P. Muralidhar et al. Int. Res. J. Pharm.

2016, 7 (10)

INTERNATIONAL RESEARCH JOURNAL OF PHARMACY

www.irjponline.com
ISSN 2230 – 8407

Review Article
NOVEL TECHNIQUES OF GRANULATION: A REVIEW
P. Muralidhar *, E. Bhargav, C. Sowmya
Center for Pharmaceutical research, Raghavendra Institute of Pharmaceutical education and research (RIPER),
Anantapuramu-515721, Andhra Pradesh, India
*Corresponding Author Email: muralip2016riper@gmail.com

Article Received on: 11/09/16 Revised on: 04/10/16 Approved for publication: 14/10/16

DOI: 10.7897/2230-8407.0710114

ABSTRACT

Granulation is an important unit process in the production of pharmaceutical dosage forms like tablets, capsules and other dosage forms. Granulation
process increases flow, compressibility and content uniformity of the powders. It inhibits the separation of blend components and reduces excessive
amount of fine particles. This process helps to achieve improved yields with less tablet manufacturing defects. Particle size of granules depends on the
quantity and feeding rate of the granulating liquid. Selecting a method of granulation requires comprehensive study of each ingredient in the formula,
the combination of ingredients and their compatibility with each other is checked after, which appropriate granulation process can be applied. The
recent technologies used for granulation include steam granulation, moisture activated dry granulation (MADG), moist granulation technique (MGT),
extrusion-spheronization granulation, fluidized bed granulation, thermal adhesion granulation process (TAGP) and foam granulation etc. have their
own advantages and overcome the disadvantages of conventional granulation process such as dust generation or deteriorating effect of heat as drying
step. The objective of present work is to focus on the novel granulation technologies.

Key words: Granulation, Granulation technology, Advances, Pharmaceutical industry.

INTRODUCTION Classification of Granulation Technologies11

Basing upon the type of processing, that had been involved, GT
Granulation is process making separate powder particles in to a can be classified as follows:
group by using granulating fluid.1 Granulating fluid may be 1. Conventional methods
water including or water heating, this depend on the nature of · Dry granulation
drug and other excipients used. The process of making of · Wet granulation
granules is granulation and technique and equipment used is a) High-shear wet granulation
granulation technology.2-5 b) Low-shear wet granulation
2. Novel/advanced methods
Stages of granulation:6-10 · Moisture activated dry granulation
a) Pendular stage: This is initial stage just after addition of · Thermal adhesion granulation
binding agent. · Pneumatic dry granulation
b) Funicular stage:This is second stage where adequate · Melt/thermoplastic granulation
binding solution incorporated between the particles. · Fluidized bed granulation
c) Capillary stage:In this stage binding solution entrapped by
· Extrusion-spheronization granulation
capillary action. This is a perfect stage where good granules
· Spray drying granulation
can be obtained.
d) Droplet stage:Here over wetting, particles may form. This · Freeze granulation
stage is not desirable stage.(Shown in Figure 1)4. · Foam binder granulation
· Steam granulation

Dry Granulation
This method is cheapest method of granulation and suitable for
hydro-sensitive products. In this method granules are prepared
without binding solution and heat. This method involves two
steps. One is preparing large particles called slugging. Second
one is milling and screening of slugs into small granules. 12-16

Advantages
a) Less equipments are needed
b) Eliminate binding solution process

Disadvantages
a) Requires specialized heavy duty tablet press.
Figure 1: Stages in granulation b) Does not permit uniform colour distribution.

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c) Tends to create more dust with respect to wet Advantages

granulation. · Requires less amount of granulation fluid and forms
d) Increases the potentiality of cross contamination. granules with good flow property
· Reduces the dust generation during powder processing.
Applications
Suitable for hydrophobic andoily substances. Disadvantages
· Not suitable for substances with more than 1300C melting
Wet granulation point andfor materials with binding solvents other than
This method involves several steps. Initially by the addition of water and ethanol.
binding agent (hydrophilic or hydrophobic) to get wet mass.
This wet mass is passed through the sieves followed by Applications: Applicable in R&D systems
drying.5,8
Pneumatic Dry Granulation (PDG):
Advantages It is a novel dry granulation method developed by Atacama Labs
Easy process and no need of experts (Helsinki, Finland). It involves production of compact mass by
using roller compaction method with little compression force.
Disadvantages This material is introduced into a newly innovated fractionating
Time consuming, Labor cost is more, several steps are involved device that separates the granules and recycles rejected
fraction.24-28
Moisture Activated Dry Granulation (MADG)
Advantages
MADG is also known as ‘Single-Pot’ granulation or moist · Can achieve high drug loading of traditionally proven
granulation. Here drying step is eliminated because very less difficult materials.
amount of binding agent is used to activate binding process and · Faster development (within weeks) even with historically
moreover moisture absorbing agents like microcrystalline proven difficult materials.
cellulose (MCC), potato starch, a mixture of MCC and potato · Decreases cost of product by minimizing waste through
starch (50% w/w), silicon dioxide, Spress® B818 Pregelatinized recycling and production cost.
Corn Starch NF 17, Maltrin®maltodextrins 18, etc. used to · Excellent stability with enhanced shelf-life.
remove moisture present in the granules.16-18 This technology
· Compatible with other technologies like coating, sustained
involves wet agglomeration of the powder mixture to form a
release, fast release.
tacky mass followed by moisture absorption to dry the granules.
· Suitable for thermo-labile and moisture sensitive drugs.
In this technology small amount of water (1–4%) is added to
agglomerate the powder blend.19,20 · Taste masking and tailoring of release rate and time can be
achieved.
Advantages · Produce soft and porous granules with high compressibility
· A simple, clean, lean process that utilizes very little and Flowability.
granulating fluid. · Possesses potentiality to handle sterile products or toxic
· Produce granules with more uniform particle size materials
distribution (particle size range of 150-500 μm) and · Lowers scale-up cost and problems.
excellent flowability.
· Economical and time efficient, as requires less energy and Disadvantages
eliminates drying step. · Due to usage of double compression force materials used
· Suitable for continuous processing, and for preparation of may undergo degradation.
floating and sustained release products. · High cost due to novelty in process.

Disadvantages Applications
· Unsuitable for thermo-labile, moisture sensitive, high · Applied widely because of compliment with regulatory
moisture absorbing substances. bodies.
· Difficult to develop formulations with high drug loading. · Suitable for drugs with high melting point.

Applications High Shear Mixture Granulation

· Suitable for eutectic and hydro-phobic substances.

Thermal Adhesion Granulation (TAG)

It is a novel GT, patented by Wei-Ming Pharmaceutical
Company (Taipei, Taiwan) that involves granulation by adding
very less amount of granulation fluid. In this process the
binder&/diluent mixture is first wetted by pouring water or
ethanol (2.0–3.6%).17-19 Then this blend is placed in a pre-
warmed glass bottle, sealed and then heated by an IR lamp to
raise surface temperature of the equipment to 900C–1050C for
water as solvent, 700C–900C for ethanol as a binding agent and
mixed under tumble rotation for 3–20 min until granules are
formed. Resulted granules were immediately sifted with proper
sieve 22.21-23 Figure 2: Rapid mixture granulator

Rapid mixture granulator(RMG) is a simple and easily cleanable

equipment developed in accordance to Good Manufacturing

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Practice requirements, to reduce the cross-contamination and the It is an air suspension technique, of pharmaceuticals was first
environmental hazards and to get spherical and well-compacted reported by Wurster to coat tablets that are later used for
granules in a relatively short time. This equipment can be granulating and drying of pharmaceuticals and particle/granule
operated in a closed unit and it involves mixing, primary and coating. 31-34
secondary granulation, drying steps. Primary granulation step Fluidized bed granulation process involves spraying of binder
involves spraying of the binding agent onto the powder bed solution onto the fluidized powder bed (FPB) to get finer, free
while the secondary granulation involves kneading of the wet flowing and homogeneous granules employing single equipment
product to produce and to enlarge the granules. Subsequent known as FBP. FBP contains air-handling unit, product
drying of final material is done suitably under low pressure at container and air distributor, spray nozzle, disengagement area
moderate temperature. 29,30,31,32 and process filters, exhaust blower or fan, control system,
solution delivery system (shown in figure 3)4.
Impeller speed, chopper speed, water addition method and rate, Advantages
massing (mixing) time, load of the RMG, feed material · Reduces dust formation during processing.
characteristics, drug substance particle size are the granulation · Improves housekeeping and worker safety.
process parameters that requires monitoring to get granules with · Suitable for subsequent coating and controlled release
desired characteristics. Volume of load in RMG should be less products and reduces product loss
than two-thirds of its capacity (shown in figure 2)4.
Disadvantages
Advantages · Cleaning was labor-intensive, time consuming and assuring
· It involves Short processing time. reproducibility was troublesome.
· Requires less amount of liquid binders required with respect
to fluidized bed granulation technology. Applications: Applicable for granulation, drying, coating,
· Highly cohesive material can be handled. mixing, etc.

Disadvantages Extrusion-Spheronization Granulation

· Mechanical degradation could take place in case of fragile
particles.
· Results in the uneven distribution of binder solution
throughout moving powder bed during high-shear
granulation.
· Unsuitable for thermo-labile material.
· Over wetting leads to formation of lumps and large size
granules.

Applications
· Used in pharmaceutical industry and as well as in paint,
cosmetic industries

Fluidized Bed Granulation

Figure 4: Extrusion-Spheronization Granulation process

A multiple step process involves five-steps capable of making

uniform sized spherical particles with narrow size distribution
that were suitable for controlled release formulations by
extruding the tacky mass through extruder and subsequent
pelletization or spheronization using pelletizer or spheronizer. 31-
34
Pellets are prepared by employing wet or hot melt extrusion
techniques.
Wet extrusion technique involves extrusion of wet agglomerate
(tacky mass) of the powder mixture through extruder. Hot melt
extrusion technique involves extrusion of thermoplastic
materials through a thermostatically controlled extruder.
Processing parameters like extruder pore size, spheronization
speed and operational conditions need to be optimized which
influences particle size, size distribution and morphology of
Figure 3: Fluidized bed granulator granules (shown in figure 4)35

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Advantages Disadvantages
· Incorporates higher levels of active without producing · Substances which are sensitive to heat are poor candidates.
excessively larger particles · Improper spray leads to inadequate sized particles.
· Easy to combine two or more active agents within the same
unit, in any ratio Applications: Applicable in the preparation of dry syrups and
· Modification of physical characteristics of the active dusting powders.
ingredients and excipients
· Can produce spherical particles with high bulk density, low Freeze Granulation
hygroscopicity, narrow particle size distribution and Integrated Biosystems, Inc. (California, USA) had patented
smoother surface. freeze GT that results in spherical and free flowing granules
with optimal homogeneity. FG involves spraying of suspension
Disadvantages containing powder into liquid nitrogen where the drops were
· Needs more labor and time for granulation instantaneously frozen to form granules which upon subsequent
· Cannot be used for moisture sensitive and thermo-labile freeze-drying yields dry granules. 12-17
materials.
Advantages
Applications: Used inpreparation of granules for tablets, · Granule density can be controlled by the solid contents of
capsules, suspensions and for dry powders. the suspension.
· Non-oxides and metals can be handled as mild drying
Spray Drying Granulation prevents serious oxidation.
It is a continuous process where a dry granular product is · Results solid granules with no cavities.
obtained by feeding a binding solution or a suspension of active · High yield with low material waste.
agent with or without excipients to the drying system where the · Low to high quantities of granules can be produced with
feed is atomized and dried with a heated gas stream followed by reproducibility.
subsequent separation of granular product from the gas stream. · Equipment can be easily cleaned up and Organic solvents
Alternately particle agglomeration was brought about by can be recycled.
spraying the binder solution onto bed of powder particles in
fluidized state achieved with the passage of air followed by Disadvantages
drying using hot air. 19,20,27,28 There may be a chance of degradation of drug due to use of
temperature which is less than 0 0C.
Advantages
· It is a fast and continuous process. Applications: In the formation of injectable granules.
· Low cost.
· Reduces operator exposure to dust.

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Foam Binder Granulation · Use of temperature leads to degradation and physical

FBG is a simple and safer wet granulation processing of changes.
materials and employs high shear or low shear RMG, or FBP in
both laboratory-scale and production-scale settings using Applications: Applied in the formulation of sterile products.
hydroxypropylcellulose or hypromellose as binder. This
technology involves continuous addition of liquid binders in the Advanced Granulation Equipment
form of aqueous foam either onto the previously blended Semiautomatic or fully automatic instrumentation systems had
powder bed contained in RMG with variable speeds of impeller been developed and are used for optimizing each unit operation
or chopper or in FPB contained in FBD. After attaining like granulation, slugging, compaction, and compression.
granulation endpoint the wet granules are dried in FBP till Combining all or most of the unit operation in one system are
desired moisture content was achieved. also advanced approaches in granulation equipment technology
Wet foam hasphysical characteristics and flow similar to liquid that operates with greatest reliability. 12,13,16,21,34
and dry foam has high air-to-liquid ratio that moves more like a
solid,are used for granulation; while dry foam is recommended. CONCLUSION
Foam quality was calculated from penetration time and
nucleation ratio and the data is used to determine the range of The advances in granulation technology lead to the formulation
acceptable foam quality that can be used to get granulated of better dosage forms in terms of content uniformity and
product with desired quality.11-13,15,19,20,28,33 stability aspects. Still lot of research work and study has to be
done for the promotion of content uniformity, stability not only
Advantages in tablets and capsules but also in dry syrups and various other
· Eliminates use of spray nozzle thereby eliminates plugging formulations in Pharmaceutical industries.
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