Chapter Twenty Eight: Granulation

Pharmaceutical Granulation
Processes
1. Wet Granulation - utilizes a liquid in
the process
2. Dry Granulation - no liquid is used
Excipients added in a formulation:
• Diluents - used to produce a unit dose
weight of suitable size
• Disintegrating Agent - added to aid the
break-up of the granule when it
reaches a liquid medium
• Adhesive (aka Binder) - in the form of a
dry powder
Dry Granulation - the primary
powder particles are aggregated at high
pressure
- used for products which are sensitive
to moisture
Two Intermediate Processes:
1. Slugging - production of a large
tablet in a heavy-duty tableting press
2. Roller Compaction - the powder is
squeezed to produce a sheet or
flakes of material
Wet Granulation - the massing of
dry primary powder particles using a
granulating fluid (volatile solvent and
non-toxic e.g water, ethanol,
isopropanol)
- the fluid may contain a dissolved
adhesive to ensure particle
adhesion
• Water is commonly used for economic
and ecological reasons
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Disadvantages:
- adversely affects drug stability
(hydrolysis)
- takes longer to dry (affects chemical
stability due to extended exposure to
heat)
Advantage: non-flammable
• Organic Solvents are used as an
alternative to dry granulation - used for
rapid drying time or water sensitive
drugs
Melt Granulation - an alternative to
wet granulation where thermosetting
polymers are used
Effect of Granulation Method on
Granule Structure - affect intragranular
pore structure by changing the degree of
packing within individual granules
Granulation Mechanisms

Particle Bonding Mechanisms - bonds
must be formed for particles to adhere
- bonds must be sufficiently strong to
prevent break-down
Five Primary Bonding Mechanisms
1. Adhesion and Cohesion Forces
2. Interfacial Forces
3. Formation of Solid Bridges
4. Attractive Forces
5. Mechanical Interlocking
Adhesion and Cohesion Forces in
Immobile Films
- a decrease in interparticulate distance
and an increase in contact area
- bond strength increases
- granules present as residual liquid
after drying
• immobile layers may be formed by
highly viscous solutions of adhesives
ex. Starch Mucilage
Interfacial Forces in Mobile Liquid
Films
3 States of Water Distribution
1. Pendular State - particles are held
together by lens-shaped rings of
liquid (due to hydrostatic function in
liquid bridge)
2. Capillary State - particles are held by
capillary suction
3. Funicular State (Intermediate State) -
between pendular and capillary state
• Moist granule tensile strength increases
thrice from pendular to capillary state
• The droplet (further state) - important
by spray drying of a suspension. It's
strength is dependent upon the surface
tension of liquid used
Solid Bridges
Can be formed by:
• Partial Melting
• Hardening Binders
• Crystallization of Dissolved Substances
Partial Melting - not a predominant
mechanism
Hardening Binders - common mechanism
with adhesives
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- forms liquid bridges and hardens or
crystallize upon drying
ex. Polyvinylpyrrolidone, cellulose
derivatives (carboxymethylcellulose), and
pregelatinized starch
Crystallization of Dissolved Substances
- the solvent used may partially dissolve
one of the powders during wet
granulation, this then acts as a
hardening binder
- the size of crystals produced is
influenced by the rate of drying
- drug should not dissolve in
granulating liquid and recrystallize
Attractive Forces between Solid
Particles
2 Types of Attractive Forces
1. Electrostatic Force - useful in
powder cohesion and initial
formation of agglomerates
2. Van der Waals Forces - has four
orders of magnitude > than ElectroS.
forces and contribute significantly to
the strength of granules via dry
granulation
Mechanisms of Granule
Formation
3 Stages:
1. Nucleation - particle-particle contact
and adhesion due to liquid bridges
- Agitation converts pendular to
capillary bodies acting as 'nuclei'
for further growth
2. Transition - presence of a large
number of small granules with a fairly
wide size distribution
3. Ball Growth - large, spherical
granules are produced with its mean
particle size increasing in time
- further agitation results to coalesce
- four possible mechanisms:
• Coalesce - joining of two or more
granules to form a larger one
• Breakage - granules breaks into
fragments, adheres to other granules
• Abrasion Transfer - attrition of material
from granules (via agitation of granule
bed)
• Layering - formation of layer over the
surface, increasing granule size
Granulation Endpoint Control - stop the
granulation at a predetermined point to
prevent an overmassed system
Pharmaceutical Granulation
Equipment and Processes
1. Wet Granulators
Shear Granulators - obsolete
- dry-powder blending is done
separately
High-speed Mixers / Granulators - used
extensively for pharmaceutical
granulation
- were developed from traditional
planetary mixers to speed up the
process
- all processes are done in this
equipment
ex. Colette UltimaGral Mixer
Fluidized-bed Granulators - powders are
fluidized in a steam of air, granulation
fluid is sprayed from a nozzle
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- heated and filtered air is blown or
sucked through the bed
- very efficient mixing process

Advantages:
- all processes are performed in one unit
- automation of the process
Disadvantages:

- optimization of process needs extensive
development of work
- expensive
Spray Driers - a dry granular product is
made from a solution or suspension
- can be used to make tablet granules
- can convert elastic materials into more
ductile materials
- short drying time and minimal
exposure to heat
Spheronizers / Pelletizers - some are
used for controlled drug release products
- involves a separate process of wet
massing and extrusion into rod-shaped
granules
- used frequently to produce modified-
release multiparticulates
2. Spheronization / Extrusion - multi-
step process used to make uniformly
sized spherical particles
- ability to incorporate high levels of
active ingredients without producing
large particles
- a versatile process capable of
producing spherical granules having
useful properties (such as controlled-
release)
STEPS:
• Dry mixing of ingredients
• Wet massing Wet Massing - two amount of fluid and
• Extrusion achievement of uniform dispersion of
• Spheronization fluid (only difference with wet
• Drying granulation)
• Screening Extrusion - produces rod-shaped
particles with uniform diameter
Applications of Extrusion / 3 Classes:
Spheronization - labour-intensive - screw-feed extruders (axial or
process than other forms of granulation endplate, dome and radical)
Controlled Drug Release - both - gravity-feed extruders (cylinder roll,
immediate-release and controlled-release gear roll, radial)
pellets can be formed - piston-feed extruders (ram)

Processing - used to increase bulk Spheronization - round off the rods

density, improve flow properties and produced by extrusion into spherical
reduce problems of dust particles

Desirable Properties of Pellets
 Drying - required in order to achieve

Uncoated pellets have: desired moisture content
• UNIFORM:
- spherical shape Screening (Optional) - may be done to
- size achieve desired narrow size distribution
• Good flow properties - normal sieves are used
• Reproducible packing
• High Strength 3. Rotorganulation - allows the direct
• LOW: manufacture of spheres suitable for
- friability controlled-release solid dosage forms
- dust
• Smooth surface 4. Melt Granulation - size enlargement
• Ease of coating process in which a thermosetting
material (hot-melt binder) is used
Coated pellets have: - a water-free alternative to wet
• ^maintain all properties granulation
• have desired drug release - liquid bridges are formed by the
characteristics
 molten binder and powder
agglomeration takes place
Process
 - particle bonds are formed due to
Dry Mixing of Ingredients - uses normal surface tension of a liquid
powder mixing equipment

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 2 Variants:
1. Hot melt binder is added as a solid
powder to the mixture at room
temperature and mixed while the
temperature is raised to above the
melting point of the binder
2. the hot-melt binder is heated and
melted then sprayed on the powder
in a fluidized bed granulator or HSM
granulators
Roller Compaction - the powder is
squeezed to produce a sheet or flakes of
material
- adjusted and maintained by a
hydraulic control system
ex. The Protec or Hutt type

Hot-melt Binders - can be hydrophilic /

hydrophobic (particularly useful in
controlled-release dosage forms)

Hot-melt Processes - heating procedure

can be performed in a mixing vessel that
is jacketed with hot water
Factors influencing the efficiency:
• Melting point of the binder
• Viscosity when molten (binder)
• Impellor rotation speed
• Massing time
• Temperature
Advantages:
- use of organic solvents is avoided
- use of water is avoided

Disadvantages:
- thermal degradation

5. Dry Granulators - use pressure

without the intermediate of a liquid
- avoids heat / temperature combinations
Slugging - production of a large tablet in
a heavy-duty tableting press
Work Hardening - poor recompaction

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