Syllabus

• ADVANCED GRANULATION TECHNOLOGY (DESIGN &

PRACTICE):
• 1. Spray Drying Granulation Technology;
• 2. Roller Compaction Technology;
• 3. Extrusion/Spheronization as a Granulation Technique;
• 4. Single-Pot Processing Granulation Technology: Rapid Release
Granulation Technique;
• 5. Particle Coating by Centrifugation Granulation Technology.
Granulation Technology

Granulation: Perry’s Chemical Engineer’s Handbook defines

the granulation process as ‘‘any process whereby small
particles are gathered into larger permanent masses in which
the original particles can still be identified.’’
 INTRODUCTION: Definition
Granulation:
1. Granulation may be defined as a size enlargement process in
which primary powder particles are made to adhere to form
physically stronger and multi particles entities called agglomerates
or granules. In other words It is the process of collecting particles
together by creating bonds between them.
2. Granules have a size range of between 0.2 and 4.0 mm, depending
on their subsequent use.
3. The term ‘granulated’ material is derived from the Latin word
‘granulatum’ meaning grained.
 Granulation: Description
• A granulation process typically consists of a mixture of solid
ingredients, referred to as a formulation, which includes an
active or key ingredient, binders, diluents, flow aids,
surfactants, wetting agents, lubricants, fillers.
• These materials are brought together, most commonly in a
high shear mixer or in a fluidized bed, such that the binder will
`stick´ together the individual powder particles to form larger
particles known as granules. This process is also often referred
to as agglomeration.
 Granulation: Description
1. Agglomerates and granules are descriptive terms that refer to
the accumulation of small particles into larger aggregates.
2. Agglomeration refers to the buildup of small particles into
larger aggregates without the addition of a binding agent or
use of mechanical force.
3. while the Granulation refers to the buildup of small particles
into larger aggregates with the aid of binding agent or
mechanical force, water, povidones, roller compaction, etc.
So granulation is a planned operation
 Reasons For Granulation
The reasons why granulation is necessary are as follow:

1. To improve powder flow.

2. To improve compressibility.
3. To reduce fines.
4. To control the tendency of powders to segregate.
5. To control density.
6. To capture and fuse small quantities of active material.
7. To increase the uniformity of drug distribution in the product.
 Mechanisms of Granulation

Granules are formed by the binding together of powder particles.

Sufficiency strong bonds formed between particles so that they
adhere and do not break. There are five recognized bonds that
form between particles:
Bonds established between particles in granulation
There are five recognized bonds that formed between particles:
1. Adhesive and cohesive forces in the immobile liquid between
particles.
2. Interfacial forces in mobile liquid films within granules.
3. Formation of a solid bridge after subsequent solvent evaporation.
It is the main mechanism in dry granulation
4. Attractive forces between solid particles, here the presence of
liquid is not required.
5. Mechanical interlocking of particles often between fibrous or flat
particles appears.
Bonds established between particles in granulation
• In dry granulation there are two types of irresistible attractive
physical forces between particles that cause them to bind
them together
• Electrostatic forces – there are generally weak but may cause
cohesion when the material is mixed initially.
• Vand der Waals forces – these are stronger than electrostatic
forces and they increase as the inter-particulate distances
decrease during the compression of powders.
 Granulation process
• Granulation process transforms fine powders into free-flowing,
dust free granules that are easy to compress.

• Granulation poses numerous challenges due to high quality

requirement of the formed granules in terms of content
uniformity and physicochemical properties such as granule
size, bulk density, porosity, hardness, moisture,
compressibility, etc. together with physical and chemical
stability of the drug.
 cont
A granulation process is very complex, with several competing
mechanisms.

1. Wetting and Nucleation – the first interaction between the

powder and binder.

2. Consolidation and Growth – the densification of the granules

formed and their growth via layering and agglomeration.

3. Attrition and Breakage – the breakage and wearing of the

granules as they impact against each other and the inside of
the granulator.
 Granulation Processes
1. Granulation process can be divided into two
types: wet granulation that utilize a liquid in
the process and dry granulation that requires
no liquid.
2. The type of wet or dry process selection
requires a thorough knowledge of
physicochemical properties of the drug,
excipients, required flow and release
properties.
WET GRANULATION
 WET GRANULATION
1. The particles need to be combined and attached using a
pharmaceutical glue called a binder.
2. When the binder is put into water or a solvent solution and is
sprayed or metered into the powders this process is called
”The Wet Granulation Process”.
Steps in The Wet Granulation Process:

1. Dry mixing
2. Wet mixing/Wet massing
3. Milling of the wetted mass/Wet sieving
4. Drying
5. Milling of the dried mass/Dry sieving
 Mechanisms of Granule Formation
1. In wet granulation methods, liquid added to dry powders has to
be distributed throughout the powder by the mechanical agitation
created in the granulator.
2. The particles adhere to each other because of liquid films, and
further agitation and/or liquid addition causes more particles to
adhere.
3. The granulation mechanisms can be divided into three stages.
 Nucleation
 Transition
 Ball Growth or Enlargement Of The Granule
• Nucleation :
In this case 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:
In 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
Granule growth produces large, spherical granules and the
mean particle size of the granulating system will increase with
time.
Ball growth occurs by four possible mechanisms

1. Agglomeration: A larger granule is formed when two or more granules are

united.
2. Breakage: In Breakage granules break and the fragments of granule adhere to
other granules. This forms a layer of material over intact granules.
3. Abrasion Transfer: Granule material are abraded through attrition by the
agitation of granule bed and abraded material adheres to other granules
resulting into enlarged granules.
4. Layering: particles adheres to the already formed granules increasing their size.
 Advantages of Wet Granulation
1. A wide variety of powder materials can be processed into a
uniform mix with improved flow.
2. Optimum fill density can be achieved by adjusting the process to
create the optimum final particle size distribution.
3. Compressibility and consolidation are improved via the choice of
the correct binder and the moisture content of the granules.
4. Dissolution is modified, with the choice of more insoluble binders,
to obtain a modified release pattern.
5. Dust and segregation tendencies are reduced.
 Disadvantages of Wet Granulation
1. Large number of process steps; each step requires qualification
and cleaning validation.
2. Long process time, particularly for drying.
3. High labor and manufacturing costs.
4. Some material loss during processing.
5. Problems associated with heat and solvent sensitive drugs.
6. Capital requirements for extra building space and equipment.
7. Upon aging, dissolution from granules can be slowed after
tableting.
DRY GRANULATION
 DRY GRANULATION
• In dry granulation process the powder mixture is compressed
without the use of heat and solvent.
• It is the least desirable of all methods of granulation.
• The two basic procedures are to form a compact of material by
compression and then to mill the compact to obtain a granules.
• Two methods are used for dry granulation.
 Slugging
 Roll Compaction
 Steps in Dry Granulation: Slugging
1. Milling of drugs and excipients
2. Mixing of milled powders
3. Compression into large, hard tablets to make slug
4. Screening of slugs
5. Mixing with lubricant and disintegrating agent
6. Tablet compression
 Slugging Process
1. Granulation by slugging is the process of
compressing dry powder of tablet formulation
with tablet press having die cavity large enough
in diameter to fill quickly.
2. The accuracy or condition of slug is not too
important.
3. Only sufficient pressure to compact the powder
into uniform slugs should be used.
4. Once slugs are produced they are reduced to
appropriate granule size (for final compression)
by screening and milling.
Roller Compactor
 Advantages
• The main advantages of dry granulation or slugging are that it
uses less equipments and space.
• It eliminates the need for binder solution, heavy mixing
equipment and the costly and time consuming drying step
required for wet granulation.
 Slugging is useful in the following situations

1. For moisture sensitive material

2. For heat sensitive material

3. For improved disintegration since powder particles are not

bonded together by a binder

4. Improves flow of powders by increasing particle size.

 Disadvantages

1. It requires a specialized heavy duty tablet press to form slug

2. It does not permit uniform colour distribution as can be
3. Achieved with wet granulation where the dye can be
incorporated into binder liquid.
4. The process tends to create more dust than wet granulation,
increasing the potential contamination.
DIRECT COMPRESSION
 DIRECT COMPRESSION

Definition:
• The term “direct compression” is defined as the process by which
tablets are compressed directly from powder mixture of API and
suitable excipients.
• No pretreatment of the powder blend by wet or dry granulation
procedure is required.
• Amongst the techniques used to prepare tablets, direct
compression is the most advanced technology.
• It involves only blending and compression.
 Merits
1. Direct compression is more efficient and economical process as
compared to other processes, because it involves only dry
blending and compaction of API and necessary excipients.
2. The most important advantage of direct compression is
economical process. Reduced processing time, reduced labor
costs, fewer manufacturing steps, and less number of equipments
are required, less process validation, reduced consumption of
power.
3. Elimination of heat and moisture, thus increasing not only the
stability but also the suitability of the process for thermolabile and
moisture sensitive API’s.
4. Particle size uniformity.

5. Prime particle dissolution.

In case of directly compressed tablets, each primary drug particle is liberated.
(While in the case of tablets prepared by compression of granules, small drug
particles with a larger surface area adhere together into larger agglomerates
thus decreasing the surface area available for dissolution).

6. The chances of batch-to-batch variation are negligible.

7. Chemical stability problems for API and excipient would be avoided.

8. Provides stability against the effect of aging which affects the dissolution rates.
 Demerits
Drug and Excipient Related:
1. Problems arise in the uniform distribution of low dose drugs.
2. High dose drugs (having high bulk volume), poor compressibility and poor
flowability are not suitable for direct compression. For example,
Aluminium Hydroxide and Magnesium Hydroxide.
3. The choice of excipients for direct compression is extremely critical.
Direct compression diluents and binders must possess both good
compressibility and good flowability.
4. Many active ingredients are not compressible either in crystalline or
amorphous forms.
5. Non-uniform distribution of colour, especially in tablets of deep colors.
Formulation related problems
1. Capping, lamination, splitting, or layering of tablets is sometimes
related to air entrapment during direct compression.
2. When air is trapped, the resulting tablets expand when the
pressure of tablet is released, resulting in splits or layers in the
tablet.
3. In some cases require greater sophistication in blending and
compression equipments.
4. Direct compression equipments are expensive.
 Thank you for your concentration
• Remington’s Pharmaceutical Sciences
• Handbook of Pharmaceutical Granulation Technology a series
of DRUGS AND THE PHARMACEUTICAL SCIENCES, Executive
Editor James Swarbrick PharmaceuTech, Inc. Pinehurst, North
Carolina, 2005 by Taylor & Francis Group, LLC