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Recent Advances in Granulation Techniques

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Asian J. Res. Pharm. Sci. 2014; Vol. 4: Issue 1, Pg 38-47 [AJPSci.]

ISSN- 2231–5640 (Print) www.asianpharmaonline.org

ISSN- 2231–5659 (Online) 0974-3618

REVIEW ARTICLE

Recent Advances in Granulation Techniques

Namdeo Shinde1*, Nagesh Aloorkar1, Ajit Kulkarni1, Bhaskar Bangar1, Suyog Sulake1,
Pratik Kumbhar2
1
Department of Pharmaceutics, Satara College of Pharmacy, Degaon, Satara-415004 (MS) India
2
Department of Pharmaceutics, Yashoda Technical Campus, Wadhe, Satara- 415011 (MS) India
*Corresponding Author E-mail: pr.shindenamdeo@gmail.com

ABSTRACT:
Granulation is one of the most important unit operation in the production of pharmaceutical oral dosage forms.
Granulation is used mainly to improve flow, compressibility of powders, and to prevent segregation of the blend
components, improve content uniformity, and eliminate excessive amounts of fine particles. The results will be
improved yields, reduced tablet defects, increased productivity, and reduced down time. Particle size of the granules is
mainly affected by the quantity and feeding rate of granulating liquid. Pharmaceutical granules typically have a size
range between 0.2 and 4.0 mm, depending on their subsequent use. Among all granulating techniques, Moisture
Activated Dry Granulation (MADG) technology is widely used in granulation of moisture sensitive active
pharmaceutical ingredients. The objective of present work is to focus on the novel granulation technologies.

KEYWORDS: Granulation, content uniformity, Moisture Activated Dry Granulation (MADG) technology, active
pharmaceutical ingredients.

INTRODUCTION:
Granulation may be defined as a size enlargement process
which converts fine or coarse particles into physically
stronger and larger agglomerates having good flow
property, better compression characteristics and uniformity.
The art and science for process and production of granules
is known as Granulation Technology.
Granulation is the process in which primary powder
particles are made to adhere to form larger, multiparticle
entities called granules. Pharmaceutical granules typically
have a size range between 0.2 and 4.0 mm, depending on
their subsequent use. In the majority of cases this will be in
the production of tablets or capsules, when granules will be
made as an intermediate product and have a typical size
range between 0.2 and 0.5 mm, but larger granules are used
as a dosage form in their own right. Granulation normally
commences after initial dry mixing of the necessary
powdered ingredients so that a uniform distribution of each
ingredient through the mix is achieved. 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.
Received on 25.11.2013 Accepted on 15.01.2014
© Asian Pharma Press All Right Reserved
Asian J. Res. Pharm. Sci. 4(1): Jan.-Mar. 2014; Page 38-47
Reasons for granulation (3)
 To prevent segregation of the constituents of the
powder mixture
 To improve the flow properties of the mixture
 To improve the compaction characteristics of the
powder
 The granulation of toxic materials will reduce the
hazard associated with the generation of toxic dust that
may arise when handling powders. Suitable
precautions must be taken to ensure that such dust is
not a hazard during the granulation process. Thus,
granules should be non-friable and have a suitable
mechanical strength.
 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.
 Granules, being denser than the parent powder mix,
occupy less volume per unit weight. They are therefore
more convenient for storage or shipment.
 Increase the uniformity of drug distribution in the
product
 Improve appearance of the product
 Improve compression properties of the mixture

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Asian J. Res. Pharm. Sci. 2014; Vol. 4: Issue 1, Pg 38-47
The effectiveness of granulation depends on the following
properties:
 Particle size of the drug and excipients
 Type of binder (strong or weak)
 Volume of binder (less or more)
 Wet massing time (less or more)
 Amount of shear applied
 Drying rate (Hydrate formation and polymorphism)
Methods of granulation:
Generally, there are three methods of granulation
 Dry granulation
 Direct compression
 Wet granulation
In a suitable formulation a number of different excipients
are used. The common types used are diluents, to produce a
unit dose weight of suitable size, and disintegrating agents,
which are added to aid the break-up of the granule when it
reaches a liquid medium, e.g. on ingestion by the patient.
Adhesives in the form of a dry powder may also be added,
particularly if dry granulation is employed. These
ingredients will be mixed before granulation.
Dry granulation
In the dry methods of granulation the primary powder
particles are aggregated under high pressure. There are two
main processes. Either a large tablet (known as a ‘slug’) is
produced in a heavy-duty tabletting press (a process known
as ‘slugging’) or the powder is squeezed between two
rollers to produce a sheet of material (‘roller compaction’).
In both cases these intermediate products are broken using a
suitable milling technique to produce granular material,
which is usually sieved to separate the desired size fraction.
The unused fine material may be reworked to avoid waste.
This dry method may be used for drugs that do not
compress well after wet granulation, or those which are
sensitive to moisture. 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. 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
Chilosonator. Steps involved in dry granulation process are
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
39
[AJPSci.]
Advantages of dry Granulation:
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 can be advantages for moisture and heat sensitive
materials and improved disintegration since powder
particles are not bonded together by a binder.
Disadvantages of dry granulation
It requires a specialized heavy-duty tablet press to form
slug. It does not permit uniform color distribution as can be
achieved with wet granulation where the dye can be
incorporated into binder liquid. The process tends to create
more dust than wet granulation, increasing the potential
contamination.
Direct compression:
Direct compression involves comparatively few steps:
1. Milling of drug and excipients
2. Mixing of drug and excipients
3. Tablet compression
Disadvantages:
Capping, lamination, splitting, or layering of tablets is
sometimes related to air entrapment during direct
compression. When air is trapped, the resulting tablets
expand when the pressure of tablet is released, resulting in
splits or layers in the tablet. In some cases, require greater
sophistication in blending and compression equipments.
Direct compression equipments are expensive.
Wet Granulation:
Wet granulation involves the massing of a mix of dry
primary powder particles using a granulating fluid. The
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 granulation liquid may be used alone or,
more usually, as a solvent containing a dissolved adhesive
(also referred to as a binder or binding agent) which is used
to ensure particle adhesion once the granule is dry. Water is
commonly used for economical and ecological reasons. Its
disadvantage is, solvents may adversely affect drug
stability, causing hydrolysis of susceptible products, and it
needs a longer drying time than do organic solvents. This
increases the length of the process and again may affect
stability because of the extended exposure to heat. The
primary advantage of water is that it is non-flammable,
which means that expensive safety precautions such as the
use of flameproof equipment need not be taken. Organic
solvents are used when water-sensitive drugs are processed,
as an alternative to dry granulation, or when a rapid drying
time is required. In the traditional wet granulation method
the wet mass is forced through a sieve to produce wet
granules which are then dried. A subsequent screening stage
breaks agglomerates of granules and removes the fine
material, which can then be recycled. Variations of this
traditional method depend on the equipment used, but the
Asian J. Res. Pharm. Sci. 2014; Vol. 4: Issue 1, Pg 38-47 [AJPSci.]

general principle of initial particle aggregation using a done in a normal high shear processor; however, care must
liquid remains in all of the processes. Important steps be taken to avoid the formation of lumps as they cannot be
involved in the wet granulation are, broken down before drying. There are various options for
1. Mixing of the drug(s) and excipients drying in Single Pots. The basic drying principle relies on
2. Preparation of binder solution the application of a vacuum in the bowl thus lowering the
3. Mixing of binder solution with powder mixture to form evaporation temperature of the used granulation liquid
wet mass drastically. The traditional heat source comes from the
4. Coarse screening of wet mass using a suitable sieve heated dryer walls. The heat transfer is related to the surface
(6-12 # screens) area of the dryer walls and the volume of product treated.
5. Drying of moist granules Therefore, this direct heating method is most effective for
6. Screening of dry granules through a suitable sieve small scale, organic solvents or low quantities of binder
(14-20 # screen) fluids. Introducing stripping gas into the pot allows lower
7. Mixing of screened granules with disintegrant, glidant, final moisture content to be achieved. This very low
and lubricants. moisture content is only required in some particular
applications. A small quantity of gas is introduced in the
Role of binder in wet granulation: bottom of the equipment, which passes through the product
Binders are adhesives that are added to solid dosage bed, improving the efficiency of vapour removal. However,
formulations. The primary role of binders is to provide the as the heated wall is the only source of drying energy, linear
cohesiveness essential for the bonding of the solid particles scale-up is not possible.
under compaction to form a tablet. In a wet-granulation
process, binders promote size enlargement to produce High shear mixture granulation:
granules and thus improve flowability of the blend during High shear mixture has been widely used in pharmaceutical
the manufacturing process. Binders may also improve the industries for blending and granulation. In this type of
hardness of the tablets by enhancing intragranular as well as equipment, the particles are set into movement by an
intergranular forces. In a direct compression process, impeller rotating at a high speed (50- 100 rpm). Equipment
binders often act as fillers and impart compressibility to the also contains a chopper which rotates at around 1500-4000
powder blend. The cohesive properties of binders may rpm. The primary function of chopper is to cut large lumps
reduce friability of the tablets and thus aid in their into smaller fragments thus increases the binder distribution
durability and elegance. into the blend. The binder liquid is added by pouring,
pumping or spraying from the top. Wet agglomeration in a
Examples: high-shear mixer involves typically three phases,
Natural Polymers: Starch, pregelatinized starch 1 Dry Powder mixing
Synthetic polymers: PVP, methylcellulose, HPMC 2 Liquid binder addition
New Natural and Synthetic binders: Khaya gum, 3 Wet massing
leucocephala seed gum, anacardium occidentale gum,
gellan gum, combination of detarium gum and veegum. After the wet mass is produced, it is further processed to
New synthetic binders: Maltrodextrins, chitosan derivatives obtain dried grade particle size granules.
1 Wet sieving of granules
Limitations of wet granulation: 2 Drying
 The greatest disadvantage of wet granulation is its cost. 3 Dry sieving of granules
It is an expensive process because of labor, time,
equipment, energy and space requirements. First the materials are dry, mixed, where after liquid is
 Loss of material during various stages of processing added during mixing. Then the moist mass is wet massed in
 Stability may be major concern for moisture sensitive order to achieve a narrow particle size distribution.
or thermo labile drugs Thereafter the granules are wet sieved, dried and sieved
 Multiple processing steps add complexity and make again. The liquid amount is critical, because the process is
validation and control difficult susceptible for over-wetting, which leads to uncontrollable
 An inherent limitation of wet granulation is that any agglomerate growth.
incompatibility between formulation components is
aggravated. Advantages:
1. Short processing time
Wet granulation techniques (9) 2. Lesser amount of liquid binders required compared
Following are the four major techniques which are used for with fluid bed granulation.
wet granulation process. 3. Highly cohesive material can be granulated.

Single pot granulation Disadvantages:

A mixer/granulator that dries granules in the same 1 Mechanical degradation could take place in case of
equipment without discharging is commonly called a Single fragile particles.
Pot Processor (or One-Pot Processor). The granulation is

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Asian J. Res. Pharm. Sci. 2014; Vol. 4: Issue 1, Pg 38-47 [AJPSci.]

2 Due to increase in temperature chemical degradation of 1 Dry mixing of materials to achieve homogeneous
thermolabile material could be resulted. dispersion
3 Over wetting of granules may leads to large size lumps 2 Wet granulation of the resulted mixture to form wet
formation. mass
3 Extrusion of wet mass to form rod shaped particles.
Fluid bed granulation (9) 4 Rounding off (in spheronizer)
Fluidization is the operation by which fine solids are 5 Drying
transformed into a fluid like state through contact with a
gas. At certain gas velocity, the fluid will support the These dried rounded particles can be optionally screened to
particles giving them free mobility without entrapment. achieve a targeted mean size distribution. Following figure
Fluid bed granulation is a process by which granules are describes schematically the steps involved in the extrusion
produced in single equipment by spraying a binder solution spheronization process.
onto a fluidized powder bed. The material processed by
fluid bed granulation are finer, free flowing and
homogeneous. The system involves the heating of air and
then directing it through the material to be processed. Later,
the same air exit through the voids of the product. Fluid bed
processing of pharmaceuticals was first reported by
Wurster, by using air suspension technique to coat tablets
later used this technique in granulating and drying of
pharmaceuticals, for the preparation of compressed tablets.
Fluidized bed system contains various components such as,
 Air Handling Unit (AHU)
 Product container and air distributor
 Spray nozzle
 Disengagement area and process filters
 Exhaust blower or fan
Figure 1: Different steps involved in the Extrusion- Spheronization
 Control system process
 Solution delivery system

Advantages:
1 It reduces dust formation during processing, thus
improves housekeeping
2 It reduces product loss
3 It improves worker safety

Disadvantages:
1 The Fluid Bed cleaning is labor-intensive and time
consuming
2 Difficulty of assuring reproducibility

Application of Fluid bed granulator:

 In pharmaceutical industry: Tablet, capsule, low sugar
or no sugar granule of chinese medicine.
 Foodstuff: Cocoa, coffee, milk powder, juices
 Other industries: Pesticide, feed chemical fertilizer,
pigment, dyestuffs
 Drying: Powder or granule material
 Coating: Granule, protecting coat of pellet, spare color,
slow release film, bowel dissolve coating,
Extrusion-Spheronization:
This process is primarily used as a method to produce
multi-particulates for controlled release application. It is a 3 Physical characteristics of the active ingredients and
multiple step process involving at least five steps capable of
making uniform sized spherical particles.
Figure 2: Extrusion Spheronizer
Advantages:
1 Ability to incorporate higher levels of active
components without producing excessively larger
particles.
2 Two or more active agents can be easily combined in
any ratio in the same unit.
excipients can be modified.
4 Particles having high bulk density, low hygroscopicity,
high spherocity, dust free, narrow particle size
distribution and smoother surface can be produced.

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Asian J. Res. Pharm. Sci. 2014; Vol. 4: Issue 1, Pg 38-47 [AJPSci.]

Disadvantages:  Drug dramatization such as a strong electrolyte salt

This process is more labor and time intensive than other forms that usually have higher dissolution rate
commonly used granulation techniques  Manipulation of solid state of drug substance to
improve drug dissolution, i.e. by decreasing
Spray drying: crystallinity of drug substance through formation of
Spray Drying as a process has been used to produce solid solutions
microcapsules, food ingredients, flavors and various
biotechnological preparations. This process differs from the The use of water soluble salts and polymorphic forms, the
methods discussed above in that it is a continuous process formation of water soluble molecular complexes, drug
in which a dry granular product is made from a solution or a micronization, solid dispersion, co-precipitation,
suspension rather than initially dried the primary powder lyophilization, microencapsulation and the inclusion of drug
particles. The solution or suspension may be of drug alone, solutions or liquid drugs into soft gelatin capsules are some
a mixture of different excipients or a complete formulation. of the major formulation tools which have been shown to
As long as the liquid solution or suspension feed to the enhance the dissolution characteristics of water-insoluble
drying system, dry powder product continues to be drugs. However, among them, the technique of ‘‘liquisolid
produced. The spray drying process involves three compacts” is one of the most promising technique. The
fundamental steps, most common method is to increase surface area of the drug
1. Atomization of a liquid feed into fine droplets by micronization. But in practice, the effect of
2. Mixing of these sprays droplets with a heated gas micronization is often disappointing, especially when the
stream, allowing the liquid to evaporate and leave dried drugs are encapsulated or tableted. Micronized drugs also
solids. have the tendency to agglomerate as a result of their
3. Separation of the dried powder from the gas stream hydrophobicity, thus reducing their available surface area.
Several researchers have shown that the liquisolid technique
Advantages: is the most promising method for promoting dissolution rate
1 Rapid and continuous process of poorly water-soluble drugs.
2 Reduces overall cost by avoiding labor intensive
drying and granulation steps Advantages:
3 Offers minimal product handling and operator Simplicity, Low cost, Capability of industrial production.
exposure to dust.
4 OTC products are good candidates. Application of Liquisolid Techniques (4)
5 Suitable for heat sensitive product Solubility and dissolution improvement:
In order to overcome the limited solubility of the
Liquisolid technique(4) pharmaceutical, pharmaceuticals were formulated as
The poor dissolution rate of water insoluble drugs is still a liquisolid tablets. In fact, when the therapeutic dose of drug
substantial problem confronting the pharmaceutical is more than 50 mg, dissolution enhancement in the
industry. A great number of new and possibly, beneficial presence of low levels of hydrophilic carrier and coating
chemical entities do not reach the public merely because of material is not significant. However, by adding some
their poor oral bioavailability due to inadequate dissolution. materials such as poly Vinyl Pyrrolidone (PVP) to liquid
Over the years, various solid dosage formulation medication (Microsystems), it would be possible to produce
techniques, to enhance the dissolution of poorly soluble dry powder formulations containing liquid with high
substances, have been introduced with different degrees of concentration of drug. By adding such materials to the
success. The technique of ‘liquisolid compacts’ is a new liquid medication, low amount of carrier is required to
and promising addition towards such a novel aim. The obtain dry powder with free flowability and good
active ingredient in a solid dosage form must undergo compatibility.
dissolution before it is available for absorption from the
gastrointestinal tract. The poor dissolution characteristics of Flowability and compressibility:
water-insoluble drugs are a major challenge for Liquisolid compacts possess acceptable flowability and
pharmaceutical formulation scientists. The absorption rate compressibility properties. They are prepared by simple
of a poorly water-soluble drug, formulated as an orally blending with selected powder excipients referred to as the
administered solid dosage form, is controlled by its carriers and the coating materials. Many grades of cellulose,
dissolution rate in the fluid present at the absorption site, starch, lactose, etc. can be used as carriers, whereas silicas
i.e. the dissolution rate is often the rate-determining step in of very fine particle size can be used as coating materials. In
drug absorption. There are several methods for enhancing order to have acceptable flowability and compactability for
dissolution rate of poorly water-soluble drugs includes, liquisolid powder formulation, high levels of carrier and
 Reducing particle size to increase surface area, thus coating materials should be added and that in turn will
increasing dissolution rate of drug increase the weight of each tablet above 1 gm which is very
 Solubilization in surfactant systems difficult to swallow. Therefore, in practice it is impossible
 Formation of water-soluble complexes with conventional method to convert high dose drugs to
liquisolid tablet with the tablet weight of less than 1 gm.

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Asian J. Res. Pharm. Sci. 2014; Vol. 4: Issue 1, Pg 38-47 [AJPSci.]

For designing of sustain release tablet: Advantages:

Development of sustained release oral dosage forms is 1 Uniformly distributed in the powder particles
beneficial for optimal therapy in terms of efficacy, safety 2 Higher diffusion rate
and patient compliance. Liquisolid technique is a new and 3 Results in more spherical granule formation
promising method that can change the dissolution rate of 4 Thermally aids in drying process
drugs. It is claimed that if hydrophobic carriers such as 5 Higher dissolution rate of granules because of larger
Eudragit RL and RS are used instead of hydrophilic carries surface area generated
in liquisolid systems, sustained release systems can be 6 Time efficient
obtained. Therefore, it is suggested that the method have the 7 Environment friendly
potential to be optimized for the reduction of drug 8 No health hazards to operator
dissolution rate and thereby production of sustained release 9 Regulatory compliance
systems. 10 Maintain sterility

Bioavailability improvement: Disadvantages:

In the liquisolid and powdered solution systems the drug 1 Requires special equipment for steam generation and
might be in a solid dosage form, it is held within the powder transportation
substrate in solution, or in a solubilized, almost molecularly 2 Requires high energy inputs
dispersed state. Therefore, due to their significantly 3 Thermolabile materials are poor candidates
increased wetting properties and surface of drug available 4 More safety measure required
for dissolution, liquisolid compacts of water insoluble 5 Not suitable for all the binders
substances may be expected to display enhanced drug
release properties, and consequently, improved Melt granulation(1)
bioavailability. Melt granulation process has been widely used in the
pharmaceutical industry for the preparation of both
Table 1. Various Drying Techniques for Granulation immediate and controlled release formulations such as
Sr. Granulation Drying techniques pellets, granules, and tablets. This process has also been
No. Techniques
widely accepted for the enhancement of dissolution profile
1 Wet granulation Tray or fluid-bed dryer
Tray or fluid-bed dryer and bioavailability of poorly water soluble drugs by
Vacuum/gas stripping/microwave forming solid dispersion. Melt Granulation is also known as
Spray dryer “Thermoplastic Granulation” as the granulation is achieved
Extrusion/ Spheronization / by adding a meltable binder which is in solid state at room
Pelletization temperature but preferably melts in the temperature range of
2 Dry granulation Direct compression
Process Slugging Mill
50oC-80oC. No further addition of liquid binder or water is
Roller compactor Compacts milled required in the process as the binder in the melted state
itself act as granulating liquid and dried granules can be
Advanced granulation techniques: easily obtained by simple cooling at room temperature.
Over a period of time, due to technological advancements
and in an urgue to improve commercial output various, Advantages:
newer granulation technologies have been evolved such as, 1 Time and cost effective, as it eliminates the liquid
 Steam Granulation addition and drying steps
 Melt Granulation Technology 2 Water sensitive drugs are good candidates
 Moisture Activated Dry Granulation (MADG) 3 Controlling and modifying the release of drugs
4 Regulatory compliance
 Moist Granulation Technique (MGT)
 Thermal Adhesion Granulation Process (TAGP)
Disadvantages:
 Foamed Binder Technologies (FBT) 1 Heat sensitive materials are poor candidates
 Pneumatic Dry Granulation (PDG) 2 Binders having melting point in the specific range can
 Freeze granulation Technology only be utilized in the process

Steam granulation(8) Table 2. Hydrophilic meltable binders used in the melt granulation
Pure steam is a transparent gas. At standard temperature technique
and pressure, pure steam (unmixed with air, but in Hydrophilic Meltable Binder Typical Melting Range (°C)
equilibrium with liquid water) occupies about 1,600 times Gelucire 50/13 44 – 50
Poloxamer 188 50.9
the volume of an equal mass of liquid water. This process is Polyethylene glycols :
simply a modification of conventional wet granulation PEG 2000 42 – 53
method. Here steam is used as a binder instead of water. PEG 3000 48 – 63
Process offers several advantages and disadvantages over PEG 6000 49 – 63
other conventional granulation methods such as, PEG 8000 54 – 63

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Asian J. Res. Pharm. Sci. 2014; Vol. 4: Issue 1, Pg 38-47 [AJPSci.]

Table 3. Hydrophobic meltable binders used in the melt Disadvantages:

granulation technique 1 Moisture sensitive and high moisture absorbing APIs
Hydrophobic Meltable Binder Typical Melting Range (°C)
are poor candidates
Bees wax 56 – 60
Carnauba wax 75 – 83 2 Formulations with high drug loading are difficult to
Cetyl Palmitate 47 – 50 develop
Glyceryl stearate 54 – 63
Hydrogenated castor oil 62 – 86 Moist Granulation Technique (MGT):
Microcrystalline wax 58 – 72 MGT works on the same principle as Moisture Activated
Paraffin wax 47 – 65
Stearic acid 46 – 69
Dry Granulation (MADG) described earlier. It involves
Stearic alcohol 56 – 60 binder activation by adding a minimum amount of liquid.
Then, excess of moisture present in the blend is removed by
In pharmaceutical industry the melt extrusion has been used adding moisture absorbing material like Microcrystalline
for various purposes, such as, Cellulose (MCC) which eliminates the drying step. It is
 Improving the dissolution rate and bioavailability of applicable for developing a controlled release formulation.
the drug by forming a solid dispersion or solid solution
 Controlling or modifying the release of the drug Thermal Adhesion Granulation Process (TAGP):
 Masking the bitter taste of an active drug TGAP involves granulation by adding very less amount of
water or solvent as compared to the traditional wet
Moisture Activated Dry Granulation (MADG) (1) granulation methods. In this process drug and excipient
MADG is a process in which moisture is used to activate mixture heated at a temperature range from 30oC to about
o
granule formation, without the need to apply heat to dry the 130 C in a closed system under mixing by tumble rotation
granules. There are two main stages in MADG are, until the formation of granules take place. Drying step is not
required in most instances due to low amount of moisture
1. Agglomeration
added in the process. Granules of required particles size can
2. Moisture distribution/ Absorption
be obtained after cooling and screening. It provides
granules with good flow properties and binding capacity to
During agglomeration, drug is blended with diluents and
binder in the powder form, to obtain a uniform mixture. form tablets of low friability, adequate hardness and have a
This blend constitutes approximately 50-80% of formula high uptake capacity for active substances.
weight. While mixing, a small amount of water (1-4%) is
sprayed as small droplets onto the powder blend, which Foam Granulation(1)
moistens the binder and makes it tacky. The binder Here liquid binders are added as aqueous foam. It has
several benefits over spray (wet) granulation such as it
facilitates the binding of the drug and excipients as they
requires less binder than spray granulation, requires less
move in a circular motion forced by the mixer blades. The
water to wet granulate. The rate of addition of foam is
process does not results in larger lumps formation as the
amount of water used in this process is very small as greater than rate of addition of sprayed liquids, no
compared to the other conventional wet granulation detrimental effects on granulate, tablet, or in vitro drug
dissolution properties, no plugging problems since use of
techniques. The particle size of the agglomerates generally
falls in the range of 150-500 μm. In moisture spray nozzles is eliminated, no over wetting. It is useful for
distribution/absorption, moisture absorbents, such as granulating water sensitive formulations, reduces drying
microcrystalline cellulose or silicon dioxide, are addedtime, uniform distribution of binder throughout the powder
while mixing continues. When they come into contact, thebed, reduce manufacturing time, less binder required for
moisture absorbents pick up moisture from the moist Immediate Release (IR) and Controlled Release (CR)
formulations. Foam granulation technique involves addition
agglomerates, resulting in moisture redistribution within the
mixture. When this happens, the entire mixture becomes of liquid binders as aqueous foam. The advantages of
foamed binder addition conventional binder addition
relatively dry. While some of the moisture is removed from
the wet agglomerates, some of these agglomerates remain method includes,
almost intact and some usually the larger particles may 1 No spray nozzle is used
break up. This process results in granulation with more 2 Improve process robustness
uniform particle size distribution. 3 Less water required for granulation
4 Time efficient drying
5 Cost effective
Advantages:
6 Uniform distribution of binder
1. Applicable to more than 90 % of the granulation need
7 No over wetting
for pharmaceutical, food and nutritional industry
8 Applicable for water sensitive formulation
2. Time efficient
3. Very few variables involved in the process
4. Suitable for continuous processing
5. Less energy involved during processing

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Asian J. Res. Pharm. Sci. 2014; Vol. 4: Issue 1, Pg 38-47 [AJPSci.]

Pneumatic Dry Granulation Technology (PDGT)(1)

Is based on a pneumatic dry granulation process, a novel
dry method for automatic or semi-automatic production of
granules. This enables flexible modification of drug
loading, disintegration time and tablet hardness. It is
compatible with other technologies, such as sustained
release, fast release, coating etc. It is suitable for heat labile
and moisture sensitive drugs. The PDG Technology
produces porous granules with excellent compressibility
and flowability characteristics. The pneumatic dry
granulation process can granulate virtually any
pharmaceutical solid dosage ingredient. The granulated
material has exceptionally good flowability and
compressibility properties. PDG Technology has been used
with superior results in developing fast-release, controlled-
release, fixed-dose, and orally disintegrating tablets. The
technology is applicable to practically any solid dosage
pharmaceutical product. PDG technology can achieve,
 High drug loading, even with difficult APIs and
combinations Figure 3: PDG Technology and wet granulation Comparison
 Taste masking
 Excellent stability

Today, wet granulation is the most commonly used Advantages:

granulation method. Formulation teams will usually target a
direct compression or dry granulation formulation where
possible but in approximately 80 % of the cases they end up
with a wet granulation formulation due to processing issues.
Wet granulation is also unsuitable for moisture sensitive
and heat sensitive drugs, it is more expensive than dry
granulation, it is relatively labour 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. Scale up is usually an issue, and there are
considerable capital requirements. 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 flowability.
The results can be archived without using exotic and
expensive excipients.
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.
1. Good granulation results even at high drug loading
have been achieved even with materials known to be
historically difficult to handle,
2. Faster speed of manufacturing compared with wet
granulation
3. Lower cost of manufacturing compared with wet
granulation
4. The system is closed offering safety advantages due to
low dust levels and potential for sterile production or
handling of toxic materials
5. The end products are very stable - shelf life may be
enhanced
6. Little or no waste of material
7. Scale-up is straightforward
8. The granules and tablets produced show fast
disintegration properties, offering the potential for fast
release dosage forms
9. Release time can be tailored to requirements
Freeze Granulation Technology:
Swedish Ceramic Institute (SCI) has adopted and developed
an alternative technique that is freeze granulation, 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.

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Asian J. Res. Pharm. Sci. 2014; Vol. 4: Issue 1, Pg 38-47 [AJPSci.]

resultant alterations in their binding mechanisms. Tablets

from these granules have excellent hardness and stability.
TOPO granulation requires only a very small quantity of
liquid to start the chain reaction. In contrast to other
technologies that require e.g. acetone, TOPO uses only pure
water or water-ethanol mixtures for granulation. As a result,
there are no solvent residues in the finished products.

Continuous Flow Technology (CFT):

Continuous Flow (CF) technology is our second generation
granulation technology and is designed especially for high
throughput granulation. The technology does not need any
liquid to start the chain reaction. Granulation is carried out
in an inclined drum into which powder is fed at one end and
granulate removed at the other. The drum is rotated in a
way, which is designed to eliminate almost all shear forces.
The process results in granules with a surface protected by
Figure 4: Freeze granulation inactive components that do not harm sensitive APIs. CF
technology enables us to produce up to 12 tons of granules
every day – ideal for products that require large volumes of
Melt Extrusion Technology: granules per single dosage form. With no need to add any
Melt extrusion technology has proven to be a suitable solvents like acetone, there are no solvent residues in the
method for the production of controlled release reservoir finished product.
systems consisting of polyethylene vinyl acetate (EVA) co-
polymers. Based on this technology, two controlled release Advantages:
systems Implanon® and Nuvaring® have been developed. 1. Sensitive APIs are protected against acids or bases
A melt extrusion process for manufacturing matrix drug 2. Granules are less sensitive to humidity and high
delivery system was reported by Sprockel and co-workers. temperature
In 1994, Follonier and co-workers investigated hot-melt 3. Granules form extremely stable products
extrusion technology to produce sustained-release pellets. 4. No solvent residues in the final products
Another application of hot-melt extrusion was described by
Miyagawa, Sato, and coworkers in 1996 and 1977-8. They Granulation characterization:
studied the controlled release and mechanism of release of Granulation is a process used to prevent segregation of
diclofenac. formulation components in a powder blend, bulk volume of
granulation, improve blend flow, content uniformity,
Melt Agglomeration (1) compressibility, and other properties. Chemical properties
Melt agglomeration is a process by which the solid fine are equally important due to their impact on specifications
particles are bound together into agglomerates, by agitation, of a dosage form such as content uniformity, chemical
kneading, and layering, in the presence of a molten binding purity, and in vitro performance. In vivo performance such
liquid. Dry agglomerates are obtained as the molten binding as bioequivalence done because it determines whether a
liquid solidifies by cooling. Typical examples of melt pivotal bioequivalency batch passes or fails. Granule Size
agglomeration processes are melt pelletization and melt affect the dissolution performance which ultimately affect
granulation. During the agglomeration process, a gradual bioequivalence study. Physical characterization can be
change in the size and shape of the agglomerates would take performed at molecular, particulate, or bulk (macroscopic)
place. It is usually not possible to differentiate between levels.
granulation and pelletization. Thus granulation is
Table No. 4. Different Parameters and Methods for
considered a pelletization process when highly spherical Characterization of Granules
agglomerates of narrow size distribution are produced. Sr. No. Parameters Method
1 Particle Morphology Optical microscopy
TOPO Technology(6) 2
Particle Size Sieve analysis, laser light
Hermes Pharma has developed unique technology for Distribution scattering
3 Nature Powder X-Ray Diffraction
carrying out single pot granulation. Patented TOPO
4 Thermal Analysis DSC, TGA, DTA
technology produces granules for tablets which contain at Near-infrared (NIR)
least one solid crystalline, organic acid and one alkaline or 5 Identification
spectroscopy
alkaline earth metal carbonate that reacts with the organic 6 Surface Area Gas adsorption
acid in aqueous solution to form carbon dioxide. TOPO 7 Granule Porosity Mercury intrusion methods
granulation technology comprises a one-step vacuum Development of a
8 Granule Strength
Formulation
system, under fully instrumented in-process control (IPC). Granule Flowability Mechanical Method, Hopper
The process modifies the surface of carrier materials with 9
and Density Method, Density Apparatus

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 Asian J. Res. Pharm. Sci. 2014; Vol. 4: Issue 1, Pg 38-47 [AJPSci.]

CONCLUSION: granular properties. International journal of pharmaceutics,

Pharmaceutical products are processed all over the world
using the direct compressing, wet-granulation, or dry
granulation methods. Which method is chosen depends on
the ingredients individual characteristics and ability to
properly flow, compresses, eject, and disintegrate.
Choosing a method requires thorough investigation of each
ingredient in the formula, the combination of ingredients,
and how they work with each other. Then the proper
granulation process can be applied. A judicial selection of
appropriate technology for carrying out the granulation
process is the key to achieve a targeted granulation and final
product parameters. In depth knowledge of the processing
techniques and their merits and demerits is required to
adopt during development stage of product. A systematic
approach should be followed for selecting the suitable
granulation process.
ACKNOWLEDGEMENTS:
The authors express their sense of gratitude towards
management of Satara College of Pharmacy, Satara for 24.
providing all obligatory facilities necessary to carry out
present work. Also Prof. (Dr.) S. P. Gawade, Dr. A. S. 25.
Kulkarni deserves a special mention for their timely
suggestions.
357(1-2) 2008: 206-212.
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Pharmaceutical Granulation Technology. Marcel Dekker INC,
New York, 1997: 7-13.
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The Theory and Practice of Industrial Pharmacy, 3rd edition,
Varghese publishing house, Bombay, 1991: 320-321.
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and breakage phenomena in agitated wet granulation processes: a
review. Powder Technol. 2001; 117:3-39.
20. Kristensen HG, Schaefer T. Granulation, a review on wet
granulation, Drug Dev. Ind. Pharm.; 13 (4&5) 1987: 803-872.
21. Knight PC, Instone T, Pearson JMK, Hounslow MJ. An
investigation into the kinetics of liquid distribution and growth in
high shear mixer agglomeration. Powder Technol. 97 1998: 246-
257.
22. Ismat U, Jennifer W. Moisture-activated dry granulation: The one
pot process. Pharma Tech Eur 22(3) 2010.
23. Yeh TS, Sheu MT, Chen SJ, Tseng CB, Yeh DH, Ming W.
Pharmaceutical Mfg. Co. Ltd., Taipei Medical University
“Application of Thermal Adhesion Granulation –a Novel Low-
Moisture Granulation” Method – for the Production of Direct-
Tabletting Formulations and Aids.
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