GRANULATION I

RAHUL SINGOUR
Formulation &
Development

Content

Definition and concept

Objective and mechanism
Granulation characteristic
Technique for granulation
process
Direct compression
Dry compression
Wet granulation

Littelford loading Diosna mixer/ Littelford MGT

mixer
granulator
mixer

Gral mixer/
granulator

FBD
granulator
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Granulation: definition &

concept
A process whereby small particles gathered into large,
permanent masses in which the original particles can still
be identified.
Granulation is Joining particles within a given granulation
process will improve flow and compression characteristics,
reduce segregation, improve content uniformity, and
eliminate excessive amounts of fine particles. The results
will be improved yields, reduced tablet defects, increased
productivity, and reduced down time.
The ability to produce reproducible tablet , batch to batch,
lot to lot, is directly treated to the ability to produce
reproducible granulation.
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Objective & mechanism

The objective of the granulation process is to combine ingredients to
produce a quality tablet.
Granulation is process of collecting particles together by creating
bonds between then and these bonds are formed by compression or by
using a binding agent.
Particles-particles bonding mechanisms involved in adhesion and
cohesion of particles. Several forces that can be act :
Valency, Van der waals forces and electrostatic forces.
In wet granulation
Liquid bridges developed between particles with tensile strength.
Surface tension forces and capillary pressure
are primarily
responsible for initial granulation and strength.
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mechanism
Nucleation: Here, the particles adhere due to liquid bridges
which are the initiation step of Granulation. These adhered
particles play a role of nucleus for further enlargement of
granules.
Transition: Enlargement of nucleus takes place by two
possible mechanisms. Individual particle adhere to the
nucleus or two or more nuclei combine among themselves.
Ball growth or enlargement of the granule

Granules characteristic

Particle size
Av. Tablet weight
Tablet weight variation
Disintegration (DT)
Granules friability
Granules flow ability
Dry rate kinetic of wet
granules
Surface area
Dissolution rate

Methods:
Gas adsorption
Air permeability
Density
Compressibility
Tablet porosity
Dissolution and other

Granules characteristic
Denseand
andhard
hardgranules
granules
Dense
Bulk density largely depend on particle shape
More spherical particle have higher density
Increasing granules size then decreasing bulk
density

Higher compression load

Smaller granules size are able to close packing

decreasing DT and dissolution rate

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Granules characteristic..
Strength and friability
Depend on Granulating agent
Granulator
Effect on Particle size
Compressibility
Flow properties
Friction force
Surface tension
Mechanical force
Electrostatic
Cohesive force

Method
Response angle
Hopper flow rate
Larger granules possess more
strength the smaller ones.
Mixing time is increase,
strength also increased.

Granules characteristic..
Increasing granules
particle size

Increasing granules
density

Addition of water
Inlet air temperature increased
Nozzle height above the grid was
increased, density decrease.
Binder weight is increased

Increasing weight of binder

Increasing weight of solution
Increasing in the addition rate
of granulating solution
Decrease air inlet temperature
Decrease in the air pressure
Decrease in the nozzle height
above the distribution grid.

% Compressibility
CARRS INDEX
% Compressibility = (Tapped density Bulk density/Tapped density)*100
% COMPRESSIBILITY

FLOW DESCRIPTION

5 15

Excellent

12 16

Good

18 21

Fair

23 28

Poor

28 35

Poor

35 38

Very Poor

> 40

Extremely Poor
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Flow Properties
HAUSNER RATIO

Hausner Ratio = Tapped Density / Bulk

Density

HAUSNER
RATIO

TYPE OF FLOW

Less than 1.25

Good Flow

1.25 1.5

Moderate

More than 1.5

Poor Flow

ANGLE OF REPOSE

= tan-1 (h / r)

ANGLE OF
REPOSE

TYPE OF FLOW

< 25

Excellent

25 30

Good

30 40

Passable

> 40

Very Poor

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Techniques for granulation

process
Three basic techniques are used to prepare powders for compression
into a tablet:
1.Direct compression
2.Dry compression &
3.Wet granulation

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Basic processing step of

granulation

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Direct compression
This method is used when a group of ingredient can be blended and placed
in a tablet press to make a tablet without any of the ingredients having to be
changed.
Crystalline API
Direct compressible diluent
Limitation
Low dose API, poor content uniformity
High dose API which not easily compress, then it require usually restricted
to about 30 % of direct compression formula hence tablet will costly and
difficult to swallow.
Direct compression diluent may interact with the API.
Because of the dry nature of direct compression, static charge developed
then cause uniform distribution.
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Compression granulation

This process is used when the product needed to be granulated may be

sensitive to moisture and heat. Dry granulation can be conducted on a pres
using slugging tooling or on a roller compactor commonly referred to as a
chilsonator.
The initial bland of powders is forced into the die of a large-capacity
tablet press and is compacted by means of flat-faced punches, the
compacted mass called slugs and the process is referred to asSlugging.
Effective dose too high
Moisture and heat sensitive material (API)
e.g. Aspirin, Vitamins

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Roller compactor

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roller compactor.
The compaction force of the roller compactor is controlled by three
variable
The hydraulic pressure exerted on the compaction roller,
The rotational speed of the compaction rolls,
The rotational speed of the feed screws.
Advantages
Increased production capacity
Greater control of compaction pressure
Dwell time and no need for excessive
lubrication of the powder.
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Wet granulation

Wet granulation form the granules by binding the powder together with an
adhesive, instead of by compaction.
Binder may have different form
Solution
Suspension
Slurry
Binder depends on
Solubility (aqueous or non-aqueous solution)
Component mixture
When small quantity is permissible, then binder is blended in dry powder
initially.
In large quantity is refried, then binder is usually dissolved in liquid.

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Wet granulation.

LIQUID PLAY A KEY ROLE

Granules strength increased with addition of liquid.
Granules formation and strength depend:
Surface tension force
Capillary pressure.
Length of time depends on:
Wetting properties of powder mix.
Granulation fluid.
Efficiency of granulator (RMG > PLM)
End point determination

Amount of water used to granulate is increase. Granules porosity decrease,

and granules strength increased.
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Granulator for wet granulation

These type of granulators are applicable:

Littleford loading mixer
Diosna (RMG type)
Littleford MGT
Gral mixer/granulator (modified industrial planetary mixer)
Fluid bed granulator

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Littleford Loding mixer

First high shear powder blender capable of rapidly

pharmaceutical powder and wet massing
The equipment may also capable of producing
agglomerated granular particles that are ready for fluid bed or other
Spray nozzles
drying methods.
Time 30-60 sec.
Temperature rise
Horizontal cylindrical shell
10-150 C
Plow-shaped mixing tools

Chopper blades

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Littleford

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Diosna mixer or granulator

Diosna mixer are as follow:

Mixing time 2 min
Granulation time 8 min or less
Discharge time 1min

(1) Mixer bowl

(2) High speed mixer blade
(3) High speed chopper blade
(4) Pneumatic discharge port
(5) Mixed lid
(6) Exhaust air sleeve
(7) Mixer control panel
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Diosna mixer or
Uniform
distribution of all formulation ingredients.
granulator..
Short mixing and granulation time.
Useful working capacity of upto 80% to 40% of bowl volume.
Uniform granules by gentle processing.
mixer blade
Wide range of applications.
Easy scale up & Scale down between machine sizes.
Bowl shape design to have no dead spaces.

chopper blade

(1) Mixer bowl

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Littleford MGT mixer-granulator

(1) Bowl
(2) Lid with counter weight
(3) Exhaust sleeve
(4) Discharge port
(5) Control panel

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Gral mixer-granulator
2

Modification of industrial
planetary mixer

(1) Mixing arm

(2) Bowl
(3) Chopper blade
(4) Bowl cover
(5) Hydraulic discharge port
(6) Mixer controller panel
(7) Bowl elevator cradle

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Gral mixer-granulator.

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Difference between Gral and

Planetary mixer

Having two mixing device

Provide large scale mixing motion on the
powder
Small chopper blade enter off center
Advantage
Hydraulic discharged part more effective
Easily clear because mixing blade is not
part of the bowl.

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Fluid Bed Granulation

Homogeneous granules.
Gentle product handling.
Intensive mixing of the solid
material. Uniform spraying
of all particles in the fluid
bed.
Uniform, reproducible
product quality.

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Fluid Bed Granulation

Batch fluid bed

Principle:
Principle:
Batch fluid bed granulation, Top Spray Batch fluid bed granulation, Bottom Spray

Principle:
continuous fluid bed granulation in the
Glatt fluid bed (GF)
Top Spray

Continuous fluid bed

Principle:
continuous fluid bed granulation in the
Glatt fluid bed (GF)
Bottom Spray

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References

Lachman L., Lieberman H.A., and Kanig J.L. The theory and practice of
industrial pahrmacy. Thired edition; Varghese publishing house, Bombay; 1991.
Lieberman H.A. and Lachman L. Pharmaceutical dosage forms: tablet. Vol 1;
Marcel Dekker, INC. New York; 1980.
Lieberman H.A. and Lachman L. Pharmaceutical dosage forms: tablet. Vol 2;
Marcel Dekker, INC. New York; 1980.
Tousey M.D. The granulation process 101 Basic technologies for tablet
making. Pharmaceutical technology tableting and granulation; 2002.
http:// www.mcc-online.com/granulation.htm
http://www.pharmpedia.com/Tablet:Formulation_of_tablets/Binders

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Granulation I I

Excipients of granulation and selection criteria

Factor affecting granulation
Selection criteria of granulation technique
Example of different critical API granulation
Granulation technique of Floating tablet and others.

To be continued!!
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