PHR311

Pharmaceutical Engineering-I

SIZE REDUCTION AND

SEPARATION
Zaki Farhad Habib
With much appreciated help from Professor Sohel Rana

Size Reduction
Definition: The reduction of materials to smaller pieces, to coarse
particles, or to powder. Alternate name for the operation is
comminution derived from the Latin minuere, meaning less.
Another name: grinding

Objectives or Purposes:
To obtain the desired particle size. Very rarely, the materials to be
used in pharmaceutical formulations exist in the optimum size;
therefore majority of them will have to be reduced to a desired
size at one stage or the other during the formulation of a dosage
form.

Application of size reduction

o Size reduction helps in rapid solution formation in the case of
chemical substances by increasing the surface area of drugs.
o Extraction from animal glands (liver and pancreas) and from crude
vegetable drugs is facilitated because solvent can easily penetrate
into the tissues due to increase in surface area and resulting quick
extraction of their active constituents.
o Therapeutic effectiveness of some drugs is increased by reducing the
particle size e.g. the dose of griseofulvin is reduced to half that of
originally required.
o Mixing of powders since different sized particles do not mix uniformly.
o Size reduction is very important in case of suspensions. If the size of
the particles is too small, they can form a cake which may not redisperse easily, so suitable particle size is important.
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o Size reduction is an important step of tablet production.

o In case of inhalers, appropriate particle size is crucial. Very small particles may
be exhaled out of the bronchioles along with air without producing effect
whereas very large ones may not even reach the alveoli and be absorbed into
the blood stream.
o Size reduction improves the physical appearance of ointments, pastes and
creams.
o All the ophthalmic preparation and topical preparation should be free from gritty
particles to avoid irritation. So size reduction is very important.
o Increase stability of some preparation e.g. the stability of emulsion is increased
by decreasing the size of the oil globules.
o Increases the rate of absorption of a drug.
o Increases the rate of drying due to exposure of larger surface area.
o To reduce the bulk of a material since shipping charges maybe based on
volume.
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Limitations of size reduction operation

Not suitable for all drugs e.g. drugs containing volatile oils
(cinnamon, clove) must not be subjected to heavy grinding to
prevent the loss of volatile oils.

Due to increase of surface area oxidation and hydrolysis may

occur when exposed to atmospheric condition. Therefore, these
drugs must be stored in a well closed container and at a cool
place.

Factors affecting size reduction

1. HARDNESS It is a surface property of the material. Thus it is
possible for a material to be hard, but if it is brittle also, then size
reduction may present no special problem.
Mohs Scale arbitrary scale of hardness of mineral substances
ranging from 1 to 10. Upto 3 is soft and above 7 is hard.
Generally the harder the material the more difficult it is to reduce in
size.

2. TOUGHNESS More important property than hardness since a soft

but tough material is harder to reduce in size compared to a hard but
brittle material.
Toughness can be reduced by treating the material with liquefied gas
(e.g. nitrogen). At temperatures lower than -100C to -150C even
rubber becomes brittle and will break. This method is not always
employed since such low temperatures might spoil the drug and/or
the materials that the machines are made of may become brittle and
break too.

3. ABRASIVENESS A property of hard materials, particularly those

of mineral origin and may limit the type of machinery that can be
used as the material being grinded can be contaminated with the
worn out material of the machinery due to high abrasiveness of the
material.
4. STICKINESS Gummy materials may adhere to grinding surfaces
especially if the method used for size reduction generate heat.
Complete dryness may help.
The opposite of this, i.e. slipperiness may also pose problem to size
reduction since the material acts as a lubricant and lowers the
efficiency.
5. SOFTENING TEMPERATURE Waxy substances can soften due
to heat generated from the grinding process.
6. MATERIAL STRUCTURE minerals may have lines of weakness,
cellular structure of vegetable drugs.

7. MOISTURE CONTENT Amount of water a substance holds.

Affects properties like hardness, toughness and stickiness. In
general materials should be dry or wet and not merely damp.
Less than 5% moisture suitable for dry grinding
More than 50% moisture suitable for wet grinding
8. RATIO OF FEED SIZE TO PRODUCT SIZE - If the size of original
drug is too large it may be reduced to small particles in stages.
9. COST - (overall costs of process involved including power
consumption, space occupied, labor expenditure and time
involved).
10. PURITY REQUIRED may need to carry out grinding in aseptic
conditions in case it is essential to keep the material free from
bacterial contamination.
11. ENVIRONMENT If the drug is very potent then closed mills need
to be used to reduce the drug particles spreading.

Energy requirements of size reduction process

As little as 2% of the total energy consumption is only used for size reduction
process, the remainder being lost in many ways including:

Elastic deformation of particles

Plastic deformation of particles without fracture
Deformation to initiate cracks that cause fracture
Deformation of metal machine parts
Interparticulate friction
Particle-machine wall friction
Heat
Sound
Vibration

Principle of size reduction

A number of hypotheses and theories have been

proposed in an attempt to relate energy input to the
degree of size reduction produced:
1. Rittingers hypothesis Energy, E used in size reduction
process, is proportional to the new surface area produced, Sn

E = KR (Sn - Si)
Si is the initial surface area, KR is Rittingers constant of
energy per unit area.
1. Kicks Theory Energy used in deforming or fracturing a set of
particles of equivalent shape is proportional to the ratio of the
change in size

E = KK log (di/dn)
KK is Kicks constant of energy per unit mass, di is the initial
particle diameter, dn is the new particle diameter
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3. Walkers theory generalized differential form of the energysize relationship that can be shown to link the theories of
Rittinger and Kick:

E = - KW (d/dn)
KW is Walkers constant, d is a size function which could be
characterized by mean size or by a weight function, n is an
exponent.
When n=1 for particles defined by a weight function, integration
of Walkers equation corresponds to a Kicks type theory;
when n=2 a Rittinger type solution results.
When designing milling for coarse particles > 1 m, most
appropriate value for n is 1; whereas for particles < 1 m, value
of n is 2. At n = 1.5, neither Rittingers nor Kicks theory is
appropriate.

None of these laws apply well in practice and are

mainly of historical interest.
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Mechanism of size reduction

Cutting:
During this process the material is cut into small pieces by means of a
sharp blade or any other sharp instruments.
Compression:
During this process the material is crushed by application of pressure with
a suitable device.
Impact:
During impact the material which is more or less stationary, is hit by an
object moving at a high speed or the moving particles strike a stationary
surface and the material is broken into smaller particles.
Attrition:
During attrition the material is subjected to pressure as in the case of
compression but the surfaces are in motion in relation to each-other,
resulting in shear force which breaks the particles into still smaller
particles.
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Methods of size reduction

Size reduction is divided into two general categoriesManual size reduction:

On small scale the size reduction may be carried out

manually by
a) Trituration
b) Levigation
c) Intervention
Mechanical size reduction:

Mechanical size reduction is used for large scale work which

is mostly done by using different kinds of mills by milling
process.
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Size reduction equipment

Selection of equipment depends on
The properties of the material to be reduced
Initial particle size
Degree of size reduction required
Various size reduction equipment are used which are
Ball mill
Hammer mill
Cutter mil
Fluid-energy mill
Roller mil
End runner mill
Edge runner mill
Hand mill
Bohr stone mill
Colloid mill
Among these the most commonly used mills in pharmaceutical manufacturing
are the Ball mill
Cutter mill
Hammer mill
Roller mill
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Fluid mill

BALL MILL
The mill which is partially filled with balls of steel or pebbles is
called ball mill. It is also called jar mills.
Basis:
This will works on the principle of impact and attrition.
Construction:
The ball mill consists of a cylindrical container. The length of the
cylinder is slightly greater than its diameter which is partially filled
with balls made from the same material as that of cylindrical vessel.
The cylindrical vessel is mounted on a metallic frame and rotates
horizontally by hand or mechanically. The upper side of the vessel is
fitted with a highly closed lid through which the material is
introduced.

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Mechanism of action
The material to be ground is put into the mill through the lid

Rotation of the mill at a slow speed

Avoid the rotation with high speed

Taken out of the material from the vessel (After an appropriate time).

Passing through a suitable sieve

Desired particle size

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Use
1. Used for time grinding of hard, abrasive materials.
2. They can be easily sterilized therefore can be used for grinding the
materials to be used in parenteral and ophthalmic preparation.
3. Used for batch or continuous operation.
Advantage
1. They are economical and simple to operate.
2. They can be used for wet and dry grinding.
3. They afford a large grinding surface within a compact space
4. A wide variety of materials can be ground with it.
5. They are easy to clean as compared to other mills.
Disadvantage

Not applicable for soft materials.

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CUTTER MILL
Basis:
It works on the principle of cutting.
Construction:
Cutter mill is fitted with two types of knives i.e.
stationary and rotating.
The stationary knives are mounted in the casing
of the machine and at the lower part of the machine
a screen of desired size is attached.

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Mechanism of Action

Feeding of particle

Milling through the movement of rotating knives against

stationary knives.

Size reduction occurs by fracture of particles between

two sets of knives.

The screen retain the particles until a sufficient degree

of size reduction
occurs.
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Use
Used to obtain a coarse degree of size reduction of soft
materials such as roots and peels before its extraction.
Used for crude animal & vegetable drugs.
Limitations
Not used for friable materials.
The feed size should be less than 1 inch thick & should not
exceed the length of the cutting knife.
The material is pre-milled and is usually suspended in a
stream of air or liquid when fed to the mill.

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HAMMER MILL
The hammer mill is an impact mill using a high speed rotor up to
10,000 rpm to which a number of swinging hammers are
mixed.
Basis:
It works on the principle of impact.
Construction:
The hammer mill consists of a steel casing in which a central
shaft is enclosed to a number of swinging hammers are
attached. On the lower part of the casing a screen of desired
size is fitted. In this mill there is also Hopper
Product Outlet

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Mechanism of Action

Milling the hammers

Swing out radially undergo brittle fracture (because, angular velocity

of the hammers is so high, 80s-1)

Continuous particle size reduction occurs (Here, the particles, are

reduced by hitting the hammer)

Particles are retained by the screen & passing through the meshes.

Obtain the desirable particle size.

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Advantage
They are simple to install and operate, the operation is
continuous.
They are rapid in action and many different types of materials
can be ground with them.
There is no chance of contamination due to abrasion of metal
from the mill because no surfaces of the mill move against each
other.
The particle size of the material to be reduced can be easily
controlled by changing the speed of the rotor, hammer type,
shape & size of the screen.

They are easy to clean and may be operated as a closed system

to reduce dust and explosion hazards.
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Disadvantage
A hammer mill must be operated with internal or
external classification to produce ultra fine particles.
Cannot be used for abrasive material.

Use
In pharmaceutical industry they are used for grinding
dry materials, wet filter cakes, ointments and
slurries.
Can be used for granulation and close control of the
particle size of powders.

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Size separation
Definition :

Size separation is a process by which particles are

separated into fraction of known particle size.
For pharmaceutical purpose various types of powders
separated through various types of sieves.
British pharmacopoeia states that the degree of
coarseness or fineness of a powder is differentiated
& exposed by the size of the mesh of the sieve
though which the powder is able to pass.

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Objectives of size separation

In pharmaceutical field, the objectives of particle size
separation is to separate the drug materials
according to our desired size or requirements.
In solid separation process, powered particles are
removed from gases or liquids and has two main
aims
To recover valuable products or by
products
To prevent environmental pollution

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The B.P. specifies five grades of powder are

Grade of powder

Sieve through which

all particle must pass
Coarse.10
Moderately coarse.22
Moderately fine..44
Fine..85
Very fine..120
Number of Sieves:
This is the number of meshes in a length of 25.4 mm (1in.) in
each direction parallel to the wires.
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Size Separation Methods

Size Separation by sieving:
Sieving method
Size separation by fluid classification
Sedimentation methods
Elutriation methods
Cyclone methods

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Fluid Classification
Principles of operation

Sedimentation methods are based on the measurement of the

rate at which particles of the powder settle out from a liquid in
which they have been dispersed.
This method is based on the dependence of the rate of
sedimentation of the particles on their size as expressed by
stocks equation:

dstokes = 18/(-0)g.x/t
Where,
dstokes = Effective or stoke diameter
=Viscosity of the dispersion liquid.
x/t = Rate of the sedimentation.
g = Gravitational constant.
= Density 1of the particles.
0 =Density of the medium.
This equation applies strictly only to dilute dispersion
where the concentration of the solids does not exceed 2%
w/w.
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Sedimentation Equipment
The simplest method is the pipette method which is
known as Andreasen method.
Construction
The apparatus used for this purpose is known as
Andreasen apparatus, which consist of a fall vessel
called sedimentation vessel having capacity of 500 ml.
The vessel is fitted with ground glass joint through a
10ml pipette fitted with two way stop cock for draining
sample is passed.

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Mechanism

A 1% suspension of the powder in a suitable liquid medium is

placed in the sedimentation vessel.

At given intervals of time, samples are withdrawn from a

specified depth without disturbing the suspension

The samples are dried & residues are weighed

By means of Stokes equation, the particle diameter

corresponding to each interval of time is calculated.

Elutriation method
Principle:
Elutriation is a technique in which the fluid flows in an opposite direction
to the sedimentation to the movement.
Therefore in the case of elutriation particles are divided into different size
fraction depending on the velocity of the fluid.
Mechanism
Separation of powders into several size fractions can be effected by using
a number of elutriators connected in series.
The suspension is fed into the bottom of the narrowest column,
overflowing from the top into the bottom of the next widest column and
so on.
Because the mass flow remains the same, as the column diameter
increases and therefore particles the fluid velocity decreases and
therefore particles of decreasing size will be separated.

Fig: Multistage elutriator. Particle Outlets 1 to 4 Collect Fraction of

Decreasing Particle Size

Comparison of sedimentation & elutriation

In sedimentation method the fluid is stationary & the separation of particles of

various sizes depends on particles velocity.
In elutriation method the fluid flows & the separation of particles depends on
the velocity of the fluid.

Cyclone separation
Principle:
Cyclone separation is a form of sedimentation.
But instead of gravitational force the centrifugal force is
used.
Structures
It consist of cylindrical vessel with a conical base fitted with
a tangential inlet and a fluid outlet and at the base it is
fitted with solids outlet.

Mechanism
The suspension is introduced tangentially at a high speed resulting a
rotary movement inside the vessel

The fluid is removed by the fluid outlet fitted at the top.

The rotary movements within the cyclone causes the particles to move
by centrifugal force

The solids are thrown out to the walls of the cyclone from where they
fall to the conical base and ultimately removed from there through
the solids outlet.
Application
Cyclone separators used for separating suspension of solid in liquids
but preferably they are used for suspension of solid in a gas usually
air.

Selection of a size separation process

Selection may be limited by pharmacopoeial requirements,
but for general cases the most efficient method should be
selected based on particles properties.
Among particles properties, size is particularly important as
each separation method is most efficient over a particular
size range.
Particles that have undergone size reduction will already be
in suspension in a fluid, and can be separated quickly by
elutriation or cyclone separation method.
Many pharmaceutical powders are soluble in water and size
separation may have to be restricted to air classification
method.