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Shanmugam, BioImpacts, 2015, 5(1), 55-63
doi: 10.15171/bi.2015.04 TUOMS
http://bi.tbzmed.ac.ir/ Publishing
BioImpacts Group
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Granulation techniques and technologies: recent progresses
Srinivasan Shanmugam*
Pharm. R&D Institute, Hanmi Pharm. Co., Ltd., Hwasung, Gyeonggi, Korea
Article Type Abstract
Granulation, the process of particle enlargement by
agglomeration technique, is one of the most significant
unit operations in the production of pharmaceutical
dosage forms, mostly tablets and capsules. Granulation
process transforms fine powders into free-flowing, dust-
free granules that are easy to compress. Nevertheless,
Article Type: granulation poses numerous challenges due to high
Mini-review quality requirement of the formed granules in terms
of content uniformity and physicochemical properties
Article History: such as granule size, bulk density, porosity, hardness,
Received: 08 Dec. 2014 moisture, compressibility, etc. together with physical
Revised: 10 Dec. 2014 and chemical stability of the drug. Granulation process
Accepted: 27 Dec. 2014 can be divided into two types: wet granulation that
ePublished: 18 Feb. 2015 utilize a liquid in the process and dry granulation that
Keywords: requires no liquid. The type of process selection requires thorough knowledge of physicochemical
Granulation technique and properties of the drug, excipients, required flow and release properties, to name a few. Among
technology; currently available technologies, spray drying, roller compaction, high shear mixing, and fluid
Pneumatic dry granulation; bed granulation are worth of note. Like any other scientific field, pharmaceutical granulation
Reverse wet granulation; technology also continues to change, and arrival of novel and innovative technologies are inevitable.
Steam granulation; This review focuses on the recent progress in the granulation techniques and technologies such
Moisture-activated dry as pneumatic dry granulation, reverse wet granulation, steam granulation, moisture-activated
granulation; dry granulation, thermal adhesion granulation, freeze granulation, and foamed binder or
Thermal adhesion granu- foam granulation. This review gives an overview of these with a short description about each
lation development along with its significance and limitations.
Introduction so that it occupies less volume per unit weight for better
Granulation, a technique of particle enlargement by storage and shipment, to facilitate metering or volumetric
agglomeration, is one of the most significant unit dispensing, to reduce dust during granulation process to
operations in the production of pharmaceutical dosage reduce toxic exposure and process-related hazards, and to
1 2
forms, mostly tablets and capsules. During the granulation improve the appearance of the product. Consequently, the
process, small fine or coarse particles are converted into ideal characteristics of granules include spherical shape for
large agglomerates called granules. Generally, granulation improved flow, narrow particle size distribution for content
commences after initial dry mixing of the necessary uniformity and volumetric dispensing, sufficient fines to
powder ingredients along with the active pharmaceutical fill void spaces between granules for better compaction
ingredient (API), so that a uniform distribution of each and compression characteristics, and adequate moisture
ingredient throughout the powder mixture is achieved. and hardness to prevent breaking and dust formation
Although granules used in the pharmaceutical industry during process.
have particle size in the range of 0.2-4.0 mm, they are Granulation is an exemplary of particle design and the
primarily produced as an intermediary with a size range properties of the particles acquired after granulation
of 0.2-0.5 mm to be either packed as a dosage form or be depend on particle size of the drug and excipients,
mixed with other excipients before tablet compaction or the type, concentration, and volume of binder and/or
capsule filling.1,2 solvents, granulation time, type of granulator, drying rate
Granules are produced to enhance the uniformity of the (temperature and time), etc. The primary methods by
API in the final product, to increase the density of the blend which the agglomerated granules are formed include solid
*Corresponding author: Srinivasan Shanmugam, Email: rxsrinivasan@gmail.com
© 2015 The Author(s). This work is published by BioImpacts as an open access article distributed under the terms of
the Creative Commons Attribution License (http://creativecommons.org/licenses/by-nc/4.0/). Non-commercial uses of the work are
permitted, provided the original work is properly cited.
Shanmugam
bridges, sintering, chemical reaction, crystallization and Recent progress in dry granulation
deposition of colloidal particles.1,3 Besides, binding can Dry granulation could be achieved either by roller
also be accomplished through adhesive and cohesive forces compaction or by slugging. The two different types are
by utilizing high viscous binders. The series of mechanisms illustrated in the schematic diagram Fig. 2. There has not
by which granules are formed from the powder particles been much progress in the dry granulation technique
encompass wetting and nucleation, coalescence or growth, and technology in comparison to wet granulation, except
consolidation, and attrition or breakage.3-5 for one important innovation known as pneumatic
Blend of powders containing pharmaceutical excipients dry granulation technology developed by Atacama
6
and API can be compressed into tablets either by direct LabsOy (Helsinki, Finland), which is described below.
compression or after making granules by agglomeration or The description of its significance and limitations are
granulation techniques (Fig. 1). The granulation technique summarized in Table 1.
may be widely categorized in to two types, dry granulation
and wet granulation, based on the type of method used Pneumatic Dry Granulation (PDG)
to facilitate the agglomeration of powder particles (Fig. Pneumatic dry granulation (PDG), an innovative dry
1). Dry granulation uses mechanical compression (slugs) granulation technology, utilizes roller compaction
or compaction (roller compaction) to facilitate the together with a proprietary air classification method to
agglomeration of dry powder particles, while the wet produce granules with extraordinary combination of
6,7
granulation uses granulation liquid (binder/solvent) to flowability and compressibility. In this method, granules
facilitate the agglomeration by formation of wet mass by are produced from powder particles by initially applying
adhesion. Among these two techniques, wet granulation is mild compaction force by roller compactor to produce a
the most widespread granulation technique used despite compacted mass comprising a mixture of fine particles and
the fact that it involves multiple unit processes such as granules. The fine particles and/or smaller granules are
wet massing, drying and screening, which are complex, separated from the intended size granules in a fractioning
time consuming, and expensive requiring large space and chamber by entraining in a gas stream (pneumatic
1,2,5
multiple equipment. system), whereas the intended size granules pass through
The type of process selection requires thorough knowledge the fractioning chamber to be compressed into tablets.
of physicochemical properties of the drug, excipients, The entrained fine particles and/or small granules are
required flow and release properties, etc. Granulation then transferred to a device such as a cyclone and are
technologies like roller compaction, spray drying, either returned to the roller compactor for immediate re-
supercritical fluid, low/high shear mixing, fluid bed processing (recycling or recirculation process) or placed in
granulation, extrusion/spheronization, etc. have been a container for reprocessing later to achieve the granules
7,8
successful for many decades in the preparation of various of desired size. The schematic diagram of this process is
pharmaceutical dosage forms. Pharmaceutical granulation represented as Fig. 3.
technology continues to change, and various improved, PDG technology could successfully be used to produce
modified, and novel techniques and technologies have been good flowing granules for any formulations that produce
made available along the course. The aim of this review is compacts with a tensile strength of ~ 0.5 MPa. Also, this
to give the reader a glimpse of the latest techniques and technology enables the use of high drug loads of up to
technologies with regard to pharmaceutical granulation. 70-100%, because sufficient flowability could be achieved
Subsequently, this review gives a short description even at lower roll compaction forces (lower solid fractions)
9
about each development along with its significance and compared to usual roller compaction. In addition to these,
limitations, which are summarized in Table 1.
Fig. 2. Schematic diagram of dry granulation and two different
techniques. Method I is roller compaction and Method II is
Fig. 1. Schematic diagram of tablet compression techniques slugging.
56 BioImpacts, 2015, 5(1), 55-63
Recent progresses in granulation tech
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BioImpacts, 2015, 5(1), 55-63 57
Shanmugam
this technology avails various other benefits such as faster solution was prepared initially and the dry powder
processing speed, low cost, little or no material wastage, excipients were added to the binder solution under
low dust exposure due to the closed nature of this unit, mixing in granulator. Alternatively, the drug was mixed
etc. However, the influence of recycling on the granule with a solution of hydrophilic polymer and/or binder to
quality, suitability with low dose formulations, friability, form a drug-polymer/binder slurry as a granulating fluid.
etc. remains a major issues regarding this technology. Granules were then formed by immersing a mixture of
The description of its significance and limitations are other dry excipients into the drug-polymer/binder slurry.
summarized in Table 1. The resulted wet granules were milled after drying. The
granules produced by this process were found to have good
Recent progress in wet granulation flow and handling characteristics like those produced with
Wet granulation is the widely used technique and the wet granulation process. In addition, tablets formed from
granules are produced by wet massing of the excipients and these granules eroded more uniformly during dissolution
API with granulation liquid with or without binder. The testing as compared to usual wet granulation technique.
steps involved in conventional wet granulation technique The schematic diagram of this process is presented in Fig. 5.
could be seen in Fig. 4. Wet granulation has witnessed Controlled breakage was proposed to be the predominant
various technical and technological innovations such as granule formation mechanisms in reverse wet granulation
11,12
steam granulation, moisture-activated dry granulation or technique. It is purported that this technique improves
moist granulation, thermal adhesion granulation, melt the dissolution characteristics of the poorly water-soluble
granulation, freeze granulation, foamed binder or foam drugs by allowing uniform distribution of the binder that
granulation, and reverse wet granulation. The significance acts as a wetting agent and enable adequate wetting of the
and limitations of the recent wet granulation techniques drug substance during granulation. It also increases the
and technologies are summarized in Table 1. chances of adequate and uniform contact between the
drug and hydrophilic polymer for better dissolution. These
Reverse wet granulation improved granule characteristics result in even erosion of
Reverse wet granulation or reverse-phase wet granulation tablets during dissolution.11,12
is a new development in the wet granulation technique The advantages of this technique over conventional wet
that involves the immersion of the dry powder formulation granulation include small and spherical-shaped granules
into the binder liquid followed by controlled breakage to with improved flow properties, uniform wetting and
form granules.10 According to this invention, the binder erosion of the granules. This technique could be suitable
for poorly water-soluble drugs because of the intimate
association between a drug and the polymer. Usability
of currently available equipment such as high speed
mixer is another merit of this technique. However, this
technique produced granules with a greater mass mean
diameter and lower intragranular porosity when compared
to the conventional wet granulation at lower binder
concentrations.11,12
Steam Granulation
In steam granulation as a new wet granulation technique,
water steam is used as binder instead of traditional liquid
13
water as granulation liquid. Fig. 6 shows the schematic
diagram of steam granulation. Steam, at its pure form is
transparent gas, and provides a higher diffusion rate into
the powder and a more favorable thermal balance during
Fig. 3. Schematic diagram of pneumatic dry granulation the drying step. After condensation of the steam, water
forms a hot thin film on the powder particles, requiring
Fig. 4. Schematic diagram of conventional wet granulation Fig. 5. Schematic diagram of reverse wet granulation
58 BioImpacts, 2015, 5(1), 55-63
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