GRANULATION

primary powder particles are made to adhere to form larger multi-particle entities
commences after initial dry mixing of powders
typical size: 0.2 - 4.0 mm | tablet or capsule production : 0.2 - 0.5 mm

Reasons for granulation

prevent
segregation
of
the
constituents of the powder mix
control particle size distribution
machines fill by volume
improve flow properties of the mix
larger & isodiametric granules

improve compaction characteristics of

the mix
direct binder-binder bonding
reduce hazard of toxic materials
for slightly hygroscopic materials
convenient for storage & shipment

Granulation Methods
Dry Granulation
for drugs that do not compress well after wet granulation
for moisture-sensitive drugs
Slugging produce large tablet or slug by heavy-duty tableting press
Roller Compaction produce sheet of material by squeezing powder between 2 rollers
Wet Granulation
granulating fluid volatile & non-toxic
removed by drying
water, ethanol, isopropanol
water adv: non-flammable
disadv: affect drug stability (hydrolysis) ; longer drying time
Granulation Mechanisms
Pharmaceutical Granulation Equipment
Wet granulators
1) Shear granulators
have largely disappeared
traditional shear aka planetary
disadvantages:
long duration
need for several pieces of equipment
high material losses
2) High-speed mixer/granulators
mixing bowl stainless steel
three-bladed main impeller revolves horizontally
three-bladed auxiliary chopper breaker blade
revolves horizontally/vertically
switched on when moist mass is formed
break up wet mass
adv: powder blending, wet massing, granulation are all performed in same equipment
disadv: rapid progress from usable granule to unusable
High-speed
mixer/granulator

Collette UltimaGral
mixer

Oscillating
granulator

extensively used

two mixing shafts

granulate moist mass

type

Diosna type

variation of Diosna
type

mixing
bowl

1 L - 1250 L volumes

10 L - 200 L volumes

main blade

revolves horizontally; 150300 rpm

450-600 rpm (10 L)

150-200 rpm (200 L)

1500-3000 rpm

1500-300 rpm

60-100 rpm
wet mass: 300-500
kg/h
dry mass: 700-1200
kg/h

high-speed
chopper
rotor bars
optimum
fill capacity

3kg - 80kg batches

3) Fluidized-bed granulators
Fluidization air is blown/sucked through bed of unmixed powders to fluidize then mix
the particles
used extensively for fertilizers, herbicides, foodstuffs
granulating fluid sprayed from nozzle onto bed of powders
cause powder particles to adhere
exhaust filters prevents escape of material from granulation chamber
adv: all granulation processes are performed in one unit; process optimization
disadv: expensive; optimization of process needs extensive development work
4) Spray driers
dry granular product made from a solution/suspension
resultant granules: free-flowing hollow spheres
to make tablet granules
to convert hard elastic materials to ductile ones
adv: short drying time; minimal exposure to heat
for heat-sensitive materials
5) Spheronizers/pelletizers
pellets: for controlled drug release products
produce modified-release multiparticulates
Extrusion/Spheronization
make uniformly sized spherical particles
to produce multiparticulates for controlled drug release applications
adv: can incorporate high levels of active ingredients without producing large paticles;
minimal necessary excipients
Application
Controlled drug release pellets can contain 2 or more ingredients
incompatible ingredients can be manufactured in separate pellets
Processing increase bulk density
improve flow properties
reduce problems of dust
more labour-intensive process than other forms of granulation
last option to be considered for granulation methods
Desirable properties of pellets
uniform spherical shape
uniform size

good flow properties

reproducible packing

high strength
low friability

low dust
smooth surface

ease of coating

when coated: desired

drug release

Process/Main Steps
Dry mixing of ingredients achieve homogeneous powder dispersion
Wet massing produce sufficiently plastic wet mass
difference in granulation step: greater amount of granulation fluid;
importance of uniform dispersion of fluid
Extrusion form rod-shaped particles of uniform diameter
wet mass forced through dies
designs of extruder: 1) screw-feed (axial/endplate, dome, radial)
2) gravity-feed (cylinder roll, gear roll, radial
3) piston-feed
variables: 1) feed rate of wet mass
2) diameter of die
3) length of die
4) water content of wet mass
Spheronization round off the rods
dependent on frictional forces
spheres will not be formed if moist mass is too dry
Drying achieve desired moisture content
solute migration results to: 1) increased initial rate of dissolution
2) stronger pellets
3) modified surfaces
Screening (optional) achieve desired narrow size distribution
1) Melt granulation
heated extrusion of formulations
excipients melt & bind together

use of low melting point waxes

Rotorgranulation
direct manufacture of spheres from dry powder in one process
produce layered pellets
centrifugal force due to base plate high speed rotation
keeps moist mass at the edges of rotor
toroidal motion movement of mass
results in formation of spherical pellets
heated inlet air dries the resulting spheres
acts as positive-pressure seal
size range : 45 L 450 L
bowl & rotor disc diameters: 300-1400 mm
adjustable air gap manipulate resulting granule size
Dry Granulators
application of pressure to convert powders into granules
no use of a liquid
avoids heat/temperature combinations
necessary equipment: 1) machine for compressing dry powder into compacts/ flakes
2) mill for breaking intermediate products into granules
Slugging
large heavy-duty rotary press compact dry powders
slugs compacts made in the process
compacts are typically 25mm diameters by 10-15mm thick

hammer mill for breaking the compacts

disadv: work hardening results in poor compaction
compaction
powder mix squeezed between two counterrotating rollers
compressed sheet weak & brittle; breaks into flakes immediately
oscillating granulator convert flakes into granules
Protec or Hutt type vertical use feeder in the hopper for even flow of material
size range: 10-2000 kg/h
roller diameters: 100-450 mm
compaction forces: 16-64 kN/cm
roller lengths: 30-115 mm
advantages:
- economical
- low investment cost
- can cope with a wide range of materials
- process easily scaled up &
has uniform properties

Roller