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RECENT ADVANCES IN GRANULATION TECHNOLOGIES
Harshada S. Chaudhari*, Vidya P. Sable, Ujwala N. Mahajan
Department of Pharmaceutics, Dadasahheb Balpande College of Pharmacy, Besa, Nagpur.
ABSTRACT
The process of granulation is to transform fine powders into free-
flowing, dust-free granules that are easy to compress. During preparing
granules numerous challenges, we need to overcome due to a high-
quality requirement of the formed granules in terms of content
uniformity and physicochemical properties such as granule size, bulk
density, porosity, hardness, moisture, compressibility, etc. and also
together with physical and chemical stability of the drug. Granulation
process can be divided into two types: dry granulation that requires no
liquid and wet granulation that utilize a liquid in the form of
granulating fluids. The type of process selection requires a thorough
knowledge of physicochemical properties of the drug, excipients, required flow and release
properties. Conventionally, roller compaction and slugging are types of dry granulation. On
the other side, in wet granulation low shear mixing, high shear mixing, and fluid bed
granulation are present. As like any other scientific field, pharmaceutical granulation
technology also continues to change, and the arrival of the novel and innovative technologies.
Recent progress in the granulation techniques and technologies such as in dry granulations,
pneumatic dry granulation. In wet granulation wide range of innovations like reverse wet
granulation, steam granulation, moisture-activated dry granulation, thermal adhesion
granulation, freeze granulation, and foamed binder or foam granulation.
KEYWORDS: Granulation technologies, dry granulation, wet granulation.
INTRODUCTION
Granulation is a technique of particle enlargement by agglomeration, in which small fine or
coarse particles are converted into large agglomerates called granules. Granulation process is
one of the significant unit operations in the production of pharmaceutical dosage forms,
mostly tablets and capsules. In granulation technique, initial dry mixing of the necessary
WORLD JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES
SJIF Impact Factor 7.421
Volume 8, Issue 5, 1467-1491 Review Article ISSN 2278 – 4357
Article Received on
19 March 2019,
Revised on 09 April 2019,
Accepted on 30 April 2019,
DOI: 10.20959/wjpps20195-13786
*Corresponding Author
Harshada S. Chaudhari
Department of
Pharmaceutics, Dadasahheb
Balpande College of
Pharmacy, Besa, Nagpur.
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powder ingredients along with the active pharmaceutical ingredient (API), so that a uniform
distribution of each ingredient throughout the powder mixture is achieved.[1]
Reasons for conducting granulation process
a. To enhance the API uniformity in the final product,
b. To increase the density of the blend so that it occupies less volume per unit weight for
better storage and shipment, to facilitate metering or volumetric dispensing,
c. To reduce dust during granulation process
d. To improve the appearance of the product and flow properties.
Ideal characteristics of granules include,
a. Spherical shape for improved flow,
b. Narrow particle size distribution for content uniformity and volumetric dispensing,
c. Sufficient fines to fill void spaces between granules for better compaction and
compression characteristics,
d. Adequate moisture and hardness to prevent breaking and dust formation during the
process.
The properties of the particles acquired after granulation depend on the particle size of the
drug and excipients, the type, concentration, and volume of binder and/or solvents, type of
granulator, granulation time, drying rate (temperature and time), etc. The primary methods by
which the agglomerated granules are formed include solid bridges, sintering, chemical
reaction, crystallization and deposition of colloidal particles.
The series of mechanisms by which granules are formed from the powder particles are
wetting and nucleation, coalescence or growth, consolidation, and attrition or breakage. The
blend of powders containing pharmaceutical excipients and API can be compressed into
tablets either by direct compression or after making granules by agglomeration or granulation
techniques. There are two types of granulation technique, dry granulation and wet
granulation, based on the type of method used to facilitate the agglomeration of powder
particles. Granulation technologies like roller compaction, spray drying, low/high shear
mixing, supercritical fluid, extrusion/ spheronization, fluid bed granulation, etc. have been
successfully used for the preparation of various pharmaceutical dosage forms. Pharmaceutical
granulation technology continues to change, and various improved, modified, and novel
techniques and technologies have been made available.[1-5]
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The changing description of granulation processes[3]
Quantitative prediction of granule attributes is difficult. In addition, the demarcation between
these mechanisms arbitrarily depends on the cut off size between granule and non-granular
material, which depends on the measurer’s interests and ability to count small particles.
These mechanisms could all be considered as cases of coalescence and/or breakage. It is
simply the size of the coalescing particles and the availability of surface liquid which varies
from case to case.
Fig 1: Granulation processes.
1. Wetting and nucleation, where the liquid binder is brought into contact with a dry powder
bed and is distributed through the bed to give a distribution of nuclei granules.
2. Consolidation and growth, where collisions between two granules, granules and feed
powder, or a granule and the equipment lead to granule compaction and growth.
3. Attrition and breakage, where wet or dried granules break up due to impact or
compaction in the granulator or during subsequent product handling.
Methods of granulation
Dry granulation technique uses mechanical compression (slugs) or compaction (roller
compaction) to facilitate the agglomeration of dry powder particles. Where the wet
granulation uses granulation liquid (binder/solvent) to facilitate the agglomeration by the
formation of wet mass by adhesion. Among these two techniques, wet granulation technique
involves multiple unit processes such as wet massing, drying, and screening, which are
complex, time-consuming, and expensive requiring large space and multiple equipments.
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The type of process selection requires a thorough knowledge of physicochemical properties
of the drug, excipients, required flow and release properties, etc.[1]
I. Recent progress in dry granulation
Pneumatic Dry Granulation (PDG)
II. Recent progress in wet granulation
Reverse Wet Granulation
Steam Granulation
Moisture-Activated Dry Granulation or Moist Granulation
Thermal Adhesion Granulation
Melt Granulation
Freeze Granulation
Foamed Binder or Foam Granulation[6-8]
I. Dry granulation Technique[9-28]
Dry granulation is a simple and low-cost method. This becoming more popular because of its
simplicity and cost efficiency. To improve dissolution, there are various methods like salt
formation, micronization, and addition of solvent or surface active agents. In a dry
granulation method, initially the primary powder particles are aggregated at high pressure.
There are two main processes,
1. Large tablet (known as a slug) is produced in a heavy duty tableting press (known as
slugging).
2. The powder is squeezed between two rollers to produce a sheet of material (roller
compaction).
This is a valuable alternative to direct compression, where the dose of a drug is too high or
too wet granulation when the drug is sensitive to heat, moisture or both. This method is also
used when other methods of granulation yield granules with a poor flow or compression
properties because there are fewer chances of segregation of drug and excipients. Long
processing time, relatively high capital investment on heavy-duty presses or compactors.
A. Slugging process
Slugging is the process of compressing dry powder of tablet formulation with the help of
tablet press having die cavity large enough in diameter to fill quickly. The accuracy or
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condition of a slug is not too important. Only sufficient pressure required to compact the
powder into uniform slugs should be used. Once slugs are produced they are reduced to
appropriate granule size for final compression by screening and milling.
B. Roller compaction[11, 16]
The compaction of powder by using pressure roll can also be accomplished by a machine
called chilsonator. Unlike tablet machine, the chilsonator turns out a compacted mass of
powder in a steady continuous flow. The powder is fed down between the rollers from the
hopper which contains a spiral auger to feed the powder into the compaction zone by which
density of powder enhanced. As like slugs, the aggregates are screened or milled for
production into granules.
Fig 2: Schematic diagram of dry granulation and two different techniques. Method I is
roller compaction and Method II is slugging.
Recent progress in dry granulation
Dry granulation achieved, either by roller compaction or by slugging. There has not been
much progress in the dry granulation technique, except for one important innovation known
as pneumatic dry granulation technology developed by Atacama Labs Oy (Helsinki, Finland).
Pneumatic Dry Granulation (PDG)
Pneumatic dry granulation (PDG), an innovative dry granulation technology, this technique
involved utilization of roller compaction together with a proprietary air classification method
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to prepare granules with the combination of compressibility and flowability. In this method,
granules are produced from powder particles by initially applying mild compaction force by
roller compactor to produce a compacted mass comprising a mixture of fine particles and
granules. The fine particles and/or smaller granules are separated from the intended size
granules in a fractioning chamber by use of gas stream (pneumatic system), whereas the
intended size granules are passed through the fractioning chamber to be compressed into
tablets. The fine particles and/or small granules are then transferred to a device such as a
cyclone and are either returned to the roller compactor for immediate reprocessing (recycling
or recirculation process) or placed in a container for reprocessing later to achieve the granules
of the desired size. This technique could successfully use to produce granules having good
flow property, for any formulations that produce compacts with a tensile strength of ~ 0.5
MPa.
Fig. 3: Schematic diagram of pneumatic dry granulation.
Merits of Pneumatic Dry Granulation
The faster speed of manufacturing compared with wet granulation.
Lower cost of manufacturing compared with wet granulation.
The system is closed offering safety advantages to the operators, due to low dust levels
and potential for sterile production or handling of toxic materials,
The end products are very stable - shelf life may be enhanced because of less moisture
content.
Little or no waste of material,
Scale-up is straightforward,
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The granules and tablets produced show fast disintegration properties, offering the
potential for fast release dosage forms, and Release time can be tailored to requirements.
II. Wet granulation Technique[29-38]
Wet granulation involves the preparing wet mass of dry primary powder particles using a
granulating fluid. The granulating fluid contains a solvent that must be volatile so that it can
be removed by drying for proper granulation. Granulating fluid includes water, ethanol, and
isopropanol either alone or in combination.
Merits of wet granulation
1. The cohesiveness and compressibility of powders are improved.
2. Good distribution and uniform content.
3. A wide variety of powders can be possessed together in a single batch.
4. Controlled release dosage form can be accomplished by the selection of a suitable binder
and solvent.
Demerits of wet granulation
1. Because of large number of processing steps, it requires a large area with temperature and
humidity.
2. It requires a number of pieces of expensive equipment also time consuming.
3. There is a possibility of material loss during processing due to transfer of materials from
one unit to another and have possibility of cross contamination.
Conventional wet granulation process involved low shear granulation, high shear granulation,
and fluid bed granulation.
A. Low shear granulation
It is the traditional method of making granules. Four types of equipment are mainly used in
this case.
1. Mixer machine to mix the ingredients.
2. Planetary mixer to make the wet mass.
3. Oscillating granulator to make the wet granules.
4. Dryer to dry the wet granules (Tray dryer or fluidized dryer).
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B. High shear mixture granulation
The high shear mixture has been widely used in Pharmaceutical industries for blending and
granulation. Blending and wet massing are accompanied by high mechanical agitation with
an impeller and a chopper. Mixing, densification, and agglomeration are achieved with the
help of shear and compaction force exerted by the impeller.
C. Fluid bed granulation
Fluidization is the operation by which fine solids are transformed into a fluid-like state
(dispersion) through contact with a gas. The fluid will support the particles at a certain gas
velocity, giving them free mobility without entrapment. Fluid bed granulation is a process by
which granules are prepared by spraying a binder solution onto a fluidized powder bed within
single equipment. The system involves the heating of air and then directing it through the
material to be processed for granulation. After that, the same air exit through the voids of the
product7. Fluid bed processing of pharmaceuticals was first reported by Wurster, and he used
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), Spray Nozzle, Product container, and
air distribution, Disengagement area and process filters, Exhaust blower or Fan, Control
system and Solution delivery system.
Fig. 4: Fluid Bed granulation.
Recent progress in wet granulation
Wet granulation is the more popular technique, in which granules are produced by wet
massing of the excipients and API with granulation liquid with or without binder. Wet
granulation has various technical and technological innovations such as steam granulation,
moisture-activated dry granulation or moist granulation, thermal adhesion granulation, melt
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granulation, freeze granulation, foamed binder or foam granulation, and reverse wet
granulation.
1. Reverse wet granulation[39-41]
Reverse wet granulation process involving immersion of dry powder into the binder liquid,
thus eliminating the traditional granule nucleation process. The reverse-phase process
proceeds in such a way to reduced liquid saturation, thus decreasing the risk of uncontrolled
growth and batch loss. It improves the dissolution characteristics of poorly water-soluble
drugs by allowing uniform distribution of binder. The primary mechanism of the reverse-
phase granulation process was breakage of large moist agglomerates and mechanical
dispersion of the binder solution throughout the powder formulation. The size and porosity of
reverse-phase granules are controlled by the liquid saturation and impeller speed, with these
physical properties being best described by the dimensionless stokes deformation number and
the growth regime map.
Merits of Reverse Wet Granulation over Conventional Wet Granulation
This improves the dissolution characteristics of the poorly water-soluble drugs by
allowing uniform distribution of the binder and also improved flow properties of
powders.
This increases the chances of adequate and uniform contact between the drug and
hydrophilic polymer for better dissolution.
Uniform wetting and erosion of the granules.
The small and spherical-shaped granules with improved flow properties, uniform wetting
and erosion of the granules.
Use 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.
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Fig. 5: Reverse wet granulation.
2. Steam Granulation[42-45]
In steam granulation technique, steam is used as a binder instead of water or other granulating
fluids. A steam granulation technique involves the injection of a jet of steam into a bed of
fluidized particles of powder blend to be granulated. The jet of steam is substantially
enveloped by a jet of air to inhibit the premature condensation of the steam onto the fluidized
particles of powder blend and/or the condensation of the steam onto the neighboring walls of
an apparatus employed to fluidize the particles since this process inhibits excessive wetting
and lumping of the particles during their granulation.
Merits
Uniformly distributed in the powder particles.
Higher diffusion rate.
Results in more spherical granule formation.
No health hazards.
Maintain sterility.
Demerits
Requires special equipment for steam generation and transportation.
Requires high energy inputs.
Thermo labile materials are poor candidates.
More safety measure required.
Not suitable for all the binders.
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Fig. 6: Steam granulation.
3. Moisture-Activated Dry Granulation (MADG)[46-50]
In the moist granulation technique (MGT), a minimum amount of liquid is used to activate a
binder in a planetary mixer. Then, any excess moisture is absorbed by the addition of a
moisture-absorbing substance. Moist granulation yielded an increase in particle size
compared to direct compression method; these results are comparable to those from the
traditional wet granulation after drying and screening. The moist granulation technique
appears to have the potential for the development of controlled-release formulations.
In MADG, moisture is used to activate granule formation, there is no need to apply heat to
dry the granules. MADG is suitable for continuous processing. There are two main stages in
MADG: Agglomeration and Moisture distribution/ Absorption.
Benefits
This is applicable to more than 90% of the granulation need for pharmaceutical, food and
nutritional industry.
Time efficient and suitable for continuous processing.
Less energy involves during processing.
Drawbacks
Moisture sensitive and high moisture absorbing APIs are poor candidates.
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Fig. 7: Moisture-Activated Dry Granulation (MADG).
4. Thermal Adhesion Granulation (TAG)[51, 52]
Wei-Ming Pharmaceutical Company (Taipei, Taiwan) has developed this technique, and the
thermal adhesion granulation, analogous to moist granulation, utilizes the addition of a small
amount of granulation liquid and heat for agglomeration. It’s analogous to moist granulation
and utilizes the addition of a small amount of granulation liquid and heat for agglomeration.
This process uses both water and solvent as granulation fluids, also in this heat is used to
facilitate the granulation process. Drug & excipient mixture is heated to a temperature of 30-
130oC in a closed system under tumble rotation to facilitate the agglomeration of the powder
particle.
In this method of granulation, the drying process was eliminated, due to the addition of a low
amount of granulation liquid, which is mostly consumed by the powder particles during
agglomeration. Granules of the required particle size can be obtained by cooling and sieving.
It is applicable for preparing direct tableting formulations. This technique is quite simple and
convenient with low moisture and binder contents in a closed system for preparing highly
compressible materials or for modifying the poor characteristics of excipients. Besides, this
technique provides granules with better particle size, good flow properties and high tensile
strength that could be directly compressed into tablets with adequate hardness and low
friability.
The limitations of this technique are the requirement of considerably high energy inputs and
special equipment for heat generation and regulation. This technique is not suitable for all
binders and this is sensitive to thermolabile drugs.
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Fig. 8: Thermal Adhesion Granulation (TAG).
5. Melt granulation[53-62]
Melt granulation or thermoplastic granulation is a technique that facilitates the agglomeration
of powder particles using meltable binding agents, which melts or softens at relatively low
temperature (50-90°C). After cooling of the agglomerated powder and the consequent
solidification of the molten or soften binder complete the granulation process. Moreover,
Low melting binders can be added to the granulation process.
Addition of binders, either in the form of solid particles that melt during the process (melt-in
procedure or in situ melt granulation) or in the form of molten liquid. Optionally binder
containing the dispersed drug (spray-on or pump-on procedure), which displays a variety of
options to design final granular properties. Specifically, the melt-in procedure of melt
granulation process includes heating a mixture containing drug, binder and other excipients to
a temperature within or above the melting range of the binder.
Advantage
Time and cost-effective.
Controlling and modifying the release of drugs.
Water sensitive drugs are good candidates.
Disadvantage
Heat sensitive materials are poor candidates.
Lower melting point binder may melt or soften during handling or storage.
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Fig. 9: Melt granulation.
6. Freeze Granulation[63-70]
Freeze granulation technology, spray freezing, and subsequent freeze drying involves
spraying droplets of a suspension into liquid nitrogen followed by freeze-drying of the frozen
droplets. Powder suspension is sprayed into liquid nitrogen, by which drops are instantly
frozen into granules, and in the subsequent freeze-drying process. After that, the granules are
dried by sublimation of ice without any segregation effects. This process yields spherical as
well as free-flowing granules that could be formed by using both water based and solvent
based slurries. The great significance of this technology is that the structure and homogeneity
of the particles in the slurry or suspension are retained in the granules.
There are various kinds of material in dispersed form can be granulated using this
technology. This is suitable for the preparation of fine powder mixes with proper additives
for subsequent processing. This technology could be useful for the preparation of granules
that needs to formulate specific suspensions whose particle size and homogeneity need to be
preserved. Eventually, re-dispersible parenteral formulations, nanomaterials, solid self-
emulsifying drug delivery systems, etc. could benefit from this technology gives its ability to
maintain size and homogeneity.
The suspension quality always determines and reflects the quality of granule formed in terms
of homogeneity. In the pharmaceutical industry, the low-temperature and soft freeze-drying
have a vital advantage to minimize the damage of organic compounds and improve stability
and/or solubility. According to PowderPro AB, compared with spray drying, freeze
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granulation obviously produces protein particles with light and porous characteristics and
making powders with superior aerosol performance due to favorable aerodynamic properties.
Advantages
Freeze granulation technology, able to control the granule density through the solid
content of the suspension, preparation of granules with no cavities
The technique is useful for the preparation of granules that needs to be prepared from
suspensions whose particle size and homogeneity need to be preserved.
Improve stability and/or solubility because of minimizing the damage of organic
compounds.
High productivity yield due to low waste of material.
Recycling organic solvents will be possible.
Fig. 10: Freeze granulation.
7. Foam Granulation[71-90]
Foam granulation or foamed binder granulation technology, similar to spray agglomeration,
involves the addition of liquid/aqueous binder as foam instead of spraying or pouring liquid
onto the powder particles to be formulated. This foam binder technology was firstly
introduced by Dow Chemical Company (Midland, MI) in 2003 for delivering aqueous binder
systems in high shear and fluid bed wet granulation applications. To generate foam, foam
generator can be installed in the binder solution tank with high-shear granulator or fluid bed
granulator. Which helps to introduce the binder as foam rather than spraying or pouring in a
binder onto the moving powder particles. A simple foam generation by incorporating air into
a conventional water-soluble polymeric excipients binder such as METHOCEL.
Adding the binder solution as foam eliminates the problems of inconsistent and unpredictable
binder distribution that can affect tablet hardness and drug release. Compare to the sprayed
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water, the surface area and volume of the foamed binder/water are phenomenally high. Foam
granulation process, effectively improves the distribution of binder, even at a lower amount
of binder than that required in the conventional spray granulation method. Sprayed liquid
droplets have a low spread-to-soak ratio, which means they tend to soak into powders and
cause overwetting instate of spreading on the surface of the particles. This requiring high
levels of water and binder, and eventually drying to remove excess water.
On the other side, foamed binders have a high spread to-soak ratio, and because of this, the
binders are coated onto the particles rather than soaked, leading to less amount of binder and
more consistent binder distribution. These factors help to improve the reproducibility and
shorten the processing time. This process of granulation eliminates the spray nozzles and its
related processing variables and clogging problems.
Advantages
No spray nozzle is used.
Improve process robustness.
Less water required for granulation.
Time efficient drying.
Cost effective.
Uniform distribution of binder.
No over wetting.
Applicable for water sensitive formulation.
Fig. 11: Foam granulation.
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CONCLUSION
The pharmaceutical granulation techniques and technologies have improved over the years.
The research and development of new and efficient technologies by the interdisciplinary
scientists of pharmaceutical companies globally. Innovations with techniques and
technologies in granulation processes, which improves processability and quality of the
product formulations in addition to a substantial impact on the product development, time and
economy. During the formulation development, each drug substance poses a unique
challenge that must be taken into consideration at the process selection stage by the
formulation development scientists. The type of technique and technology selection requires
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thorough knowledge of physicochemical properties of the drug, excipients, required flow and
release properties, etc. because of each technique has its own merits and limitations. In the
pharmaceutical industry, although various technologies have been introduced from time to
time, only few have emerged as successful for real time utilization due to different kinds of
hurdles such as manufacturing efficiency, economy, regulatory issues, etc.
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