DEFINITION: The mechanical process of reducing the particle size of solids.

Other terms used for milling are: Crushing, disintegration, dispersion, grinding and
pulverization.
Pharmaceutical Applications of Milling:
Surface area per unit weight known as specific surface, increased by size
reduction. This affects the therapeutic efficiency of low solubility medicinal
compounds.

Increased antiseptic action for calomel ointments is due to reduced particle

size

Size may affect texture, taste and rheology of oral suspensions in addition to
absorption.

Extraction from animal glands (liver and pancreas) and from crude vegetable
drugs is facilitated by comminution.
The drying of wet masses may be facilitated by milling, which increases the
surface area and reduces the distance the moisture must travel within the
particle to reach the outer surface.

The mixing of several solid ingredients of a pharmaceutical is easier and

more uniform if the ingredients are approximately the same size.

A fine particle size is essential for proper function of Lubricants used in

compressed tablets and capsules function by their ability to coat the surface
of granulation or powder.
Milling equipments

Milling equipment is usually Classified as:

1. Coarse Milling: produces particles larger than 20-mesh
2. Intermediate Milling: produces particles larger than 200 to 20-mesh
(74-840 microns)
3. Fine Milling: produces particles smaller than 200-mesh
Size Distribution and Measurements
In naturally occurring particulate solids and milled solids, the shape of
particles is irregular and the size of the particles varies within the range of
the largest and smallest particle.

There is no known method of defining an irregular particle in geometric

terms; however, statistical methods have been developed to express the size

of an irregular particle in terms of a single dimension referred to as its

diameter.
For convenience of mathematical treatment, an irregular particle is
considered in terms of an equivalent spheres. The size of the particles can
then be expressed by a single parameter, d (diameter). The volume of
particles may be determined by displacement in a liquid . As the volume of a
sphere is d3 /6. The equivalent diameter of an irregular particle with a
volume V is: d = 3 6 V/

Methods of Size Distribution

1. MICROSCOPY
2. SIEVING
3. Electrical stream sensing zone method
a. (Coulter counter)
4. SEDIMENTATION
5. Other methods
1. Microscopy
The most direct method of size distribution measurement. For White light, an
ordinary light is used to measure particles from 0.4 to 150 microns. With
special lenses and ultraviolet light, the lower limit may be extended to 0.1
micron. The size range of ultra microscope is from 0.01 to 0.2 micron. The
diameters of the particles on the slide are measured by means of a calibrated
filar micrometer eyepiece.

2. Sieving
It is the most widely used method for measurement of particle size
distribution b/c it is inexpensive, simple and rapid with little variation b/w
operators. The limit is 50 to 10 microns. The procedure involves the
mechanical shaking of a sample through a series of successively smaller

sieves and the weighing of the portion of the sample retained on each sieve.
Sieving or screening is a method of separating a mixture or particles into 2 or
more size fractions, the over sized materials are trapped above the screen,
while undersized materials can pass through the screen. Sieves and screen
are usually used for larger particle sized materials i.e., greater than
approximately 50m (0.050mm).

Size Equivalents
Two scales that are used to classify particle sizes are the US Sieve Series and
Tyler Equivalent, sometimes called Tyler Mesh Size or Tyler Standard Sieve
Series.

3. Electrical stream sensing zone method (Coulter counter)

Sample preparation and analysis conditions

Powder samples are dispersed in an electrolyte to form a very dilute suspension,
which is usually subjected to ultrasonic agitation for a period to break up any
particle agglomerates. A dispersant may also be added to aid particle deagglomeration.
Principle of measurement
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 and surrounded by an electrolyte solution, monitor the
change in electrical signal that occurs when a particle. The range of particle is 0.1 to
1000 microns, momentarily occupies the orifice and displaces its own volume of
electrolyte. The volume of suspension drawn through the orifice is determined by
the suction potential created by a mercury thread rebalancing in a convoluted Utube. 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 that is proportional to the volume of the particle. The change in
resistance is converted into a voltage pulse which is amplified and processed
electronically. Pulses falling within precalibrated limits or thresholds are used to split
the particle size distribution into many different size ranges. In order to carry out
size analysis over a wide diameter range it will be necessary to change the orifice
diameter used, to prevent coarser particles blocking a small-diameter orifice.
Conversely, finer particles in a large-diameter orifice will cause too small a relative
change in volume to be accurately quantified.

4. Sedimentation Method

This method is used over a size range from 1 to 200 microns. This method is
based on the dependence of the rate of sedimentation of the particles on
their size as expressed by Stokes equation: d

stokes

Where
d

stokes

= Stokes diameter,

= viscosity of dispersion fluid, x/t = rate of sedimentation or distance of fall x in

time t,
g = gravitational constant, and 0 are the densities of the particle and the
medium
Stokes equation is applicable to free spheres that are falling at a constant rate. If
the concentration does not exceed 2 %, there is no significant interaction b/w the
particles, and they settle independent of one another.
The pipette method (Andreasen) is the simplest method of incremental particle size
analysis. A 1% suspension of powder in a suitable liquid medium is placed in the
pipette. At given interval of time, samples are withdrawn from a specified depth
without disturbing the suspension and they are dried so that the residue may be
weighed. By means of Stokes equation, the particle diameter corresponding to each
interval of time is calculated, with x being the height of the liquid above the lower
end of the pipette at time t when each sample is withdrawn. As the sizes of the
particles are not uniform, the particles settle at different rates.

5. Other Methods
The other methods include adsorption, electrical conductivity, light and x-ray
scattering