Micromeretics and Powder Rheology

By: Dr. MA Jahangir

(M. Pharm; PhD)
Nibha Institute of Pharmaceutical Sciences
Topics: Particle size distribution; Methods for determining particle size-Optical
microscopy, Sieving, Sedimentation, Particle volume measurement, Particle shape and
surface area, Methods for determining Surface area- Adsorption methods, Air
permeability methods, Derived properties of powders, density of powders, flow
properties of powders
POWDERS-PARTICLE SIZE DISTRIBUTION

• Size distribution: The number of particles present in each size range

in a given weight of powder.
• Such a notation and helps in comparing the powder obtained from
one batch with other.
• It is an imp quality control tool in order to obtain powders with
reproducible physical, chemical and pharmacological properties.
• Particle size and size distribution are not only essential for drugs, but
also for excipients such as fillers, disintegrating agents, lubricants etc.
POWDERS-PARTICLE SIZE DISTRIBUTION

• Particle size distribution is expressed as the number or weight of the

particles lying within a certain size range.
• The weight of the drug and its distribution should be same in each
tablet to reproduce same therapeutic action.
• For a given weight of a tablet or capsule, number of particles and
their distribution should also remain same.
 Powder-Distribution curves—Frequency
distribution curve
• Two powder samples may have the same
mean size but may be different in the
distribution of sizes above and below the
mean.
• Such differences can be seen readily, if results
are presented in the form of frequency
curves.
• In this type , number or weight of particles
lying within a particular size range is plotted
against the mean particle size.
• In general, the normal distribution curve is
symmetrical(bell shape) around the mean,
which is also the mode.
• In this distribution Positive and negative
deviations from the mean are uniform.
Frequency distribution curve

• Normal distribution is usually

not found in pharmaceutical
powders because of uneven size
reduction processes.
• The distribution of particles in a
powder is termed as
unsymmetric or skewed i.e.
uneven around the mean.
• It normally shows a long tail of
larger particle size.
 Log-Normal distribution curve
• In this type, frequency on Y-axis is
plotted against log mean particle
size on X-axis.
• Advantage of this curve is that the
distribution pattern is made
symmetrical, when compared to
normal distribution curve.
• Powders obtained by crystallization
and milling methods exhibit log-
normal distribution.
 Cumulative frequency distribution curves
• In this plot, cumulative over size or
under size is drawn against particle
size.
• If summation of frequencies is
carried out from the bottom
upward i.e. higher size to lower
size, the result is expressed as the
Percentage particle oversize.
Summation downwards gives
percentage undersize.
• Adv: can directly read the % within
any given size range without any
difficulty
• Disadv: Scattering of points can not
be identified
 Log-Probability plot
• A plot is drawn by taking log particle
size on x axis and cumulative %
frequency on Y-axis. In this plot, the
cumulative curve is converted into a
straight line.
• For the number distribution, slope
gives geometric standard deviation.
The reference point gives geometric
mean diameter.
• However, these values have little
significance in pharmacy
 Interconversion of Distribution data
• Number or Weight distribution of a powder can be obtained
independently by selecting an appropriate method.
• Ex: Number distribution is obtained by microscopy, while weight
distribution is obtained by sedimentation or sieve method. sometimes it
may be necessary to convert one distribution data into another.
• Number distribution can be converted to weight distribution using:
 PARTICLE SIZE DETERMINATION

• The particle size of a pharmaceutical substance is strictly maintained

in order to get optimum biological activity.
• Methods:
1. Optical microscopy
2. Sieving method
3. Sedimentation method
4. Conductivity method
 OPTICAL MICROSCOPY
• Particle size in the range of 0.2-100 µm can be measured by optical
microscopy.
• Size is expressed as dp (projected diameter), which describes the
diameter of a sphere having the same area as the asymmetric particle
when observed under a microscope.
• This method directly gives number distribution, which can be converted
to weight distribution.
• Optical microscope has a limited resolving power.
• The low limit can be brought down using ultra microscope & electron
microscope.
• Optical microscopy is used to determine :
1. Particle size analysis of suspensions
2. Globule size distribution in emulsions
3. Particle size analysis in aerosols
Method:
Eye-piece of the microscope is fitted with micrometer.
This eye piece micrometer is calibrated using a standard stage micrometer.
Take the powder sample and prepare a suspension with a suitable vehicle
such as paraffin oil.
The sample of suspension is mounted on a slide or a ruled cell and placed it
on a mechanical stage.
The size of the particle is estimated with the help of the eyepiece
micrometer.
Around 300-500 particles must be counted in order to estimate true mean.
The size frequency distribution curves such as normal, log-normal,
cumulative frequency and probability curves are plotted.
Finally statistical diameters for the powders are estimated.
OTHER DIAMETERS
1.Martin diameter : It is the length of the
line that bisects the particle image. A
line may be drawn in any direction but
must be drawn in the same direction for
other particle measured.
2.Feret diameter: It is the distance
between two tangents on opposite
sides of the particle to same fixed
direction.
3.Projected area diameter: It is the
diameter of a circle with the same area
as that of the particle observed to the
surface on which the particles rest.
 OPTICAL MICROSCOPY
Advantages: Disadvantages:

• Allows the observer to view the • Diameter is obtained from only

particles directly. two dimensions i.e. length and
• Agglomeration of particles and breadth. Depth of the particles
any contamination can be is not measurable.
detected. • Slow and tedious
• Easy and simple • Large sample is required
 SEIVING METHOD
• Particles having size range between 50-1500 µm are estimated by this
method.
• Size is expressed as dsieve, which describes the diameter of a sphere that
passes through the sieve aperture as the asymmetric particle.
• This method directly gives the weight distribution.
• This method finds application in dosage form development of tablets
and capsules.
• Normally 15% of fine powder should be present to get proper flow.
• Sieves are constructed from wire cloth with square meshes, woven from
wire of brass, bronze, stainless steel.
• Sieves should not be coated or plated. There must be no reaction
between the material of the sieve and the substance to be sieved.
SEIVING METHOD

• METHOD: Sieves are arranged in a nest with the coarsest at the top.
• A sample (50 g) of the powder is placed on the top sieve.
• This sieves set is fixed to the mechanical shaker apparatus and
shaken for a certain period of time (20 minutes).
• The powder retained on each sieve is weighed.
• Data are analyzed for normal, log-normal, cumulative percent
frequency distribution and probability curves.
SEIVING METHOD

ADVANTAGES DISADVANTAGES
• Inexpensive. • Lower limit of particle size is 50
• Simple and rapid method. µm.
• If the powder is not dry,
apertures become clogged with
particles, leading to improper
sieving.
• During shaking, attrition occurs
causing size reduction of
particles.
 SEDIMENTATION METHOD
• Sedimentation method may be used over a size range of 1 -200µm.
• In this method, size is expressed as Stoke’s diameter, dst, which describes
the diameter of an equivalent sphere having the same rate of
sedimentation as that of the asymmetric particles.
• Methods:
Andreason Pipette Method
Applications:
• Formulation and evaluation of suspensions, emulsions
• Determination of mol. wt of polymers
 SEDIMENTATION METHOD
• PRINCIPLE: The rate of settling of particles in a suspension or emulsion may be
obtained by Stokes law.

h=distance of fall in time

ŋ=viscosity of the medium
ϸs=density of the particles
ϸo=density of the dispersion medium
g=acceleration due to gravity

v=h/t= v=rate of settling

This equation holds good for spheres falling freely at a constant rate without
hindrance.
This can be extended to largely particles of various shapes.
When the powder is suspended in a vehicle, initially the particles of large diameter
settle due to heavy weight. After some time, particles of intermediate diameter will
settle. Finally, particles of smaller size settle. Hence, the study involves the sampling
during sedimentation at different time intervals.
 PRACTICAL CONSIDERATIONS
1.The suspension should be dilute
2.Flow should be laminar: i.e rate of sedimentation of particles must not be
too rapid to create turbulence.
Any turbulent flow will affect the sedimentation of other particles there
by causing error in estimation
The type of flow is indicated by Reynolds number.
If the Reynolds number is greater than 0.2,the flow is turbulent.
Sedimentation method predicts the exact particle size, if the Reynolds
number does not exceed 0.2
 Reynolds’ Number

Reynolds’ number is a dimensionless quantity that is used to determine the type of flow
pattern as laminar or turbulent while flowing through a pipe. Reynolds’s number is defined
by the ratio of inertial forces to that of viscous forces.
Reynolds Number=Inertial Force/Viscous Force
Re = ρVD/μ

Re is the Reynolds’s number

ρ is the density of the fluid
V is the velocity of flow
D is the pipe diameter
μ is the viscosity of the fluid

If the Reynolds’s number calculated is high (greater than 2000), then the flow through the
pipe is said to be turbulent. If Reynolds’s number is low (less than 2000), the flow is said to
be laminar. Numerically, these are acceptable values, although in general the laminar and
turbulent flows are classified according to a range. Laminar flow falls below Reynolds’s
number of 1100 and turbulent falls in a range greater than 2200.

Laminar flow is the type of flow in which the fluid travels smoothly in regular paths.
Conversely, turbulent flow isn’t smooth and follows an irregular math's with lots of mixing.
Method: Andreasen • It usually consists of a 500 ml cylindrical
apparatus for vessel containing a 10 ml pipette sealed to
determining particle size a ground glass stopper. When the pipette is
placed in the cylinder, its lower tip is 20 cm
below the surface of the suspension.
• Procedure: Prepare 1 or 2 % suspension of
the powder in a suitable medium. A
deflocculating agent will help in uniform
dispersion of the suspension. Transfer the
suspension into the Andreasen vessel. Place
the stopper and shake the vessel to
distribute the suspension uniformly.
Remove the stopper and place the two way
pipette and securely suspend the vessel in a
constant temp water bath.
• At different time intervals, 10 ml samples
are withdrawn using two way stopcock and
collected in a watch-glass. Samples are
evaporated and weighed. The weight or the
amount of particles obtained in each time
interval is referred to as weight undersize.
The weights are converted into cumulative
weight undersize.
 CONDUCTIVITY METHOD
• Particle size ranging from 0.5 to 500 µm is measured by this method.
• This method gives number distribution.
• In fact, particle volume is measured and converted into particle
diameter.
• Coulter counter is used to measure the particle volume.
• In this method, size is expressed as volume diameter (dv)which describes
the diameter of the sphere having the same volume as that of the
asymmetric particle.
• This is quick and accurate method, but the instrument is expensive.

APPLICATIONS:
• Study of particle growth in suspensions and solutions.
• Dissolution of drugs
• Effect of antibacterial agents on the growth of micro organisms.
CONDUCTIVITY METHOD (COULTER COUNTER)
 CONDUCTIVITY METHOD (COULTER COUNTER)
• PRINCIPLE:
Particles are suspended in a conductivity electrolyte (sodium
chloride). This dispersion is filled in a sample cell, that has an orifice and
maintains contact with the external medium. Electrolytes are placed in
the solution (inside the cell) and suspension (outside).

• A constant voltage is applied across the two electrodes. In this position

current passes. When the suspended particle travels through the orifice,
it displaces its own volume of electrolytes into the beaker.

• The net result is a change in electric resistance. This change in electric

resistance is termed as voltage pulse, which is related to the particle
volume. This voltage pulse is amplified and fed to a pulse height
analyzer.
 COULTER COUNTER METHOD
• This analyzer is previously calibrated in terms of particle size for different
threshold settings.
• For a given threshold value, the pulses are electronically counted.
• By changing the threshold settings gradually, number of particles of each
size range is obtained. Thus the particle size distribution can be
obtained.
• Conductivity method is also known as stream scanning.
• Adv: Approximately 4000 particles per second can be counted.
Therefore size distribution analysis can be completed in a relatively
shorter period of time. It gives reasonably accurate results.
• Disadv: Unsuitable for polar and highly water-soluble materials due to
solvation .
POWDER
SURFACE AREA-
METHODS

• SPECIFIC SURFACE: It is
defined as the Surface
area per unit weight (Sw)
or unit volume (Sv) of the
material.
• Sw= surface area/weight
• n= no. of particles
• αs= surface area factor
• αv= Volume factor
• Where, dvs is Volume
surface diameter
• The above method of estimation is based on particle diameter data.
This method can estimate the specific surface accurately for non-porous
solids.
• Normally, porous solids have high specific surface. These materials have
irregular surfaces and contain pores or crevices. Hence, above method
can not account for the powder directly.
• METHODS:
1.Adsorption method
2.Air permeability method
Adsorption method
• Particles having large specific surfaces are good adsorbents of gases
and solutes from solution.
• Amount of gas that is adsorbed to form a monomolecular layer on
the adsorbent is a function of surface area of the powder. This
principle is used to estimate the specific surface.(also to estimate
surface diameter). Quantasorb instrument is utilized to study this.
• Powder whose surface area is to be determined is introduced into
the cell. Nitrogen as adsorbate gas and helium as inert gas is passed
over it. A thermal conductivity detector measures the amount of
nitrogen adsorbed at equilibrium pressure and a bell-shaped curve is
obtained in the recorder. The signal height gives the rate of
adsorption of nitrogen gas and area under the curve gives the
amount of gas adsorbed.
• The volume of nitrogen gas Vm in cm3 adsorbed by 1 gm of powder in
monolayer is given by BET equation:
AIR PERMEABILITY METHOD (Fisher Subsieve
sizer)
AIR PERMEABILITY METHOD

• Instrumentation is simple and determination is quick.

• This method is useful for controlling batch to batch variations in
production of powders.
• PRINCIPLE: An air pump generates air pressure to a constant head by
means of the pressure regulator. Under this head the air is dried and
conducted to the powder sample packed in the tube. The flow of air
through the powder bed is measured by means of a calibrated
manometer and is proportional to the surface area or the average
particle diameter.
• The permeability of air for a given pressure drop is inversely
proportional to specific surface.
• Method: Fisher subsieve sizer consists of a sample tube containing the
packed powder sample with one end connected to an air pump
through a constant pressure regulator.
• The other end is attached to a calibrated manometer containing a
suitable liquid of low viscosity and negligible vapour pressure.
• The air pump builds up air pressure and is connected to a constant
pressure regulator.
• Air is passed through the dryer to remove any moisture.
• Air is then allowed to flow through the packed powder in the sample
tube. The flow of the air is measured by manometer.
• The level of the fluid in the manometer indicates the average
diameter of the particles.
• The porosity of the powder and viscosity of air are estimated
separately. A and L are constants represent sample holder. ∆P and V
can be obtained from the experiment and substituted in equation to
estimate the surface area.
 AIR PERMEABILITY METHOD
• The kozeny-carman equation is used to estimate the surface area by this method.

Where

A=cross sectional area of the bed

∆P= pressure difference of the plug
T=time of flow
L=length of the sample holder
ᵋ =Porosity of the powder
Sw=surface area per gram of the powder
ŋ= viscosity of the air
K= constant
V=volume of the air flowing through the bed
Derived Properties of Powders
• Properties which are derived from the fundamental properties of
powders.
Packaging arrangements
Porosity
Density
Bulkiness
Flow properties

• Bulk volume: The volume per unit mass of a dry material plus the
volume of the air between its particles.
• True volume: It is the space occupied by the powder/particles
exclusively.
Packaging Arrangements
• There are basically two types of packaging arrangements possible.
a) Cubical Packing: It is the loosest type of packing arrangement.
b) Rhombohedral Packing: It is the closest packing possible in a heap
of powder
Porosity
• It is the measure of the empty spaces or voids in a material.
• Most pharmaceutical solids are porous, thus the bulk volume is
greater than the true volume.
• The volume of the space, i.e. void volume is given by:
v=Vb-Vp
• Vb Bulk Volume
• Vp True Volume
• Porosity is defined as the ratio of the void volume to the bulk
volume of the powder packing.
E=void volume/bulk volume E=Vb-Vp/Vb

Porosity is expressed in terms of percentage E X 100

Density of Powder
• Density is defined as mass per unit volume. However, different types
of empty spaces can be found like internal pores and capillary spaces
can influence the density of the material.
• True Density: Density of materials without pores
• Bulk Density: It determines the density of the materials based on the
bulk volume.
• Granule Density: It is the density determined by the displacement of
mercury which does not penetrate into pores smaller than 10
micrometer at ordinary pressure.
• True Density (ρ)
• It is the density of the actual solid material without any free spaces. It
is the ratio of the given mass of powder and its true volume.
True volume= Bulk volume- Void volume
• True density can be determined by:
a) Liquid displacement method b) Gas displacement method

Liquid displacement method

Weight of the empty pycnometer (Mo) is determined.
Pycnometer is filled with liquid and weighed again (ML= Total wt.–Mo)
Now volume of the working liquid is determined
VL = ML/ ρL
Now, 1/3 of pycnometer volume is filled with powder sample (Ms) and
total wt. is measured (Mo+ Ms). Pcynometer is filled with working
liquid and wt. determined (MT)
Mass of liquid added is calculated as:
MLA = MT – (Mo + Ms)
Volume of liquid added is
VLA = MLA / ρL
Volume of the measured solid object (VS) = VL – VLA
Density of the measure solid object is
ρs= Ms / VS
 Gas displacement method
• In this method a gas (H or He) is used instead of liquid.
• It gives better result for true volume determination as gas can
penetrate into smallest pores.
• In this a weighed quantity of powder is introduced in sample tube
and the absorbed gases are removed from powder is removed.
• Helium is introduced which gets adsorbed by the powder. The
pressure difference before and after the introduction of helium is
determined by manometer.
• The difference between the volume of helium filling the empty
apparatus and volume of helium filling the presence of powder gives
the true volume of powder. The ratio of the mass of powder and its
true volume gives its true density.
 Granule density (ρg) : It is determined similarly as gas displacement
method, just mercury is taken in place of any gas (H, He).
• It is the ratio of the mass of the granular powder and the volume
occupied by the granular material together with its intraparticle
spaces.
• Granule Density = mass of the granular powder/granule volume

 Bulk density (ρb) : It is the ratio of the mass of powder and its bulk
volume.
• Bulk Density = mass of the powder/bulk volume
• For its determination, a weighed quantity of powder is introduced
into a graduated measuring cylinder. It is then tapped mechanically
or manually till a constant volume is attained. This volume is known
as bulk volume. It includes the true volume plus volume occupied by
interparticle and intraparticle spaces.
• Bulk density depends upon particle size distribution, particle shape
and packing arrangement.
• Eintraparticle = 1-Granule density/True density = 1- ρg /ρ
• Einterparticle = 1-Bulk density/Granule density = 1- ρb /ρg
• ETotal = 1- ρb /ρ = 1- Bulk density/True density

 Bulkiness: The reciprocal of bulk density is known as bulkiness or

bulk or specific bulk volume of the particle. It usually increases with
the decrease in particle size.

 Flow Properties of Powders: It is an important parameter in the

production process of different pharmaceutical dosage forms.
Powders may be free flowing or poor flowing. The poor flow of
powders may be due to-
Cohesiveness or stickiness between particles due to Van der Waals,
surface tension or electrostatic forces.
Adhesion between particles and container walls
Friction between particles due to surface roughness
Physical interlocking of particles due to its irregular shape
• Assessment of Flow Properties of Powders : The flow properties of
powders is 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.
• A mass of powder is allowed to flow freely through an orifice from a certain
height and allowed to form a conical heap. Once the heap is formed it is
allowed to settle down so that no particle is rolling down due to
gravitational pull. The angle which the heap forms with the horizontal
surface is the angle of repose-
tan θ = h/r
θ = angle of repose
h = height of the heap of powder
r = radius of the base of the heap of powder
• Angle of repose is the measure of the surface roughness. The more rough
or irregular particle is, the higher will be the angle of repose.
• If the angle of repose is less the flow property of the powder will be good
• Addition of glidants like talc in low concentration decreases the angle of
repose.
Relationship between angle of repose (θ) and flow properties of powders

Improvement in the flow properties of powders can done by:

1. Altering the particle size: Increasing the average particle size of
particles improves flow properties due to reduction in cohesive forces.
2. Removal or addition of fines: Presence of small portion of fines or
granular mass in powder improve its flow properties by fill up the pits
and empty spaces.
3. Altering the particle shape and texture: Spherical particles have
better flow.
4. Altering the surface forces: Reduction of electrostatic charges on
particle surface reduces the friction and hence enhance the flow
properties.
5. Removing extra moisture: Drying of powder to remove extra
moisture improves its flow properties.
6. Adding flow activators or glidants: Glidants act by forming a thin
uniform film on the surface of particles to reduce the adhesion and
cohesion between particles.
 REFERENCES
1. A.N. Martin, Arthur Cammarata and J.Swarbrick. Physical Pharmacy by 3rd
ed, K.M. Varghese & Co, Bombay.
2. C.V.S. Subrahmanyam. Textbook of Physical Pharmaceutics,2nd edition,
Vallabh Prakashan, Delhi, 2004.
3. S.P. Aggarwal, Rajesh Khanna. Physical Pharmacy, 2nd edition, CBS
Publishers, New Delhi, 2006.