GRANULATION TECHNIQUE

Granulation, the process of particle enlargement by agglomeration technique, is

one of the most significant unit operations in the production of pharmaceutical
dosage forms, mostly tablets and capsules. Granulation process transforms fine
powders into free-flowing, dustfree granules that are easy to compress.
Nevertheless, 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. Granulation process can be divided into two types: wet granulation that
utilize a liquid in the process and dry granulation that requires no liquid. The type
of process selection requires thorough knowledge of physicochemical properties of
the drug, excipients, required flow and release properties, to name a few. Among
currently available technologies, spray drying, roller compaction, high shear
mixing, and fluid bed granulation are worth of note. Like any other scientific field,
pharmaceutical granulation technology also continues to change, and arrival of
novel and innovative technologies are inevitable. This review focuses on the recent
progress in the granulation techniques and technologies such as pneumatic dry
granulation, reverse wet granulation, steam granulation, moisture-activated dry
granulation, thermal adhesion granulation, freeze granulation, and foamed binder
or foam granulation. This review gives an overview of these with a short
description about each development along with its significance and limitations
Why Granulation ?
The reasons why granulation is often necessary are as follows.
1. To prevent segregation of the constituents of the powder mix
2. To improve the flow properties/fluidity of the mix
3. To improve the compaction characteristics of the mix
4. Other reasons

To prevent segregation of the constituents of the powder mix :

Segregation (demixing) is because there are differences in the size or density of the
components of the mix, the smaller and/or denser particles concentrating at the
base of a container while the larger and/or less dense ones above them (on the top).
An ideal granulation will contain all the constituents of the mix in the correct
proportion in each granule, and segregation of the ingredients will not occur.

To improve the flow properties/fluidity of the mix

Flow property/Fluidity is required to produce tablets of a consistent weight and
uniform
strength. Many powders not flowing well because they had small size, irregular
shape or surface characteristics. Poor flow will often result in a wide weight
variation within 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.

To improve the compaction characteristics of the mix

Compressibility is required to form a stable, intact compact mass when pressure is
applied. 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 and is a function of the method
employed to produce 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.

Other reasons
The above are the primary reasons for the granulation of pharmaceutical/consumer
good products, but there are other reasons that may necessitate the granulation of
powdered material:
1. Avoid dustiness. The granulation of toxic materials will reduce the hazard
associated with the generation of toxic dust that may arise when handling
powders. Thus granules should be non-friable and have a suitable
mechanical strength.
2. 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 flowability because of
their size.
3. Granules, being denser than the parent powder mix, occupy less volume per
unit weight. They are therefore more convenient for storage or shipment.
 4. mprove appearance, mixing properties in general to either eliminate
undesirable properties or to improve the physical and chemical properties of
fine powders.

Purpose
Granulation is carried out for various reasons, one of which is to prevent the
segregation of the constituents of powder mix. Segregation is due to
differences in the size or density of the component of the mix. Normally, the
smaller and/or denser particles tend to concentrate at the base of the
container with the larger and/or less dense ones on the top. An ideal
granulation will contain all the constituents of the mix in the correct
proportion in each granule and segregation of granules will not occur.
Many powders, because of their small size, irregular shape or surface
characteristics, are cohesive and do not flow well. Granules produced from
such a cohesive system will be larger and more isodiametric, both factors
contributing to improved flow properties.
Some powders are difficult to compact even if a readily compactable
adhesive is included in the mix, but granules of the same powders are often
more easily compacted. This is associated with the distribution of the
adhesive within the granule and is a function of the method employed to
produce the granule.
For example, if one were to make tablets from granulated sugar versus
powdered sugar, powdered sugar would be difficult to compress into a tablet
and granulated sugar would be easy to compress. Powdered sugar’s small
particles have poor flow and compression characteristics. These small
particles would have to be compressed very slowly for a long period of time
to make a worthwhile tablet. Unless the powdered sugar is granulated, it
could not efficiently be made into a tablet that has good tablet characteristics
such as uniform content or consistent hardness.

Techniques:

Wet granulation

In wet granulation, granules are formed by the addition of a granulation liquid onto
a powder bed which is under the influence of an impeller (in a high-shear
granulator), screws (in a twin screw granulator) [2] or air (in a fluidized bed
granulator). The agitation resulting in the system along with the wetting of the
components within the formulation results in the aggregation of the primary
powder particles to produce wet granules.[2] The granulation liquid (fluid) contains
a solvent or carrier material which must be volatile so that it can be removed by
drying, and be non-toxic. Typical liquids include water, ethanol and isopropanol
either alone or in combination. The liquid solution can be either aqueous based or
solvent-based. Aqueous solutions have the advantage of being safer to deal with
than other solvents.

Water mixed into the powders can form bonds between powder particles that are
strong enough to lock them together. However, once the water dries, the powders
may fall apart. Therefore, water may not be strong enough to create and hold a
bond. In such instances, a liquid solution that includes a binder (pharmaceutical
glue) is required. Povidone, which is a polyvinyl pyrrolidone (PVP), is one of the
most commonly used pharmaceutical binders. PVP is dissolved in water or solvent
and added to the process. When PVP and a solvent/water are mixed with powders,
PVP forms a bond with the powders during the process, and the solvent/water
evaporates (dries). Once the solvent/water has been dried and the powders have
formed a more densely held mass, then the granulation is milled. This process
results in the formation of granules.

The process can be very simple or very complex depending on the characteristics
of the powders, the final objective of tablet making, and the equipment that is
available. In the traditional wet granulation method the wet mass is forced through
a sieve to produce wet granules which is subsequently dried.

Dry granulation

The dry granulation process is used to form granules without using 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. Sweying granulator or 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 tabletting press or the powder is squeezed between two
counter-rotating rollers to produce a continuous sheet or ribbon of materials (roller
compactor, commonly referred to as a chilsonator which received its name from its
inventor, Francis Xavier Chilson).

When a tablet press is used for dry granulation, the powders may not possess
enough natural flow to feed the product uniformly into the die cavity, resulting in
varying degrees of densification. The roller compactor (granulator-compactor) uses
an auger-feed system that will consistently deliver powder uniformly between two
pressure rollers. The powders are compacted into a ribbon or small pellets between
these rollers and milled through a low-shear mill. When the product is compacted
properly, then it can be passed through a mill and final blend before tablet
compression.[8]

Typical roller compaction processes consist of the following steps: convey

powdered material to the compaction area, normally with a screw feeder, compact
powder between two counter-rotating rolls with applied forces, mill resulting
compact to desired particle size distribution. Roller compacted particle are
typically dense, with sharp-edged profiles.

ADVANTAGES:

It improves flow property and compression characteristics and increases density of

granules. Better distribution of color and soluble drug if added in the binding
solution. It reduces dust hazards. Prevents segregation of powders. Makes
hydrophobic surfaces more hydrophilic

DISADVANTAGES:

Process is expensive because of labor, space, time special equipment and energy
requirement. Loss of material during various stages of processing. Moisture
sensitive and thermo labile drugs are poor candidates. Any incompatibility between
the formulation components is aggravated during the processing

CONCLUSION:
1. Every technique has unique characteristic.
2. Ideal characteristics of granules: uniformity, flow & compatibility.

3. Selection depends on product quality, labour availability & their skill,

processing time & cost.

4. In-depth knowledge of the processing techniques & their merits &demirits

are required.

5. Methodical approach should be followed for selecting the suitable

granulation process of sago pearls.
REFERENCES:
1. Ax K., Feise H., Sochon R., Hounslow M., Salman A. Influence of liquid
binder dispersion on agglomeration in an intensive mixer. Pow. Tech.
2008;179(3):190–194.
2. Bauer K.H., Frömming K.H., Führer C. 9th ed. Wissenschaftliche
Verlagsgesellschaft; Stuttgart: 2012. Pharmazeutische technologie, mit
einführung in die biopharmazie.
3. Jachowicz R. first ed. PZWL; Warsaw: 2013. The drug form. Optimisation
of Oral and Eye Medications in Modern Pharmaceutical Technology.
4. Kraciuk R., Sznitowska M. Effect of different excipients on the physical
characteristics of granules and tablets with carbamazepine prepared with
polyethylene glycol 6000 by Fluidized Hot-Melt Granulation (FHMG)
AAPS Pharm. Sci. Technol. 2011;12(4):1241–1247. [

Rajniak P., Mancinelli C., Chern R.T., Stepanek F., Farber L., Hill B.T.
Experimental study of wet granulation in fluidized bed: Impact of the binder
properties on the granule morphology. Int. J. Pharm. 2007;334(1):92–102.