MICROMERITICS

M.S. BINDU
What is Micromeritics?
The Science and Technology of small
particles is known as Micromeritics.

It is the study of various characteristics like

 Particle size and size distribution
 Particle shape and surface area
 Porosity, Density, Flow property etc…

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Need/ Importance/ Application of
Micromeritics
Knowledge and control of the size and the size
range of particle is of profound importance in
pharmacy
Size and surface area can be related to the
physical, chemical and pharmacological
properties of a drug.
1. Drug release and dissolution: Particle size affects
drug release from dosage forms that are
administered orally, parenterally, rectally and
topically. Higher surface area brings about close
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contact of the drug with the dissolution fluids.
Need/ Importance/ Application of
Micromeritics
2.Absorption and drug action: Particle size and
surface area influence the drug absorption and
subsequently the therapeutic action. Higher the
dissolution faster the absorption. Hence quicker
the drug action

3.Physical stability : Particle size influences the

physical stability of suspensions and emulsions.
Smaller the size better is the physical stability (as it
would take more time for particles to agglomerate)
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4. Dose uniformity: Particle size and shape
also governs flow properties of powders and
granules in tabletting.
Any interference in the flowability of
powders or granules may alter the weight of
the powder blend and thus amount of drug
incorporated into the tablet or capsules and
thereby reduce the uniformity of the dose.

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Examples…
 Reduction of particles size improves surface area
and can help in improving solubility of certain
drugs. e.g. The solubility of Griseofulvin can be
greatly increased by particle size reduction.

 Reduction of particles size can increase the rate of

absorption of and consequently bioavailability of
many drugs e.g. tetracycline, aspirin and
sulphonamides, nitrofurantoin etc..

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 Properties of Powders
1. Fundamental properties :-These
properties relate to the individual particle.

2. Derived properties :- They are dependent

on fundamental properties & define the
factors relating to their measurement.

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Fundamental properties:-
1. Particle size and size distribution
2. Particle shape
3. Particle surface area
4. Particle weight
5. Particle number

Derived properties:
1. Density of powders (a) bulk density (b)tapped
density (c) granular density (d)true density
2. Flow properties of powders
3. Porosity
4. Bulkiness
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Fu ndamental properties of

powders

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 I. Particle size
Denoted in micrometers
(formerly called as microns)
One micrometer is equal to 10-3 mm or 10-6 m
One millimicrometer is called one nanometer (nm)
One nanometer = 10-9 m or 10-6 mm or 10-3 µm

1 m = 1000 mm
1 mm = 1000 µm
1 µm = 1000 nm
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Particle size determination (PSD) -Methods
1. Optical Microscopy
2. Sieving Method
3. Sedimentation Method
4. Conductivity Method

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 1. Optical Microscopy
Particle size in the range of 0.2 – 100 µm can be
measured.
This method gives number distribution which can be
converted to weight distribution
Optical microscope lens has limited resolving power
Advanced microscopes have better resolving power and
can measure size in nano range: Ultramicroscope,
Electron microscope- Scanning Electron microscope
(SEM), Transmission Electron microscope (TEM).

Application: Particle size analysis in suspensions,

ae1r3osols, globule size analysis in emulsion
Procedure:
1. Eye piece of the microscope is fitted with a
micrometer.
2. This eye-piece micrometer is calibrated using a
standard stage micrometer.
3. The powder sample is dispersed in a suitable
vehicle in which it does not dissolve and its
properties are not altered. (eg. water, paraffin oil.)
4. This sample is mounted on a slide and placed on
the stage under the objective of microscope.
5. Around 625 particles are visualized. their
d14iameter is noted and mean is computed.
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 Advantages
One can view particles
Any aggregates detected
Contamination of particles detected
Use of cover slip for arresting motion of particles
Easy and simple
Disadvantages
Length and breadth can be detected but depth or
thickness of particles cannot be measured
Slow- time consuming , tedious
Number of particles to be measured is more
1L
9 arge sample required
 2. Sieving Method

Sieving method is an ordinary and simple

method.
It is widely used as a method for the particle
size analysis
Sieve analysis is usually carried out using dry
powders. Although, for powders in liquid
suspension or which agglomerate during dry
sieving, a process of wet sieving can be used.

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Sieving method directly gives weight
distribution.
It find application in dosage form
development of tablets and capsules.
Normally, 15% of fine powder should be
present in granulated material to get
proper flow of material and achieve good
compaction.
Thus percent of coarse, moderate, fine
powder is estimated by this method.
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Method:
Sieve analysis utilizes a wire mesh made of
brass, bronze or stainless steel with known
aperture (hole) diameters which form a
physical barrier to particles.
The standard sieve sizes are as per the
pharmacopoeia
Most sieve analyses utilize a series, stack
(layer) of sieves which have the coarser
mesh at the top of the series and smallest
mesh at the bottom above a collector tray
(The mesh size goes on decreasing from top
to22bottom)
Method:
A sieve stack usually comprises 6-8 sieves.
Powder is loaded on to the coarsest sieve of the
stack and then it is subjected to mechanical
vibration for specified time, eg 20 minutes.
After this time, the powder retained on each
sieve is weighed
The particles are considered to be retained on
the sieve mesh with an aperture corresponding
to the sieve diameter.
The size is estimated as per the standards
given in pharmacopoeia
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 Care should be taken to get reproducible results.
The type of motion, time of operation, speed,
weight of powder should be fixed and standardized.

Advantages- Inexpensive, Simple, Rapid,

Reproducible results (if parameters are
standardized)

Disadvantages- lower limit is 50 microns

Powder if moist, can cause clogging of apertures
Attrition between particles during the process may
ca2u8 se size reduction giving inaccurate results.
 3. Sedimentation Method
In this method particle size can be determined
by examining the powder as it sediments out.
Sample preparation: Powder is dispersed in
a suitable solvent
If the powder is hydrophobic, it may be
necessary to add dispersing agent to aid
wetting of the powder.
In case where the powder is soluble in water it
will be necessary to use non- aqueous liquids
or carry out the analysis in a gas.
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Principle of Measurement
Particle size analysis by sedimentation method
can be divided into two main categories
according to the method of measurement
used.
One of the type is based on measurement of
particle in a retention zone.
Another type uses a non-retention
measurement zone.
An example of a non-retention zone
measurement is known as the pipette method.
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Andreasen pipette method:
One of the most popular of the pipette
methods was that developed by
Andreasen and Lundberg and commonly
called the Andreasen pipette.
In this method , known volumes of
suspension are drawn off and the
concentration differences are measured
with respect to time.
It involves measuring the % of solids that
settle with time in a graduated vessel.
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Construction:
The Andreasen fixed-position pipette
consists of a 200 mm graduated cylinder
which can hold about 500 ml of suspension
fluid.
A pipette is located centrally in the cylinder
and is held in position by a ground glass
stopper so that its tip coincides with the
zero level.
A three way tap allows fluid to be drawn
into a 10 ml reservoir which can then be
e32mptied into a beaker or centrifuge tube.
Method:
A 1% suspension of the powder in a suitable
liquid medium is placed in the pipette.
At a given intervals of time, samples are
withdrawn from a specified depth without
disturbing the suspension.
The amount of powder can be determined by
weight following drying or centrifuging;
alternatively, chemical analysis of the
particles can be carried out.

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The particle size is determined in terms of stokes’
diameter (the diameter of a particle measured during
sedimentation at constant rate) using modified
Stokes' equation.

dst: stokes’ diameter

n: viscosity of medium
h: sedimentation height
ps- pf: difference in density of particle and fluid
Fg: force of gravity
t: sedimentation time
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A pipette is located centrally in the cylinder
and is held in position by a ground glass
stopper so that its tip coincides with the zero
level.
A three way tap allows fluid to be drawn into
a 10 ml reservoir which can then be emptied
into a beaker or centrifuge tube.
The amount of powder can be determined by
weight following drying or centrifuging.
The data of cumulative weight is used for the
determination of particle weight distribution,
n35umber distribution etc..
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The second type of sedimentation size
analysis, using retention zone methods,
also uses Stokes' law to quantify particle
size.
One of the most common retention zone
methods uses a sedimentation balance.
In this method the amount of sedimented
particles falling on to a balance pan
suspended in the fluid is recorded.
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 4. Conductivity methods
There are various subtypes. Two popular methods are-
Electrical stream sensing zone method
(Coulter counter)
Laser light scattering methods
It is based on the principle of change in light
intensity. The measurement of this change in
light intensity gives estimate of particle size.

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Electrical stream sensing zone method(Coulter
counter)

Sample Preparation:
Powder samples are dispersed in an electrolyte
to form a very dilute suspension.
The suspension is usually subjected to
ultrasonic agitation to break up any particle
agglomerates.
A dispersant may also be added to aid particle
deagglomeration.

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Electrical stream sensing zone method(Coulter
counter)
Method
The particle suspension is drawn through an
aperture accurately drilled through a sapphire
crystal set into the wall of a hollow glass tube.
Electrodes, situated on either side of the
aperture are surrounded by an electrolyte
solution.
These electrodes monitor the change in
electrical signal which occurs when a particle
momentarily occupies the orifice and displaces
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its own volume of electrolyte.
Electrical stream sensing zone method(Coulter
counter)
Method
The volume of electrolyte fluid which is
displaced in the orifice by the presence of
a particle causes a change in electrical
resistance between the electrodes which
is proportional to the volume of the
particle.

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Advantage:
Particle size ranging from 0.5 – 500 microns
Gives number distribution, Particle volume measured
and can be converted to diameter.
Accurate, sensitive, fast technique.
4000 particles per second can be counted.

Disadvantage
Expensive

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 II. Particle Shape Determination
Particle shape also has influence on surface area,
flow properties, packing and compaction of the
particles.

Spherical particles have minimum surface area

and better flow properties.

Shape can also have influence on rate of

dissolution of drugs.

Techniques of determination are:

 Microscopy (refer in particle size determination)
 Light scattering 45
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 III. Surface Area Determination
1. Adsorption method:
 Surface area is most commonly determined based on
Brunauer-Emmett-Teller (BET) theory of adsorption.
 Most substances adsorb a monomolecular layer of gas
under certain conditions of partial pressure of gas and
temperature.
 The adsorption process is carried out at liquid nitrogen
temperatures -196˚C.
 Once surface adsorption has reached equilibrium, the
sample is heated at RT and Nitrogen gas is desorbed. Its
volume is measured.
 As each N2 mol. occupies fixed area, one can compute
surface area of pre-weighed sample.
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 Surface Area Determination
2. Air Permeability method (Fisher subsieve sizer):
Powder is packed in sample holder
Packing appears as series of capillaries
Air is allowed to pass through the capillaries at
constant pressure
Resistance is created as air passes through
capillaries thus causing pressure drop.
Greater the surface area greater the resistance
Air permeability is inversely proportional to
the surface area
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 Manometer

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 Surface area of a powder can be calculated using
particle size data obtained from any suitable method.
 Specific surface area i.e. surface area per unit weight
(Sw) or unit volume (Sv) can be estimated as follows:
 Sv = surface area of particles
volume of particles
 Sv = no. of particles x surface area of each particle
no. of particles x volume of each particle
Surface area is an important parameter as the
bioavailability of certain drugs is dependant on surface
area. eg. Bephenium (anthelminitic), Griseofulvin (anti-
fungal)- if the surface area is less than specified, the
absorption decreases. 50
 Derived properties of
powders

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 Derived properties of powders
Size or diameter is a fundamental
property of a particle.
Volume, density, porosity etc. are the
properties derived from fundamental
properties.
e.g. Volume can be calculated from the
diameter of the particle (4/3 πr3).
However, derived properties can also
be calculated without the use of
fundamental properties.
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DENSITY

 Apparent bulk density- is determined

by pouring presieved (40#) bulk drug
into a graduated cylinder via a funnel
and note the volume as is (g/ml) without
subjecting to any external force.

 Tapped density: The cylinder is subjected

to fixed no. of taps on a mechanical
tapper apparatus (approx. 100) until the
powder bed has reached minimum.
(useful for determining the appropriate size
for capsule formulation)
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Bulk Density Apparatus
Bulk density
= Mass of the powder
Bulk volume

Tapped bulk density

= Mass of the powder
Tapped Bulk volume

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Applications
Decides the size of the capsule based on bulk
and tapped volume of a given sample
Higher the bulk volume, lower the bulk density
and bigger the size of the capsule

Helps to decide proper size of a container or

packing material

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 Light powders
When particles packed loosely
Lots of gaps between particles

Bulk volume increases

Light powders have high bulk volume

hence low density

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DENSITY
 True density: Volume occupied by voids
particle
(inter- spaces) and intraparticle pores are
not included in this measurement.
 Calculated by suspending drug in
solvents of various densities & in which
the compound is insoluble.
 After vigorous agitation, samples are
centrifuged briefly, and then left to stand
undisturbed till settling/ flotation has
reached equilibrium. The sample that
remains suspended corresponds to the
true density of the material. Calculated
with a pycnometer. 62
TRUE DENSITY DETERMINATION

 Helium displacement method (for

powders)
porous
 Liquid displacement method (for non
porous powders)

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TRUE DENSITY DETERMINATION
Liquid displacement method
(for non porous powders)
 Select the solvent in which powder is insoluble
 Pycnometer or sp. gravity bottle is used.
 Wt. of pycnometer: w1
 Wt. of pycnometer + sample: w2
 Sample wt.: w3= w2-w1
 Wt. of pycnometer + sample + solvent: w4
 Wt. of liquid displaced by sample: w5 = w4-w2
 Thus, true density = w3/ w5

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Helium displacement Method
Helium gas is selected as it does
not adsorb on solid sample.
It enters the pores.
very useful for estimating the true
density of porous solids

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Helium Pycnometer
Sample holder (A)
Valve (B)
Pressure detector (C)
Piston (D)

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Sample holder
Sealed after placing the sample
Valve
Connected to sample holder
Has provisions for removing air from the
sample holder and introducing helium gas
Pressure detector
Maintains preset constant pressure
Piston
Reads the corresponding pressure
It is also related to the volume of the
powder
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Working:
Air in the sample holder removed by vacuum
Helium gas introduced through valve
Pressure adjusted and set at particular value
with the help of piston
At this position, the reading on the scale
denotes U1
U1 = volume of empty sample holder

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Place standard known true volume Vstd of stainless
steel spheres
Air removed and helium gas introduced through
valve
Pressure adjusted to preset value with the help of
piston. At this position, the reading on
the scale denotes U2
The difference between U1 and U2 gives the
volume occupied by the standard.
The last step involves determination of volume of
sample. The standard is replaced with sample and
the reading is noted, Us.
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The difference between U1 and Us gives the

volume occupied by the test sample.
 Vstd = True volume of std. sample
Vtest = true volume of the test sample
U1 - U2 = Volume occupied by the std. sample
U1 - Us = Volume occupied by the test sample

Vtest = Vstd . (U1 - Us )

U1 - U2

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 Powder flow properties

 P’ceutical powders may be broadly classified

as free-flowing or cohesive.
 Most flow properties are significantly affected
by changes in particle size, density,
electrostatic charges, adsorbed moisture.
 Good flow property is required for easy and
uniform flow from hopper to die cavity
ensuring accurate weight and dose.

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Angle of repose is calculated for estimating flow
properties.
It is defined as the maximum angle possible
between the surface of a pile of the powder
and the horizontal plane

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 Powder flow properties estimation
 Simple flow rate apparatus consisting of a metal tube from which
drug flows through an orifice onto an electronic balance, which is
connected to a recorder.
 Angle of repose determination using reposograph

 Another method is % compressibility (Carr’s index)

= (bulk volume- tapped volume) x 100
bulk volume

Hausner’s ratio = tapped density/ Bulk density

Or
Bulk volume/ tapped volume

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Compres Angle of
sibility Repose
Flow (degrees)
Index Characte Hausner Flow Property
(%) r Ratio Excellent 25–30
10 Excellent 1.00–1.11
Good 31–35
11–15 Good 1.12–
1.18
Fair—aid not 36–40
16–20 Fair 1.19–
needed
1.25
21–25 Passable 1.26– Passable—may 41–45
1.34 hang up
26–31 Poor 1.35– Poor—must agitate, 46–55
1.45 vibrate
32–37 Very poor 1.46–
Very poor 56–65
1.59
>38 Very, very >1.60
poor Very, very poor >66
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Packing properties (Porosity)
Porosity definition: It is the ratio of the volume
of voids between particles, plus the volume of
pores, to the total volume occupied by
the powder, including voids and pores.
A set of particles can be filled into a volume of space in
different ways.
This is because by slight vibration, particles can be
mobilized and can occupy a different spatial volume
than before.
This changes the bulk volume because of
rearrangement of the packing geometry of the
particles.
In general, such geometric rearrange7m1 ents result in a
Packing properties (Porosity)
Example: : A set of monosized spherical particles can be
arranged in many different geometric configurations.
In Fig.a, when the spheres form a cubic arrangement, the
particles are most loosely packed and have a porosity of
48%
In Fig.b, when the spheres form a rhombohedral
arrangement, they are most densely packed and have a
porosity of only 26%
The porosity used to characterize packing geometry is linked
to the bulk density of the powder.
.
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Packing properties (Porosity)
Thus bulk density, is a characteristic of a powder rather than
individual particles and can be variable.
The bulk density of a powder is always less than the
true density of its component particles because the
powder contains interparticle voids.
Thus, powder can possess a single true density
but can have many different bulk densities,
depending on the way in which the particles are
packed and the bed porosity.

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 Powder fluidization
Fluidization can be a highly effective method for
handling a fine bulk material in an aerated or liquid-
like condition. Air or another gas can be used for
powder fluidization either in a fully fluidized state or
only in a localized manner with small amounts of gas
flow.
Typical bulk solids suitable for fluidization have a fine
particle size, a low permeability, and low cohesive
strength.
Advantages:
Elimination or reduction of poor flow problems of
powder, Increased discharge rate from hopper
Reduction in mixture segregation 75