UNIT-III 10Hours

Micromeretics: Particle size and distribution, average particle size, number and
weight distribution, particle number, methods for determining particle size by
(different methods), counting and separation method, particle shape, specific
surface, methods for determining surface area, permeability, adsorption, derived
properties of powders, porosity, packing arrangement, densities, bulkiness & flow
properties
MICROMERITICS

MICROMERITICS is the science and technology of small particles. The unit of

particle size used is the micrometer (μm) micron (μ) .The knowledge and control
of the size of particles is very important in pharmacy and materials science. The
size & hence the surface area of a particle can be related to the physical, chemical
& pharmacologic activity of drug.

Application
1. Release & dissolution:
Particle size & surface area influence the release of a drug from a dosage
form. Higher surface area allows intimate contact of the drug with the
dissolution fluids in vivo & increases the drug solubility & dissolution. The
particle size of dispersed drug in ointment or suppositories also affects its
release characteristics from to the skin or mucous membrane.
2. Absorption & drug action:
Particle size & surface area influence the drug absorption & subsequently
the therapeutic action. Higher the dissolution, faster the absorption & hence
quicker & greater the drug action
3. Physical stability:
The particle size in a formulation influences the physical stability of the
suspensions & emulsions. With optimum size of the particle, better the
physical stability of the dosage form. If optimum partical size not achieved it
may lead to faster sedimentation or creaming.
4. Dose uniformity:
Good flow properties of granules & powders are important in the
manufacturing of tablets & capsules to get dose uniformity.

Fundamental properties
 Particle size and particle size distribution
  Particle shape
 Particle volume
 Particle number
 Particle surface area

Particle size and particle size distribution

Powders have collection of particles of more than one size and shape. For
symmetric particles like spheres its easy to describe the size in terms of diameter
but most of the powders are not symmetric in their shape, hence the particle size of
asymmetric particles are expressed in terms of equivalent diameter.

Surface diameter (ds):- The diameter of a sphere having the same surface area as
the particle

Volume diameter(dv) :- The diameter of a sphere having the same volume as the
particle

Projected diameter (dp):- The diameter of a sphere having the same observed
area as the particle.

Stokes’diameter(dst) :-An equivalent sphere undergoing sedimentation at the

same rate as the asymmetric particle.

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. •

Any collection of particles is usually polydisperse. It is therefore necessary to

know not only the size of a certain particle, but also how many particles of the
same size exist 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 the particle-size
distribution, and from it, we can calculate an average particle size for the sample.
Average Particle Size (edmundson equation)
The general equation for the average particle size:

n = is the number of particles in a size range whose midpoint, d, is one of the

equivalent diameters.

P= is an index related to the size of an individual particle, because d raised to the

power p = 1, p = 2, or p = 3 is an expression of the particle length, surface, or
volume, respectively.
When the frequency index, f, has values of 0, 1, 2, or 3, then the size frequency
distribution is expressed in terms of the total number, length, surface, or volume of
the particles, respectively.

Particle-Size Distribution
When the number, or weight, of particles lying within a certain size range is
plotted against the size range or mean particle size, a so-called frequency
distribution curve is obtained. Such plot given below a visual representation of the
distribution that an average diameter cannot achieve. This is important because it is
possible to have two samples with the same average diameter but different
distributions. Moreover, it is immediately apparent from a frequency distribution
curve what particle size occurs most frequently within the sample. This is termed
the mode.
The normal distribution is shown in Fig A, is not commonly found in
pharmaceutical powders, which are frquently prossed by milling or precipitation.
Rather, these systems tend to have an nonsymmetric or skewed, distribution of
type showed in Fig B

Fig:A frequency distribution curve

 FIG:B (Frequency distribution plot of the data)

An alternative method of representing the data is to plot the cumulative percentage

over or under a particular size versus particle size as shown in Fig C (cumulative
frequency plot). This gives a sigmoid curve with the mode being the particle size
of the greatest slope.

Fig C cumulative frequency plot

When the data is plotted as %frequency verses the logarithm a typical bell shaped
curve is frequently obtained. This is shown in the Fig D
 Fig D: log normal distribution curve for polydispersed powder

When the logarithm of the particle size is plotted against the cumulative
percentage on a log probabilty scale, a linear relationship is observed as shown in
Fig E (log probability Plot). Such a linearplot characterize a log normal distribution
curve by means of two parameters,
 The slope of the line
 A reference point

The reference point used is the logarithm of the particle size equivalent to 50% on
the probabilty scale, that is the 50% size. This is known as the geometric mean
diameter and is given the symbol d g. The slope is given by the geometric standard
deviation, .

Log probability plot data

Methods for determining particle size
1. Microscopy ( Optical Microscopy)
2. Sieve Analysis
3. Sedimentation Method

Optical Microscopy : Used for partical size determination in size range of 0.2-100
micrometre. Atleast 300 -500 Particals must be counted.
Procedure:
1. A dilute suspension of the powder particles whose sizes are to be determined
is prepared in liquid vehicle in which the powder is insoluble.
2. A drop of suspension is mounted on a slide & observed under the
microscope.
3. The Eye piece of the microscope is fitted with the micrometre (which is
calibrated using stage micrometer) so that, particle size can be measured.
4. All the particles observed in the field are counted & measured through the
eye piece.
5. The dat a is represented as size frequency distribution curve.
6. From the data the avg. particle size & size is determined.
7. For ease of counting the particles, the field viewed through microscope can
be projected on screen or photographed & be measured later.
8. Also particles can be counted with electronic scanner to avoid strain of
visual observation for very small particle.
9. An electron microscope or scanning electrone microscope can be used
Disadvantage

1. The diameter is obtained from only two dimensions of the particle.

2. The number of particles that must be counted (300-500) to obtain a good
estimation of the distribution makes the method somewhat slow and tedious

Advantages
1. Able to examine each particle individually has led to microscopy being
considered as an absolute measurement of particle size.
2. Can distinguish aggregates from single particles
Sieve Analysis:- Sieves are generally used for grading coarser particles
Procedure:
1. This method uses a series of standard sieves.
2. 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.
3. According to the method of the U.S. Pharmacopeia for testing powder
fineness, a mass of sample is placed on the proper sieve in a mechanical
shaker.
4. The powder is shaken for a definite period of time, and the material that
passes through one sieve and is retained on the next fine sieve is collected
and weighed.
5. The mean weight diameter can be obtained from plot of the cumulative
weight percent of powder retained on the sieves against the logarithm of the
arithmetic or geometric mean size of the openings of each of two successive
screens.
Disadvantages
1. Sieving errors can arise from a number of variables including sieve loading
and duration and intensity of agitation
2. sieving can cause aggregation and attrition of granular pharmaceutical
materials.
3. Moisture present may cause error
 Sedimentation Method
The particle size in the subsieve range can be obtained by gravity
sedimentation as expressed in Stokes's law,

ν: rate of settling
h : distance of fall in time t
ρs: density of particle
ρ0: density of dispersion medium
g : Acceleration due to gravity
η0 : Viscosity of medium

The law is applicable to irregularly shaped particles of various sizes as long as one
realizes that the diameter obtained is a relative particle size equivalent to that of
sphere falling at the same velocity as that of the particles under consideration. The
particles must not be aggregated or clumped together in the suspension because
such clumps would fall more rapidly than the individual particles 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.
Procedure
1. The Andreasen apparatus usually consists of a 550 mL vessel containing 10
mL pipette sealed into a ground-glass stopper.
2. When the pipette is in place in the cylinder, its lower tip is 20 cm below the
surface of the suspension.
3. 1-2% suspension of the powder is prepared in suitable medium and placed in
the Andreasen apparatus
4. The stoppered vessel is shaken to distribute the particles uniformly
throughout the suspension, and the apparatus, with pipette in place, is
clamped securely in a constant-temperature bath.
 5. At various time intervals, 10 mL samples are withdrawn into pre weighed
china dish and discharged by means of the two-way stopcock.
6. The samples are evaporated and weighed or analyzed by other appropriate
means, correction for the deflocculating agent that has been added.
7. The particle diameter is calculated from stokes law where ‘h’ is is the height
of the liquid above the lower end of the pipette at the time of withdrawing
the samples.

The residue of dried sample obtained at particular time is is having particles of

sizes less than the size obtained by the stokes law, hence the weight of sample s
called weight undersize.

Andreasen apparatus
Advantage
1. The apparatus is inexpensive and the technique is standardized
2. The method used is simple
Disadvantage
1. Very small particles cannot be determined since their ettling is unduly
prolonged

Particle volume measurement

A popular instrument for measuring the volume of particles is the Coulter

counter. This instrument operates on the principle that 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.
Procedure
1. The sample to be analysed is suspended in a suitable electrolyte in a beaker
and placed on the beaker platform.
2. A glass orifice tube, having an accurately made aperture in the lower end
projects into the beaker, the inside of the tube being filled with the same
electrolyte as in the beaker. On either side of the orifice is an immersed
electrode.
 3. By applying a controlled vacuum to the orifice and with the help of mercury
manometer situated behind it, liquid and the suspended particles are drawn
through the aperture.
4. The passage of the particle through the orifice causes a momentary increase
in the resistance to the current which is simultaneously passing through the
orifice.
5. This increase is detected as a voltage pulse, which is proportional to the
volume of the particle.
6. This pulse is then amplified, scaled, passed through an adjustable threshold
and counted
7. The volume distribution can be converted to weight distribution.
8. By systematically varying the threshold setting and counting the number of
particles in a constant sample size, it is possible to obtain a particle
distribution.
9. The instrument is capable of counting particles at rate of approximately 4000
per sec and both gross count and particle size distribution are obtained in
relatively short period of time .

Particle Shape
A sphere has minimum surface area per unit volume. The more asymmetric a
particle, the greater is the surface area per unit volume. The surface area of a
sphere is given as follows (derivation refer class notes)

Volume =𝝅𝒅³𝟔
Surface Area = πd²
Specific Surface
The specific surface is the surface area per unit volume, Sv, or per unit weight, Sw.

𝑺𝒖𝒓𝒇𝒂𝒄𝒆𝒂𝒓𝒆𝒂𝒐𝒇𝒑𝒂𝒓𝒕𝒊𝒄𝒂𝒍
Sv =
𝑽𝒐𝒍𝒖𝒎𝒆𝒐𝒇𝒑𝒂𝒓𝒕𝒊𝒄𝒍e

6
= ---------
d

S W= 𝑺𝒖𝒓𝒇𝒂𝒄𝒆 𝒂𝒓𝒆𝒂𝒐𝒇𝒑𝒂𝒓𝒕𝒊𝒄𝒂𝒍

Weight of 𝒑𝒂𝒓𝒕𝒊𝒄𝒍e

== 𝑺𝒖𝒓𝒇𝒂𝒄𝒆 𝒂𝒓𝒆𝒂𝒐𝒇 particle

Voume *density
 dvs is volume surface diameter

Particle Number (N)

Number of particles per unit weight

Particle surface area

(refer class notes)

Adsorption Method
Particles with a large specific surface are good adsorbents for the adsorption of gases and of solutes from solution.
In determining the surface of the adsorbent, the volume in cubic
centimeters of gas adsorbed per gram of adsorbent can be
plotted against the pressure of the gas at constant temperature
to give a type II isotherm as shown in Figure 18–10.
The adsorbed layer is monomolecular at lowpressures and
becomes multimolecular at higher pressures. The completion
of the monolayer of nitrogen on a powder is shown as point B
in Figure 18–10. The volume of nitrogen gas, Vm, in cm3 that
Fig. 18–10. Isotherm showing the volume of nitrogen adsorbed on a
powder at increasing pressure ratio. Point B represents the volume
of adsorbed gas corresponding to the completion of a monomolecular
film. Key: STP = standard temperature and pressure.
1 g of the powder can adsorb when the monolayer is complete
is more accurately given by using the Brunaver, Emmett, and
Teller (BET) equation, which can be written as
p
V(p0 − p)
=1
Vm b
+ (b − 1)p
Vmbp0
(18–18)
where V is the volume of gas in cm3 adsorbed per gram
of powder at pressure p, p0 is the saturation vapor pressure
of liquefied nitrogen at the temperature of the experiment,
and b is a constant that expresses the difference between the
heat of adsorption and heat of liquefaction of the adsorbate
(nitrogen). Note that at p/p0 = 1, the vapor pressure, p, is
equal to the saturation vapor pressure.
An instrument used to obtain the data needed to calculate
surface area and pore structure of pharmaceutical powders is
the Quantasorb QS-16, manufactured by the Quantachrome
Corporation (Boynton, FL). Absorption and desorption of
nitrogen gas on the powder sample is measured with a thermal
conductivity detector when a mixture of helium and nitrogen
is passed through a cell containing the powder. Nitrogen is
the absorbate gas; helium is inert and is not adsorbed on the
powder surface. A Gaussian or bell-shaped curve is plotted
on a strip-chart recorder, the signal height being proportional
to the rate of absorption or desorption of nitrogen and the area
under the curve being proportional to the gas adsorbed on the
particles. Quantasorb and similar instruments have replaced
the older vacuum systems constructed of networks of glass
tubing. These required long periods of time to equilibrate and
were subject to leakage at valves and breaks in the glass lines.
The sensitivity of the new instrument is such that small powder
samples can be analyzed. Quantasorb’s versatility allows
the use of a number of individual gases or mixtures of gases
as adsorbates over a range of temperatures. The instrument
can be used to measure the true density of powdered material
and to obtain pore-size and pore-volume distributions. The
characteristics of porous materials and the method of analysis
are discussed in the following sections.

Derived properties of powders

 Porosity
  Packing arrangement
 Densities of particles
 Bulkiness
 Flow properties
 Compaction

I. Porosity
Porosity:

 Suppose a powder (Zinc), is placed in a graduated cylinder:

 The volume occupied is known as the bulk volume Vb .
 Bulk volume = true volume + volume of spaces between particles.
 The volume of the spaces, the void volume, v = Vb - Vp
 Vp is the true volume of particles.
 The porosity or voids ε of powder is determined as the ratio of void volume
to bulk volume.

Porosity = ε = Vb– Vp

Vb
Vp
= 1−
Vb

Porosity is frequently expressed in percent, ε x 100 .

II. DENSITY:Density is defined as weight per unit volume (W/V)

  Bulk density
 True density
 Granular density

Bulk density:
 The bulk density value includes the volume of all of the pores within the
sample
 The mass of a powder divided by the bulk volume, bulk volume is the
volume including the volume of solid and void volumes (intra and inter)

ρb = mass of powder
Bulk volume
True density
 The true density, or absolute density, of a sample excludes the volume of the
Pores and voids within the sample.
ρ = mass of powder
True volume
True volume is the volume of the solid alone (excluding intra and inter particular
voids)
Granular density:
 The mass of particles divided by the volume as determined by the
liquid(mercury) displacement method(granular volume)
 Granular volume: Volume of powder + (intra particle spaces)
ρg = mass of powder
granular volume

Bulk density determination

a) Bulk density: (Tapping method -3 tap method)

1. Take an empty measuring cylinder of 10ml capacity, note the weight.

 2. Fill the cylinder with the given power up to 2ml mark.
3. Drop the cylinder of a hard wooden surface 3times from a height of 1 at 2
seconds interval.
4. Note the volume and the weight.
5. Repeat the experiment at 4ml, 6ml, 8ml, and 10ml mark.
6. Plot a graph of weight Vs. Volume. Find out the slope, which given the bulk
density.

b) Bulk density:(Tapping method used bulk density apparatus)

1. Pass the given powder through sieve No.20
2. Weight about 20gm of powder and place in the measuring cylinder – 100ml
3. Fix the measuring cylinder in the bulk density apparatus. Note the volume of
the powder
4. Adjust the knob for 125 tapping. Note the volume of the powder.
5. Adjust the knob for another 50 tapping’s note the volume again. If the two
values are same switch of the apparatus and note the volume. Otherwise
repeat tapping for another 50 tapping.
6. Calculate bulk density using the formula.
ρb = mass of powder
bulk volume

True density determination

 True density: (liquid Displacement method)
1. First, note down the weight of empty specific gravity bottle (W1).

2. Then liquid (benzene or water) is added to displace the voids filled in the
empty bottle and the weight should be recorded again as (W2).
 3. Dry the bottle and fill it with the powder and weigh (W3).

4. Then the liquid is allowed to drain in to the bottle with the powder in it,
till no more liquid is going in to the bottle and weigh the bottle again
(W4).

5. Use the formula to determine true density.

W3-W1_
(W2-W1) – (W4-W3)
ρ of liquid

 Helium displacement method

a. If the material is porous, as is the case with most powders, the true
density can be determined by use of a helium densitorneter.
b. The volume of the empty apparatus (dead space) is first determined
by introducing a known quantity of helium.
c. A weighed amount of powder is then introduced into the sample
tube, adsorbed gases are removed from the powder by an outgassing
procedure. Helium which is not adsorbed by the material is again
introduced.
d. The pressure is read on a mercury manometer, and by application of
the gas laws, the volume of helium surrounding the particles and
penetrating into the small cracks and pores is calculated.
e. The difference between the volume of helium filling the empty
apparatus and the volume of helium in the presence of the powder
sample yields, the volume occupied by the powder.
f. Knowing the weight Of the powder, one is then able to calculate the
true density.
g. The procedure is equivalent to the first step in the BET method for
determining the specific surface area of particles.
Granular density determination
 Mercury displacement method

 Granule density p gcan be determined by a method similar to the liquid

displacement method.
 Mercury is used because it fills the void spaces but fails to penetrate into the
internal pores of the particles.
 The volume of the particles together with their intraparticle spaces then
gives the granule volume, and from a knowledge of the powder weight
one finds the granule density

Intraparticle porosity

The intraparticle porosity of the granules can be computed from a knowledge of

the true and granule density. The porosity is given by the equation
 Intraparticle porosity
Interspace or void porosity

The interspace or void porosity of a powder of porous granules is the relative

volume of interspace voids to the bulk volume of the powder, exclusive of the
intraparicle pores. The interspace porosity is computed from knowledge of bulk
density and granular density.

III. PACKING ARRANGEMENTS

Powder beds of uniform-sized spheres can assume either of two ideal packing
arrangement:
(a) closest or rombohedral
(b) Loosestor cubic packing.
 The theoretical porosity of a powder consisting of uniform spheres in closest
packing is 26% and for loosest packing is 48%.
 The particles in real powders are neither spherical in shape nor uniform in size.
 It is to be expected that the particles of ordinary powders may have any
arrangement intermediate between the two ideal packings and most powders
in practice have porosities between 30% and 50%.
 If the particles are of greatly different sizes, however the smaller ones may
shift between the larger ones to give porosities below the theoretical minimum
of 26%.
  In powders containing flocculates or aggregates, which lead to the formation of
bridges and arches in the packing, the porosity may be above the theoretical
maximum of 48%.
 In real powder systemsalmost any degree of porosity is possible.

IV.BULKINESS
Specific bulk volume, the reciprocal of bulk density, is often called bulkiness or bulk.
It is an important consideration in the packaging of powders. The bulk density of
calcium carbonate can vary from 0.1 to 1.3, and the lightest or bulkiest type would
require a container about 13 times larger than that needed for the heaviest variety.
Bulkiness increases with a decrease in particle size. In a mixture of materials of
different sizes however, the smaller particles shift between the larger ones and tend
to reduce the bulkiness.

Light and Heavy Powders

 Light: low bulk density or large bulk volume
 Heavy: high bulk density or small bulk volume Light

V. FLOW PROPERTIES

Powders may be free flowing or cohesive (“sticky”).

Flow property is dependent on particle size, shape, porosity, density, and surface
texture
Many common manufacturing problems are attributed to powder flow:
Powder transfer through large equipment such as hopper.
 Uneven powder flow due to
 excess entrapped air within powders results in capping or lamination.
 increase particle’s friction with die wall causing lubrication problems, and
increase dust contamination during powder transfer.
 non-uniformity (segregation) in blending
 Powder storage- which for example result in cakingtendencies within a vial or
bag after shipping or storagetime.
 Separation of small quantity of the powder from thebulk- specifically just
before the creation of individualdoses such as during tableting, encapsulation
 and vialfilling which affect the weight uniformity of the dose(under or over
dosage).

Improvement of Powder Flow ability

1. Alteration of Particle’s size & Distribution

 There is certain particle size at which powder’s flow ability is optimum.
 Coarse particles are more preferred than fine ones as they are less cohesive.
 The size distribution can also be altered to improve flowability by removing
a proportion of the fine particle fraction or by increasing the proportion of
coarser particles, such as occurs in granulation
2. Alteration of Particle Shape & texture
 Particle Shape:Generally, more spherical particles have better flow
properties than more irregular particles. Spherical particles are
obtained by spray drying, or by temperature cycling crystallization
 Particle's texture:particles with very rough surfaces will be more
cohesive and have agreater tendency to interlock than smooth
surfaced particles.
3. Alteration of Surface Forces
 Reduction of electrostatic charges can improve powder flow ability.

Electrostatic charges can be reduced by altering process conditions to

reduce frictional contacts.

 Moisture content of particle greatly affects powder’s flowability

Adsorbed surface moisture films tend to increase bulk density and
reduce porosity. Drying the particles will reduce the cohesiveness
and improve the flow. Hygroscopic powders stored and processed
under low humidity conditions.
4. Formulation additives ( Flow activators)
 Flow activators are commonly referred as glidants. Flow activators
improve the flowability of powders by reducing adhesion and
cohesion.
 e.g. talc, maize starch and magnesium stearate
Tests to evaluate the flow ability of a powder
1) Carr’s compressibility index
 A volume of powder is filled into a graduated glass cylinder and
repeatedlytapped for a known duration. The volume of powder after tapping
ismeasured.
Carr’s index (%) =Tapped density – Poured or bulk density x 100
Tapped density

2) Hausner ratio: given as

Tapped density
Poured or bulk density
3) The angle of repose φ:
The frictional forces in a loose powder can bemeasured by the angle of repose φ.
φ = the maximum angle possible between the surfaceof a pile of powder and
horizontal plane = coefficientof friction μ between the particles:
tan φ = μ
tan φ = h / r
r=d/2
 The sample is poured onto a horizontal surface and the angle of the resulting
pyramid is measured.
 The user normally selects the funnel orifice through which the powderflows
slowly and reasonably constantly.
 Angle of repose less than 20 (excellent flow)
 Angle of repose between 20-30 (good flow)
 Angle of repose between 30-34 (Pass flow)
 Angle of repose greater than 40 (poor flow)
The rougher and more irregular the surface of the particles, the higher will be the
angle of repose
VI. COMPACTION: COMPRESSED TABLETS

Neumann" found that when powders were compacted under a pressure of about 5
kg/cm2, the porosities of the powders composed of rigid particles (e.g., sodium
carbonate) were higher than the porosities of powders in closest packing as
determined by tapping experiments. Hence. These powders were dilatant, that is,
they showed an unexpected expansion, rather than contraction, under the influence
of stress. In the case of soft and spongy particles (e.g., kaolin), however, the
particles deformed on compression, and the porosities were lower than after
tapping the powder down to its condition of closest packing. Similar experiments
might be conducted to determine the optimum condition for packing powders into
capsules on the manufacturing scale