Dr.

Mohammad Shariare
Associate Professor
North South University
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 Disperse system
0.5 - 10.0 µm Suspension, fine emulsion
10.0 - 50.0 µm Coarse emulsion, flocculated
suspension
50.0 - 100.0 µm Fine powder range
150.0 - 1000.0 µm Coarse powder range
1000.0 - 3360.0 µm 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 = πd2 and the volume is given by V =
πd3/6
 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
• Stoke’s 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 Stoke’s 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 1/p
= ∑ndf

 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 Frequency Size Frequency Mean diameter Edmundson
index [p] index [f] parameter equation
1 0 Length Number Length number ∑nd
mean (dln) ∑n

2 0 Surface Number Surface number √∑nd2

mean (dsn) ∑n

3 0 Volume Number Volume number 3√∑nd2

mean (dvn) ∑n

1 1 Length Length Length weighted ∑nd2

∑nd
mean (dsl)
∑nd3
1 2 Length Surface Surface weighted
∑nd2
mean (dvs)
∑nd4
1 3 Length Weight Volume weighted ∑nd3
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.

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

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 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 πdvn3/6 and the mass is πdvn3ρ/6 g per
particle where dvn is the mean diameter based on volume and number and ρ 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 =
πdvn3ρ/6
6
Or N = πd 3ρ
vn
 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.

• Ease of handling
• Cost effectiveness
• Specification requirement
• Speed of measurement
1. Microscopic technique:
Optical microscopy is generally used for particle size measurement in the range of 0.2
µm to about 100.0 µm. 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 µm)
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 µm 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 : 5µm - ~3mm
 Standard woven wire sieves
 Electroformed micromesh sieves at the lower end or range (< 20µm)
 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 FI NENESS

Classification of Powders by Fineness

Classification of Powder d50 Sieve Opening (µm)

Very Coarse > 1000
Coarse 355– 1000
Moderately Fine 180– 355
Fine 125– 180
Very Fine 90– 125

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 Stoke’s
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.
 The angles of diffraction are, in the
simplest case inversely related to
the particle size.
 The particles pass through an
expanded and collimated laser
beam in front of a lens in whose
focal plane is positioned a • Volume distribution
photosensitive detector consisting
of a series of concentric rings.
 Distribution of scattered intensity is
analysed by computer to yield the
particle size distribution.
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 particle’s 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 =
Surface area of particles
Volume of particles
Sw = Sv /ρ
Where ρ is the density of particles
 Particle volume measurement

1. Coulter counter method (Electrical stream sensing method)

 Methods of determining surface area

1. Adsorption method
2. Air permeability method
• 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
 Methods of determining surface area
1. 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 ε is defined as the ratio of the void volume to the bulk volume of
the powder packing

Vb - V p
Thus, ε = Vb

 Porosity is expressed as percentage i.e., ε 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 found-
1.True density – density of materials exclusive of pores

Mass of the powder

True density = True volume

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 density = Granule volume
3. Bulk density – bulk density of a powder is defined as the ratio of the mass of the
powder and its bulk volume.
Mass of the powder
Bulk Density =
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 µm 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 θ = h/r
Where, θ 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.
 tapped density – initial bulk density
Carr′s Index (%) = ˣ 100

tapped density

 Hausner′s ratio =
tapped density
Initial bulk density

 Hausner′s 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.