Granules

&Granulation
Prepared by Israt Jahan Bulbul

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Granulation
Granulation is the process in which primary powder
particles are made to adhere to form larger multi-particle
entities called granules .
Pharmaceutical granules typically have a size range
between 0. 2 and 4.0 mm, depending on their subsequent
use.
In the majority of cases this will be in the production of
tablets or capsules.
When granules will be made as an intermediate product,
they have a typical size range between 0. 2 and 0.5 mm.
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continued
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Reasons for Granulation

1. To prevent segregation of the constituents of the powder mix.

Segregation occurs due to differences in the size or density of the

components of the mix. The smaller and/or denser particles components
of the mix concentrating at the base of a container with the larger less
dense ones above them.

An ideal granulation will contain all the constituents of the mix in the
correct proportion on in each granule and segregation of the ingredients
will not occur.
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Reasons for Granulation

2. To improve the flow properties of the powder mix

Many powders because of their small size, irregular shape or surface
characteristics are cohesive and do not flow well. Poor flow will often
result in a wide weight variation with in the final product owing to variable
fill of tablet dies etc.
Granules produced from such a cohesive system will be larger and more
isodiametric, both factors contributing to improved flow properties.
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Reasons for Granulation

3. To improve the compaction characteristics of the mixture
Some powders are difficult to compact even if a readily compactable
adhesive is included in the mix, but granules of the same formulation are
often more easily compacted and produce stronger tablets.
This is associated with the distribution of the adhesive within the granule.
Often solute migration occurring during the post-granulation drying stage
results in a binder rich outer layer to the granules.
This in turn leads to direct binder– binder bonding, which assists the
consolidation of weakly bonding materials .
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Reasons for Granulation

3. Reduce the hazard of toxic dust powders
The granulation of toxic materials will reduce the hazard associated with
the generation of toxic dust that may arise when handling powders.
Suitable precautions must be taken to ensure that such dust is not a hazard
during the granulation process. Thus granules should be non-friable and
have mechanical strength.
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Reasons for Granulation

4. Reduced the hazard of hygroscopic powder adhesion
Materials which are slightly hygroscopic may adhere and form a cake if
stored as a powder. Granulation may reduce this hazard, as the granules
will be able to absorb some moisture and yet retain their flow ability
because of their size.

5. More convenient for storage

Because granules are denser than the powder mix, they occupy less volume
per unit weight. They are therefore more convenient for storage or
shipment .
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Dry Granulation
The dry granulation process is used to form granules without a liquid solution
because the product granulated may be sensitive to moisture and heat.
Forming granules without moisture requires compacting and densifying the
powders. In this process the primary powder particles are aggregated under
high pressure. A roll compactor can be used for the dry granulation.
Dry granulation can be conducted under two processes; either a large tablet
(slug) is produced in a heavy duty tableting press or the powder is squeezed
between two counter-rotating rollers to produce a continuous sheet or
ribbon of material.
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Dry granulation
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Dry granulation by Slugging

 The powders is forced into the dies
M
ii
l
x
l
ii
n
n
g

of a large capacity tablet press and is

S
compacted by means flat and faced c
punches, the compacted mass r
called Slugs and the process is e
e
called to as a Slugging. The resulting n
slugs are milled to yield a tablet i
granulation. n
g
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Roller Compactor
 Roller compaction is a unit operation in dry granulation process in which
the powders containing active ingredients and excipients are agglomerated
between the rollers of compactor to form granules with good flow
properties and stability.
 During roller compaction the dry powders of the active ingredients and
excipients are blended in a blender and further roller compacted and milled
to form granules.
 The resulting granules are then blended within in a blender and used for
compression into tablets or for capsule filling.
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The purpose of roller compaction

• Improve powder flow properties.
• To avoid wet granulation induced degradation.
• To improve product stability.
• To prevent segregation.
• To reduce bulk volume hence minimizes storage volume and hence
improves transport efficiencies.
• To reduce potential environmental hazards and ensures safety.
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Advantages of dry granulation over other

granulation techniques
• It is suitable for heat labile and moisture sensitive
products.
• It improves flow properties of powders.
• It is economical process as it requires low personnel cost.
• It reproduces constant particle density.
• It is environment friendly.
• It prevents particle segregation.
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Disadvantages
1. Roller compaction densifies the powder or particle which can adversely
affects the dissolution of product.
2. The powder to be compacted must be compressible or have to add
compressible excipients or additives to the formulation.
3. The various process parameters involved in roller compaction process
and its interrelation are given in figure.
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Equipment of roller compaction

The roller compactor used for
compaction having major
components as:
1. Feed hopper
2. Screw feeder
3. Rollers
4. Flake crusher
5. Pre and fine granulator
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Equipment of roller compaction

1. Feed hopper
Material is filled into feed hopper
through the opening at the top
which falls down in the direction of
rotating chopper of the feed hopper.
The rotor arms transport the
material evenly downwards through
the hopper in the direction of screw
feeder.
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Equipment of roller compaction

2. Screw feeder
Functions- it helps to carry material to the rollers. Generally three
types of screw feeder used in industrial practice. They are Vertical,
Inclined, Horizontal
3. Rollers: It compacts to the material in the gap area of the
compacting rollers. The various types of rollers are, flat, punch and
pocketed shaped and many more available in market.
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Equipment of roller compaction

4. Flake crusher: It serves for the coarse crushing of compacted
flakes. It is having six blades to break or cut the flakes coming
from rollers into small pieces. The speed of flake crusher is very
important parameter to optimize which may affect the ratio of
granules to fines.
5. Pre and fine granulator: Granule size is determined or
maintained by choice of suitable mesh size.
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What is wet granulation?

Wet granulation involves the massing of a mix of dry primary powder
particles using a granulating fluid. The fluid contain a solvent which
must be volatile so that it can be removed by drying.
•Typically liquid include water, ethanol or isopropanol either alone or in
combination.
Primary advantages of water are that:
•it is non-flammable, which means that expensive safety precautions not
be taken
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Method of Wet Granulation

 Mixing:

The first stage in the wet granulation process is often a dry mixing stage
in which the active component is mixed with a diluents as well as
other excipients. The purpose of the mixing stage is to ensure that the
powder blend and hence the resulting tablets are homogeneous in
content.
 Wet granulation:

It is a unit operation in which mixed powders are simultaneously mixed

with a suitable fluid, e.g. water, isopropanol or ethanol.
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Method of Wet Granulation

DRYING:
After the process of granulation, the product exists as a wet mass from
which the liquid must be removed. Water is usually removed by
evaporation for which energy is needed.
SIZING AND SEIVING:
When the drying process is completed, it is likely that the product will
have cohered into relatively large masses, especially if tray drying has
been used. The dried material is therefore passed through a sieve
(usually 250–700 mm) to break up aggregates and to give a relatively
uniformly sized granules.
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Method of Granulation
 Secondary Mixing of additives:
A second mixing stage now follows in which several important ingredients
of the formulation are added.
 Glidant :
To increase flow of material during manufacturing processes
 Lubricant:
To avoid sticking with wall of dyes.
 Disintegrating agent:
To disintegrate in GIT tract.
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Shear granulators
Planetary mixer e.g. Hobart, Collette, Beken
High shear mixture has been widely used Pharmaceutical industries for
blending and granulation. Wet agglomeration in a high-shear mixer
involves typically 3 phases:
 Dry Powder mixing ( 2-5 mins)
 Liquid binder addition (1-2 mins)
 Wet massing
Advantages:
 Highly cohesive material can be granulated.

Disadvantages:
 Mechanical degradation.
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Planetary Mixer
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Oscillating Granulator
1. The moist mass has been transferred to a granulator, as
oscillating to a granulator.
2. The rotor bars of the granulator oscillate and force the moist
mass through the sieves , the size of the mass should be sufficiently
moist to form discrete granules when sieved.
If excess liquid is added, string (filament) of material will be
formed and if the mix is too dry then granules will be converted
into primary particles.
3. The granules can be collected on trays and transferred to a
drying oven like Tray Dryer.
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Oscillating Granulator
Tray drying has the following disadvantages :
a. The drying time is long.
b. Dissolved material can migrate to upper surface of granules’ bed,
as the solvent is only removed from the upper surface of the bed on
the tray .
An alternative is to dry the granules by using Fluid Bed Dryer(FBD)
in which individual granules are dried separately. It reduces the
rate aggregation and also the rate of inter-granular solute
migration.
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Wet Granulation Equipment

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High Speed Mixer Granulator

 The granulator has a stainless steel mixing bowl containing a three-
bladed main impeller which revolves in the horizontal plane, and a
three-bladed auxiliary chopper (breaker blade) which revolves either
in the vertical or the horizontal plane.
 The unmixed portion of the powder are placed in the bowl and mixed
by the rotating of the impeller for few minutes.
 The granulating liquid is then added with the help of a port to the lid
of the powder mix and mixed with the help of the impeller.
 The Chopper is usually switched off but after wet massing it will be
rotated with high speed for granulation and then passed through the
screen and collected.
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Rapid Mixer Granulator

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RMG
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Planetary Mixer
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Oscillating Granulator
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RMG
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Fluid Bed Granulator

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FBG
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Fluid Bed granulator

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FBG
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FBG
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Recent progress in dry granulation

There has not been much progress in the dry granulation
technique and technology in comparison to wet granulation,
except for one important innovation known as pneumatic dry
granulation technology developed by Atacama LabsOy
(Helsinki, Finland), which is described below.
Pneumatic Dry Granulation (PDG)
Pneumatic dry granulation (PDG), an innovative dry granulation
technology, utilizes roller compaction together with a
proprietary air classification method to produce granules with
extraordinary combination of flowability and compressibility.
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Methods of Pneumatic Dry Granulation

 In this method, granules are produced from powder particles by initially
applying mild compaction force by roller compactor to produce a
compacted mass comprising a mixture of fine particles and granules.
 The fine particles and/or smaller granules are separated from the
intended size granules in a fractioning chamber by entraining in a gas
stream (pneumatic system), whereas the intended size granules pass
through the fractioning chamber to be compressed into tablets.
 The entrained fine particles and/or small granules are then transferred
to a device such as a cyclone and are either returned to the roller
compactor for immediate reprocessing (recycling or recirculation
process) or placed in a container for reprocessing later to achieve the
granules of desired size.
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Pneumatic Dry Granulation

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Advantages and Disadvantages of Pneumatic Dry

Granulation
Advantages:
 PDG technology could successfully be used to produce good flowing granules for
any formulations that produce compacts with a tensile strength of ~ 0.5 MPa.
 Also, this technology enables the use of high drug loads of up to 70-100%,
because sufficient flowability could be achieved even at lower roll compaction
forces (lower solid fractions) compared to usual roller compaction.
 In addition to these, this technology avails various other benefits such as faster
processing speed, low cost, little or no material wastage, low dust exposure due
to the closed nature of this unit, etc.
Disadvantages:
However, the influence of recycling on the granule quality, suitability with low dose
formulations, friability, etc. remains a major issue regarding this technology.
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