GRANULATION

Submitted to
Dr.Imran
Submitted by
Sadia Shabir (403788)
Memoona Tariq (403782)
 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 to 4.0 mm, depending on their
subsequent use.
 After granulation the granules will either be
packed (when used as a dosage form) or they may
be mixed with other excipients prior to tablet
compaction or capsule filling.
Ideal Characteristics Of Granules:
The following are ideal characteristics of
granules.
 Spherical shape
 Smaller particle size distribution with
sufficient fines to fill void spaces between
granules
 Adequate moisture content [1-2 %]
 Good flow
 Good compressibility
Sufficient hardness
Reasons For Conducting Granulation
Process:
To enhance the flow properties
To prevent the problems of dust during
compression
To produce uniform size particles
 To improve drug compression ability
For regulate the drug releasing from the
tablet.
 It is use full to densifying the material.
 Types of Granulation
Granulation can be broadly classified into 2
types.
Dry Granulation
Wet Granulation
 Dry Granulation
In dry granulation process the powder mixture is
compressed without the use of heat and solvent.
The more widely used method is slugging, where
the powder is precompressed and the resulting
tablet or slug are milled to yield the granules.
The other method is to precompress the powder
with pressure rolls using a machine such as a
Chilosonator.
Steps involved in the dry granulation

 Milling of drugs and excipients

 Mixing of milled powders
 Compression into large, hard tablets to make
slug
Screening of slugs
Mixing with lubricant and disintegrating agent
 Wet granulation
The most widely used process of
agglomeration in pharmaceutical industry
is wet granulation. Wet granulation process
simply involves wet massing of the powder
blend with a granulating liquid, wet sizing
and drying.
 Steps involved in the wet granulation
Mixing of the drugs and excipients
Preparation of binder solution
Mixing of binder solution with powder
mixture to form wet mass.
Coarse screening of wet mass using a
suitable sieve (6-12 screens)
Drying of moist granules.
Novel Granulation Technique:
 Pneumatic Dry Granulation
 Freeze granulation Technology
 Foamed Binder Technologies
 Melt Granulation Technology
 Steam Granulation
 Moisture Activated Dry Granulation (MADG)
 Granulex Technology
 Thermal Adhesion Granulation Process (TAGP)
 Spheronization
 Continuous Flow technology
 Pneumatic Dry Granulation
The PDG technology produces porous granules with
excellent compressibility and flow ability
characteristics.
The dry granulation process involved initially
conversion of powder blend tablet in to slug or
compact masses which are then screened to from
uniform sized fine granules.
The pneumatic dry granulation process is suitable
for Moisture sensitive drugs and Drugs that
undergo degradation at high temperature.
 Pneumatic Dry Granulation Replaces Wet Granulation
Wet granulation is unsuitable for moisture sensitive and
heat sensitive drugs, it is more expensive than dry
granulation, it is relatively labor intensive and can take a
long time. There are a large number of process steps and
each step requires qualification, cleaning, and cleaning
validation, high material losses can be incurred because of
the transfer between stages, there is the need for long
drying times. PDG Technology solves the above problems.
PDG Technology granules have excellent properties
compared to wet granulation, dry granulation and direct
compression. At the same time, the granules show both
high compressibility and flow ability. The results can be
archived without using exotic and expensive excipients.
Comparison Of PDG & Wet Granulation:

PDG Wet Granulation

Suitable for moisture Unsuitable for moisture
sensitive & heat sensitive sensitive & heat sensitive
product. product.
Low expensive. High expensive.
Short time process Long time process.
Materials losses low. Materials losses high.
Granules properties Low excellent granules
excellent. properties.
Dust problem. Low dust problem.
Advantages of PDG:

 The PDG technology has a number of advantages to

support the above claims including the following :-
 Good granulation results.
 Faster speed of manufacturing compared with wet
granulation.
 Lower cost of manufacturing compared with wet
granulation..
 The end products are very stable.
 Little or no waste of material.
Benefits To Pharmaceutical Companies:
 PDG Technology is the key solution to challenges
faced by pharmaceutical companies in
development of solid oral dosage forms.
 The technology replaces existing solid dosage
form development and manufacturing
technologies, offering more rapid development
and better quality.
 The unique capabilities of the technology have
been demonstrated in number of evaluation
studies with top-tier pharmaceutical companies.
 Foamed Binder Technologies (FBT)
Foam granulation technique involves addition of liquid
binders as aqueous foam.
Advantages:
 No spray nozzle is used
 Improve process robustness
 Less water required for granulation
 Time efficient drying
Cost effective
 Uniform distribution of binder
 No over wetting
 Applicable for water sensitive formulation
HOW FOAM BINDER TECHNOLOGY WORKS:

A simple foam generation apparatus is used

to incorporate air into a conventional water
soluble polymeric excipients binder such as
METHOCEL hypromellose ( hydroxypropyl
methylcellulose).
In a small- scale laboratory setting or in a
fullscale production setting, the foam
generator can be connected directly to high-
shear, lowshear, or fluid bed granulation
equipment.
Benefits To Pharmaceutical Companies:

Overall, foam binder processing is easier, faster,

and allows safer handling of potent drug
compounds.
 Melt Granulation Technology
This process also called melt agglomeration and
thermoplastic granulation. In this process the granules are
obtained by the addition of either molten binder or a solid
binder which melts during the process.
Principle of MGT:
The process of granulation consists of a combination of
three phase :-
(1)Wetting and nucleation.
(2) Coalescence step.
(3) Attrition and breakage
(1)Wetting and nucleation:
During the nucleation step the binder comes in to contact
with the powder bed and some liquid bridges are formed,
leading to the formation of small agglomerates.
(2) Coalescence Step:
It involves nuclei that have residual surface liquid to
promote successful fusion of nuclei.
The surface liquid imparts plasticity to the nuclei and is
essential for enabling the deformation of nuclei.
(3) Attrition And Breakage:
Attrition and breakage refer to the phenomenon of
granulation fragmentation in that are solidified by tray
coading to ambient temperature without the need for
drying by a tumbling process.
Consequently, breakage is known to have a more essential
role in affecting the resultant properties of the melt
granulation during the granulation during the
granulation phase.
Requirements Of Melt Granulation:

 Amount of 10-30% w/w of meltable binder, with

respect to that of fine solid particle, is used.
 A melt able binder suitable for melt a
granulation has a melting point typically within
the range of 50 to 100˚c .
 Steam Granulation
In steam granulation as a new wet granulation technique,
water steam is used as binder instead of traditional liquid
water as granulation liquid.
An equipment such as high-shear mixer coupled with a
steam generator would be enough for this technique.
Steam, at its pure form is transparent gas, and provides a
higher diffusion rate into the powder and a more favorable
thermal balance during the drying step.
After condensation of the steam, water forms a hot thin
film on the powder particles, requiring only a small
amount of extra energy for its elimination, and evaporates
more easily.
Advantages:
Higher ability of the steam to distribute uniformly and
diffuse into the powder particles.
Production of spherical granules with larger surface area.
The granules produced by this process have higher
dissolution rate due to increased surface area of the
granules compared to conventional wet granulation
process.
Disadvantages:
This method requires high energy inputs for steam
generation.
This process is not suitable for all binders and is sensitive
to thermo labile drugs.
 Moisture-Activated Dry Granulation
(MADG):
This technique is a variation of conventional wet granulation
technique. It uses very little water to activate a binder and initiate
agglomeration.
This technique involves two steps,
1) wet agglomeration of the powder particles
2) moisture absorption or distribution.
Agglomeration is facilitated by adding a small amount of water,
usually less than 5% (1-4% preferably), to the mixture of drug, binder
and other excipients. Agglomeration takes place when the
granulating fluid (water) activates the binder.
Once the agglomeration is achieved, moisture-absorbing material
such as microcrystalline cellulose, silicon dioxide, etc is added to
facilitate the absorption of excess moisture.
The moisture absorbents absorb the moisture
from the agglomerates, resulting in moisture
redistribution within the powder mixture, leading
to relatively dry granule mixture. During this
moisture redistribution process, some of the
agglomerates remain intact in size without change,
while some larger agglomerates may break leading
to more uniform particle size distribution.
It does not require an expensive drying step.
The process does not lead to larger lumps
formation since the amount of water used is very
small compared to usual wet granulation.
The application of MADG to an immediate-release and
controlled release dosage forms showed the advantages of
wet granulation such as increased particle size, better flow
and compressibility.
Advantages of this technique is wide applicability, time
efficiency and less energy input, and involvement of few
process variables with suitability of continuous process.
Advantages:
wide applicability
time efficiency
less energy input
 Thermal Adhesion Granulation (TAG):

Wei-Ming Pharmaceutical Company (Taipei,

Taiwan) has developed this technique, and the
thermal adhesion granulation, analogous to
moist granulation, utilizes addition of a small
amount of granulation liquid and heat for
agglomeration.
 Unlike moisture activated dry granulation
which uses water alone as granulation liquid,
this process uses both water and solvent as
granulation liquid.
 In addition to this, heat is used to facilitate the
granulation process. In this process, the drug and
excipient mixture is heated to a temperature
range of 30–130 °C in a closed system under
tumble rotation to facilitate the agglomeration of
the powder particles.
 This technique eliminates the drying process due
to the addition of low amount of granulation
liquid, which is mostly consumed by the powder
particles during agglomeration. Granules of the
required particle size can be obtained after
cooling and sieving.
 Freeze Granulation Technology
This technology was developed by Swedish Ceramic
Institute (SCI) – freeze granulation (FG) – which enables
preservation of the homogeneity from suspension to dry
granules by spraying a powder suspension into liquid
nitrogen, the drops (granules) are instantaneously
frozen.
In a subsequent freeze-drying the granules are dried by
sublimation of the ice without any segregation effects as in
the case of conventional drying in air.
The result will be spherical, free flowing granules, with
optimal homogeneity.
Diagrammatic Representation Of Freeze Granulator (FDG)
 Granulex® Technology

The Granulex® precisely and consistently

performs both coating and powder layering
processes.
Key features:
Unique, efficient granulation processes: Granules
produced by the Granurex® are dense and spherical
in shape. The Vector Corporation demonstrated
that the Granurex® processes of Ciprofloxacin from
a 7 μm poorly flowing powder to 200 μm granules
with excellent flow characteristics.
One pot processing: A patented feature of the
granulator Granurex® is having unique ability to dry
product within the same processing chamber. This
unique drying method, provides a true one-pot
system, ideal for manufacturing highly potent and
expensive pharmaceutical compounds.
Increased batch capacities: In comparison to
traditional rotor processors, the patented conical
rotor plate has tremendous capacity in increasing
the batch capacity. The designed machine contains
the product within the processing area and the
peripheral spray guns are embedded into the
product, which provides accurate coating with
minimal spraying effect.
Maximum process flexibility: The Corporation has
demonstrated maximum process flexibility using
micronized acetaminophen as the base material;
the Granurex® produced both a 100 μm granulation
and a 200 μm spherical bead. In both of the
examples, the acetaminophen core material had
the same initial Mean Particle Size (X50) of 40 μm..
..
 Spheronization
Spheronization also known as Marumerization.
The credentials for development of this technique
reserved for Caleva Process Solutions Ltd, UK.
It is the process where pellets (size from about 0.5
to 2.0 mm) are produced from mixtures of solids
and liquids by the involvement of forming and
shaping forces. During this process, extrudates are
shaped into rounded or spherical granules.
This process was first reported by Reynolds and by
Conine and Hadley in 1970.
Advantages of spheronisation relevant to
pharmaceutical industries
Easy to coat.
Separation of incompatible drugs.
Ability to mix pellets with different release
rates.
Reduced risk of dose dumping.
Reduced risk of local irritation in the gastro-
intestinal tract.
Less variable bio-availability. Particles of 1mm
or less behave more like liquids in terms of
gastric emptying Even distribution over the
gastro-intestinal tract.
 Process
Mixing:
The ingredients are generally mixed in either a high-
shear granulator or a more simple planetary mixer.
Extrusion:
The extrusion of the materials is a necessary step
prior to spheronization. The size of the spheres is
governed by the diameter of the extrudate used for
the spheronization process. In a spheronizer, it is
possible to obtain spheres with a diameter ranging
from about 0.5 mm to 2 mm.
Spheronisation:
The ongoing action of particles colliding with the wall and
being thrown back to the inside of the
plate creates a "rope-like" movement of product along the
bowl wall. The continuous collisions of the particles with the
wall and with the friction plate gradually turn the cylindrical
segments into spheres, provided that the granules are plastic
enough to allow the deformation without being destroyed.
When the particles attained the desired spherical shape, the
discharge valve of the chamber is opened and the granules
(pellets) are discharged by the centrifugal force. The design
principle of the spheronizer is relatively simple but additions
and adaptations are possibility to change bowl sizes according
to the requirements for the development of different batch
sizes.
Drying:
Pellets are dried in a fluid bed drier.
 Continuous Flow Technology
This method does not require any liquid to start
the chain reaction. In this case granulation is
carried out in an inclined drum into which
powder is fed at one end and granulate is
removed at the other. The process produces
granule with surface protected by inactive
component that do not harm the sensitive API.
CF technology can produce up to 12 tons of
granules every day.
Advantages
1. Sensitive APIs are protected.
2. Granules and effervescent become less
sensitive to humidity and high temperature.
3. Granules form extremely stable products.
4. No solvent residues in the final products.
 Reference
Granulation techniques and technologies: recent
progresses -Srinivasan Shanmugam. BioImpacts, 2015,
5(1), 55-63.
 Advanced granulation techniques for pharmaceutical
formulations - P. Thejaswini International Journal of
Research in Pharmaceutical and Nano Sciences. 2(6), 2013,
723 - 732.
Himanshu K. solanki,Tarashankar basuri Recent Advance
In Granulation Technology. International Journal of
Pharmaceutical Sciences Review and
Research,5(3),2010,48-54.