size data quantitatively. This is made possible by
summarizing the distributions using statistical methods.
• In order to quantify the degree of skewness o a particle population, the interquartile
coefficient of skewness (IQCS) can be determined as bellow
• The IQCS can take any value between −1 and +1. I the IQCS is zero then the size distribution
is practically symmetrical between the quartile points. To avoid ambiguity in interpreting
values or IQCS, a large number of size intervals is required.

where a is the median diameter and

b and c are the lower and upper
quartile points
Statistical methods to
summarize size distribution data
• To quantify the degree of symmetry o a particle size distribution, a
property known as kurtosis can be determined. ‘Thick’-tailed, ‘sharp’
peaked curves are described as leptokurtic, whereas ‘thin’-tailed,
‘blunt’ peaked curves are platykurtic
• The coefficient of kurtosis, k, has a value of 0 for a normal curve, a
negative value or curves showing platykurtosis and positive values or
leptokurtic size distributions
Particle size analysis methods
• In order to obtain equivalent sphere diameters with which to characterize the particle size of
a powder, it is necessary to carry out a size analysis using one or more different methods.
Particle size analysis methods can be divided into different categories based on several
different criteria: size range of analysis; wet or dry methods; manual or automatic methods or
speed of analysis.

The methods are:

1. Sieve methods
2. Microscope methods
3. Sedimentation methods
4. Electrical sensing zone method (Coulter Counter®)
5. Laser diffraction (low angle laser light scattering)
6. Photon correlation spectroscopy (dynamic light scattering)
1. Sieve methods
• Sieve diameter is the width of the minimum square aperture through which the
particle will pass.
• Sieve analysis is still largely a non-automated process
• Sieve analysis is usually carried out using dry powders, although or powders in
liquid suspension or which agglomerate during dry sieving, a process of wet
sieving can be used.
• The International Standards Organization (ISO) sets a lowest sieve diameter of 45
µm and, as powders are usually defined as having a maximum diameter of 1000
µm, this could be considered to be the upper limit. In practice, sieves can be
obtained or size analysis over a range rom 5 to 125 000µm.
 2. Microscope methods
• Projected area diameter, da; perimeter diameter, dp
• Specimens prepared or light microscopy must be adequately dispersed on a
microscope slide to avoid analysis of agglomerated particles.
• Alternatives to light microscopy include scanning electron microscopy (SEM) and
transmission electron microscopy (TEM), SEM is particularly appropriate when a
3-dimensional particle image is required.
• Advantages: Fully automated image analysis has the advantage of being more
objective and very much faster, also enables a much wider variety of size and
shape parameters to be processed.
 3. Sedimentation methods
• Particle size distributions can be determined by
examining the powder as its sediments. In cases
where the powder is not uniformly dispersed in a
fluid, it can be introduced as a thin layer on the
surface of the liquid. If the powder is
hydrophobic it may be necessary to add a
dispersing agent to aid wetting. In cases where
the powder is soluble in water, it will be
necessary to use non-aqueous liquids or carry
out the analysis in a gas.
• In general, gravity sedimentation methods tend
to be less automated than those using
centrifugal forces
• The advantages of this method are that sizing is
carried out relatively rapidly and the analysis is
virtually automatic.
4. Electrical sensing zone
method (Coulter Counter®)
• Powder samples are dispersed in an electrolyte to form a very dilute suspension, which is
usually subjected to ultrasonic agitation or a period to break up any particle aggregates. A
dispersant may also be added to aid particle deaggregation.
• Some instruments of this type use the change in reflectance, whereas others use the change
in transmittance of light. It is also possible to use ultrasonic waves generated and monitored
by a piezoelectric crystal at the base of a flow-through tube containing particles in fluid
suspension.
5. Laser diffraction (low angle laser
light scattering)
• Projected area diameter is used
• Moncohromatic light from a helium-neon laser is incident on the sample of particles and
diffraction occurs. The scattered light is focused by a lens directly on to a photodetector,
comprising a series of detectors.
• For particles that are much larger than the wavelength of light, any interaction with particles
causes light to be scattered in a forward direction with only a small change in angle. This
phenomenon is known as Fraunhofer diffraction
• Most of the instruments based on laser diffraction produce a full particle size analysis
automatically, with data are presented in graphical and tabular form.
 6. Photon correlation spectroscopy
(dynamic light scattering)
• In photon correlation spectroscopy (PCS), also called dynamic light scattering (DLS) and
quasielastic light scattering (QELS), the intensity of scattered light at a given angle is measured as
a function of time or a population of particles. The rate of change of the scattered light intensity is
a function of the movement of the particles by Brownian motion. Brownian motion is the random
movement of a small particle or macromolecule caused by collisions with the smaller molecules of
the suspending fluid.
• Advantages: The instruments vary according to their ability to characterize different particle size
ranges, produce complete size distributions, measure dispersions of both solid and liquid
particles, and determine molecular weights, diffusion coefficients, zeta potential or
electrophoretic mobility. Automated.