DEFINITION : Granulation is the act or process of forming or crystallizing into grains.

[1]

Granules typically have a size range between 0.2 to 4.0 mm depending on their subsequent
use.
Synonym "Agglomeration": Agglomeration processes or in a more general term particle size
enlargement technologies are great tools to modify product properties. Agglomeration of
powders is widely used to improve physical properties like: wettability, flowability, bulk
density and product appearance.
Pharmaceutical industry[edit]
In the pharmaceutical industry, granulation refers to the act or process in which primary
powder particles are made to adhere to form larger, multiparticle entities called granules. It is
the process of collecting particles together by creating bonds between them. Bonds are
formed by compression or by using a binding agent. Granulation is extensively used in the
manufacturing of tablets and pellets (or spheroids).
The granulation process combines one or more powder particles and forms a granule that will
allow tableting or spheronization process to be within required limits. This way predictable
and repeatable process is possible and quality tablets or pellets can be produced using
tabletting or spheronization equipment.
Purpose[edit]
Granulation is carried out for various reasons, one of those 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 sugars 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.
Granulation techniques[edit]
In pharmaceutical industry, two types of granulation technologies are employed, namely, wet
granulation and dry granulation.
Wet granulation[edit]
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 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 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[edit]
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 high shear mixer-
granulator 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).
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.









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.


Granulation is the process of agglomeration of a powder mixture, which results in the
enlargement of the particles. This is often necessary for manufacturing of solid dosage
forms such as tablets. The materials, which are compressed into tablets, must possess adequate
flowability, density, and compressibility. This is because the requisite amount of
powder mixture required to compress each tablet is filled into the die cavity by volume
and not by weight. This requirement of adequate flowability, density, and compressibility
is particularly important during a high-speed tablet production where the dwell time is
often short. the overall purpose of
granulation is to improve the flowability and compressibility of the powder mixture.
Besides improving the flowability and compressibility, the granulation process can also
_ Densify the powder mixture and reduce dust
_ Narrow the particle size distribution of the powder mixture
_ Ensure uniform distribution of the drug in the powder mixture
_ Improve the dissolution characteristics of the finished tablets.
The three commonly used granulation methods include wet granulation, dry
granulation, and hot-melt granulation. These methods are categorized based on
the type of binder and the process employed during granulation.

Granulation is an example of particle design. The desired attributes of the
granule are controlled by a combination of the formulation and the process.
Granulation methods can be divided into two major types: wet methods which
utilize some form of liquid to bind the primary particles, and dry methods which do
not utilize any liquid.
The reasons for granulating a pharmaceutical
compound are listed as follows:
1. To increase the uniformity of drug distribution in the product
2. To densify the material
3. To enhance the flow rates and rate uniformity
4. To facilitate metering or volumetric dispensing
5. To reduce dust
6. To improve the appearance of the product.

Five primary methods exist to form an agglomerated granule. They are formation
of solid bridges, sintering, chemical reaction, crystallization, or deposition of
colloidal particles. Binding can also be achieved through adhesion and cohesion
forces in highly viscous binders.
Successful processing for the agglomeration of primary particles depends on
proper control of the adhesional forces between particles, which encourage agglomerate
formation and growth and provide adequate mechanical strength in the
product. Furthermore, the rheology of the particulate system can be critical to
the rearrangement of particles necessary to permit densification of the agglomerate
and the development of an agglomerate structure appropriate for the end-use
requirements. If the particles are close enough then the surface forces such as van
der Waals forces (short-range) and electrostatic forces can interact to bond particles.
Decreasing particle size increases surfacemass ratio and favors the bonding. van der
Waals forces are sevenfold stronger than electrostatic forces and increase substantially
when the distance between them is reduced, which can be achieved by applying
pressure as in dry granulation method.
The cohesive forces that operate during the moist agglomerates are mainly due
to the liquid bridges that develop between the solid particles. Electrostatic forces
keep particles in contact long enough for another mechanism to govern the agglomeration
process.
1. INTRODUCTION
1.1. Overview
At the level of a manufacturing plant, the size-enlargement process involves
several peripheral, unit operations such as milling, blending, drying, or cooling, and classification,
referred to generically as an agglomeration circuit.
Aprimary purpose of wet granulation in the case of pharmaceutical processing is to create free-
flowing, nonsegregating
blends of ingredients of controlled strength.
Table 1 Objectives of Size Enlargement
Production of a useful structural form
Provision of a defined quantity for dispensing, with improved flow properties for metering
Improved product appearance
Reduced propensity to caking
Increased bulk density for storage
Creation of nonsegregating blends of powder ingredients
Control of solubility
Control of porosity, hardness, and surface-to-volume ratio and particle size
1.2. Granulation Mechanisms
Four key mechanisms or rate processes contribute to granulation, These
include wetting and nucleation, coalescence or growth, consolidation, and attrition
or breakage (Fig. 4).
Wetting promotes
nucleation of fine powders, or coating in the case of feed particle size in excess
of drop size. Often wetting agents such as surfactants are carefully chosen to enhance
poorly wetting feeds. In the coalescence or growth stage, partially wetted primary
particles and larger nuclei coalesce to form granules composed of several particles.
The term nucleation is typically applied to the initial coalescence of primary particles
in the immediate vicinity of the larger wetting drop whereas the more general term of coalescence
refers to the successful collision of two granules to form a new, larger
granule. In addition, the term of layering is applied to the coalescence of granules
with primary feed powder. Nucleation is promoted from some initial distribution
of moisture, such as a drop, or from the homogenization of a fluid feed to the
bed, as with high-shear mixing. The nucleation process is strongly linked with the
wetting stage. As granules grow, they are consolidated by compaction forces due
to bed agitation. This consolidation stage controls internal granule voidage or granule
porosity, and therefore end-use properties such as granule strength, hardness, or
dissolution. Formed granules may be particularly susceptible to attrition if they are
inherently weak or if flaws develop during drying.
These mechanisms or rate processes can occur simultaneously in all granulation
units, ranging from spray drying to fluidized beds to high-shear mixers. However,
certain mechanisms may dominate in a particular manufacturing process. For example,
fluidized bed granulators are strongly influenced by the wetting process, whereas
mechanical redispersion of binding fluid by impellers and particularly high-intensity
choppers diminishes the wetting contributions to granule size in high-shear mixing.
On the other hand, granule consolidation is far more pronounced in high-shear
mixing than in fluidized-bed granulation. These simultaneous rate processes taken
as a wholeand sometimes competing against one anotherdetermine the final granule
size distribution and granule structure and voidage resulting from a process, and
therefore the final end-use or product quality attributes of the granulated product.

Drug Substance and Excipient
Characterization
1. INTRODUCTION
Characterization of drug substances and excipients is a very important step at the
preformulation phase of product development. Preformulation characterization of raw materials
creates a body of information
which is very useful in the development of products. It is therefore important to have a system of in-
house characterization of raw
materials alongside the stability and functional tests for the finished product.
Retrospective studies of the finished product test
results together with well-documented production process validation and characterization
tests of raw materials can provide directions for refinement of the production
process and improve the specifications for raw materials.
The method of material characterization varies considerably as it depends on
the nature and form of material used as well as the process involved in the conversion
of the raw materials to the finished products. The desirable characterization test
for each material depends on the material itself and the likely use or influence of
a particular material property on the process or product.
2. PARTICLE SHAPE, SIZE, AND SURFACE AREA
2.1. Particle Shape
Particle shape is an important parameter which can have a significant effect on the
bulk properties of a powder. It is well known that spherical particles flow better,
pack better, and have a lower surface to volume ratio. There are a large number of transformation
models which can be used to
analyze the image dimensional parameters in the determination of particle shape.
2.2. Particle Size
methods of particle sizing:
2.2.1. Microscopy
Microscopy is a very old technique capable of sizing fine powders accurately.
2.2.2. Sedimentation
Sedimentation technique for particle sizing and classification has been in use for
a long time. In recent years, however, the success of light scattering particle sizers
has effectively eroded away the market for sedimentation-based particle sizers.
Sedimentation technique for sizing is based on the settling of particles under gravity
described by Stokes law. For a particle of diameter, d, and density, r1, under the
force of gravity, g, in a fluid of viscosity, Z, and density, r2, at its terminal velocity,
n, the accelerating force due to gravity is balanced by the viscous drag and
n
d2gr1 _ r2
18Z
2.2.3. Sieving
Sieving is probably the oldest method of sizing, used initially for particle classification
rather than size analysis. The process of sieving involves a nest of sieves, usually five to eight,
arranged
from the largest apertures to the finest followed by a receiving pan. The sieves with a
lid and receiving pan are then placed on a sieve shaker, which may gyrate, oscillate,
or vibrate the sieves. Most commonly used shakers are vibrators. It is important to
determine the time required for completion of sieving. This is commonly taken as the
time when there is no further change in the weight of material retained on each sieve after additional
sieving time is given. The load for sieve analysis should be sufficient
in order that the amount present after sieving on each mesh can be accurately
weighed.
In size analysis using sieves, it must be borne in mind that the aperture size of a
given sieve is not an absolute cut-off value for the size of particles permitted to pass
through. The permitted aperture tolerance is much wider and following the maximum
tolerance allowed by the British Standard 410 (1976), particles from 55 to
95 mm may go through or be arrested by a 75 mm aperture size sieve. Particles tend
to pass through based on their narrower cross-sectional area. Size analysis by sieving is a relatively
slow process and there may be problems
with dust pollution. For many drugs, the safety of the operator needs to be considered.
In addition, wire mesh stretches with repeated use. Apertures may be blanked
by improper or inadequate washing. For fine powders, aggregation of powders due
to cohesive or electrostatic charges can give inaccurate results. Inadequate sieving
time will also produce unreliable data. It is also important to ensure that the sieving
process itself does not bring about size reduction.

2.2.4. Electrical Sensing
The electrical sensing zone principle, which is more commonly known as the Coulter
principle, is based on a simple electrical property that the electrical resistance between two
compartments containing an electrolyte and connected by an aperture
is proportional to the electrical conducting area of the aperture. Figure 2 illustrates
the basic Coulter principle. By drawing electrolyte from one compartment to the
other, particles streaming through will decrease the conducting area of the aperture.
By fast time-based tracing of the resistance, resistance pulses coinciding with the passage
of particles through the aperture will be obtained. The amplitude of the pulse is
proportional to the volume of the particle. With a pulse analyzer, the Coulter counter
can analyze a large number of particles within a short time.
2.2.5. Light Scattering
particle sizers using this
principle can be roughly divided into three groups, two for determining particle size
down to about 1 mm using light obscuration and laser diffraction and the third, for
submicron particle size using photon correlation spectroscopy.
2.3. Particle Surface Area
Surface area measurement is usually carried out by either gas permeability or
adsorption. The technique of gas permeability depends on measuring the resistance
to gas flow through a packed bed of particles.
3. SOLUBILITY
3.1. Nature of Solvent - Some materials dissolve very readily in a solvent while others dissolve
sparingly. The
solubility of the material in a given solvent depends on the ability of the solvent to
overcome the forces that bind the atoms or molecules of the material.
3.2. Temperature
The solubilities of most materials increase with rising temperature due to their
endothermic dissolution process. Similarly, the solubilities of materials which exhibit
exothermic dissolution decrease with rising temperature.
3.4. Particle Size
Smaller particles have a higher intrinsic solubility compared with their larger
counterparts.
3.5. pH
The solubility of a material will be affected by the pH of the liquid medium if the
material is acidic or basic. For example, a weakly acidic drug is more soluble in
an alkaline solution while a weakly basic drug is more soluble in an acidic solution.
The relationship between pH and solubility of a material is given by Eqs. 3.1
and 3.2.
For acidic materials,
pH pKa log
S _ S0
S0
3:1
For basic materials,
pH pKa log
S0
S _ S0
3:2
where S is the overall solubility of the drug and S0 is the solubility of its unionized
form.
3.6. Additives
Additives refer to other substances incorporated into the solvent in which the drug
is dissolved.

6. COMMONLY USED EXCIPIENTS IN GRANULATION
Excipients for granulation can be largely divided into two categories, as bulking
agents and as functional additives. It is true that bulking agents or fillers also serve
a function in that they form the core or structure of a dosage form. Nevertheless,
bulking agents generally differ from the functional additives in that they are usually
inert materials that are relatively inexpensive. Functional additives include binders,
disintegrants, lubricants, colorants, and stabilizing agents.
The choice of excipients depends on a number of factors, namely, the drug
used, the process involved, the formulator, and the cost of excipient. A very common filler is lactose,
although other sugars, dicalcium phosphate,
starch, pregelatinized starch, and microcrystalline cellulose are also used. The
starches and microcrystalline cellulose are also disintegrants in tablets. For tablets,
other commonly used disintegrants include sodium starch glycolate, croscarmellose,
crospovidone, and low-substituted hydroxypropylcellulose. Lubricants are usually
not added till prior to filling or tableting of the granules. The most commonly used
lubricant is magnesium stearate. Other lubricants used include calcium stearate,
stearic acid, wax, hydrogenated vegetable oil, talc, and starch.
Binders used in granulation consist of a wide variety of sugars and polymers
natural, semisynthetic, and synthetic. Sugars used include sucrose, glucose, and sorbitol.
Examples of natural polymers are acacia, alginic acid, sodium alginate, gelatin,
and starch.
The semisynthetic binders include ethylcellulose, sodium carboxymethylcellulose,
methylcellulose, hydroxypropylcellulose, and hydroxypropylmethylcellulose.
The
two types of synthetic binders in use are polyvinylpyrrolidone and polyethylene glycol.
Polyvinylpyrrolidone is widely used in both wet massing and fluid bed granulation.
The main application of polyethylene glycol as a binder is in melt granulation.
Other excipients employed in pharmaceutical products include colorants,
coating aids, stabilizers, pH modifiers, and release rate modifiers. They play very important roles and
would require specific characterization tests. In the making of a
product, the functional excipients to be added must be carefully selected to ensure
that the final product is bioavailable and esthetically pleasing.

Binders and Solvents
1. INTRODUCTION
Binders are adhesives that are added to solid dosage formulations. The primary role
of binders is to provide the cohesiveness essential for the bonding of the solid particles
under compaction to form a tablet. In a wet-granulation process, binders promote
size enlargement to produce granules and thus improve flowability of the blend during
the manufacturing process. Binders may also improve the hardness of the tablets
by enhancing intragranular as well as intergranular forces. In a direct compression
process, binders often act as fillers and impart compressibility to the powder blend.
The cohesive properties of binders may reduce friability of the tablets and thus aid
in their durability and elegance. Although the purpose of using binders in a tablet formulation
is not to influence its disintegration and dissolution rate, these properties
may be modified due to the altered wettability of the formulation.
2. TYPES OF BINDERS
Binders are usually natural polymers, synthetic polymers, or sugars. Selection of the quantity of
binder required in a particular
system can be determined by optimization studies, using parameters such as
granule friability, tablet friability, hardness, disintegration time, and the drug dissolution
rate.
2.1. Natural Polymers
2.1.1. Starch
Starch is a polymeric carbohydrate obtained from various plant sources, such as
potato, wheat, maize, rice, and tapioca. It is insoluble in cold water and in
alcohol but it gelatinizes in hot water to form a paste. Starch paste can be prepared
by dispersing starch in 11.5 parts of cold water for initial wetting followed by addition
of two to four times as much boiling water with continuous stirring until a translucent
paste is obtained. This paste is further diluted by cold water to the desired
concentration. Alternatively, starch paste can also be prepared by heating the cold
water suspension of starch to boiling in a steam-jacketed kettle with constant stirring.
Freshly prepared starch paste is used at a concentration of 525% (w/w) in a
tablet granulation. Relatively soft and friable granules are produced when starch
paste is used as a binder. Consequently, it yields tablets that disintegrate readily.
During the wet-massing process, high viscosity of the starch paste can sometime
make it difficult to evenly distribute the binder in the powder blend.
2.1.2. Pregelatinized Starch
Pregelatinized starch is a modified starch used in tablet formulations as a binder,
diluent, and disintegrant. 2.1.3. Gelatin
Gelatin is a mixture of purified protein fractions obtained by partial acid hydrolysis
(Type A gelatin) or alkali hydrolysis (Type B gelatin) of animal collagens. It is insoluble
in cold water and in alcohol, but is soluble in hot water. In hot water, gelatin forms
a gel on cooling to 3540_C. At temperatures >40_C, the system exists as a solution.
Therefore, the gelatin solutions must be used when warm to avoid gel formation.
During the preparation of gelatin solution, gelatin must be wetted in cold water
and then heated with gentle agitation to ensure dissolution. The agitation intensity must
be kept low to prevent air entrapment in the viscous solution. Use of gelatin as a binder
is limited in general-purpose tablets because it produces tablets characterized by high
hardness and slow disintegration. However, these properties of gelatin along with its
smooth mouth feel can prove to be advantageous in a lozenge formulation.
The gelatin solutions are susceptible to microbial
contamination upon storage, therefore freshly prepared solutions should be used.

2.1.4. Acacia
Acacia is a natural gum obtained from the acacia trees. It is a complex, loose
aggregate of sugars and hemicelluloses. It is commercially available in a powdered
form, a granular form, or as a spray-dried product. As a tablet binder, it is used
in an aqueous solution or added in dried form prior to moistening with water. Acacia
forms very hard tablets, which disintegrate slowly. Aqueous solutions are susceptible
to bacterial and enzymatic degradation. Acacia, which was
widely used in the past as a tablet binder, is rarely used today, in favor of one of
the many synthetic polymers.
2.1.5. Tragacanth
Tragacanth is a naturally occurring dried gum. It poses similar problems as those of
acacia. Dry addition to the blend followed by addition of water works better than
addition of the solution, because it is difficult to prepare and use the mucilage.


2.1.6. Alginic Acid
Alginic acid is a polymannuronic acid extracted from seaweed. It is used as a binder
and disintegrating agent at concentrations between 1% and 5%.It slowly hydrolyzes
at room temperature and is insoluble in water.
These alginates may delay disintegration of the tablets due to their gelling
properties.

2.1.7. Sodium Alginate
Sodium alginate slowly dissolves in water to form a viscous solution. A 35% solution
typically is used in wet-granulation processes. It has also been used in sustained
release formulations because it delays the dissolution of a drug from tablets. It is
hygroscopic and its aqueous solution is susceptible to microbial contamination.

2.2. Synthetic Polymers
2.2.1. Polyvinylpyrrolidone (Povidone)
Polyvinylpyrrolidone (PVP) is versatile and one of the most commonly used binders.
It is readily soluble in water and freely soluble in alcohol and many other organic
solvents. It is available in a variety of grades of different molecular weights. PVP
is generally used in the form of a solution; however, it can be added to the blends
in the dry form and then granulated in situ. It is frequently used as a binder in effervescent
and chewable tablets because the tablets manufactured using PVP as a binder
generally harden with age. It is used as a binder at concentrations between 0.5% and 5%.
2.2.2. Methyl Cellulose
It may be added as a dry powder or as a solution. Although an
aqueous solution of 15% can be used to granulate soluble or insoluble excipients,
Granulation produced using 5% MC solution is
equivalent in hardness to 10% starch paste. It produces robust tablets with moderate
hardness, which does not increase with age.
MC is practically insoluble in hot water, ethanol, chloroform, ether, and saturated
salt solutions.
2.2.3. Hydroxypropyl Methyl Cellulose (Hypromellose)
Hydroxypropyl methyl cellulose (HPMC) is a ether of MC. Concentrations of 25% (w/w) may be used
as a binder in either wetor
dry-granulation processes. HPMC is soluble in cold water and forms a viscous
colloidal solution.
2.2.4. Sodium Carboxymethyl Cellulose
A 515% solution may be used for the granulation
of soluble as well as insoluble powders. The granulations produced using Na-CMC
as a binder are softer, but have good compressibility. It forms tough tablets of
moderate hardness.
2.2.5. Ethyl Cellulose
used as binders in concentrations of
210% in ethanol. Ethyl cellulose produces softer granules, which compress into
tablets that easily disintegrate.
2.2.6. Polyethylene Glycol
Polyethylene glycols (PEGs), have limited binding action.



2.3. Sugars
2.3.1. Glucose (Dextrose)
2.3.2. Sucrose
2.3.3. Sorbitol
Sorbitol is an optical isomer of mannitol. property of sorbitol as a moisture control agent is desirable, it
can be
used as a binder. Up to 220% of sorbitol can be added as 1025% aqueous solution
in wet-granulation formulations.





The equipment that
is used during the granulation processes is classified into the following three major
categories, based on the shearing strength it generates on the powder bed:
1. Low-shear granulatorstwin shell (Peterson Kelly, PK) with an agitator
bar, dough mixer or planetary mixer, ribbon blenders, and fluid bed
granulator without the rotogranulator
2. Medium-shear granulatorsfluid bed granulators with a rotogranulator
attachment
3. High-shear granulators.
High-shear granulation has been one of the most commonly used methods
to produce granules. 2. HIGH-SHEAR GRANULATORS
Most of the high-shear granulators consist of a mixing bowl, a three-bladed impeller,
and an auxiliary chopper. The shape of the mixing bowl could be cylindrical or conical.
The mixing bowl can be jacketed for heating or cooling the contents in the bowl,
by circulating hot or cool liquid or steam through the jacket. An impeller is
employed to mix the dry powder and spread the granulating fluid. The impeller of
the high-shear mixer granulator normally rotates at a speed ranging from 100 to
500 rpm. The function of the chopper is to break down the wet mass to produce
granules. The rotation speed of the chopper ranges from 1000 to 3000 rpm. The
high-shear granulator could be termed as either vertical or horizontal, based on
the orientation and the position of the impeller. The vertical high shear granulator could be either a
top-driven or a bottom-driven unit. The size of the high-shear granulators varies considerably from the
small
laboratory-scale models to large production-scale models, depending on the type of
the model and end use. High-shear granulators are often equipped with granulation
end-point control devices, which are used to detect the end point of the granulation
process. Some of the recently introduced features in high-shear mixer granulators are
clean in place (CIP) or wash in place (WIP), and one-pot processing. High-shear
granulators with CIP or WIP features can be cleaned easily, without removing the
bowl, the impeller, and the chopper. The advantage of the one-pot processing system
is that the wet granules can be dried in the same bowl without additional equipment
for drying.

3. HIGH-SHEAR GRANULATION PROCESS
3.1. Wet Granulation
The composition of a powder mixture for granulation generally consists of an active
pharmaceutical ingredient (API), a filler, a disintegrant (usually not included in controlled
release tablets), and a binder.
A high-shear wet-granulation process includes the following steps:
1. Loading all the ingredients into the mixing bowl, which can be accomplished
by either of the following methods: gravity feeding with manual
or pneumatic valve, and vacuum feeding.
2. Mixing of dry ingredients such as API, filler, and disintegrant, at high
impeller and chopper speeds for a short period of time (25 min).
3. Addition of a liquid binder (either binder solution or solvent) into the powder
mixture, while both the impeller and the chopper are running at a low
speed.
4. Wet massing with both the impeller and the chopper running at a high
speed.
5. Removal of the resulting wet granules from the granulator bowl, and drying
them using an appropriate drying technique such as fluid-bed or tray
drying.
6. Sieving the dried granules.
The high-shear wet-granulation process offers several advantages over the
other granulation processes. These include:
_ Short processing time
_ Use of less binder solution
_ Granulation of highly cohesive materials containing hydrophilic polymers,
which is not achievable with low-shear granulation processes
_ Greater densification and production of less friable granules
_ Production of reproducible granules with a uniformparticle size distribution
_ Reduction of process dust, thus minimizing exposure to workers
_ Obtaining predictable granulation end-point determination.
Despite the above advantages, the process is not immune to challenges such as:
_ Production of less compressible granules, compared to low-shear granulation
processes
_ Narrow range of operating conditions
A commonly employed high-shear granulation process requires multiple unit
operations, such as drying and sieving after wet granulation. The preferred drying
method is fluid-bed drying, because of the distinct advantages over tray drying.
4. MECHANISM OF HIGH SHEAR WET GRANULATION
The high-shear wet-granulation process can be divided into five stages as shown
below, namely, mixing, adding binder solution, wetting and nucleation, consolidation
and growth, and granule attrition and breakage.
The binder solution or the granulating liquid is distributed through the powder
bed by mechanical agitation created by the impellers. At this stage, the powder mixture
becomes wetted and initiates agglomeration via nucleation. Nucleation of particles
occurs by the formation of liquid bridges between primary particles, which
adhere together to form agglomerates. At this stage, the concentration of liquid
phase in the powder mixture is relatively low, but high enough to establish liquid
bridges. The addition and distribution of binder solution can have a major impact
on the particle size distribution and quality of the granules. Poor liquid distribution
produces granules with a wide particle size distribution. These granules could include
large, overwetted particles, as well as small dry particles.
Granule growth is dominated by one of the two mechanisms: coalescence
or layering (14). Coalescence is agglomeration which occurs by collision and consolidation
of deformable nuclei/granules, provided the agglomerates could withstand
the shear forces applied by the impellers. Layering occurs when fine particles stick
to larger particles or granules coated with binder. Free liquid on the surface of
agglomerates, which renders the necessary bonding strength and plasticity to the
agglomerate, is required for coalescence or layering. The free liquid on the surface
of the agglomerates can be from the addition of more binder solution or from the expulsion of liquid
inside the agglomerates due to the consolidation of the
agglomerates.
Granule attrition and breakage reduce the granule size. Granule breakage
is determined by the dynamic granule strength and the shear forces within the granulator. If the
impact forces are larger than the granule strength, continuous
breakage and immediate coalescence of the granules takes place (15). However, when
the granule strength exceeds the impact forces, granules will not break. In that case,
granule growth is more static, i.e., the exchange of primary particles between the granules is minimal.
Thus, there is a balance between agglomerate growth and degradation
of the granules.