WET

GRANULATION
Definition
Granulation is a particle design
process whereby small
particles are brought together
to form physically strong
agglomerates
Reasons to granulate
Improve flow
Densify materials
Improve content uniformity
Improve compression
characteristics
Control the rate of drug release

 Facilitate metering or volume

dispensing
Decrease dust generation and
reduce employee exposure to drug
product
Improve the appearance of the
tablet

Scheme
Drug
Filler

Mixing
Binders
Wetting
Desintegrant
Water/Solvents
Granulation
Drying
Sizing

Lubricant

Glidant

Mixing

Compression

MIXING
To ensure homogeneity of
drug content
Segregation (demixing) :
differences in particle size,
shape and density

INDUSTRIAL
POWDER MIXER

Tumbling mixer
- often used to blend in
lubricant with
tablet granules prior to
compression

- Y-cone mixer, cube or

double cone
Agitator mixer
- ribbon mixer, nautamixer
High speed granulators
- diosna mixer/granulator,
T.K. Fielder

WETTING

Typical solvents : water,

ethanol, and isopropanol
either alone or in
combination
The solvent may be
used alone or it may
contain a dissolved
adhesive
GRANULATING AGENTS
Acacia mucilage
up to 20%
Glucose
up to 50%
Gelatin
5 20%
PVP
2 10%

 Sucrose
up to 70%
Tragacanth mucilageup to 20%
Water
PARTICLE BONDING
MECHANISM
Adhesion and cohesion forces
in immobile liquid film
Interfacial forces in mobile
liquid films
Solid bridges
Attractive forces between solid
particles
Interlocking bonds

 INTERFACIAL FORCES
IN MOBILE LIQUID
FILMS
STATES OF LIQUID
CONTENT
PENDULAR : surface tension
at the solid-liquid-air interface
& hydrostatic suction pressure
of the liquid bridge
FUNICULAR
CAPILLARY
DROPLET : only surface
tension holds the drop together
& there are no longer any
internal interfacial forces

 LEVELS OF MOISTURE
CONTENT (% MC by
VOLUME)
Penduler : 0 < %MC < 13,6
Funicular : 13,6 < %MC < 100
Capillary : % MC = 100
Droplet state : the liquid
completely surrounds the
granule, resulting in an
external phase consisting of
liquid, with an internal solid
phase.

GRANULE GROWTH
MECHANISMS

 Nucleation
Transition
Ball growth
NUCLEATION
Nucleation is the start of
granulation as particles contact
each other & adhere owing to
liquid bridges
TRANSITION
Nuclei grow by two possible
mechanisms :
single particle can be added to
the nuclei by penduler bridges
two or more nuclei may
combine. The combine nuclei

will be reshaped by the

agitation of the bed

This stage is characterized by

the presence of a large number
of smaal granules with a fairly
wide size distribution.
BALL GROWTH
Further granule growth results
in large, spherical granules &
the mean particle size of the
granulating systems increases
with time.
If agitation is continued,
granule coalescence will
continue & produce an
unusable, overmassed system.

VARIOUS
MECHANISMS OF THE
GRANULATION
Layering : the powder mix
that is added to the
granulation adheres to
existing granules forming a
surface layer & increasing
the granule size
2. Crushing & layering : some
granules break into
fragments that adhere to
other granules forming a

layer of material over the

surviving granule
3. Coalescence : two or more
granules join to form a larger
granule
4. Abrasion transfer : abraded
material caused by atrition of
granules adheres to other
granules, thereby increasing
their size

WET GRANULATORS
Shear granulators

- Traditional wet granulators

- Planetary mixer & Oscillating
granulator
High speed granulators/mixer
- Diosna, Fielder
Fluidized bed granulators
- Aeromatic, Glatt
Spray driers
Spheronizers/pelletizers
- Freund granulator, Caleva
spheroniser

 DRYING
Fixed (static) bed convective
drying
tray drier

Dynamic convective drier

Fluidized bed drier

TRAY DRIER
Air flows in the
direction of the arrows
over each shelf in turn.
The wet material may be
spread directly on the
shelves of on shallow

trays resting on the

shelves.
FLUIDIZED BED DRIER
Particulate matter is
contained in a vessel, the
base of which is perforated,
enabling a fluid to pass
through the bed of solids
from below.
ADVANTAGES OF
FLUIDIZED BED DRYING
Efficient heat and mass
transfer give high drying
rates, shorter than static

bed convection driers (20

30 min.)
Gives drying from
individual particles and not
from the entire bed
The temperature is
uniform and can be
controlled precisely
The free movement of
individual particles
eliminates the risk of
soluble materials
migrating
The containers can be
mobile, making handling
simple and reducing labour
costs

DISADVANTAGES OF
FLUIDIZED BED
DRYING
The turbulence of the
fluidized state may cause
attrition of some materials,
with the production of fines
Fine particles may become
entrained and must be
collected by bag filters,
with care to avoid
segregation and loss of
fines
The vigorous movement of
particles in hot dry air can
lead to the generation of
charges of static electricity

SOLUTE MIGRATION
DURING DRYING
Intergranular migration
During the convective
drying of granulates in
shallow beds
The solutes move from
granule to granule, may
result in gross
maldistribution of active
drug
Intragranular migration

 The solutes move towards

the periphery of each
granule, may take place.

SECOND MIXING
The lubricant should be
admixed for a short time only
REFERENCES
Aulton. 1988. Pharmaceutics :
The Science of Dosage Form
Design
Lund.1994.The Pharmaceutical
Codex : Principles & Practice of
Pharmaceutics, 12th ed.

 Gennaro. 1995. Remington : The

Science and Practice of Pharmacy,
19th ed.
Parikh, D.M.1996. Handbook of
Pharmaceutical Granulation
Technology
Bolhuis.2002. Pharmaceutical
Industry, Univ. of Groningen