granulation pharmaceutical

2. Granulation is the process in which primary powder
Granulation is the process in which primary powder
particles are made to adhere to form larger,
particles are made to adhere to form larger,
multiparticle entities called granules.
multiparticle entities called granules.
Pharmaceutical granules typically have a size range between
Pharmaceutical granules typically have a size range between
0.2 and 4.0 mm, depending on their subsequent use.
0.2 and 4.0 mm, depending on their subsequent use.
In the majority of cases this will be in the production of
In the majority of cases this will be in the production of
tablets or capsules, when granules will be made as an
tablets or capsules, when granules will be made as an
intermediate product and have a typical size range between
intermediate product and have a typical size range between
0.2 and 0.5 mm,
0.2 and 0.5 mm,
Granulation
Granulation

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

4. Powder
Powder Granules
Granules
Granulation
Granulation
sieving
sieving
Segregated Powder
Segregated Powder Monosized
Monosized
Granules
Granules

5. It is also important to control the particle size distribution
It is also important to control the particle size distribution
of the granules because, although the individual
of the granules because, although the individual
components may not segregate, if there is a wide size
components may not segregate, if there is a wide size
distribution the granules themselves may segregate.
distribution the granules themselves may segregate.
If this occurs in the hoppers of capsule-filling machines or
If this occurs in the hoppers of capsule-filling machines or
tablet machines, products with large weight variations will
tablet machines, products with large weight variations will
result. This is because these machines fill by volume
result. This is because these machines fill by volume
rather than weight, and if different regions in the hopper
rather than weight, and if different regions in the hopper
contain granules of different sizes (and hence bulk
contain granules of different sizes (and hence bulk
density), a given volume in each region will contain a
density), a given volume in each region will contain a
different weight of granules. This will lead to an
different weight of granules. This will lead to an
unacceptable distribution of the drug content within the
unacceptable distribution of the drug content within the

6. Many powders, because of their small size, irregular
Many powders, because of their small size, irregular
shape or surface characteristics, are cohesive and do not
shape or surface characteristics, are cohesive and do not
flow well.
flow well.
Poor flow will often result in a wide weight variation within
Poor flow will often result in a wide weight variation within
the final product owing to variable fill of tablet dies etc.
the final product owing to variable fill of tablet dies etc.
Granules produced from such a cohesive system will be
Granules produced from such a cohesive system will be
larger and more isodiametric, both factors contributing to
larger and more isodiametric, both factors contributing to
improved flow properties.
improved flow properties.
To improve the flow properties of the mix
To improve the flow properties of the mix

7. Some powders are difficult to compact even if a readily
Some powders are difficult to compact even if a readily
compactable adhesive is included in the mix, but granules
compactable adhesive is included in the mix, but granules
of the same formulation are often more easily compacted
of the same formulation are often more easily compacted
and produce stronger tablets. This is associated with the
and produce stronger tablets. This is associated with the
distribution of the adhesive within the granule. Often
distribution of the adhesive within the granule. Often
solute
solute
migration occurring during the postgranulation drying
migration occurring during the postgranulation drying
stage results in a binder-rich outer layer to the granules.
stage results in a binder-rich outer layer to the granules.
This in turn leads to direct binder–binder bonding, which
This in turn leads to direct binder–binder bonding, which
assists the consolidation of weakly bonding materials.
assists the consolidation of weakly bonding materials.
To improve the compaction characteristics of the
To improve the compaction characteristics of the
mixture
mixture

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

9. Materials which are slightly hygroscopic may adhere and
Materials which are slightly hygroscopic may adhere and
form a cake if stored as a powder.
form a cake if stored as a powder.
Granulation may reduce this hazard, as the granules will
Granulation may reduce this hazard, as the granules will
be able to absorb some moisture and yet retain their
be able to absorb some moisture and yet retain their
flowability because of their size.
flowability because of their size.
More convenient for storage
More convenient for storage
Because granules are denser than the powder mix, they
Because granules are denser than the powder mix, they
occupy less volume per unit weight. They are therefore
occupy less volume per unit weight. They are therefore
more convenient for storage or shipment.
more convenient for storage or shipment.
Reduce the hazard of hygroscopic powder adhesion
Reduce the hazard of hygroscopic powder adhesion

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

11. In the dry methods of granulation the primary powder
In the dry methods of granulation the primary powder
particles are
particles are
 Granulation: (aggregation) under high pressure without
Granulation: (aggregation) under high pressure without
the use of
the use of a liquid
a liquid using one of the following processes.
using one of the following processes.
 Using
Using Sluggers
Sluggers: large tablet compacts (known as a
: large tablet compacts (known as a slug
slug)
)
is
is
produced in a heavy-duty tabletting press (a process
produced in a heavy-duty tabletting press (a process
known as
known as sluggin
sluggin’)
’)
 or using
or using Roller compactors
Roller compactors the powder is squeezed
the powder is squeezed
between two rollers to produce a sheet of material
between two rollers to produce a sheet of material
(
(roller
roller
compaction
compaction).
).
 Milling: the intermediate products are broken using a
Milling: the intermediate products are broken using a
suitable milling technique to produce granular material,
suitable milling technique to produce granular material,
dry Granulation
dry Granulation

12. roller coMpactors
roller coMpactors
Alexanderwerk
Alexanderwerk
Roller compactor
Roller compactor

13. Hutt Roller
Hutt Roller
compactor
compactor

14. Advantages of dry granulation:
Advantages of dry granulation:
 Avoids heat–temperature combinations that might cause
Avoids heat–temperature combinations that might cause
degradation of the product.
degradation of the product.
 This dry method may be used for drugs which are
This dry method may be used for drugs which are
sensitive to moisture.
sensitive to moisture.

15. Wet granulation
Wet granulation
 Wet granulation involves the massing of a mix of dry primary
Wet granulation involves the massing of a mix of dry primary
powder particles using a granulating fluid.
powder particles using a granulating fluid.
 The fluid contains a solvent which must be volatile so that it
The fluid contains a solvent which must be volatile so that it
can be removed by drying, and be non-toxic.
can be removed by drying, and be non-toxic.
 The granulation liquid may be used alone or, more usually,
The granulation liquid may be used alone or, more usually,
as a
as a
solvent containing a dissolved adhesive (binding agent)
solvent containing a dissolved adhesive (binding agent)
which
which
is used to ensure particle adhesion once the granule is dry.
is used to ensure particle adhesion once the granule is dry.
 In the traditional wet granulation method the wet mass is
In the traditional wet granulation method the wet mass is
forced through a sieve to produce wet granules which are
forced through a sieve to produce wet granules which are
then
then
dried.
dried.

16.  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
because of the extended exposure to heat.
 Organic solvents are used when water-sensitive drugs are
processed, as an alternative to dry granulation, or when a

17. EffEct of granulation mEthod on granulE
EffEct of granulation mEthod on granulE
structurE
structurE
The properties of the granules are influenced by the
The properties of the granules are influenced by the
manufacturing process.
manufacturing process.
The method and conditions of granulation affect intergranular and
The method and conditions of granulation affect intergranular and
intragranular pore structure by changing the degree of packing
intragranular pore structure by changing the degree of packing
within the granules.
within the granules.
Precompressed granules (dry granulation),
Precompressed granules (dry granulation), consisting of
consisting of
compressed drug and binder particles, are held together by
compressed drug and binder particles, are held together by
simple bonding during compaction.
simple bonding during compaction.
Granules prepared by wet massing (wet granulation),
Granules prepared by wet massing (wet granulation), consist of
consist of
intact drug particles held together in a sponge-like matrix of
intact drug particles held together in a sponge-like matrix of
binder.
binder.
Fluidized-bed granules
Fluidized-bed granules are similar to those prepared by the wet
are similar to those prepared by the wet
granulation, but possess greater porosity and the granule
granulation, but possess greater porosity and the granule
surface is covered by a film of binding agent.
surface is covered by a film of binding agent.
With
With spray-dried systems
spray-dried systems the granules consist of spherical
the granules consist of spherical
particles composed of an outer shell and an inner core of
particles composed of an outer shell and an inner core of
particles.
particles.

18. There are many types of granulator used in the
There are many types of granulator used in the
pharmaceutical industry for wet granulation.
pharmaceutical industry for wet granulation.
WEt granulators
WEt granulators
Shear granulators
Shear granulators
High-speed mixer/granulators
High-speed mixer/granulators
Fluidized-bed granulators
Fluidized-bed granulators
Rotor granulators
Rotor granulators
Spray-driers
Spray-driers
Spheronizers /Pelletizers
Spheronizers /Pelletizers

19. Powder mixing in a separate
Powder mixing in a separate
operation
operation
using suitable mixing equipment.
using suitable mixing equipment.
A planetary mixer is used for wet
A planetary mixer is used for wet
massing of the powders
massing of the powders
With some formulations, such as
With some formulations, such as
those containing two or three
those containing two or three
ingredients in equal quantities, it
ingredients in equal quantities, it
is
is
suitable to mix powder in the
suitable to mix powder in the
planetary mixer.
planetary mixer.
The mixed powders are fed into the
The mixed powders are fed into the
bowl of the planetary mixer and
bowl of the planetary mixer and
granulating liquid is added as the
granulating liquid is added as the
Shear granulators
Shear granulators
Planetary Mixer
Planetary Mixer
Mixing
Mixing
bowl
bowl
Mixing
Mixing
arm
arm

20. The moist mass has been
The moist mass has been
transferred
transferred
to a granulator, as oscillating
to a granulator, as oscillating
granulator.
granulator.
The rotor bars of the granulator
The rotor bars of the granulator
oscillate and force the moist mass
oscillate and force the moist mass
through the sieve screen, the size
through the sieve screen, the size
of
of
which determines the granule size.
which determines the granule size.
The mass should be sufficiently moist to form discrete
The mass should be sufficiently moist to form discrete
granules
granules
when sieved. If excess liquid is added, string (filament) of
when sieved. If excess liquid is added, string (filament) of
material will be formed and if the mix is too dry the mass will
material will be formed and if the mix is too dry the mass will
Oscillating
Oscillating
Granulator
Granulator
Rotor
Rotor
Siev
Siev
e
e

21. The granules can be collected on trays and transferred to a
The granules can be collected on trays and transferred to a
drying
drying
oven.
oven.
Tray drying has three major disadvantages:
Tray drying has three major disadvantages:
1. The drying time is long.
1. The drying time is long.
2. Dissolved material can migrate to
2. Dissolved material can migrate to
the
the
upper surface of granules’ bed, as
upper surface of granules’ bed, as
the
the
solvent is only removed from the
solvent is only removed from the
upper surface of the bed on the
upper surface of the bed on the
tray.
tray.
3. Granules may aggregate owing to
3. Granules may aggregate owing to
bridge formation at the points of
bridge formation at the points of
To deaggregate the granules and remix them, a sieving stage
To deaggregate the granules and remix them, a sieving stage
is necessary after drying.
is necessary after drying.

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

23. Advantages of Shear granulation process:
Advantages of Shear granulation process:
 The process is not very sensitive to changes in the
The process is not very sensitive to changes in the
characteristics of the granule ingredients (e.g. surface
characteristics of the granule ingredients (e.g. surface
area variations in different batches of an excipient)
area variations in different batches of an excipient)
The end-point of the massing process can often be
The end-point of the massing process can often be
determined by examination.
determined by examination.
The disadvantages of Shear granulation process:
The disadvantages of Shear granulation process:
 Long duration
Long duration
 the need for several pieces of equipment
the need for several pieces of equipment
 The high material losses because of the transfer
The high material losses because of the transfer
stages.
stages.

24. High-speed mixer/granulators
High-speed mixer/granulators
The granulator has a stainless
The granulator has a stainless
steel mixing bowl containing a
steel mixing bowl containing a
three-bladed main impeller
three-bladed main impeller ,
,
which revolves in the horizontal
which revolves in the horizontal
plane,
plane,
and a
and a three-bladed auxiliary
three-bladed auxiliary
chopper
chopper (breaker blade) which
(breaker blade) which
revolves either in the vertical or
revolves either in the vertical or
the horizontal plane.
the horizontal plane.
c
h
o
p
p
e
r
c
h
o
p
p
e
r

25. The unmixed dry powders are placed in the bowl and
The unmixed dry powders are placed in the bowl and
mixed
mixed
by the rotating impeller for a few minutes.
by the rotating impeller for a few minutes.
Granulating liquid is then added via a port in the lid of
Granulating liquid is then added via a port in the lid of
the
the
granulator while the impeller is turning.
granulator while the impeller is turning.
The granulating fluid is mixed into the powders by the
The granulating fluid is mixed into the powders by the
impeller.
impeller.
The chopper is usually switched on when the moist mass
The chopper is usually switched on when the moist mass
is
is
formed, as its function is to break up the wet mass to
formed, as its function is to break up the wet mass to
produce a bed of granular material.
produce a bed of granular material.
Once a granule has been produced,
Once a granule has been produced,
the granular product is discharged,
the granular product is discharged,
passing through a wire mesh which
passing through a wire mesh which
breaks up any large aggregates,
breaks up any large aggregates,
into the bowl of a fluidized-bed
into the bowl of a fluidized-bed

26. Advantages of High-speed mixer/granulation:
Advantages of High-speed mixer/granulation:
Mixing and granulation are all performed within a few
Mixing and granulation are all performed within a few
minutes in the same piece of equipment.
minutes in the same piece of equipment.
Disadvantages of High-speed mixer/granulation:
Disadvantages of High-speed mixer/granulation:
 The process needs to be controlled with care as the
The process needs to be controlled with care as the
granulation progresses so rapidly that a usable
granulation progresses so rapidly that a usable
granule
granule
can be transformed very quickly into an unusable,
can be transformed very quickly into an unusable,
overmassed system. Thus it is often necessary to use
overmassed system. Thus it is often necessary to use
a
a
suitable monitoring system to indicate the end of the
suitable monitoring system to indicate the end of the
granulation process, i.e. when a granule of the desired
granulation process, i.e. when a granule of the desired
properties has been attained.
properties has been attained.
 The process is also sensitive to variations in raw
The process is also sensitive to variations in raw

27. glatt
glatt
Air inlet
Air inlet
Air filter
Air filter
Air outlet
Air outlet
Spray
Spray
nozzle
nozzle
Product
Product
container
container
Granulating
Granulating
liquid
liquid
Exhaust
Exhaust
filter
filter
Fluidized-bed granulator
Fluidized-bed granulator

28. The powder particles are
The powder particles are
fluidized in a stream of air.
fluidized in a stream of air.
Granulation fluid is pumped
Granulation fluid is pumped
from a reservoir and
from a reservoir and
sprayed
sprayed
from a nozzle on to the bed
from a nozzle on to the bed
of powders.
of powders.
Heated and filtered air is
Heated and filtered air is
blown through the bed of
blown through the bed of
unmixed powders to fluidize
unmixed powders to fluidize
fluidizEd-bEd granulator (glatt)
fluidizEd-bEd granulator (glatt)
Air inlet
Air inlet
Air filter
Air filter
Air outlet
Air outlet
Spray
Spray
nozzle
nozzle
Product
Product
container
container
Granulating
Granulating
liquid
liquid
Exhaust
Exhaust
filter
filter

29. The fluid causes the primary
The fluid causes the primary
powder particles to adhere when
powder particles to adhere when
the droplets and powders collide.
the droplets and powders collide.
Escape of material from the
Escape of material from the
granulation chamber is prevented
granulation chamber is prevented
by exhaust filters, which are
by exhaust filters, which are
periodically agitated to
periodically agitated to
reintroduce the collected material
reintroduce the collected material
into the fluidized bed.
into the fluidized bed.
Sufficient liquid is sprayed to
Sufficient liquid is sprayed to
produce granules of the required
produce granules of the required
size, at which point the spray is
size, at which point the spray is
turned off but the fluidizing air
turned off but the fluidizing air
continued.
continued.
The wet granules are then dried
The wet granules are then dried
in the heated fluidizing air
in the heated fluidizing air
Air inlet
Air inlet
Air filter
Air filter
Air outlet
Air outlet
Spray
Spray
nozzle
nozzle
Product
Product
container
container
Granulating
Granulating
liquid
liquid
Exhaust
Exhaust
filter
filter

30. All the granulation processes, which require separate
All the granulation processes, which require separate
equipment in the conventional method, are performed
equipment in the conventional method, are performed
in
in
one unit, saving labour costs, transfer losses and time.
one unit, saving labour costs, transfer losses and time.
The process can be automated once the conditions
The process can be automated once the conditions
affecting the granulation have been optimized.
affecting the granulation have been optimized.
The equipment is expensive.
The equipment is expensive.
Optimization of process parameters affecting
Optimization of process parameters affecting
granulation
granulation
needs extensive development work.
needs extensive development work.
Advantages of fluidized-bed granulation
Advantages of fluidized-bed granulation
Disadvantages of fluidized-bed granulation
Disadvantages of fluidized-bed granulation

31. Spray-driers
Spray-driers
Granular product is made
Granular product is made
from a solution or a
from a solution or a
suspension rather than
suspension rather than
initially dry primary powder
initially dry primary powder
particles.
particles.
The resultant granules are
The resultant granules are
free-flowing hollow spheres
free-flowing hollow spheres
and the distribution of the
and the distribution of the
binder in such granules
binder in such granules
results in good compaction
results in good compaction
properties.
properties.
suspension
suspension
Fluidization air
Fluidization air
screen
screen

32. Spray-drying can convert hard
Spray-drying can convert hard
elastic materials into more ductile
elastic materials into more ductile
ones.
ones.
The primary advantages of the
The primary advantages of the
process are the short drying time
process are the short drying time
and the minimal exposure of the
and the minimal exposure of the
product to heat owing to the short
product to heat owing to the short
residence time in the drying
residence time in the drying
chamber.
chamber.
This means that little
This means that little
deterioration
deterioration
of heat-sensitive materials takes
of heat-sensitive materials takes
suspension
suspension
Fluidization air
Fluidization air
screen
screen

33. Spheronizers /Pelletizers
Spheronizers /Pelletizers
For some applications it may be desirable to have
For some applications it may be desirable to have
a
a
dense, spherical pellet of the type difficult to
dense, spherical pellet of the type difficult to
produce with the previous equipments. Such
produce with the previous equipments. Such
pellets are used for controlled drug release.
pellets are used for controlled drug release.
A commonly used process
A commonly used process
involves:
involves:
 Separation of wet massing.
Separation of wet massing.
 Extrusion of this wet mass into
Extrusion of this wet mass into
rod-shaped granules and
rod-shaped granules and
subsequent spheronization of
subsequent spheronization of
these granules.
these granules.

34. Extrusion/spheronization process is used to make uniformly
Extrusion/spheronization process is used to make uniformly
sized spherical particles.
sized spherical particles.
It is used primarily to produce multiparticulates for controlled
It is used primarily to produce multiparticulates for controlled
drug release applications.
drug release applications.
The major advantage over other methods of producing drug
The major advantage over other methods of producing drug
loaded spheres or pellets is the ability to incorporat high
loaded spheres or pellets is the ability to incorporat high
levels
levels
of active ingredients without producing excessively large
of active ingredients without producing excessively large
particles (minimal excipients).
particles (minimal excipients).
Ideal flow behaviour and dosability
Ideal flow behaviour and dosability
Compact structure
Compact structure
Low hygroscopicity
Low hygroscopicity
Advantages of granulation using Extrusion/spheronization
Advantages of granulation using Extrusion/spheronization

35. The main steps of the process are:
The main steps of the process are:
1.
1. Dry mixing of ingredients to achieve a homogenous powder
Dry mixing of ingredients to achieve a homogenous powder
dispersion
dispersion
2. Wet massing to produce a sufficiently plastic wet mass
2. Wet massing to produce a sufficiently plastic wet mass
3. Extrusion to form rod-shaped particles of uniform diameter
3. Extrusion to form rod-shaped particles of uniform diameter
4. Spheronization to round off these rods into spherical particles
4. Spheronization to round off these rods into spherical particles
5. Drying to achieve the desired final moisture content
5. Drying to achieve the desired final moisture content
6. Screening to achieve the desired narrow size distribution.
6. Screening to achieve the desired narrow size distribution.

36. Schematic representation of production extruder
Schematic representation of production extruder
Extrusion
Extrusion

37. Spheronization
Spheronization
• The function of spheronization is to round off the rods
The function of spheronization is to round off the rods
produced
produced
by extrusion into spherical particles.
by extrusion into spherical particles.
• This is carried out in
This is carried out in Spheronizer
Spheronizer which consists of a bowl with
which consists of a bowl with
fixed side walls and a rapidly rotating bottom plate or disc.
fixed side walls and a rapidly rotating bottom plate or disc.
• The rounding of the extrudate into spheres is dependent on
The rounding of the extrudate into spheres is dependent on
frictional forces generated by particle–particle and particle
frictional forces generated by particle–particle and particle
equipment collisions.
equipment collisions.

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

39. The velocity difference between
The velocity difference between
the rotor and the static walls,
the rotor and the static walls,
combined with the upward flow
combined with the upward flow
of air around the rotor plate,
of air around the rotor plate,
causes the mass to move in a
causes the mass to move in a
toroidal motion, resulting in the
toroidal motion, resulting in the
formation of isolated spherical
formation of isolated spherical
pellets.
pellets.
The spheres are dried by the
The spheres are dried by the
heated inlet air from the air
heated inlet air from the air
chamber, which acts as a
chamber, which acts as a
positive
positive
pressure seal during
pressure seal during

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

41. Principle of the powder layering process
Principle of the powder layering process
Using this technique it is possible to continue the process
Using this technique it is possible to continue the process
and coat the pellets by spraying coating solution on to the
and coat the pellets by spraying coating solution on to the
rotating dried pellets.
rotating dried pellets.
In layered pellets can be produced by using uncoated pellets
In layered pellets can be produced by using uncoated pellets
as nuclei in a second granulation with a powder mix of a
as nuclei in a second granulation with a powder mix of a
second ingredient or ingredients.
second ingredient or ingredients.

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

43. The process variables involved in the granulation steps
The process variables involved in the granulation steps
(formulation ingredients and their concentrations, the type
(formulation ingredients and their concentrations, the type
of granulating equipment and processing conditions
of granulating equipment and processing conditions
employed) can affect the characteristics of the
employed) can affect the characteristics of the
granulations produced.
granulations produced.
Particle Size and Shape.
Particle Size and Shape.
Surface Area.
Surface Area.
Density
Density.
.
Strength and Friability.
Strength and Friability.
Flow Properties
Flow Properties .
.
Compaction.
Compaction.

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

45. SURfACE AREA.
SURfACE AREA.
The surface area of the drug has a significant effect upon
The surface area of the drug has a significant effect upon
dissolution rate. An inverse relationship normally exists
dissolution rate. An inverse relationship normally exists
between particle size and surface area;
between particle size and surface area;
Methods for determining surface area of solid particles are
Methods for determining surface area of solid particles are
gas adsorption and air permeability.
gas adsorption and air permeability.
In gas adsorption method
In gas adsorption method , the amount of gas that is
, the amount of gas that is
adsorbed onto the powder to form a monolayer is
adsorbed onto the powder to form a monolayer is
measured and then used to calculate the surface area of
measured and then used to calculate the surface area of
the powder sample.
the powder sample.
Air permeability
Air permeability, the rate at which air permeates a bed of
, the rate at which air permeates a bed of
powder, is used to calculate the surface area of the
powder, is used to calculate the surface area of the
powder sample.
powder sample.

46. Density
Density
.
.
 Granule density may influence compressibility, tablet
Granule density may influence compressibility, tablet
porosity and dissolution.
porosity and dissolution.
 Dense, hard granules may require higher compressible
Dense, hard granules may require higher compressible
loads to produce a cohesive compact.
loads to produce a cohesive compact.
 The higher compression load, increase the tablet
The higher compression load, increase the tablet
disintegration and drug dissolution times. Even if the
disintegration and drug dissolution times. Even if the
tablets disintegrate readily, the harder, denser
tablets disintegrate readily, the harder, denser
granules
granules
may dissolve less readily.
may dissolve less readily.

47.  Methods used to determine granule density involve the
Methods used to determine granule density involve the
use of a pycnometer.
use of a pycnometer.
 Where, the intrusion fluid is mercury, and in the other,
Where, the intrusion fluid is mercury, and in the other,
it
it
is a solvent of low surface tension (e.g., benzene) in
is a solvent of low surface tension (e.g., benzene) in
which the granules are not soluble.
which the granules are not soluble.
 These pycnometer methods depends on the ability of
These pycnometer methods depends on the ability of
the
the
intrusion fluids to penetrate the pores of the granules.
intrusion fluids to penetrate the pores of the granules.
Density is calculated from the volume of intrusion fluid
Density is calculated from the volume of intrusion fluid
displaced in the pycnometer by a given mass of
displaced in the pycnometer by a given mass of

48. strength anD Friability.
strength anD Friability.
A granule is an aggregation of component particles that
A granule is an aggregation of component particles that
is held together by bonds of finite strength.
is held together by bonds of finite strength.
The strength of a wet granule is due to the surface
The strength of a wet granule is due to the surface
tension of liquid and capillary forces.
tension of liquid and capillary forces.
These forces are responsible for initial agglomeration
These forces are responsible for initial agglomeration
of the wet powder.
of the wet powder.
Upon drying, the granule has strong bonds resulting
Upon drying, the granule has strong bonds resulting
from fusion or recrystallization of particles and curing
from fusion or recrystallization of particles and curing
of the adhesive or binder.
of the adhesive or binder.

49. Measurements of granule strength estimate the
Measurements of granule strength estimate the
magnitude of attractive forces that hold the granule
magnitude of attractive forces that hold the granule
together.
together.
The resultant strength of a granule depends on base
The resultant strength of a granule depends on base
material, the kind and amount of granulating agent used
material, the kind and amount of granulating agent used
and the granulating equipment used.
and the granulating equipment used.
Granule strength and friability are important, as they
Granule strength and friability are important, as they
affect changes in particle size distribution of
affect changes in particle size distribution of
granulations, and compressibility into cohesive tablets.
granulations, and compressibility into cohesive tablets.

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

51. Flow ProPerties
Flow ProPerties
.
.
Flow properties of a material result from many surface
Flow properties of a material result from many surface
forces:
forces:
(1)
(1)frictional forces, (2) surface tension forces,
frictional forces, (2) surface tension forces,
(3) mechanical forces caused by interlocking of
(3) mechanical forces caused by interlocking of
particles of irregular shape, (4) electrostatic forces,
particles of irregular shape, (4) electrostatic forces,
(5) cohesive or van der Waals forces.
(5) cohesive or van der Waals forces.
They can affect granule properties such as: particle
They can affect granule properties such as: particle
size,
size,
particle size distribution, particle shape, surface
particle size distribution, particle shape, surface
texture or roughness, surface energy, and surface
texture or roughness, surface energy, and surface

52. With fine powders (<150µm), the magnitude of the
With fine powders (<150µm), the magnitude of the
frictional and van der Waals forces are predominate.
frictional and van der Waals forces are predominate.
For larger particles (>150µm) such as granules
For larger particles (>150µm) such as granules
produced by a wet granulation, frictional forces are
produced by a wet granulation, frictional forces are
predominate over van der Waals forces.
predominate over van der Waals forces.
Flow measur the effect of all the interparticulate
Flow measur the effect of all the interparticulate
forces
forces
acting at once.
acting at once.
Two methods are used:
Two methods are used:
(1) angle of repose,
(1) angle of repose,
(2) hopper flow rate measurements.
(2) hopper flow rate measurements.

53. ComPaCtion
ComPaCtion
The process of compacting powder or granule materials
The process of compacting powder or granule materials
to
to
form a tablet is complex, owing to the numerous
form a tablet is complex, owing to the numerous
internal
internal
events that act simultaneously.
events that act simultaneously.
The basic tool that has been developed for studying the
The basic tool that has been developed for studying the
compression process is the tablet press.
compression process is the tablet press.
Tablet presses are instrumented by affixing transducers
Tablet presses are instrumented by affixing transducers
to measure the forces applied during the compression
to measure the forces applied during the compression
process. The signals produced by the transducer
process. The signals produced by the transducer
system
system

54. Effervescent salts are granules or coarse
Effervescent salts are granules or coarse
to very coarse powders containing a medicinal agent in a
to very coarse powders containing a medicinal agent in a
dry mixture usually composed of sodium bicarbonate,
dry mixture usually composed of sodium bicarbonate,
citric acid, and tartaric acid.
citric acid, and tartaric acid.
When added to water, the acids and base react to
When added to water, the acids and base react to
liberate carbon dioxide, resulting in effervescence.
liberate carbon dioxide, resulting in effervescence.
The resulting carbonated solution masks the usually
The resulting carbonated solution masks the usually
saline or undesirable taste of the medicinal agent
saline or undesirable taste of the medicinal agent
present.
present.

55. A good effervescent blend consists of both citric acid and
A good effervescent blend consists of both citric acid and
tartaric acid (1 :2 ratio), since the former is rather sticky to
tartaric acid (1 :2 ratio), since the former is rather sticky to
manipulate and the latter produces a chalky, friable
manipulate and the latter produces a chalky, friable
granule.
granule.
Citric Acid
Citric Acid
3 NaHC0
3 NaHC03
3 + C
+ C6
6 H
H8
8 O
O7
7 .H
.H2
2 O 4 H
O 4 H2
2 0 + 3C0
0 + 3C02
2 + Na
+ Na3
3 C
C6
6 H
H5
5 O
O7
7
3 x 84
3 x 84 210
210
One gram of citric acid (MW = 210) reacts with 1.2 g of
One gram of citric acid (MW = 210) reacts with 1.2 g of
sodium bicarbonate (MW = 84)
sodium bicarbonate (MW = 84)
210
1
=
=
84
3X
X
X = 1.2 g
X = 1.2 g

56. Tartaric Acid
Tartaric Acid
2 NaHC0
2 NaHC03
3 + C
+ C4
4 H
H6
6 0
06
6 2 H
2 H2
2 0 + 2C0
0 + 2C02
2 -+ Na
-+ Na2
2 C
C4
4 H
H4
4 O
O6
6
2 x 84 150
2 x 84 150
Since it is desired to use a 1:2 ratio of critic acid to
Since it is desired to use a 1:2 ratio of critic acid to
tartaric acid, two grams of tartaric acid (MW = 150) reacts
tartaric acid, two grams of tartaric acid (MW = 150) reacts
with 2.24 g of sodium bicarbonate.
with 2.24 g of sodium bicarbonate.
150
2
=
=
84
2X
X
X = 2.24 g
X = 2.24 g

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

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