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Powder granulation is a process of size enlargement Litster Ennis, 2004 Swarbrick Boylan, 2006 that incorporate the small particles to agglomerate together to make a larger particles in a way that the main components can still be detected (Ennis, 2005).
Generally, each tablet contains different types of ingredient but the active ingredients are more important one. During the combination of all components, it should be guaranteed that active ingredients are distributed equally in different portion. While sometimes during the blending or compression, the ingredients separate from each other; according to their difference in particle size, density, compressibility and flow characteristics. So to achieve a regular result the powders must flow constantly therefore particles should be granulated (D.Tousey, 2002)
The definition of granulation granulation contain
particle-size distribution and density to attain proper flow and
achieve volume of fill (i.e., tablet weight). In other words, the
powders must flow consistently to attain consistent results.
The chief reasons to granulate powders for the
manufacture of pharmaceutical dosage forms are
described by Kristensen and Schaefer.
. To improve powder flow properties for dosage filling
and compression processes.
. To eliminate wet granulation induced degradants and
to improve product stability.
. To prevent active product ingredient from segregating.
. To reduce bulk volume thereby minimizing storage
and enhancing transport.
. To reduce potential environmental and safety hazard (16,2806)
Wet granulation is a subset of size enlargement (1-5), which involves any process
whereby small particles are agglomerated, compacted, or otherwise brought together
into larger, relatively permanent structures in which the original particles can still be
Distinguished . Granulation technology and size-enlargement processes have been
used by a wide range of industries, from the pharmaceutical industry to fertilizer
or detergent production to the mineral processing industries. Size enlargement generally
encompasses a variety of unit operations or processing techniques dedicated to
particle agglomeration. These processes can be loosely broken down into agitation
and compression methods.(10,31)
Powder granulation is a process of powder size
enlargement that incorporates small particles into larger
ones. The definition of granulation comprises a range of
different size enlargement methods that can be classified
as either dry or wet. In wet methods, a suitable liquid is
used to agglomerate the small powder particles into a
mass. The wet mass is subsequently dried and sized for
further down-stream processing needs. Wet granulation
methods have been the most widely used powder
granulation technology in the production of pharmaceutical
products, particularly in modern pharmaceutical
Traditionally, tablets have been made by granulation, a
process that imparts two primary requisites to formulations:
compactibility and fluidity. Both wet granulation
and dry granulation (slugging or roll compaction) are used
(Table 1). Regardless of whether tablets are made by direct
compression or granulation, the first steps, milling and
mixing, are the same; the subsequent steps differ.
The wet massing of powders is typically carried out in
high-shear mixers prior to wet screening. The wet
granules are often dried in fluidized-bed equipment,
enhancing the efficiency of the process. Alternatively, wet
granulation may be carried out in fluid-bed driergranulators
in which the liquid phase is sprayed onto
fluidized powders while the hot air flow dries the granules.
This process reduces the number of handling steps and the
time and space needed for granulation; it can be
-Nonhomogeneous distribution of binder and drug
substance gives drug-rich or drug-poor fines
-Decomposition of drug substance due to residual
-Uneven granule size (too many or to few fines) leads
to compaction or uniformity problems
Naturally tablets only possess these advantages if they
are properly formulated and manufactured. A wellprepared
tablet should possess the following qualities:
1. It should, within permitted limits, contain the stated
dose of drug.
2. It should be sufficiently strong to withstand the stresses
of manufacture, transport, and handling so as to reach
the patient intact.
3. It should deliver its dose of drug at the site and at the
4. Its size, taste, and appearance should not detract from
its acceptability by the patient.(16,3174)
The process of granulation is essentially
one of size enlargement, and it serves several purposes in
the tablet manufacturing process:
1. It improves flow by increasing particle size, since large
particles flow more readily than small ones.
2. It improves compression characteristics, adding to the
cohesive strength of the tablet.
3. Once a homogeneous mixture has been achieved,
segregation is prevented, since particles that are stuck
together cannot separate.
4. It reduces dust.
Both wet and dry granulation techniques are available
The first stage in the wet granulation process is often a dry
mixing stage in which the active component is mixed with
a diluent. Many drugs need to be administered in doses of
only a few milligrams or even less, yet a tablet that weighs
less than about 50 mg is difficult for the patient to handle
conveniently. It is therefore necessary to increase the bulk
of such a tablet with a diluent. Some commonly used
diluents are listed in Table 1.
The ideal diluent would be both chemically and
physiologically inert, and would not interfere with the
bioavailability of the active ingredient. It should also be
inexpensive and be easily tabletted since, if the proportion
of active ingredient is small, the overall tabletting
properties of the mixture are largely governed by those
of the diluent.
Lactose is by far the most frequently used diluent for
solid dosage forms. An inexpensive disaccharide obtained
as a by-product of the cheese industry. Probably the second most commonly used diluent in the
wet granulation process is dibasic calcium phosphate. This
substance is virtually insoluble in water and hence is
always used in conjunction with a disintegrating agent
The purpose of the mixing stage is to ensure that the
powder blend and hence the resulting tablets are
homogeneous in content. A random mixture is defined as
one where the probability of sampling a given type of
particle is proportional to the number of such particles in
the total mixture. Thus, the aim is to produce a mixture
such that when a sample is removed, the relative
proportions of the components of that sample are the
same as in the mixture as a whole. Although in general a size difference between
components can lead to segregation, a situation where
there is a large difference in sizes between components
may be beneficial. In such circumstances, small particles
of one component can become trapped in irregularities in
the surface of the larger component. These are not random
mixtures, as the particles of the two components cannot
behave independently. This concept is called "ordered
mixing" and it has found applicability in the manufacture
of solid dosage forms containing small quantities of highly
potent active ingredients (5) (see the article on Blenders
and Blending in this encyclopedia).
The underlying process of size enlargement in wet
granulation is achieved by either one or both of two
different mechanisms. Firstly, adjacent solid particles may
be stuck together using an adhesive. Such substances are
known as binders or granulating agents. Secondly,
dissolution of the solid in the granulating liquid can
occur, followed by evaporation of the liquid phase of the
latter. This will result in the deposition of dissolved
material on particle surfaces, forming so-called crystal
bridges. The occurrence of this mechanism will depend on
the solubility of the solids in the liquid phase.
The traditional piece of granulating apparatus is the
shear granulator. Its function is to homogeneously
incorporate an adhesive and viscous liquid such as starch
paste into a mass of dry powder to form agglomerates. It
follows that a considerable shearing force needs to be
exerted. The mixed solids are loaded into the bowl of the
mixer, and the liquid added with agitation. The damp solid
is then forced through a relatively coarse screen (about
1-2 mm), often by means of oscillating bars, to give discrete granules.
the wet granulation process is a
long and hence expensive procedure, which has been
improved by the introduction of high-speed mixer
granulators. These have agitator and chopping blades,
which enable mixing, wet massing, and granulation to take
place in the same piece of apparatus. In such devices, the
granulation process takes place extremely rapidly.
A further technique is fluid-bed granulation. Air is
passed into the powder bed from below. This causes the
particle, of powder to form a suspension in the air and
gives effective mixing. The granulating fluid is then
sprayed over the particles, which adhere on collision and
they are then dried in the heated air stream.
The wet granulation process, apparatus, and pharmaceutical
applications have been comprehensively reviewed
by Kristensen and Schaefer (8) (see the article on Tablet
Granulation in this encyclopedia).
After the process of granulation, the product exists as a wet
mass from which the liquid must be removed, since the
presence of water leads to the impairment of flow properties,
and perhaps to chemical instability
The fluidized bed drier is the most commonly used
device for drying tablet granules. The solid is fluidized
from below by a jet of hot air, and so each granule
becomes separated from its neighbors. The air provides an
effective means of heat transfer, as well as of removing
water vapor. The speed of the drying process is governed
by the distance that water molecules must diffuse before
they arrive at the evaporative surface. Since the wet
granules are present as individual units, the maximum
distance over which diffusion occurs is equal to the radius
of a granule. Hence, fluidized bed drying is a rapid process. The temperature of the bed can be precisely controlled, and a free-flowing product results.
Second mixing stage
When the drying process is complete, 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 granule. A second mixing stage now follows in which
several important ingredients of the formulation are added
When the tablet formulation is compressed, the sides of the
tablet are brought into intimate contact with the die wall.
The tablet must then be ejected from the die, involving the
movement of the side of the tablet relative to the die wall.
Therefore, friction between the tablet and the die wall
must be overcome. With materials such as lactose, friction
resistance can be considerable, and it may be impossible to
remove the tablet from the die without damage to the tablet
or to the tablet press. Therefore, a lubricant is almost
invariably included in a tablet formulation. A lubricant is a
substance that deforms easily when sheared between two
surfaces, and hence when interposed between the tablet
and the die wall, provides a readily deformable film (
The mixing process is
extremely important here, and mixing time, mixer type,
and batch size (16) have all been shown to influence
tablet properties. Thus, there is a need to establish a
minimum lubricant concentration and an optimum
mixing time within which adequate lubrication is
achieved without the development of undesirable tablet
characteristics. To ensure batch-to-batch uniformity, the
parameters of the mixing process such as type of mixer,
batch size, and mixing time must be kept as constant
as possible. A mixing time of 2-5 min usually suffices
to give adequate lubrication