Granulation

Granulation is the process in which primary powder

particles are made to adhere to form larger,
multiparticle entities called granules.
Pharmaceutical granules typically have a size range
between

0.2

and

4.0

mm,

depending

on

their

subsequent use.
In the majority of cases this will be in the production of
tablets or capsules, when granules will be made as an
intermediate product and have a typical size range

Reasons for granulation

To prevent segregation of the constituents of the
powder mix
Segregation is due to differences in the size or density
of the
components of the mix, the smaller and/or denser
particles concentrating at the base of a container with
the larger and/or less dense ones above them.
An ideal granulation will contain all the constituents of
the mix in the correct proportion in each granule, and
segregation of the ingredients will not occur

Powder

Granules
Granulation

sievin
g

Segregated

Monosized

It is also important to control the particle size

distribution of the granules because, although the
individual components may not segregate, if there is
a wide size distribution the granules themselves may
segregate.
If

this

occurs

in

the

hoppers

of

capsule-filling

machines or tablet machines, products with large

weight variations will result. This is because these
machines fill by volume rather than weight, and if
different regions in the hopper contain granules of
different sizes (and hence bulk density), a given
volume in each region will contain a different weight

mprove the flow properties of the mix

improve
Many powders, because of their small size, irregular
shape or surface characteristics, are cohesive and do
not flow well.

Poor flow will often result in a wide weight variation

within the final product owing to variable fill of tablet
dies etc.

Granules produced from such a cohesive system will

be

larger

and

more

isodiametric,

both

factors

To improve the
mixture
Some powders

compaction characteristics of the

are difficult to compact even if a

readily compactable adhesive is included in the mix,

but granules of the same formulation are often more
easily compacted and produce stronger tablets. This
is associated with the distribution of the adhesive
within the granule. Often solute
migration occurring during the postgranulation drying
stage results in a binder-rich outer layer to the
granules. This in turn leads to direct binderbinder
bonding, which assists the consolidation of weakly

Reduce the hazard of toxic dust powders

The granulation of toxic materials will reduce the
hazard associated with the generation of toxic dust
that may arise when handling powders.
Suitable precautions must be taken to ensure that
such dust is not a hazard during the granulation
process. Thus granules should be non-friable and
have a suitable mechanical strength.

Reduce the hazard of hygroscopic powder adhesion

Materials which are slightly hygroscopic may adhere
and form a cake if stored as a powder.
Granulation may reduce this hazard, as the granules
will be able to absorb some moisture and yet retain
their flowability because of their size.

More convenient for storage

Because granules are denser than the powder mix,
they occupy less volume per unit weight. They are
therefore more convenient for storage or shipment.

Methods of granulation
Granulation methods can be divided into two types:
wet methods, which use a liquid in the process,
dry methods in which no liquid is used.
In a suitable formulation a number of different
excipients will be needed in addition to the drug.
Diluents, to produce a unit dose weight of suitable
size,
Disintegrating agents, which are added to aid the
break-up of the granule when it reaches a liquid
medium, e.g. on
ingestion by the patient.
Adhesives in the form of a dry powder may also be

Dry granulation
In the dry methods of granulation the primary powder
particles are

Granulation: (aggregation) under high pressure

without the use of a liquid using one of the following
processes.

Using Sluggers: large tablet compacts (known as a

slug) is
produced in a heavy-duty tabletting press (a
process
known as sluggin)

or using Roller compactors the powder is squeezed

between two rollers to produce a sheet of material
(roller
compaction).

Roller compactors

Alexanderwerk
Roller compactor

Hutt Roller
compactor

Advantages of dry granulation:

Avoids heattemperature combinations that might

cause
degradation of the product.

This dry method may be used for drugs which are

sensitive to moisture.

Wet granulation

Wet granulation involves the massing of a mix of dry

primary
powder particles using a granulating fluid.

The fluid contains a solvent which must be volatile so

that it
can be removed by drying, and be non-toxic.

The granulation liquid may be used alone or, more

usually, as a
solvent containing a dissolved adhesive (binding
agent) which
is used to ensure particle adhesion once the granule is
dry.

In the traditional wet granulation method the wet mass

is

 Typical liquids include water, ethanol and isopropanol,

either
alone or in combination.
The primary advantages of water are that:
it is non-flammable, which means that expensive safety
precautions not be taken.
Water is commonly used for economical reasons.
disadvantages of water as a solvent are that:
It may adversely affect drug stability, causing drug
hydrolysis.
It needs a longer drying time than do organic solvents,
that
increases the length of the process and again may affect
stability

Effect of granulation method on granule structure

The properties of the granules are influenced by the
manufacturing process.
The
method
and
conditions
of
granulation
affect
intergranular and intragranular pore structure by changing
the degree of packing within the granules.
Precompressed granules (dry granulation), consisting of
compressed drug and binder particles, are held together
by
simple bonding during compaction.
Granules prepared by wet massing (wet granulation),
consist of
intact drug particles held together in a sponge-like matrix
of
binder.
Fluidized-bed granules are similar to those prepared by
the wet
granulation, but possess greater porosity and the granule

Wet granulators
There are many types of granulator used in the
pharmaceutical industry for wet granulation.

Shear granulators

igh-speed mixer/granulators

luidized-bed granulators
Spray-driers

Spheronizers /Pelletizers

Rotor granulators

Shear granulators
Powder

mixing

in

separate

operation
using suitable mixing equipment.
A planetary mixer is used for wet
massing of the powders
With some formulations, such

Mixin
g arm

as
those containing two or three
ingredients in equal quantities,

Mixin
g
bowl

it is
suitable to mix powder in the
planetary mixer.
The mixed powders are fed into the
bowl of the planetary mixer and

Planetary Mixer

The

moist

mass

has

been

transferred

Roto
r

to a granulator, as oscillating
granulator.
The rotor bars of the granulator
oscillate and force the moist
mass
through the sieve screen, the

Siev
e

Oscillating
Granulator

size of
The mass should be sufficiently moist to form discrete
granules
which determines the granule
when sieved. If excess liquid is added, string (filament)
size.
of

The granules can be collected on trays and transferred to

a drying
oven.
1. drying
The drying
time is
long.disadvantages:
Tray
has three
major
2. Dissolved material can migrate
to the
upper surface of granules bed,
as the
solvent is only removed from the

upper surface of the bed on the

To tray.
deaggregate the granules and remix them, a sieving
stage
is necessary
drying.
3. Granules
may after
aggregate
owing

An alternative method is to dry the granules using a

fluidized-bed drier.
This is quicker and, as it keeps the individual granules
separated during drying, it reduces the problems of
aggregation and intergranular solute migration, thereby
reducing the need for a sieving stage after drying.

Advantages of Shear granulation process:

The process is not very sensitive to changes in the

characteristics of the granule ingredients (e.g.
surface
area variations in different batches of an
excipient)

The end-point of the massing process can often be

determined by examination.
The disadvantages of Shear granulation process:

Long duration

The granulator has a stainless

steel mixing bowl containing
a three-bladed main impeller,
which revolves in the
horizontal
plane,
and a three-bladed auxiliary
chopper (breaker blade)
which revolves either in the
vertical or the horizontal
plane.

ch
op
pe
r

igh-speed mixer/granulators

The unmixed dry powders are placed in the bowl and

mixed
by the rotating impeller for a few minutes.
Granulating liquid is then added via a port in the lid
of the
granulator while the impeller is turning.
The granulating fluid is mixed into the powders by
the
impeller.
The chopper
is usually
on when the moist
Once
a
granule
has switched
been
mass
is
produced,
the granular product

formed, as its
function
is to a
break up the wet mass
is discharged,
passing
through
to
wire mesh which breaks up any
produce
a bed ofinto
granular
material.
large
aggregates,
the bowl
of a fluidized-bed drier.

Advantages of High-speed mixer/granulation:

Mixing and granulation are all performed within a
few minutes in the same piece of equipment.
Disadvantages of High-speed mixer/granulation:

The process needs to be controlled with care as

the
granulation progresses so rapidly that a usable
granule
can be transformed very quickly into an unusable,
overmassed system. Thus it is often necessary to
use a
suitable monitoring system to indicate the end of
the
granulation process, i.e. when a granule of the

Fluidized-bed granulator
Air outlet

Exhaust
filter

Spray
nozzle
Product
containe
r
Air inlet
Air
filter

Granulatin
g liquid

Glatt

Fluidized-bed granulator (Glatt)

The powder particles are

Air outlet

fluidized in a stream of
air.
Granulation

fluid

Exhaust
filter

is

pumped
from a reservoir and
sprayed
from a nozzle on to the
bed
of powders.
Heated and filtered air is
blown through the bed of

Spray
nozzle

Product
container
Air
inlet
Air
filter

Granulatin
g liquid

The fluid causes the primary

powder
when

particles
the

to

adhere

droplets

and Air outlet

powders collide.
Escape of material from the
granulation

chamber

is

Exhaust
filter

prevented by exhaust filters,

which are periodically agitated
to

reintroduce

the collected

material into the fluidized bed.

Spray
nozzle

Sufficient liquid is sprayed to Product

produce

granules

of

the

required size, at which point

the spray is turned off but the
fluidizing air continued.
The wet granules are then
dried in the heated fluidizing

container
Air
inlet
Air
filter

Granulatin
g liquid

vantages of fluidized-bed granulation

All the granulation processes, which require
separate
equipment in the conventional method, are
performed in
one unit, saving labour costs, transfer losses and
time.

sadvantages of fluidized-bed granulation

canisbe
automated once the conditions
The process
equipment
expensive.
affecting the of
granulation
have beenaffecting
optimized.
Optimization
process parameters

granulation
needs extensive development work.

Spray-driers
Granular product is made
from a solution or a
suspension rather than
initially dry primary powder

suspension

particles.
The resultant granules
are free-flowing hollow

scree
n

spheres and the

distribution of the binder in
such granules results in
good compaction

Fluidization
air

Spray-drying can convert

hard elastic materials into
more ductile ones.
The primary advantages of
the process are the short
drying time and the minimal

suspension

exposure of the
product to heat owing to the
scree
n

short residence time in the

drying chamber.
This means that little
deterioration
of heat-sensitive materials

Fluidization
air

Spheronizers /Pelletizers
For some applications it may be desirable to
have a
dense, spherical pellet of the type difficult to
produce with the previous equipments. Such
A commonly
used
process
pellets
are used for
controlled
drug release.
involves:

Separation of wet massing.

Extrusion of this wet mass
into
rod-shaped granules and
subsequent spheronization
of

Advantages of granulation using

Extrusion/spheronization
Extrusion/spheronization

process

is

used

to

make

uniformly
sized spherical particles.
It is used primarily to produce multiparticulates for
controlled
drug release applications.
The major advantage over other methods of producing
drug
loaded spheres or pellets is the ability to incorporat
high levels
of active ingredients without producing excessively
large

he main steps of the process are:

1. Dry mixing of ingredients to achieve a homogenous

powder dispersion
2. Wet massing to produce a sufficiently plastic wet mass
3. Extrusion to form rod-shaped particles of uniform
diameter
4. Spheronization to round off these rods into spherical
particles

Extrusion

Schematic representation of production extrude

Spheronization
The function of spheronization

is to round off the rods

produced
by extrusion into spherical particles.

This is carried out in Spheronizer which consists of a bowl

with
fixed side walls and a rapidly rotating bottom plate or
disc.

The rounding of the extrudate into spheres is dependent

on
frictional forces generated by particleparticle and
particle
equipment collisions.

Rotor granulation
In the Freund granulator,
the powder mixture is
added
to the bowl and wetted
with
granulating liquid from a
spray.
The base plate rotates at
high

speed

and

centrifugal
force keeps the moist

The

velocity

difference

between
the rotor and the static
walls,
combined with the upward
flow
of air around the rotor plate,
causes the mass to move in a
toroidal motion, resulting in
the
formation
spherical
pellets.

of

isolated

Process principle

Powder is mixed and moistened and the powder bed set

into centrifugal motion (fluid bed pelletizing in the rotor).
The impact and acceleration forces that occur in this
process result in the formation of agglomerates, which
become rounded out into uniform and dense pellets and
are then dried.

Principle of the powder layering process

Using this technique it is possible to continue the

process and coat the pellets by spraying coating solution
on to the rotating dried pellets.
In layered pellets can be produced by using uncoated
pellets as nuclei in a second granulation with a powder
mix of a second ingredient or ingredients.

GRANULATION MECHANISMS
To form granules, sufficiently strong bonds must be
formed between powder particles so that they adhere
and prevent breakdown of the granule to powder during
handling.
There
are four
bonding
mechanisms
between
1. Adhesion
andprimary
cohesion
forces in
the immobile
liquid
films
particles:
between individual primary powder particles.
2. Interfacial forces in mobile liquid films within the
granules.
3. The formation of solid bridges after solvent
evaporation.

The process variables involved in the granulation

steps

(formulation

ingredients

and

their

concentrations, the type of granulating equipment

and processing conditions employed) can affect the
characteristics of the granulations produced.
Particle Size and Shape.
Surface Area.
Density.
Strength and Friability.
Flow Properties.
Compaction.

.Particle Size and Shape

The particle size of a granulation is known to
affect the average tablet weight, disintegration
time, granule friability, granulation flowability
and the ding rate kinetics of wet granulations.

Surface Area.

The surface area of the drug has a significant effect

upon

dissolution

rate.

An

inverse

relationship

normally exists between particle size and surface

area;
Methods

for

determining

surface

area

of

solid

particles are gas adsorption and air permeability.

In gas adsorption method, the amount of gas that is
adsorbed onto the powder to form a monolayer is
measured and then used to calculate the surface area
of the powder sample.
Air permeability, the rate at which air permeates a
bed of powder, is used to calculate the surface area of
the powder sample.

Granule density may influence compressibility,

.Density
tablet
porosity and dissolution.

Dense,

hard

granules

may

require

higher

compressible
loads to produce a cohesive compact.

The higher compression load, increase the tablet

disintegration and drug dissolution times. Even if
the
tablets disintegrate readily, the harder, denser
granules

use of a pycnometer.

Where, the intrusion fluid is mercury, and in the

other, it
is a solvent of low surface tension (e.g., benzene)
in
which the granules are not soluble.

These pycnometer methods depends on the ability

of the
intrusion fluids to penetrate the pores of the
granules.
Density is calculated from the volume of intrusion

Strength and Friability.

A granule is an aggregation of component particles
that is held together by bonds of finite strength.
The strength of a wet granule is due to the surface
tension of liquid and capillary forces.
These

forces

are

responsible

for

initial

agglomeration of the wet powder.

Upon

drying,

resulting

from

the

granule

fusion

or

has

strong

bonds

recrystallization

particles and curing of the adhesive or binder.

of

Measurements of granule strength estimate the

magnitude

of

attractive

forces

that

hold

the

granule together.
The resultant strength of a granule depends on
base material, the kind and amount of granulating
agent used and the granulating equipment used.

Granule strength and friability are important, as

they affect changes in particle size distribution of
granulations, and compressibility into cohesive
tablets.

Methods used for measuring granule strength are:

Compression strength. Where a granule is placed
between anvils, and the force required to break the
granule is measured.
Friability measurements. measuring the tendency
of granules to break into smaller pieces when
subjected to disturbing forces.

.Flow Properties

Flow properties of a material result from many

surface forces:
(1)frictional forces, (2) surface tension forces,
(3) mechanical forces caused by interlocking of
particles

of

irregular

shape,

(4)

electrostatic

forces, (5) cohesive or van der Waals forces.

They

can

affect

granule

properties

such

as:

particle size,
particle size distribution, particle shape, surface
texture or roughness, surface energy, and surface
area.

the
frictional and van der Waals forces are
predominate.
For larger particles (>150m) such as granules
produced by a wet granulation, frictional forces
are
predominate over van der Waals forces.
Flow measur the effect of all the interparticulate
forces
acting at once.
Two methods are used:

materials to
Compaction

form a tablet is complex, owing to the numerous

internal
events that act simultaneously.
The basic tool that has been developed for studying
the
compression process is the tablet press.
Tablet

presses

are

instrumented

by

affixing

transducers
to measure the forces applied during the
compression

Effervescent salts are granules or coarse

to very coarse powders containing a medicinal agent
in

dry

mixture

usually

composed

of

sodium

bicarbonate, citric acid, and tartaric acid.

When added to water, the acids and base react to
liberate carbon dioxide, resulting in effervescence.
The resulting carbonated solution masks the usually
saline or undesirable taste of the medicinal agent
present.

A good effervescent blend consists of both citric acid

and tartaric acid (1 :2 ratio), since the former is
rather sticky to manipulate and the latter produces a
chalky,
friable granule.
Citric Acid
3 NaHC03 + C6H8O7.H2O

4 H20 + 3C02 +

Na3C6H5O7
3 x 84

1
210

X
3X 84

210
X = 1.2 g

One gram of citric acid (MW = 210) reacts with 1.2 g

Tartaric Acid
2 NaHC03 + C4H606
2 x 84

2
150

2 H20 + 2C02 -+ Na2C4H4O6

150

X
2X 84

X = 2.24 g

Since it is desired to use a 1:2 ratio of critic acid to

tartaric acid, two grams of tartaric acid (MW = 150)
reacts with 2.24 g of sodium bicarbonate.

From the above, it has been calculated that 1.2 g and

2.24 g of sodium bicarbonate is required to react
with 1 + 2 g of the citric : tartaric acid combination.
Since it is desired to leave a small amount of the
acids unreacted to enhance palatability and taste,
2.24 g + 1.2 g= 3.44 g, only 3.4 g of sodium
bicarbonate will be utilized. Therefore, the ratio of
the effervescent ingredients is
1 : 2 : 3.4 for the citric acid : tartaric acid : sodium
bicarbonate.

The Supercell
Tablet Coater
feature continuous
small-batch
capabilities and the
coating process
are predictable and
efficient