Physical Pharmacy

Aniruddha Roy
 - [email protected]
 - 7727036088
Micromeritics
Micromeritics:
Definition: It is the science and
technology of small particles.
*The unit of particle size used is the
micrometer,(μm), micron, (μ), and equal to
10-6 m.
As particle size decreases, the surface area
increases
The knowledge and control of the size of particles are
important in pharmacy and materials science. The size &
hence the surface area of a particle can be related to the
physical, chemical & pharmacologic properties of drugs.

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.
2 Absorption & drug action:
The particle size & surface area influence the drug absorption &
subsequently, the therapeutic action. The higher the
dissolution, the 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. The smaller the
particle size, the better the physical stability of the dosage
form.
Particle Size
 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
Particle Size Distribution
Methods for Deter-
mining Particle Size
Microscopic Method
 Based on the number distribution of different particle
size
 Range: 0.2 - 100m
 The microscope eyepiece is fitted with a micrometer
by which the size of the particles may be estimated.
 1: Martin diameter
(Martin's diameter is the distance between op-
posite sides of an irregular object, measured
along a line that bisects the projected area. It's
used to measure the size of particles in mi-
croscopy.)

 2: Feret’s diameter
(Feret's diameter is a measurement of the size of
an object in a specific direction. It's also known
as the caliper diameter because it's measured
with a caliper.)

 3: Projected diameter
(Projected diameter is the diameter of a sphere
that has the same projected area as a particle
viewed from a specific direction.)
Sieving (range: 40 - 1500μm):
o Standard sized sieves are available to cover a wide range of
sizes. These sieves are designed to sit in a stack so that
material falls through smaller and smaller meshes until it
reaches a mesh that is too fine for it to pass through.
o The stack of sieves is mechanically shaken to promote the
passage of the solids.
o The fraction of the material between pairs of sieve sizes is
determined by weighing the residue on each sieve.
o The result achieved will depend on the duration and manner
of the agitation.

 Mesh number
number of openings per inch
 Sieve opening
actual size of openings between wires
⚫ Particle diameter is considered as the size of the arithmetic or geometric
mean of the opening of the two sieves.

⚫ Whichever size is chosen, it should be stated and used throughout the

study.

⚫ For example, the diameter of particles that pass a 40-mesh sieve and
are retained on a 60-mesh sieve (i.e., 40/60) may be expressed as the
arithmetic mean of the opening of two sieves

mm

⚫ The size of the particles can also be expressed as the geometric

average of the two sieve openings:

mm
 Sedimentation (range: .08 -300μm):
By measuring the terminal settling velocity of
particles through a liquid medium in a
gravitational centrifugal environment using the
Andreasen apparatus.
• Principle – Follows Stokes' Law, where larger
particles settle faster due to gravity, while smaller
particles remain suspended longer.

• Apparatus Design – Consists of a long, graduated

cylindrical vessel filled with a dispersion of the
sample in a suitable liquid.

• Procedure
o The sample is dispersed uniformly in the liquid.
o Aliquots are withdrawn at different time intervals
from a fixed height.
o The concentration of particles in each sample is
analyzed to determine size distribution.
Particle volume
measurement
(range: .5 - 300 um):
o In this type of machine the powder
is suspended in an electrolyte
solution. This suspension is then
made to flow through a short
insulated capillary section between
two electrodes and the resistance
of the system is measured.
o When a particle passes through
the capillary, there is a momentary
peak in the resistance; the
amplitude of the peak is
proportional to the particle size.
Counting is done by a computer.
 Size Distribution
⚫ Particle size can be expressed in
two ways
1. Monodisperse particle size
⚫ its characteristics can be
described by a single diameter or
equivalent diameter

frequency
2. Polydisperse particle size-

%
common encounter in
pharmaceutical powder
⚫ A poly-dispersed powder system Particle
is said to have a normal size
distribution if a typical bell-
shaped frequency distribution
curve is obtained
⚫ However, normal distribution is not common in pharmaceutical
powder which are commonly processed by milling or
precipitation

⚫ More commonly asymmetric or skewed distribution is obtained

⚫ A frequency curve with an elongated tail towards higher size

ranges is positively skeiwed; the reverse case exhibits
negative skewness.
Particle size distribution data obtained by particle size analysis

Suppose that the particle size of a powder is analyzed and the number of particles in each
size range is determined, from the data, the average particle size of the powder may be
calculated as
 In the above calculation, only the total number and mean size of the particles have
been considered for expressing the average particle size. The calculation can be
modified to take into account the surface and volume of the particle. Such a modified
equation for the calculation of the average particle size is derived by Edmundson:

n is the number of particles in a size range having mean size range or diameter d. p
is the index related to the size of particles. p= 1, 2, or 3 represents the length,

certain size range is expressed as 𝑛 𝑑 𝑓 where f is the frequency index and f= 0, 1, 2, and
surface, or volume, respectively. The frequency with which a particle occurs in a

3 correspond to number, length, surface, and volume, respectively.

Calculation of statistical diameter from data obtained from microscopic (Normal
distribution)
Andreason pipette

Where dstokes is the effective or Stokes' diameter, η the viscosity of the dispersion fluid,
x/t the rate of sedimentation or distance of fall x in time t, g the gravitational constant,
and ρ and ρ0 are the densities of the particle and the medium, respectively.

Stokes' equation is applicable to free spheres that are falling at a constant rate. In the
case of dilute suspensions (concentration <2% ), there is no significant interaction
between the particles, and they settle independently of one another.
 ⚫ For Stokes’s law to apply, a further requirement is that the flow of
dispersion medium around the particle as its sediments are laminar or
streamlined.

⚫ Whether the flow is turbulent or laminar is indicated by the

dimensionless Reynolds number, R, which is defined

⚫ According to Heywood, Stokes’s law cannot be used if R is greater

than 0.2 because turbulence appears at this value.
• the limiting particle size under a given set of conditions can be
calculated as follows
 A powdered material, density 2.7 g/cm3, is suspended in water at
20°C. What is the size of the largest particle that will settle
without causing turbulence? The viscosity of water at 20 °C is 0.01
p oise or g/cm sec, and the density is 1.0 g/cm3.
5 1

• If the material used in the above example is suspended in a syrup

containing 60% by weight of sucrose, what will be the critical diameter,
that is the maximum diameter for which R does not exceed 0.2? The
viscosity of the syrup is 0.567 poise, and the density is 1.3 g/cm3.
• When a number or weight of the particles, within
a certain range, is plotted against the size range or
the mean particle size, a frequency distribution
curve is obtained.
• The next figure represents the ideal frequency
curve for the powder material, which never
happens to the particulate matters we deal with
in the development of the dosage forms.
A typical plot of normal or Gaussian size frequency distribution curve

What does normal

distribution mean?

(S. Jambhekar, From Theory and Practice of Contemporary Pharmaceutics)

• From the figures of frequency distribution curves
and the data presented in the table, it should be
apparent what particle size in the sample occurs
most frequently.
This is termed mode.
 Number distribution and weight distribution

The number distribution implies that data were

collected by using a method that counts the
number of particles and the weight distribution
implies the data were generated by using
weighing technique.
 A typical frequency distribution plot for pharmaceutical
powders

The number distribution

implies that data were
collected by counting the
number of particles

The weight distribution

implies the data were
collected by weighing
technique

(S. Jambhekar from Theory and Practice of Contemporary Pharmaceutics)

 Cumulative frequency plot
A cumulative frequency plot is used in particle
size analysis to show the percentage of particles
smaller than a given size. It provides a clear
representation of how the particle sizes are
distributed in a sample.
•How it works:
• The x-axis represents particle size
(diameter, often in micrometers).
• The y-axis represents the cumulative
percentage (%) of particles smaller than a
given size.
• The curve starts at 0% and increases up to
100%, covering the full range of particle
sizes.
•Why it’s useful:
• Helps determine median particle size
(D50), which is the size at which 50% of
particles are smaller and 50% are larger.
• Used to estimate D10, D50, and D90,
which indicate the particle sizes at which
10%, 50%, and 90% of particles are
smaller, respectively.
 Log-probability plots
A log-probability plot is a specialized graph
used to visualize polydisperse particle size
distributions. It transforms cumulative data
into a straight-line graph to make it easier to
analyze.
•How it works:
• The x-axis uses a logarithmic scale for
particle size (since particle sizes vary
over a wide range).
• The y-axis represents the cumulative
percentage (%) on a probability scale.
• A normal distribution appears as a
straight line, while deviations indicate
skewed distributions.
•Why it’s useful:
• Helps check if the particle size follows a
log-normal distribution, which is
common in pharmaceutical powders.
• Used to determine geometric mean
diameter (dg) and geometric standard
deviation (σg).
 LOG-NORMAL DISTRIBUTION
Slope is given by geometric
standard deviation, σg

σg=50%size/16% undersize
or
84% oversize/ 50%size
 CONVERSION
Number distribution to weight distribution
Hatch Choate Equations
 PRACTICE QUESTION
Hatch Choate Equations
 Particle Number (N)

• This is another important powder property in

micromeritics and it is also related to the particle
size of the powder.
• As the name implies, it is the number of particles
(N) per unit weight (gram) of the powder.
 Particle Number (N)
Assuming that the particles are spherical, the number of
particles (N) in a unit weight of a powder may be computed as
follows:
Specific Surface (Sv or Sw)
of a Powder
a spherical particle is characterized completely by its diameter. As the particle becomes
more asymmetric, it becomes increasingly difficult to assign a meaningful diameter to the
particle—hence, as we have seen, the need for equivalent spherical diameters. It is a
simple matter to obtain the surface area or volume of a sphere because for such a particle

For a spherical particle, surface area and volume are proportional to the square and cube
of its diameter, respectively. However, for non-spherical particles, a characteristic diameter
must be chosen and adjusted using a correction factor. When viewed microscopically, the
projected diameter (dp) can be used to estimate surface area and volume, as its square
and cube remain proportional to these properties. Using proportionality constants, these
relationships can be mathematically expressed.

where αs is the surface area factor and ds is the equivalent surface diameter. For volume
we write

where αv is the volume factor and dv is the equivalent volume diameter. The surface area
and volume “shape factors” are, in reality, the ratio of one diameter to another. Thus, for
a sphere, αs = πds2/dp2 = 3.142 and αv = πdv3/6dp3 = 0.524. The ratio αs/αv is also used to
characterize particle shape. When the particle is spherical, α s/αv = 6.0. The more
asymmetric the particle, the more this ratio exceeds the minimum value of 6.
• The specific surface is defined as the surface area per
unit volume (Sv) or per unit weight (Sw) of a powder

• The specific surface of a powder may be obtained by

employing the following equation.

because αs/αv = 6.0 for a sphere.

What are the specific surfaces, Sw and Sv, of particles assumed to be spherical in
which ρ = 3.0 g/cm3 and dvs is 2.57 μm?
 True density ()
Density of the actual solid material
 Tap density
Tapped density is the mass of a powder per unit volume after
it has been tapped to remove air gaps between particles.

 Granule density (g) (Particle density)

The mass of particles divided by the volume as
determined by the liquid (mercury) displace method

 Bulk density (b) (Apparent density)

The mass of a powder divided by the bulk volume

Bulk density Tap density

Granule density True density

Bulkiness = Specific bulk volume =
reciprocal of bulk density:
It is an important consideration in the packaging of powders.
The bulk density of calcium carbonate varies from 0.1 to 1.3,
and the lightest (bulkiest) type requires a container about 13
times larger than that needed for the heaviest variety.

In a mixture of materials of different sizes, the smaller particles

sift between the larger ones and tend to reduce bulkiness.

Light powders Heavy powders

Derived properties of powders:
1 Porosity:
Suppose a nonporous powder, is placed in a graduated
cylinder:
• the total 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

• Void volume
Vp is the (v) : the
true volume volume of space
of particles.
v V  V
•The porosity or voids ε of powder is determined as the
b p
ratio of void volume to bulk volume.
Vb  Vp Vp  Bulk volume (Vb) : occupied
  1  volume
Vb Vb
 True volume (Vp)
• Porosity is frequently expressed in percent, ε x 100 .
e = 26% e = 48%
 Weight of the powder W (grams)
Vbulk = --------------------------- = --------------
Bulk density (rb)
(rb), g.cc-1

Weight of the powder W (grams)

V true = ------------------------------------------- = ---------------------

true density (r)

(r), g.cc-1

Substitution for the term Vbulk and V true in the equation:

 Vbulk – Vtrue
Vtrue
Porosity (e) = -------------- = 1 ̶
-------
Vbulk
Vbulk

Vtrue
W/r
Porosity (e) = 1 ̶ ------- = 1 ̶ ------
Vbulk
W/rb
A sample of calcium oxide powder with a true density of 3.203 and weighing 131.3 g
was found to have a bulk volume of 82.0 cm3 when placed in a 100 mL graduated
cylinder. Calculate the porosity.

The true volume of the particles is

131.3 g/(3.203 g/cm3) = 41.0 cm3

The volume of void space is v = 82.0 cm3 - 41.0 cm3 = 41.0 cm3

and the porosity is

ε = (82 – 41)/82 = 0.5 or 50%
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

The granule density, ρg, of sodium bicarbonate is 1.450 and the true density, ρ, is
2.033. Compute the intraparticle 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 intraparticle pores.

where Vb = w/ρb is the bulk volume and Vg = w/ρg is the granule volume,
that is, the volume of the particles plus pores.
The weight of a sodium iodide tablet was 0.3439 g and the bulk volume
was measured by use of calipers and found to be 0.0963 cm3. The true
density of sodium iodide is 3.667 g/cm3. What is the bulk density and
the total porosity of the tablet?
The following data apply to a 1 g sample of a
granular powder:
Volume of the solid alone = 0.3 cm3/g
Volume of intraparticle pores = 0.1 cm3/g
Volume of spaces between particles = 1.6 cm3/g
(a) What are the specific true volume, V, the
(b) Compute the total porosity, εtotal,
specific granule volume, Vg, and the specific
the interspace porosity, εinterspace, or
bulk volume, Vb? void spaces between the particles, and
the intraparticle porosity, εintraparticle, or
pore spaces within the particles.
Flow properties:
• Powders may be free-flowing or cohesive
(“sticky”).
- Many common manufacturing problems are
attributed to powder flow:
1 Powder transfer through large equipment
such as a hopper.

2 Uneven powder flow → excess entrapped air

within powders → capping or lamination.

3 Uneven powder flow → increases particle

friction with the die wall, causing lubrication
problems and increasing dust contamination risks
during powder transfer.
4. Powder storage- which, for example,
results in caking tendencies within a vial or bag
after shipping or storage time.
5 Separation of a small quantity of the powder
from the bulk- specifically just before the
creation of individual doses, such as during
tableting, encapsulation, and vial filling, affects
the weight uniformity of the dose (under or
overdosage).
Tests to evaluate the flowability of
a powder:
1- Carr’s compressibility index

A volume of powder is filled into a graduated glass cylinder

and repeatedly tapped for a known duration. The volume
of powder after tapping is measured.

Bulk density = weight / bulk volume

Tapped density = weight / tapped

volume
How Carr’s Index Relates to Powder Flowability
• Low Carr’s Index (<10%): Indicates excellent flowability with minimal interparticle
cohesion.
• Moderate Carr’s Index (10-20%): Suggests good flow properties, but some degree
of cohesiveness may be present.
• High Carr’s Index (20-35%): Indicates poor flowability with significant particle
interactions and potential caking or bridging in hoppers.
• Very High Carr’s Index (>35%): Implies extremely poor flowability, where the
powder is likely to form lumps and resist movement.

Why Higher Carr’s Index Indicates Poor Flowability

• High Compressibility: If a powder significantly reduces in volume when tapped
(high Carr’s Index), it indicates that the particles are highly cohesive, leading to
poor flowability. Such powders tend to clump together, resist flow, and cause
issues in manufacturing processes.
• Low Compressibility: If the volume remains almost the same after tapping (low
Carr’s Index), the powder is free-flowing, meaning there is minimal cohesion
between particles.
2- Hausner ratio:
Tapped density
Hausner ratio =
Poured or bulk density

Hausner ratio was related to interparticle friction:

**Value less than 1.25 indicates good flow ( = 20% Carr ).

The powder with low interparticle friction, such as coarse
spheres.

**Value greater than 1.5 indicates poor flow ( = 33% Carr ).

more cohesive, less free-flowing powders such as flakes.

**Between 1.25 and 1.5, added glidant normally improves

flow.

** > 1.5 added glidant doesn’t improve flow.

Scale of flowability for compressibility index
and Hausner ratio

A powder with a high compressibility percentage generally indicates poor

flowability; meaning, the higher the compressibility, the less readily a
powder will flow freely, as the particles tend to stick together more tightly
due to strong inter-particle forces, while a lower compressibility
percentage signifies better flowability.
Compressibility and flow properties of some common
pharmaceutical excipients
3- The angle of repose θ:
The frictional forces in a loose powder can be
measured by the angle of repose φ.
θ = the maximum angle possible between the
surface of a pile of powder and the horizontal
plane = coefficient of friction μ between the
particles:
tan θ = μ
tan θ = h / r
r=d/2
 3- The angle of repose θ (Cont.):
- 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
powder flows slowly and reasonably constantly.

***The rougher and more irregular the particles' surface,

the higher the angle of repose will be.
 Both angle of repose and Carr’s Index assess
the ability of a powder to flow but from
different perspectives:
• Angle of Repose is an indirect measure of
interparticle friction and cohesion.
• Carr’s Index is a measure of compressibility,
which relates to packing efficiency and
density variation.

• Low Angle of Repose & Low Carr’s Index → Indicates free-flowing powders, ideal
for processing.
• High Angle of Repose & High Carr’s Index → Suggests high cohesion and poor
flowability, which can lead to manufacturing challenges such as powder bridging
in hoppers or poor tablet compression.
Factors affecting the flow
properties of powders:

Improvement
of
Powder
Flowability

Particle’s
size Particle Surface Flow
& Shape forces Activators
Distrib &
ution texture
Factors affecting the flow
properties of powders (Cont.):

Alteration of Particle’s size & Distribution

• There is a 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 in granulation.
 Factors affecting the flow
properties of powders (Cont.):
Alteration of Particle Shape & texture
Particle’s 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 a greater tendency to interlock than smooth-surfaced
particles.
Factors affecting the flow
properties of powders (Cont.):
Alteration of Surface Forces
-Reduction of electrostatic charges can improve powder
flowability. Electrostatic charges can be reduced by altering
process conditions to reduce frictional contacts.

- Moisture content of particles greatly affects the 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.
Factors affecting the flow
properties of powders (Cont.):
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