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1
Pharmaceutical sciences
Product Development 1
GRANULATION TECHNOLOGY
Paper Coordinator
Content Reviewer
Dr. Vijaya Khader
Dr. MC Varadaraj
Principal Investigator
Dr. Vijaya KhaderFormer Dean, Acharya N G Ranga Agricultural University
Content Writer
Prof. Farhan J Ahmad Jamia Hamdard, New Delhi
Paper No: 05 Product Development 1
Module No: 10 Granulation Technology
Development Team
Dr. Gaurav Kumar Jain Jamia Hamdard, New Delhi
Prof Roop K. Khar BSAIP, Faridabad
Prof. Dharmendra.C.Saxena
SLIET, Longowal
Dr. Gaurav Kumar Jain Jamia Hamdard, New Delhi
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Introduction
Granulation, a technique of particle enlargement by agglomeration, is one of the most significant unit
operations in the production of solid oral dosage forms particularly tablets and capsules. During
granulation, small fine or coarse particles are converted into large agglomerates called granules. Granules
used in the pharmaceutical industry have particle size preferably in the range of 200 to 500 micrometres.
Usually, granulation commences after initial dry mixing of the necessary excipients along with the active
drug so that a uniform distribution of each ingredient throughout the powder mixture is achieved.
The main purpose of converting powder into granules is:
To enhance the uniformity of the drug in the final product,
To increase the density of the blend so that it occupies less volume per unit weight for better storage
and shipment,
Narrow particle size distribution of the granules facilitate volumetric dispensing and content
uniformity
To improve flow and compaction characteristics of the powder, and
To improve the appearance of the product.
Granulation is an exemplary of particle design and the properties of the granules depend on particle size
of the excipients and drug, the volume, concentration, and type of binder, granulation time, granulation
equipment and drying rate.
The primary methods by which the granules are formed include solid bridges, chemical reaction,
sintering, crystallization and deposition of particles. Besides, binding can also be accomplished through
cohesive and adhesive forces by utilizing high viscous binders. The mechanisms by which granules are
formed from the powder particles encompass wetting and nucleation, coalescence or growth,
consolidation, and attrition or breakage.
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Blend of powders containing excipients and drug can be compressed into tablets either by direct
compression or after making granules by agglomeration or granulation techniques as described in Fig.
The granulation technique may be categorized in to two types based on the type of method used to
facilitate the agglomeration of powder particles:
(1) Dry granulation: Dry granulation uses mechanical compression or compaction to facilitate the
agglomeration of dry powder particles.
(2) Wet granulation: Wet granulation uses granulation liquid (binder/solvent) to facilitate the
agglomeration by formation of wet mass by adhesion.
Among the two techniques described, wet granulation is widely used granulation technique despite the
fact that it involves complex, time consuming and multiple unit processes compared to dry granulation.
The selection of particular process requires thorough knowledge of physicochemical properties of the
drug and excipients and required flow and release properties. Granulation methodologies like roller
compaction, fluid bed granulation, extrusion/spheronization and spray drying have been used successful
for preparation of various pharmaceutical dosage forms.
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Granulation technology continues to evolve and various improved, modified, and novel methodologies
now available are described in this module.
DRY GRANULATION
Dry granulation also called as compression granulation is a valuable technique of granulation when the
dose of a drug is too high for direct compaction or when the drug is sensitive to heat, moisture, or both,
which precludes wet granulation. Sensitive drugs like aspirin and vitamins are prepared for tableting by
dry granulation. Dry granulation involves the mechanical compression or compaction of the components
of a tablet formulation by means of a tablet press or specially designed machinery, followed by milling
and screening, prior to final compression into a tablet. Dry granulation could be achieved either by
slugging or by roller compaction.
Slugging involves compaction of blend of powder by means of flat-faced punches. The compacted mass
is called as slug and the process is referred to as slugging. In slugging, large tablets approximately 2 inch
in diameter are made using very heavy-duty machines. These tablets may not have good fill weight
uniformity, but this does not matter, because they are broken up in the next step by coarse milling. The
slugs are then screened or milled to produce granules, which flows more uniformly than the original
powder mixture. When a single slugging process is insufficient to confer the desired granular properties
to the material, the slugs are sometimes screened, slugged again, and screened to obtain the desired
granules.
On large scale compression granulation is performed using a specially designed machine called as Roller
compactor. Roller compactors, utilize two rollers that revolve toward each other. Powdered material is
fed between the rollers by a screw conveyor system. The rollers exert known fixed pressures on the
powdered material that flows between the rollers. After passing through the rollers, the compacted mass
resembles a thin wide ribbon that has fallen apart into large segments. These are equivalent to the slugs
produced by the slugging process. The segments are then screened or milled for the production of
granules. One such roller compactor equipment which is widely utilized for preparation of granules in
pharmaceutical industry is Chilsonator.
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FIG. 11 Schematic diagram of a Chilsonator roller compactor
Since the invent of roller compactor, there has not been much progress in the dry granulation technology
in comparison to wet granulation, except for one important innovation known as pneumatic dry
granulation.
. Pneumatic Dry Granulation
Pneumatic dry granulation is an innovative proprietary technology developed by Atacama LabsOy
(Helsinki, Finland). It utilizes roller compaction together with air classification method to produce
granules with extraordinary combination of flowability and compressibility. In this method, initially a
compacted mass comprising a mixture of fine particles and granules are produced by roller compactor.
The smaller granules and/or fine particles are separated from the intended size granules in a fractioning
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chamber by entraining in a gas stream and are returned to the roller compactor for re-compression. On
the other hand the intended size granules pass through the fractioning chamber to be compressed into
tablets. The primary advantage of this technology is that it provides good flowability even with high
drug loads up to 70-100%. Further the technology offers high processing speed, little wastage of material,
low dust exposure and low cost of production. However the influence of recycling on the quality of
granules and friability problem remains a major issues regarding this technology.
(Courtesy of the Fitzpatrick Company, Elmhurst, IL.)Roller compactors, utilize two rollers that revolve
toward each other (Fig. 1112-13). By means of a hydraulic ram forcing one of the rollers against the
other, the machine is capable of exerting known fixed pressures on any powdered material that flows
between the rollers. Powdered material is fed between the rollers by a screw conveyor system. After
passing through the rollers, the compacted mass resembles a thin wide ribbon that has fallen apart into
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large segments. These are equivalent to the slugs produced by the slugging process. The segments are
then screened or milled for the production
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WET GRANULATION
Wet granulation is the widely used technique for preparation of granules by wet massing of the excipients
and drug with granulation liquid with or without binder. In wet granulation the powders are bind together
due to adhesive interactions instead of compaction. Addition of a granulating liquid to a mass of powder
may be characterized in a series of stages described by Newitt and Conway-Jones; these are as illustrated
in the Figure12.
FIG.-12. Stages in the development of granules (After Newitt and Conway-Jones.12)
At initial stage, addition of granulating liquid causes wetting of powder particles. Liquid film formed on
surface of powder particles may combine to produce discrete liquid bridges at points of contact. The
surface tension and negative capillary pressure in such bridges provide the cohesive force and result in
a condition called as the pendular state. At this moment the granules has low mechanical strength.
As the liquid content increases, several bridges may coalesce, giving rise to the funicular state and a
further modest increase in the strength of the moist granule.
Eventually, as more liquid is added and the mass is kneaded to bring particles into closer proximity, the
void spaces within the granule are entirely eliminated. At this point, bonding is affected by interfacial
forces at the granule surface and by a negative capillary pressure throughout the interior liquid-filled
space, a condition referred to as the capillary state.
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Further addition of liquid results in droplet formation in which the particles are still held together by
surface tension, but without intragranular forces. The capillary state represents the stage with the
maximum strength of the wet granules and optimization of many granulation processes involves ensuring
that this state has been achieved.
While some tablets are still made in the traditional manner, newer equipment has been developed that
can accomplish both dry mixing and wet granulation efficiently and in much less time. New
mixer/granulators such as Lodige, Diosna and Gral, allow several processes of wet granulation to be
conducted in rapid succession or to be combined in one piece of equipment. These new mixers are
classified as highspeed mixer/granulatorsThese high speed mixer/granulators are provided with
secondary chopper blades which function as a lump and agglomerate breaker so that sieving is no longer
an essential prerequisite of powder blending.
The method of introducing the binder depends on its solubility and on the components of the mixture.
Since, in general, the mass should merely be moist rather than wet or pasty, there is a limit to the amount
of solvent that may be employed. Therefore, when only a small quantity is permissible, the binder is
blended in with the dry powders initially; when a large quantity is required, the binder is usually
dissolved in the liquid.
The principle of wet granulation is to add the binder by some means so that it will form bridges between
the particles to form granules (Fig.).
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The liquid plays a key role in the granulation process. Liquid bridges are developed between particles,
and the tensile strength of these bonds increases as the amount of liquid added is increased. These surface
tension forces and capillary pressure are primarily responsible for initial granule formation and strength.
Once the granulating liquid has been added, mixing continues until a uniform dispersion is attained and
all the binder has been activated. During granulation, particles and agglomerates are subjected to
consolidating forces in large blenders for 15 min to an hour. The length of time depends on the wetting
properties of the powder mixture and the granulating fluid, and upon the efficiency of the mixer. A rough
way of determining the end point is to press a portion of the mass in the palm of the hand; if the ball
crumbles under moderate pressure, the mixture is ready for the next stage in processing, which is wet
screening. The wet screening process involves converting the moist mass into coarse, granular aggregates
by passage through a hammer mill or oscillating granulator, equipped with screens having large
perforations. Overly wet material dries slowly and forms hard aggregates, which tend to turn to powder
during subsequent dry milling.
A drying process is required in all wet granulation procedures to remove the solvent that was used in
forming the aggregates and to reduce the moisture content to an optimum level of concentration within
the granules. After drying, the granulation is screened again. The size of the screen depends upon the
grinding equipment used and the size of the tablet to be made.
Wet granulation has witnessed various technical and technological innovations which are further
described in this module.
Reverse Wet Granulation
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Reverse wet granulation involves the immersion of the dry powder into the binder liquid followed by
controlled breakage to form granules. According to this technology the drug was mixed with a solution
of binder to form a drug-binder slurry as a granulating fluid. Granules were then formed by immersing
a mixture of other dry excipients into the drug-binder slurry. Advantage of this method is that it give
better dissolution results specially with poorly water soluble drugs. Additionally tablets formed from
these granules eroded more uniformly during dissolution compared to usual wet granulation technique.
This process produced granules with lower intragranular porosity and a greater mass mean diameter at
lower binder concentrations when compared to the conventional wet granulation.
Steam Granulation
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In steam granulation, steam is used as a binder instead of liquid water. The advantage of using steam as
binder is that it provides uniform distribution and higher diffusion rate into the powder particles resulting
in production of spherical granules with larger surface area, and shorter processing time. Another
advantage is that it has a more favorable thermal balance during the drying. Upon condensation, steam
forms a hot thin film on the powder particles, requiring only a small amount of extra energy for its
elimination, and evaporates more easily. An equipment such as high-shear mixer coupled with a steam
generator would be enough for this technique. Although the granules produced by this process have
higher dissolution rate due to increased surface area but this process is not suitable for thermolabile drugs
and is not processed with all types of binders.
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Moisture-Activated Dry Granulation
This technique also known as moist granulation technique uses very little amount of water to activate a
binder and initiate agglomeration. The first step of the technique is wet agglomeration of the powder
particles followed by next step where moisture absorption or distribution occurs.
Agglomeration is enabled by adding a small amount of water, usually less than 5%, to the mixture of
drug, excipients and binder. Agglomeration takes place when the granulating fluid activates the binder.
Once the agglomeration is achieved, moisture absorbents such as silicon dioxide or microcrystalline
cellulose is added to facilitate the absorption of excess moisture. Addition of moisture absorbents results
in moisture redistribution within the powder mixture, leading to relatively dry granule mixture. During
the moisture redistribution process, some of the agglomerates remain intact in size, while some larger
agglomerates may break leading to more uniform particle size distribution. This process avoids
expensive drying step. The process does not lead to larger lumps formation and particle size of the
agglomerates usually range from 150-500 microns since the amount of water used is very small
compared to usual wet granulation.
The granules prepared via this technique has increased particle size, better flow and compressibility.
Additional advantages include time efficiency, less energy input, involvement of few process variables
and wide applicability. However, this technique could not be used for processing when dose of drug is
high or when drug is moisture sensitive or hygroscopic owing to stability and processing problems
associated with these types of drugs. A high-shear mixer coupled with a sprayer would be a suitable
equipment for the moist granulation process.
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Thermal Adhesion Granulation
Thermal adhesion granulation utilizes addition of a small amount of granulation liquid and heat for
agglomeration. Unlike moist granulation which uses water alone as granulation liquid, this process uses
both water and solvent as granulation liquid. In addition to this, heat is used to facilitate the granulation
process. In this process, the drug and excipients are heated at about 30–130 °C in a closed system under
tumble rotation to facilitate the agglomeration of the powder particles. The use of limited amount of
solvent eliminates the drying process. Granules of the required particle size can be obtained after cooling
and sieving. This technique is quite simple and easy to use with low moisture and binder contents 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. High energy
inputs and requirement of special equipment for heat generation and regulation are few of the limitations
of this technique.
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Melt granulation
Melt granulation also called as thermoplastic granulation is a technique that facilitates the agglomeration
of powder particles using binders, which melts or softens at low temperature range of about 50 to 90°C
followed by cooling and the consequent solidification of the molten binder to complete the granulation
process.
Low melting binders can be added to the granulation process either as a solid that melt during the process
a process called as in situ melt granulation or in the form of molten liquid as a spray-on. Optionally,
drugs can be dispersed in the molten liquid binder. The in situ melt granulation includes heating a mixture
of drug, binder and other excipients to a temperature within or above the melting range of the binder. In
contrast, the spray-on procedure encompasses spraying of a molten binder onto the heated blends. Melt
granulation is suitable alternative to other wet granulation techniques which are used for water sensitive
materials. The biggest advantage of this method is that the aqueous or organic solvents are not demanded
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and hence the environmental requirements of solvent capture and recycling are eliminated, while the
absence of water excludes the wetting and drying phases, making the entire process less time- and
energy-consuming. Melt granulation method could be efficiently applied in order to to improve the poor
physical properties of the drug substance and further to enhance the stability of moisture sensitive drug.
The major drawback of this process is the need of high temperature during the process, which can cause
degradation of the thermo labile drugs. The binders used for this process could be either hydrophilic or
hydrophobic. However, the selection of a meltable binder with a hydrophilic/hydrophobic feature is
critical factor for the dissolution behavior of the drugs. Owing to the numerous advantages of this
technique over conventional wet granulation process the interest in melt granulation has increased.
Freeze granulation
Freeze granulation technology also called as spray freezing involves spraying droplets of a liquid slurry
or suspension into liquid nitrogen followed by freeze-drying of the frozen droplets. By spraying a powder
suspension into liquid nitrogen, the drops are instantly frozen as granules, and in the subsequent freeze
drying process, the granules are dried by sublimation of ice without any segregation effects. The main
advantage of this process is that it yields spherical free-flowing granules that could be formed by using
both water and organic solvent.
The suspension quality always determines and reflects the granule quality in terms of homogeneity.
Using this process the structure and homogeneity of the particles in the slurry or suspension are retained
in the granules. This technology is particularly useful for the preparation of granules that needs to be
prepared from suspensions whose particle size and homogeneity need to be preserved. Although variety
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of material in dispersed form can be granulated using this technology, it is suitable for the preparation of
fine powder mixes. The powders prepare using this technology possess superior aerosol performance
due to favorable aerodynamic properties.
The major advantages of this technology include (a) preparation of granules with no cavities, (b) ability
to control the granule density through the solid content of the suspension, (c) use of heat sensitive
compounds due to mild drying procedure, (d) high product yield due to low waste of material, (e) high
degree of granule homogeneity due to the absence of migration of small particles, and (f) possibility of
recycling organic solvents.
Given the ability of this technology to maintain size and homogeneity, sooner or later it will benefit the
formulation of re-dispersible parenteral formulations, nanoparticles, self-emulsifying drug delivery
systems and liposomes. Although organic solvents with suitable freezing point (-25 to +10 °C) can be
used, water as medium is preferred in this process, which could be a limiting criteria given the poor
solubility of various drugs and processing excipients.
Foam granulation
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Foam granulation analogous to spray agglomeration, involves the addition of binder solution as foam
instead of spraying or pouring liquid onto the powder particles. Adding the binder solution as a foam
rather than a spray alleviates the problems of unpredictable and inconsistent binder distribution that can
affect tablet hardness and drug release. This technology exploits the characteristics of the foamed binder
to successfully improve the distribution of binder onto the powder particles, even at a binder amount
lower than that required in the conventional spray granulation method. This is due to the fact that the
surface area and volume of the foamed binder solution is remarkably high compared to the sprayed water.
Most importantly, the sprayed liquid droplets have a low spread-to-soak ratio, which means they tend to
soak into powders and cause over wetting rather than spreading on the surface of the powder particles,
requiring high levels of water and binder, and eventually long drying rates to remove excess water. In
contrast, 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 improve the reproducibility and shorten the processing time.
Due to the involvement of low amount of water and short process time, water sensitive drugs could also
be processed using this technology. Additionally, this technology would prove useful for potent drugs
due to its ability to distribute drugs evenly. Further, this technology eliminates the use of spray nozzles
and its related clogging problems and processing variables.
Standard equipment such as shear mixer or fluid bed granulator could be used for this technology in
association with a foam generator. A foam generator can be installed in the binder solution tank to
introduce the binder as foam onto the moving powder particles.
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Although this technology merits in countless ways, further understanding of process parameters, foam
quality, etc. needs to be explored.
Conclusion
Technological innovations that improve and ease existing processes could contribute to improved
process ability and quality of the formulations in addition to a considerable impact on the product
development, time and economy.
Obviously, the pharmaceutical granulation techniques have improved over the years. Nevertheless,
efficient and cost-effective processes have always been the keen interest of the pharmaceutical industries.
Each technique has its own merits and limitations, and the type of technique and technology selection
requires thorough knowledge of physicochemical properties of the drug, excipients, required flow and
release properties, etc. in addition to the granulation techniques and technologies itself. 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.
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. The new technologies discussed in this
module would need enhancements in terms of equipment, process, etc. before being industrialized
successfully. Nevertheless, these could provide a platform for further technological innovation.