GRANULATION
organic solvents
GRANULATION – process in which primary powder particles are
made to adhere to form larger multi-particle entities called granules
- Normally commences after initial dry mixing of the
necessary powdered ingredients so that a uniform
distribution of each ingredient through the mix is achieved
- Size range between 0.2 and 4.0 mm, depending on their
subsequent use
- Typical size range of granules between 0.2 and 0.5 mm, for
capsule and tablet
REASONS FOR GRANULATION:
1. To prevent segregation of the constituents of the powder
mix
2. To improve the flow properties of the mix. Poor flow will
often result in a wide variation within the final product
owing to variable fill of the tablet dies.
3. To improve the compaction characteristics of the mix. This
is associated with the distribution of the adhesive within
the granule and is a function of the method employed to
produce the granule.
4. Other reasons:
- Granulation of toxic materials will reduce the hazard
associated with the generation of toxic dust which may
arise when handling powders
- Materials which are slightly hygroscopic may adhere and
form a cake if stored as a powder
- Granules, being denser than the parent powder mix,
occupy less volume per unit weight
METHODS OF GRANULATION
 DRY GRANULATION – no liquid is used; primary powder
particles are aggregated at high pressure
2 MAIN PROCESSES OF DRY GRANULATION
 SLUGGING – a large tablet (slug) is produced in a heavy-
duty tabletting press
 ROLLER COMPACTION – powder is squeezed between two
rollers to produce a sheet of material
 In both cases, intermediate products are broken using a
suitable milling technique to produce granular material
which is usually sieved to separate the desired size fraction
 The unused fine material may be reworked to avoid waste
 used for drugs which do not compress well after wet
granulation or those which are sensitive to moisture
 WET GRANULATION – utilize a liquid in the process
(granulating fluid)
- granulating fluid contains a solvent that must be volatile, so
that it can be removed by drying, and non-toxic (water,
ethanol, and isopropanol either alone or in combination)
- used as a solvent containing a dissolved adhesive
(binder/binding agent) to ensure particle adhesion once the
granule is dry
- Wet mass is forced through a sieve to produce granules which
are then dried
 WATER – commonly used for economical and
ecological reasons
-the disadvantages are that it may be adversely affect
drug stability, causing hydrolysis of susceptible
products, and it needs a longer drying time than
- Advantage is it is non-flammable
 ORGANIC SOLVENTS – used when water sensitive-
drugs are processed, as an alternative to dry
granulation or when a rapid drying time is required
EFFECT OF GRANULATION METHOD ON GRANULE STRUCTURE
Precompacted granules, consisting of drug and binder particles, are
held together by simple bonding formed during consolidation.
Granules prepared by wet massing consist of intact drug particles
held together in a sponge-like matrix of binder.
 FLUIDIZED-BED GRANULES are similar to granules
prepared by wet massing process but possess greater
porosity, and the granule surface is covered by a film of
binding agent.
 SPRAY-DRIED SYSTEMS, the granules consist of spherical
particles composed of an outer shell with an inner core of
particles
GRANULATION MECHANISMS
Particle bonding mechanisms
1. adhesion and cohesion forces in the immobile liquid films
between individual primary powder particles
2. interfacial forces in mobile liquid films within the granules
3. the formation of solid bridges after solvent evaporation
4. attractive forces between solid particles
5. mechanical interlocking
Adhesion and cohesion forces in immobile films
If sufficient liquid is present in a powder to form a very thin,
immobile layer, there will be an effective decrease in
interparticulate distance and increase in contact area between the
particles.
Interfacial forces in mobile liquid films
 Pendular State – at low moisture level, the particles are
held together by lens-shaped rings of liquid which causes
adhesion because of the surface tension forces of the
liquid-air interface and the hydrostatic suction pressure in
the liquid bridge
 Capillary State – is reached when all the air has been
displaced from between the particles and held by capillary
suction at the liquid-air interface which is now only at the
granular surface
 Funicular State – represents an intermediate stage
between the pendular and capillary state
Solid bridges
1. PARTIAL MELTING – When the pressure is relieved,
crystallization will take place, binding the particles
together
2. HARDENING BINDERS – common mechanism in
pharmaceutical wet granulations when an adhesive is
included in the granulating solvent
- The liquid will form liquid bridges and the adhesive will
harden or crystallize on drying to form solid bridges to
bind the particles
 Polyvinylpyrrolidone, cellulose derivatives
(carboxymethylcellulose) and pregelatinized starch
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 3. CRYSTALLIZATION OF DISSOLVED SUBTANCES – the solvent
used to mass the powder during wet granulation may
partially dissolve one of the powedered ingredients
- When the granules are dried, crystallization of this
material will take place and the dissolved substance then
acts as a hardening binder
 Lactose incorporated into powder blends granulated
with water
Attractive forces between solid particles
1. Electrostatic forces – causing powder cohesion and the
initial formation of agglomerates
- Do not contribute significantly to the final strength
2. Van der Waals forces – four orders of magnitude greater
than electrostatic forces and contribute significantly to the
strength of granules produced by dry granulation
Mechanisms of granule formation
1. NUCLEATION – particle-particle contact and adhesion due
to liquid bridges
- Further agitation densifies the pendular bodies to form the
capillary state and these bodies act as nuclei for further
granule growth
2. TRANSITION – single particles can be added to the nuclei
by pendular bridges or two or more nuclei may combine
- Combination nuclei will be reshaped by the agitation of
the bed
3. BALL GROWTH – further granule growth produces large,
spherical granules and the mean particle size of the
granulating system will increase with time
- If agitation is continues, granule coalescence will continue
and produce an unusable, over massed system, although
this is dependent upon the amount of liquid added and the
properties of them material being granulated
 Coalescence – two or more granules join to form a
larger granule
 Breakage - granules break into fragments which
adhere to other granules, forming a layer of material
over the surviving granule
 Abrasion transfer – agitation of the granule bed leads
to attrition of material from granules. This abraded
materials adhere to other granules, increasing their
size
 Layering – when a second batch of powder mix is
added to a bed of granules, the powder will adhere to
the granules, forming a layer over the surface and
thus increasing the granule size (this mechanism is
only of relevance to the production of layered
granules using spheronizing equipment
GRANULATION ENDPOINT CONTROL – the transition from a non-
granulated to an over massed system is very rapid and monitoring
equipment is necessary to stop the granulation at a pre-determined
point
PHARMACEUTICAL GRANULATION EQUIPMENT
 Wet granulator
Shear granulators
High speed mixer/granulators
Fluidized bed granulator
 Rotor granulator
 Dry granulator
Sluggers
Roller compactors
 SHEAR GRANULATOR
- Include a planetary mixer, granular (oscillating granulator),
drying oven
- 3 major disadvantages (due to tray drying)
a. Drying time is long
b. Dissolved material can migrate to the upper surface
of the bed of granules, as the solvent is only removed
from the upper surface of the bed on the tray
c. Granules may aggregate owing to bridge formation at
the point of contact of the granules
- To disaggregate the granules and remix them, a sieving is
necessary after drying
- Alternative method is to dry granules using a fluidized bed
drier
 HIGH SPEED MIXER/GRANULATOR
- Used extensively in pharmaceutics
- Advantage
a. Mixing, massing and granulation are all performed
within a few minutes in the same piece of equipment
- The process needs to be controlled with care as the
granulation progressed so rapidly that a usable granule
can be transformed very quickly into an unusable, over
massed system
- The process is also sensitive to variation in raw materials,
but this may be minimized by using a suitable endpoint
monitor
- Diosna/Fielder and Collete-Gral Mixer
 DIOSNA/FIELDER – machine that have a stainless
steel mixing bowl containing a 3-bladed main
impeller, which revolves in the horizontal plane,
and a 3-bladed auxiliary chopper (beaker blade)
which revolves wither in the vertical or the
horizontal plane
 COLLETE-GRAL MIXER – Variation of the
Diosna/Fielder type of design
- based on the bowl and overhead drive of the
planetary mixer, but the single paddle is
replaced by two mixing shafts
- One of these carries the three blades, which
rotate in the horizontal plane at the base of the
bowl, and the second, carries smaller blades
which act as the chopper and rotate in the
horizontal plane in the upper regions of the
granulating mass. Thus the operation principle is
similar to Diosna/Fielder
 FLUIDIZED BED GRANULATORS
- Similar design and operation to fluidized bed driers
- the powder particles are fluidized in a stream of air but in
addition, granulation fluid is sprayed from a nozzle on to
the bed powder
- Fluidized granulation has many advantages over
conventional wet massing
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 a. All the granulation processed which require separate  Drying to achieve the desired final moisture content
equipment in the conventional method, are  Screening (optional) to achieve the desired narrow size
performed in one unit, saving labor costs, transfer distribution
losses and time
b. Process can be automated once the conditions DESIRABLE PROPERTIES OF PELLETS (UNCOATED PELLETS)
affecting the granulation have been optimized  Uniform spherical shape
- Disadvantages  Uniform size
a. Expensive  Good flow properties
b. Optimization of process (and product) parameters  Reproducible packing (into hard gelatin capsules)
affecting granulation needs extensive development  High strength
work, not only during initial formation work but also  Low friability
during scale up from development to production  Low dust
- Spray driers, spheronizers/pelletizers  Smooth surface
 Ease of coating
 SPRAY DRIERS – granules made from a solution
or suspension of drug alone, a single excipient  ROTOR GRANULATION
or a complete formulation - Process allows the direct manufacture of spheres from dry
- This is only used when other methods are not powder
applicable - Freund granulator
- can convert elastic materials into more ductile
ones DRY GRANULATOR
- spray dried lactose - Converts primary powder particles into granules using the
- primary advantages are short drying time and application of pressure without the intermediate use of a
minimal exposure of the product to heat owing liquid
to the short residence time in drying chamber, - It avoids heat temperature combinations that might cause
little deterioration of heat sensitive materials degradation of the product
takes place - Two pieces of equipment are necessary for dry
 SPHERONIZERS/PELLETIZERS – produce pellets granulation;
that are used for controlled drug release 1. a machine for compressing the dry powders into
products following coating with a suitable compacts or flakes
polymer coat and filling into hard gelatin 2. a mill for breaking up these intermediate products
capsules into granules
- Sluggers and Roller Compactors
 EXTRUSION/SPHERONIZATION
- Multistep process used to make uniformly sized spherical  SLUGGING
particles - Large heavy-duty rotary press can be used
- Used primarily to produce multiparticulates for controlled - The compacts made in the process (typically 25 mm
drug release application diameter by about 10-15 mm thick) being termed ‘slugs’
- Major advantage over other methods of producing drug - A hammer mill is suitable for breaking the compacts
loaded spheres or pellets is the ability to incorporate high
levels of active ingredients without producing excessively
large particles  ROLLER COMPACTION
- Alternative gentler method
MAIN STEPS OF THE EXTRUSION OR SPHERONIZATION - The powder mix being squeezed between two
counterrotating rollers to form a compressed sheet
 Drying mixing of the ingredients to achieve a homogenous - Roller pressure can be adjusted and is maintained constant
powder dispersion during a run by means of a hydraulic control system to
 Wet massing to produce a sufficiently plastic wet mass yield resulting granules of constant crushing strength
 Extrusion to form rod shaped particles of uniform - Advantages
diameter, the extrudate must have enough plasticity to a. Economical
deform, but not so much that the extruded particles b. Can cope with wide range of materials, particle size,
adhere to other particles when collected or rolled in the bulk density and flowability
spheronizer. c. Relatively low investment costs
 Three classes of extruder based on their feed mechanism d. Process is easily scaled up
a. Screw feed extruder (axial or end plate, dome and e. Product has uniform properties with respect to its
radial) mechanical strength
b. Gravity feed extruder (cylinder roll, gear roll, radial) f. The more gentle ‘squeeze’ of roller compactors leaves
c. Piston feed extruders the resulting granules capable of further compaction
 Spheronization to round off these rods into spherical into tablets without the work-hardening problems
particles, a transition from cylindrical particles into encountered with slugging
cylindrical particles with rounded edges, then dumbbells
to ellipsoids and finally spheres
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