ADVANCED

GRANULATION
TECHNOLOGY
DR. TALIB HUSSAIN
PHD.
LECTURER, IPS, UVAS,
LAHORE
 GRANULATION
• Granulation is a technique of particle enlargement by
agglomeration.
• It is one of the most significant unit operations in the
production of pharmaceutical dosage forms, mostly
tablets and capsules
• Small fine or coarse particles are converted into large
agglomerates called granules
• Granules have particle size in the range of 0.2-4.0 mm,
a size range of 0.2-0.5 mm are generally prepared to be
either packed as a dosage form or be mixed with other
excipients before tablet compaction or capsule filling
 PURPOSE OF GRANULATION
1) To enhance the uniformity of the API in the final product
2) To increase the density of the blend so that it occupies
less volume per unit weight for better storage and
shipment
3) To facilitate metering or volumetric dispensing
4) To reduce dust during granulation process and to reduce
toxic exposure and process-related hazards
5) To improve the appearance of the product
 TYPES OF GRANULATION
• Blend of powders containing pharmaceutical excipients and API can be
compressed into tablets either by direct compression or after making
granules by granulation techniques
• The granulation technique may be widely categorized into two types dry
granulation and wet granulation
• Dry granulation uses mechanical compression (slugs) or compaction
(roller compaction) to facilitate agglomeration of dry powder particles
• Wet granulation uses granulation liquid (binder/solvent) to facilitate the
agglomeration by formation of wet mass by adhesion.
• Wet granulation is the most widespread granulation technique used
despite the fact that it involves multiple unit processes such as wet
massing, drying and screening, which are complex, time consuming, and
expensive requiring large space and multiple equipment
 RECENT PROGRESS IN DRY GRANULATION

• Dry granulation by roller compactor is most appropriate

method due to its simplicity, low costs, and higher
product throughput.
• Unlike wet granulation technology, there has not been
much advances in dry granulation technology, except
for one important novel technique known as pneumatic
dry granulation
 PNEUMATIC DRY GRANULATION (PDG) TECHNOLOGY

• The process utilizes roller compaction together with an air classification

method to produce free flowing granules with improved compressibility
characteristics.
• In this technique, a compacted mass comprising a mixture of fine powder
particles and granules are produced from fine powder particles by initially
applying little compaction force by roller compactor.
• The fine particles and/or smaller granules are separated from the
intended size granules in a fractioning chamber by entraining in a gas
stream (pneumatic system), whereas the intended size granules pass
through the fractioning chamber to be compressed into tablets
• The entrained small granules are then transferred to a cyclone and are
either returned to the roller compactor for immediate reprocessing or
placed in a container for reprocessing later to achieve the granules of
desired size
 FLUIDIZED BED GRANULATION

• Fluidized bed granulation process involves spraying of binder

solution onto the fluidized powder bed (FPB) to get finer,
free flowing and homogeneous granules employing single
equipment known as FBG.
• FBG contains air-handling unit, product container and air
distributor, spray nozzle, disengagement area and process
filters, exhaust blower or fan, control system, solution
delivery system
RECENT ADVANCES IN WET GRANULATION TECHNOLOGY
REVERSE WET GRANULATION

Schematic diagram of conventional wet granulation process

 Schematic diagram of reverse phase wet granulation technique
➢ It involves the immersion of the dry powder polymer/API into the binder liquid
followed by blending dry powder excipients and then controlled breakage to form
granules
➢ The drug was mixed with a solution of hydrophilic polymer and/or binder to form
a drug-polymer/binder slurry as a granulating fluid.
➢ Granules were formed by immersing a mixture of other dry excipients into the
drug polymer/binder slurry. The resulted wet granules were milled after drying.
 ADVANTAGES OF REVERSE WET GRANULATION
1. Granules produced using this technique have improved flowability
and compressibility characteristics.
2. The technique is suitable for poorly water-soluble drug substances
because it allows uniform distribution of the granulating agent
that acts as a surfactant, thus enabling adequate wetting of the
drug substance during granulation.
3. Tablets formed from these granules break-up more uniformly
during dissolution testing.
Limitations of Reverse Wet Granulation Technology
1. The technique produces granules with a greater mass mean
diameter and lower intragranular porosity when compared to
conventional wet granulation technology.
 STEAM GRANULATION
• In steam granulation, water steam is used as binder
instead of traditional liquid water as granulation liquid.
• Steam, at its pure form is transparent gas, and provides
a higher diffusion rate into the powder and a more
favorable thermal balance during the drying step
• After condensation of the steam, water forms a hot thin
film on the powder particles, requiring only a small
amount of extra energy for its elimination, and
evaporates more easily.
The advantages of this process include the higher ability of the steam to distribute
uniformly and diffuse into the powder particles, production of spherical granules with
larger surface area, and shorter processing time ecofriendly (no involvement of
organic solvents)

Limitations: This method requires high energy inputs for steam generation. This
process is not suitable for all binders and is sensitive to thermolabile drugs
 MOISTURE-ACTIVATED DRY GRANULATION (MADG) OR
SINGLE-POT PROCESSING GRANULATION TECHNOLOGY
• It is a variation of conventional wet granulation technique.
• It uses very little water to activate binder and initiate agglomeration
• This technique involves two steps,
• 1) Wet agglomeration of the powder particles,
• 2) Moisture absorption or distribution
• Agglomeration is facilitated by adding a small amount of water,
usually less than 5% (1-4% preferably), to the mixture of drug,
binder and other excipients.
• Agglomeration takes place when the granulating fluid (water)
activates the binder.
• Once the agglomeration is achieved, moisture-absorbing material
such as microcrystalline cellulose, silicon dioxide, etc. is added to
facilitate the absorption of excess moisture.
• The moisture absorbents absorb the moisture from the
agglomerates, resulting in moisture redistribution within the powder
mixture, leading to relatively dry granule mixture
• The process does not lead to larger lumps formation since the
amount of water used is very small compared to usual wet
granulation.
• The particle size of the agglomerates is mainly accounted to be in
the range of 150-500 µm.
 THERMAL ADHESION GRANULATION (TAG)

• This process uses both water/solvent and melting binder as

granulation liquid
• Heat is used to facilitate the granulation process
• The drug and excipient mixture is heated to a temperature range
of 30–130 °C in a closed system under tumble rotation to facilitate
the agglomeration of the powder particles
• This technique eliminates the drying process due to the addition of
low amount of granulation liquid, which is mostly consumed by the
powder particles during agglomeration. Granules of the required
particle size can be obtained after cooling and sieving
 ADVANTAGES AND LIMITATIONS
• Advantages: 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
• 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
• Limitations of this technique are requirement of considerably
high energy inputs and special equipment for heat generation and
regulation. This technique is not suitable for all binders and is
sensitive to thermolabile drugs
 MELT GRANULATION
• Facilitates the agglomeration of powder particles using meltable binders,
which melts or softens at relatively low temperature (50–90 °C)
• Cooling of the agglomerated powder and the consequent solidification of
the molten or soften binder complete the granulation process
• Melt-in procedure of melt granulation process includes heating a mixture of
drug, binder and other excipients to a temperature within or above the
melting range of the binder
• The binders used for this process could be either hydrophilic or
hydrophobic. The selection of a meltable binder with a hydrophilic /
hydrophobic feature is critical factor for the dissolution behavior of the
drugs
• The equipment used for melt granulation are high-shear mixer and
fluidized bed granulator
Organic or aqueous solvents are not required for the melt granulation process, hence
environmental organic solvent capture and recycling are eliminated, while the
absence of water excludes the wetting and drying phases, making the entire process
less energy- and time-consuming. Melt granulation method could be efficiently
applied in order to enhance the stability of moisture sensitive drug and further to
improve the poor physical properties of the drug substance
Drawback of this process is the need of high temperature during the process, which
can cause degradation and/or oxidative instability of the ingredients, especially of
the thermolabile drugs
 FREEZE GRANULATION
• Spray freezing and subsequent freeze drying
• It 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 into granules, and in the subsequent freeze
drying process, the granules are dried by sublimation of ice
without any segregation effects
SIGNIFICANCE, HOMOGENEITY AND PARTICLE SIZE

• Spherical free-flowing granules are formed using both water based

and organic solvent based slurries
• The structure and homogeneity of the particles in the suspension is
retained in the granules. The suspension quality always determines
and reflects the granule quality
• Suitable for the preparation of fine powder mixes with API &
polymers having particle size and homogeneity preserved
• Examples: re-dispersible parenteral formulations, nanomaterials,
solid self-emulsifying drug delivery systems, etc.
• Use of heat sensitive compounds due to mild drying procedure,
high product yield due to low waste of material, and possibility of
recycling organic solvents
 FOAM GRANULATION
• Advancements of spray granulation technology
• Involves the addition of liquid/aqueous binder as foam instead of
spraying or pouring liquid onto the powder particles
• A foam generator installed in the binder solution tank with fluid bed
granulator to introduce binder as foam onto moving powder bed
• The surface area and volume of the foamed binder/water are
phenomenally high compared to the sprayed water
• Adding the binder solution as foam rather than a spray eliminates
the problems of inconsistent and unpredictable binder distribution
that can affect tablet hardness and drug release
• Foamed binder improve the distribution of binder onto the powder
particles, even at a low binder amount
• High spread-to-soak ratio results in binder coated onto the
particles rather than soaked requiring less binder with more
consistent binder distribution
• Useful for potent/low dose drug formulations due to its ability to
distribute drugs evenly.
• Low amount of water required for process and short processing
time allows utility of water sensitive drugs to be prepared
EXTRUSION/SPHERONIZATION GRANULATION

• Extrusion/Spheronization is a multiple step process capable of

making uniformly sized spherical particles (pellets)
• Pellets are small (0.25-1.5 mm), free flowing, spherical or
semispherical granules of API’s with excipients
• Pellets have low surface area-to-volume ratio than powder/granules
providing excellent coating surface
• Its a multiple step process (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
 EXTRUSION
• Pellets are prepared by employing wet (cold-mass)
extrusion 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
 SPHERONIZATION PROCESS
• (a) Dry Mixing: Dry mixing of ingredients is done to achieve
homogeneous powder dispersion using twin shell blender, planetary
mixer, high speed mixer and tumbler mixer
• b) Granulation: Wet or hot melt granulation is done to produce a
sufficient plastic mass for extrusion, by employing sigma / planetary
mixer in wet granulation for compaction.
• Evaporation of the high amount of fluid is a major problem with high
shear mixers (high amount of energy introduced)
which is partly transformed into heat that effects extrusion behavior
of wet mass. Cooling of the granulation bowl advised
• The granulation is usually induced by Ram extruder that gives (a)
compression (consolidation by pressure) (b) steady state flow
(pressure for flow) (c) forced flow (increased force to maintain flow)
Ram type extruder usually
known as piston feed extruder
for granulation of wet mass.
These are probably the oldest
type of extruder, a piston
displaces and forces the material
through a die at the end

C) Extrusion: It produces rod shaped particles of uniform

diameter from the wet mass
The wet mass is forced through dies and shaped into small
cylindrical particles with uniform diameter
Such shaping of the wet mass into long rods, commonly termed
‘extrudate’. The extrudate particles break at similar length under
their own weight
Extrudes must have enough plasticity to deform but not so much
to adhere to other particles when rolled in spheronizer.
 EXTRUDERS
• Extruders are classified into three categories namely, Screw,
gravity or piston feed extruders.
• Screw feed extruder include (a) axial or end plate, (b) dome (c)
radial type. Screw extruder consists of one or two (twin -screw)
feeding the wet mass to an axial or radial extrusion screen

Axial Screw feed extruder Dome Screw feed extruder Radial Screw feed extruder
• Gravity feed extruder include rotary cylinder and rotary gear
extruders, which differ mainly in the design of the two counter
rotating cylinders.
• In the rotary cylinder extruder, one of the two counter rotating
cylinders is hollow and perforated, whereas the other cylinder is
solid and acts as a pressure roller
• In the rotary gear extruders there are two hollow counter rotating
gear cylinders with counter board holes.

Rotary cylinder extruder Rotary gear extruder Rotary radial extruder

 (D) SPHERONIZATION
A spheronizer also known as merumerizer, consists of a static
cylinder and a rotating friction plate where the extrudate is broken
up into smaller cylinders with a length equal to their diameter and
these plastic cylinders are rounded due to frictional forces.
During spheronization process different stages can be
distinguished depending upon the shape. The friction plate, a
rotating disk with a characteristically grooved surface to increase
the frictional forces, is the most important component of the
equipment.
Two geometric patterns are generally used. It includes a cross-
hatched pattern with grooves running at right angle to one
another, a radial pattern with grooves running radially from the
center of the disc. The rotational speed of the friction plate varies
from 100- 2000 rpm.
• Spheronization process involves transition
from rods to spheres that might occur in
various stages which usually take 5 to 30
minutes provided mass should not be too
dry wherein no more spheres are formed
and the rods will transform as far as
dumbbells only

(A) Geometry of spheronization plate: (B) Cross-hatch, (C) radial pattern

 (E) DRYING:
• A drying stage is required in order to achieve the desired
moisture content. Drying rate is important as an increase drying
rate gave more porous pellets due to decrease pellet
densification during that drying process.
• The pellets can be dried at room temperature or at elevated
temperature in a tray drier/ microwave oven or in a fluidized bed
drier or the use of freeze dryer in order to maintain viability of
living bacterial spores.
• If solute migration occurs during drying of the wet mass, this
may result in an increased initial rate of dissolution, stronger
pellets with modified surfaces, which might reduce adhesion of
any added film coats.