granulation is the process in which primary powder particles are made to adhere to form larger,...
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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 Pharmaceutical granules typically have a size range
between 0.2 and 4.0 mm, depending on their between 0.2 and 4.0 mm, depending on their
subsequent use.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 intermediate product and have a typical size range
between 0.2 and 0.5 mm,between 0.2 and 0.5 mm,
GranulationGranulation
Reasons for granulationReasons for granulationTo prevent segregation of the constituents of the To prevent segregation of the constituents of the powder mixpowder mix
Segregation is due to differences in the size or density Segregation is due to differences in the size or density
of theof the
components of the mix, the smaller and/or denser components of the mix, the smaller and/or denser
particles concentrating at the base of a container with particles concentrating at the base of a container with
the larger and/or less dense ones above them.the larger and/or less dense ones above them.
An ideal granulation will contain all the constituents of An ideal granulation will contain all the constituents of
the mix in the correct proportion in each granule, and the mix in the correct proportion in each granule, and
segregation of the ingredients will not occursegregation of the ingredients will not occur
PowderPowder GranulesGranules
GranulationGranulation
sievinsievingg
Segregated Segregated PowderPowder
Monosized Monosized GranulesGranules
It is also important to control the particle size It is also important to control the particle size
distribution of the granules because, although the distribution of the granules because, although the
individual components may not segregate, if there is individual components may not segregate, if there is
a wide size distribution the granules themselves may a wide size distribution the granules themselves may
segregate.segregate.
If this occurs in the hoppers of capsule-filling If this occurs in the hoppers of capsule-filling
machines or tablet machines, products with large machines or tablet machines, products with large
weight variations will result. This is because these weight variations will result. This is because these
machines fill by volume rather than weight, and if machines fill by volume rather than weight, and if
different regions in the hopper contain granules of different regions in the hopper contain granules of
different sizes (and hence bulk density), a given different sizes (and hence bulk density), a given
volume in each region will contain a different weight volume in each region will contain a different weight
of granules. This will lead to an unacceptable of granules. This will lead to an unacceptable
distribution of the drug content within the batch of distribution of the drug content within the batch of
finished product.finished product.
Many powders, because of their small size, irregular Many powders, because of their small size, irregular
shape or surface characteristics, are cohesive and do shape or surface characteristics, are cohesive and do
not flow well. not flow well.
Poor flow will often result in a wide weight variation Poor flow will often result in a wide weight variation
within the final product owing to variable fill of tablet within the final product owing to variable fill of tablet
dies etc. dies etc.
Granules produced from such a cohesive system will Granules produced from such a cohesive system will
be larger and more isodiametric, both factors be larger and more isodiametric, both factors
contributing to improved flow properties.contributing to improved flow properties.
To improve the flow properties of the mixTo improve the flow properties of the mix
Some powders are difficult to compact even if a Some powders are difficult to compact even if a
readily compactable adhesive is included in the mix, readily compactable adhesive is included in the mix,
but granules of the same formulation are often more but granules of the same formulation are often more
easily compacted and produce stronger tablets. This easily compacted and produce stronger tablets. This
is associated with the distribution of the adhesive is associated with the distribution of the adhesive
within the granule. Often solutewithin the granule. Often solute
migration occurring during the postgranulation drying migration occurring during the postgranulation drying
stage results in a binder-rich outer layer to the stage results in a binder-rich outer layer to the
granules. This in turn leads to direct binder–binder granules. This in turn leads to direct binder–binder
bonding, which assists the consolidation of weakly bonding, which assists the consolidation of weakly
bonding materials.bonding materials.
To improve the compaction characteristics of the To improve the compaction characteristics of the mixturemixture
The granulation of toxic materials will reduce the The granulation of toxic materials will reduce the
hazard associated with the generation of toxic dust hazard associated with the generation of toxic dust
that may arise when handling powders. that may arise when handling powders.
Suitable precautions must be taken to ensure that Suitable precautions must be taken to ensure that
such dust is not a hazard during the granulation such dust is not a hazard during the granulation
process. Thus granules should be non-friable and process. Thus granules should be non-friable and
have a suitable mechanical strength.have a suitable mechanical strength.
Reduce the hazard of toxic dust powdersReduce the hazard of toxic dust powders
Materials which are slightly hygroscopic may adhere Materials which are slightly hygroscopic may adhere
and form a cake if stored as a powder. and form a cake if stored as a powder.
Granulation may reduce this hazard, as the granules Granulation may reduce this hazard, as the granules
will be able to absorb some moisture and yet retain will be able to absorb some moisture and yet retain
their flowability because of their size.their flowability because of their size.
More convenient for storageMore convenient for storage
Because granules are denser than the powder mix, Because granules are denser than the powder mix,
they occupy less volume per unit weight. They are they occupy less volume per unit weight. They are
therefore more convenient for storage or shipment.therefore more convenient for storage or shipment.
Reduce the hazard of hygroscopic powder adhesionReduce the hazard of hygroscopic powder adhesion
Methods of granulation
Granulation methods can be divided into two types: Granulation methods can be divided into two types:
wet methodswet methods, which use a liquid in the process, , which use a liquid in the process,
dry methodsdry methods in which no liquid is used. in which no liquid is used.
In a suitable formulation a number of different In a suitable formulation a number of different
excipients will be needed in excipients will be needed in addition to the drug.addition to the drug.
DiluentsDiluents, to produce a unit dose weight of suitable , to produce a unit dose weight of suitable
size, size,
Disintegrating agentsDisintegrating agents, which are added to aid the , which are added to aid the
break-up of the granule when it reaches a liquid break-up of the granule when it reaches a liquid
medium, e.g. onmedium, e.g. on
ingestion by the patient.ingestion by the patient.
AdhesivesAdhesives in the form of a dry powder may also be in the form of a dry powder may also be
added, particularly if dry granulation is employed. added, particularly if dry granulation is employed.
These ingredients will be mixed before granulation.These ingredients will be mixed before granulation.
In the dry methods of granulation the primary powder In the dry methods of granulation the primary powder
particles areparticles are
Granulation: (aggregation) under high pressure Granulation: (aggregation) under high pressure
without the use ofwithout the use of a liquida liquid using one of the following using one of the following
processes. processes.
Using Using SluggersSluggers: large tablet compacts (known as a : large tablet compacts (known as a
slugslug) is ) is
produced in a heavy-duty tabletting press (a produced in a heavy-duty tabletting press (a
process process
known as known as slugginsluggin’) ’)
or using or using Roller compactorsRoller 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
compactioncompaction).).
Milling: the intermediate products are broken using Milling: the intermediate products are broken using
a suitable milling technique to produce granular a suitable milling technique to produce granular
material, which is usually sieved to separate the material, which is usually sieved to separate the
desired size fraction. The unused fine material may be desired size fraction. The unused fine material may be
reworked to avoid waste. reworked to avoid waste.
Dry granulationDry granulation
Roller compactorsRoller compactors
AlexanderwerkAlexanderwerkRoller compactorRoller compactor
Hutt Roller Hutt Roller compactorcompactor
Advantages of dry granulation:Advantages of dry granulation:
Avoids heat–temperature combinations that might Avoids heat–temperature combinations that might
cause 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.
Wet granulationWet granulation Wet granulation involves the massing of a mix of dry Wet granulation involves the massing of a mix of dry
primary primary
powder particles using a granulating fluid. powder particles using a granulating fluid.
The fluid contains a solvent which must be volatile so The fluid contains a solvent which must be volatile so
that it 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 The granulation liquid may be used alone or, more
usually, as a usually, as a
solvent containing a dissolved adhesive (binding solvent containing a dissolved adhesive (binding
agent) which agent) which
is used to ensure particle adhesion once the granule is is used to ensure particle adhesion once the granule is
dry.dry.
In the traditional wet granulation method the wet mass In the traditional wet granulation method the wet mass
is is
forced through a sieve to produce wet granules which forced through a sieve to produce wet granules which
are then are then
dried. dried.
A subsequent screening stage breaks agglomerates of A subsequent screening stage breaks agglomerates of
granules granules
and removes the fine material, which can than be and removes the fine material, which can than be
recycled.recycled.
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 rapid
drying time is required.
Effect of granulation method on granule structureEffect of granulation method on granule 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 The method and conditions of granulation affect
intergranular and intragranular pore structure by changing intergranular and intragranular pore structure by changing
the degree of packing within the granules. the degree of packing within the granules. Precompressed granules (dry granulation),Precompressed granules (dry granulation), consisting of consisting of
compressed drug and binder particles, are held together compressed drug and binder particles, are held together
by 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 intact drug particles held together in a sponge-like matrix
of of
binder.binder.Fluidized-bed granulesFluidized-bed granules are similar to those prepared by are similar to those prepared by
the wet 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 systemsspray-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.
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 granulatorsWet granulators
Shear granulatorsShear granulators
High-speed mixer/granulatorsHigh-speed mixer/granulators
Fluidized-bed granulatorsFluidized-bed granulators
Rotor granulatorsRotor granulators
Spray-driersSpray-driers
Spheronizers /PelletizersSpheronizers /Pelletizers
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 powdersmassing of the powders
With some formulations, such With some formulations, such
as as
those containing two or three those containing two or three
ingredients in equal quantities, ingredients in equal quantities,
it is it 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
paddle of the mixer agitates the paddle of the mixer agitates the
powders. powders.
Shear granulatorsShear granulators
Planetary MixerPlanetary Mixer
MixinMixing g bowlbowl
MixinMixing armg arm
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 oscillate and force the moist
mass mass
through the sieve screen, the through the sieve screen, the
size of size of
which determines the granule which determines the granule
size. 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) when sieved. If excess liquid is added, string (filament)
of of
material will be formed and if the mix is too dry the material will be formed and if the mix is too dry the
mass will be mass will be
sieved as powder and granules will not be formed.sieved as powder and granules will not be formed.
Oscillating Oscillating GranulatorGranulator
RotoRotorr
SievSievee
The granules can be collected on trays and transferred to The granules can be collected on trays and transferred to
a drying a 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 2. Dissolved material can migrate
to the to the
upper surface of granules’ bed, upper surface of granules’ bed,
as the as 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 3. Granules may aggregate owing
to to
bridge formation at the points of bridge formation at the points of
contact of the granules.contact of the granules.
To deaggregate the granules and remix them, a sieving To deaggregate the granules and remix them, a sieving
stage is necessary after drying.stage is necessary after drying.
An alternative method is to dry the granules using a An alternative method is to dry the granules using a
fluidized-bed drier. fluidized-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 separated during drying, it reduces the problems of
aggregation and intergranular solute migration, thereby aggregation and intergranular solute migration, thereby
reducing the need for a sieving stage after drying.reducing the need for a sieving stage after drying.
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. characteristics of the granule ingredients (e.g.
surface surface
area variations in different batches of an area variations in different batches of an
excipient)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 durationLong 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.
High-speed mixer/granulatorsHigh-speed mixer/granulators
The granulator has a stainless The granulator has a stainless
steel mixing bowl containing steel mixing bowl containing
a a three-bladed main impellerthree-bladed main impeller, ,
which revolves in the which revolves in the
horizontalhorizontal
plane, plane,
and a and a three-bladed auxiliary three-bladed auxiliary
chopperchopper (breaker blade) (breaker blade)
which revolves either in the which revolves either in the
vertical or the horizontal vertical or the horizontal
plane.plane.
chop
per
chop
per
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 Granulating liquid is then added via a port in the lid
of the of the
granulator while the impeller is turning. granulator while the impeller is turning.
The granulating fluid is mixed into the powders by The granulating fluid is mixed into the powders by
thethe
impeller. impeller.
The chopper is usually switched on when the moist The chopper is usually switched on when the moist
mass is mass is
formed, as its function is to break up the wet mass formed, as its function is to break up the wet mass
to to
produce a bed of granular material.produce a bed of granular material.
Once a granule has been Once a granule has been
produced, the granular product produced, the granular product
is discharged, passing through a is discharged, passing through a
wire mesh which breaks up any wire mesh which breaks up any
large aggregates, into the bowl large aggregates, into the bowl
of a fluidized-bed drier.of a fluidized-bed drier.
Advantages of High-speed mixer/granulation:Advantages of High-speed mixer/granulation:
Mixing and granulation are all performed within a Mixing and granulation are all performed within a
few minutes in the same piece of equipment. few 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 process needs to be controlled with care as
the 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 overmassed system. Thus it is often necessary to
use a use a
suitable monitoring system to indicate the end of suitable monitoring system to indicate the end of
the the
granulation process, i.e. when a granule of the granulation process, i.e. when a granule of the
desired 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
materials, but this may be minimized by using a materials, but this may be minimized by using a
suitable suitable
end-point monitor.end-point monitor.
GlattGlatt
Air inletAir inletAir Air filterfilter
Air outletAir outlet
Spray Spray nozzlenozzleProduct Product containecontainerr
GranulatinGranulating liquidg liquid
Exhaust Exhaust filterfilter
Fluidized-bed granulatorFluidized-bed granulator
The powder particles are The powder particles are
fluidized in a stream of fluidized in a stream of
air.air.
Granulation fluid is Granulation fluid is
pumped pumped
from a reservoir and from a reservoir and
sprayed sprayed
from a nozzle on to the from a nozzle on to the
bed 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 unmixed powders to
fluidize fluidize
the particles and mix the the particles and mix the
powders.powders.
Fluidized-bed granulator (Glatt)Fluidized-bed granulator (Glatt)
Air Air inletinletAir Air filterfilter
Air outletAir outlet
Spray Spray nozzlenozzleProduct Product containercontainer
GranulatinGranulating liquidg liquid
Exhaust Exhaust filterfilter
The fluid causes the primary The fluid causes the primary
powder particles to adhere powder particles to adhere
when the droplets and when the droplets and
powders collide. powders collide.
Escape of material from the Escape of material from the
granulation chamber is granulation chamber is
prevented by exhaust filters, prevented by exhaust filters,
which are periodically agitated which are periodically agitated
to reintroduce the collected to reintroduce the collected
material into the fluidized bed. material into the fluidized bed.
Sufficient liquid is sprayed to Sufficient liquid is sprayed to
produce granules of the produce granules of the
required size, at which point required size, at which point
the spray is turned off but the the spray is turned off but the
fluidizing air continued. fluidizing air continued.
The wet granules are then The wet granules are then
dried in the heated fluidizing dried in the heated fluidizing
air stream.air stream.
Air Air inletinletAir Air filterfilter
Air outletAir outlet
Spray Spray nozzlenozzleProduct Product containercontainer
GranulatinGranulating liquidg liquid
Exhaust Exhaust filterfilter
All the granulation processes, which require All the granulation processes, which require
separate separate
equipment in the conventional method, are equipment in the conventional method, are
performed in performed in
one unit, saving labour costs, transfer losses and one unit, saving labour costs, transfer losses and
time.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 granulationAdvantages of fluidized-bed granulation
Disadvantages of fluidized-bed granulationDisadvantages of fluidized-bed granulation
Spray-driersSpray-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 The resultant granules
are free-flowing hollow are free-flowing hollow
spheres and the spheres and the
distribution of the binder in distribution of the binder in
such granules results in such granules results in
good compaction good compaction
properties.properties.
suspensionsuspension
Fluidization Fluidization airair
screescreenn
Spray-drying can convert Spray-drying can convert
hard elastic materials into hard elastic materials into
more ductile ones.more ductile ones.
The primary advantages of The primary advantages of
the process are the short the process are the short
drying time and the minimal drying time and the minimal
exposure of theexposure of the
product to heat owing to the product to heat owing to the
short residence time in the short residence time in the
drying chamber. drying chamber.
This means that little This means that little
deteriorationdeterioration
of heat-sensitive materials of heat-sensitive materials
takes place.takes place.
suspensionsuspension
Fluidization Fluidization airair
screescreenn
Spheronizers /PelletizersSpheronizers /Pelletizers
For some applications it may be desirable to For some applications it may be desirable to
have ahave 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 Extrusion of this wet mass
intointo
rod-shaped granules and rod-shaped granules and
subsequent spheronization subsequent spheronization
of of
these granules. these granules.
Extrusion/spheronization process is used to make Extrusion/spheronization process is used to make
uniformly uniformly
sized spherical particles. sized spherical particles.
It is used primarily to produce multiparticulates for It is used primarily to produce multiparticulates for
controlled controlled
drug release applications. drug release applications.
The major advantage over other methods of producing The major advantage over other methods of producing
drug drug
loaded spheres or pellets is the ability to incorporat loaded spheres or pellets is the ability to incorporat
high levels high levels
of active ingredients without producing excessively of active ingredients without producing excessively
large large
particles (minimal excipients).particles (minimal excipients).
Ideal flow behaviour and dosabilityIdeal flow behaviour and dosability
Compact structureCompact structure
Low hygroscopicityLow hygroscopicity
High bulk densityHigh bulk density
Advantages of granulation using Advantages of granulation using Extrusion/spheronization Extrusion/spheronization
The main steps of the process are:The main steps of the process are:
1.1. Dry mixing of ingredients to achieve a homogenous Dry mixing of ingredients to achieve a homogenous
powder dispersionpowder dispersion
2. Wet massing to produce a sufficiently plastic wet mass2. Wet massing to produce a sufficiently plastic wet mass
3. Extrusion to form rod-shaped particles of uniform 3. Extrusion to form rod-shaped particles of uniform
diameterdiameter
4. Spheronization to round off these rods into spherical 4. Spheronization to round off these rods into spherical
particlesparticles
5. Drying to achieve the desired final moisture content5. Drying to achieve the desired final moisture content
6. Screening to achieve the desired narrow size 6. Screening to achieve the desired narrow size
distribution.distribution.
Schematic representation of production extruderSchematic representation of production extruder
ExtrusionExtrusion
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 SpheronizerSpheronizer which consists of a bowl which consists of a bowl
with with
fixed side walls and a rapidly rotating bottom plate or fixed side walls and a rapidly rotating bottom plate or
disc. disc.
• The rounding of the extrudate into spheres is dependent The rounding of the extrudate into spheres is dependent
on on
frictional forces generated by particle–particle and frictional forces generated by particle–particle and
particle particle
equipment collisions.equipment collisions.
Rotor granulationRotor granulation
In the In the Freund granulatorFreund granulator,,
the powder mixture is the powder mixture is
added added
to the bowl and wetted to the bowl and wetted
with with
granulating liquid from a granulating liquid from a
spray. spray.
The base plate rotates at The base plate rotates at
high speed and high speed and
centrifugal centrifugal
force keeps the moist force keeps the moist
mass mass
at the edges of the rotor. at the edges of the rotor.
The velocity difference The velocity difference
between between
the rotor and the static the rotor and the static
walls, walls,
combined with the upward combined with the upward
flow 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 toroidal motion, resulting in
the the
formation of isolated formation of isolated
spherical 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
granulation.granulation.
Process principleProcess principle
Powder is mixed and moistened and the powder bed set Powder is mixed and moistened and the powder bed set
into centrifugal motion (fluid bed pelletizing in the rotor).into centrifugal motion (fluid bed pelletizing in the rotor).
The impact and acceleration forces that occur in this The impact and acceleration forces that occur in this
process result in the formation of agglomerates, which process result in the formation of agglomerates, which
become rounded out into uniform and dense pellets and become rounded out into uniform and dense pellets and
are then dried. are then dried.
Principle of the powder layering processPrinciple of the powder layering process
Using this technique it is possible to continue the Using this technique it is possible to continue the process and coat the pellets by spraying coating solution process and coat the pellets by spraying coating solution on to the rotating dried pellets. on to the rotating dried pellets. In layered pellets can be produced by using uncoated In layered pellets can be produced by using uncoated pellets as nuclei in a second granulation with a powder pellets as nuclei in a second granulation with a powder mix of a second ingredient or ingredients.mix of a second ingredient or ingredients.
GRANULATION MECHANISMS
To form granules, sufficiently strong bonds must be To form granules, sufficiently strong bonds must be
formed between powder particles so that they adhere formed between powder particles so that they adhere
and prevent breakdown of the granule to powder during and prevent breakdown of the granule to powder during
handling.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 Adhesion and cohesion forces in the immobile liquid
films films
between individual primary powder particles.between individual primary powder particles.
2. Interfacial forces in mobile liquid films within the 2. Interfacial forces in mobile liquid films within the
granules.granules.
3. The formation of solid bridges after solvent 3. The formation of solid bridges after solvent
evaporation.evaporation.
4. Attractive forces between solid particles.4. Attractive forces between solid particles.
The process variables involved in the granulation The process variables involved in the granulation
steps (formulation ingredients and their steps (formulation ingredients and their
concentrations, the type of granulating equipment concentrations, the type of granulating equipment
and processing conditions employed) can affect the and processing conditions employed) can affect the
characteristics of the granulations produced. characteristics of the granulations produced. Particle Size and Shape.Particle Size and Shape.
Surface Area.Surface Area.
DensityDensity. .
Strength and Friability.Strength and Friability.
Flow PropertiesFlow Properties. .
Compaction. Compaction.
Particle Size and ShapeParticle Size and Shape..
The particle size of a granulation is known to The particle size of a granulation is known to
affect the average tablet weight, disintegration affect the average tablet weight, disintegration
time, granule friability, granulation flowability time, granule friability, granulation flowability
and the ding rate kinetics of wet granulations.and the ding rate kinetics of wet granulations.
Surface Area.Surface Area.The surface area of the drug has a significant effect The surface area of the drug has a significant effect
upon dissolution rate. An inverse relationship upon dissolution rate. An inverse relationship
normally exists between particle size and surface normally exists between particle size and surface
area; area;
Methods for determining surface area of solid Methods for determining surface area of solid
particles are gas adsorption and air permeability. particles are gas adsorption and air permeability.
In gas adsorption methodIn 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 measured and then used to calculate the surface area
of the powder sample. of the powder sample.
Air permeabilityAir permeability, the rate at which air permeates a , the rate at which air permeates a
bed of powder, is used to calculate the surface area bed of powder, is used to calculate the surface area
of the powder sample. of the powder sample.
DensityDensity.. Granule density may influence compressibility, Granule density may influence compressibility,
tablet tablet
porosity and dissolution. porosity and dissolution.
Dense, hard granules may require higher Dense, hard granules may require higher
compressible 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 disintegration and drug dissolution times. Even if
the the
tablets disintegrate readily, the harder, denser tablets disintegrate readily, the harder, denser
granules granules
may dissolve less readily. may dissolve less readily.
Methods used to determine granule density Methods used to determine granule density
involve the involve the
use of a pycnometer. use of a pycnometer.
Where, the intrusion fluid is mercury, and in the Where, the intrusion fluid is mercury, and in the
other, it other, it
is a solvent of low surface tension (e.g., benzene) is a solvent of low surface tension (e.g., benzene)
in in
which the granules are not soluble. which the granules are not soluble.
These pycnometer methods depends on the ability These pycnometer methods depends on the ability
of the of the
intrusion fluids to penetrate the pores of the intrusion fluids to penetrate the pores of the
granules. granules.
Density is calculated from the volume of intrusion Density is calculated from the volume of intrusion
fluid fluid
displaced in the pycnometer by a given mass of displaced in the pycnometer by a given mass of
granulation granulation
Strength and Friability.Strength and Friability.
A granule is an aggregation of component particles A granule is an aggregation of component particles
that is held together by bonds of finite strength. that 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 These forces are responsible for initial
agglomeration of the wet powder. agglomeration of the wet powder.
Upon drying, the granule has strong bonds Upon drying, the granule has strong bonds
resulting from fusion or recrystallization of resulting from fusion or recrystallization of
particles and curing of the adhesive or binder. particles and curing of the adhesive or binder.
Measurements of granule strength estimate the Measurements of granule strength estimate the
magnitude of attractive forces that hold the magnitude of attractive forces that hold the
granule together.granule together.
The resultant strength of a granule depends on The resultant strength of a granule depends on
base material, the kind and amount of granulating base material, the kind and amount of granulating
agent used and the granulating equipment used. agent used and the granulating equipment used.
Granule strength and friability are important, as Granule strength and friability are important, as
they affect changes in particle size distribution of they affect changes in particle size distribution of
granulations, and compressibility into cohesive granulations, and compressibility into cohesive
tablets. tablets.
Methods used for measuring granule strength are: Methods used for measuring granule strength are:
Compression strengthCompression 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 measurementsFriability measurements. measuring the tendency . measuring the tendency
of granules to break into smaller pieces when of granules to break into smaller pieces when
subjected to disturbing forces.subjected to disturbing forces.
Flow PropertiesFlow Properties..Flow properties of a material result from many Flow properties of a material result from many
surface forces:surface 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 particles of irregular shape, (4) electrostatic
forces, (5) cohesive or van der Waals forces. forces, (5) cohesive or van der Waals forces.
They can affect granule properties such as: They can affect granule properties such as:
particle size,particle 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
area. area.
With fine powders (<150µm), the magnitude of With fine powders (<150µm), the magnitude of
the the
frictional and van der Waals forces are frictional and van der Waals forces are
predominate. predominate.
For larger particles (>150µm) such as granules For larger particles (>150µm) such as granules
produced by a wet granulation, frictional forces produced by a wet granulation, frictional forces
are 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.
CompactionCompaction
The process of compacting powder or granule The process of compacting powder or granule
materials to materials 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 basic tool that has been developed for studying
the the
compression process is the tablet press. compression process is the tablet press.
Tablet presses are instrumented by affixing Tablet presses are instrumented by affixing
transducers transducers
to measure the forces applied during the to measure the forces applied during the
compression compression
process. The signals produced by the transducer process. The signals produced by the transducer
system system
are monitored by computer. are monitored by computer.
Effervescent salts are granules or coarse Effervescent salts are granules or coarse
to very coarse powders containing a medicinal agent to very coarse powders containing a medicinal agent
in a dry mixture usually composed of sodium in a dry mixture usually composed of sodium
bicarbonate, citric acid, and tartaric acid. bicarbonate, 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.
A good effervescent blend consists of both citric acid A good effervescent blend consists of both citric acid
and tartaric acid (1 :2 ratio), since the former is and tartaric acid (1 :2 ratio), since the former is
rather sticky to manipulate and the latter produces a rather sticky to manipulate and the latter produces a
chalky, friable granule. chalky, friable granule. Citric AcidCitric Acid
3 NaHC03 NaHC033 + C + C66HH88OO77.H.H22O 4 HO 4 H220 + 3C00 + 3C022 + +
NaNa33CC66HH55OO77
3 x 843 x 84 210 210
One gram of citric acid (MW = 210) reacts with 1.2 g One gram of citric acid (MW = 210) reacts with 1.2 g
of sodium bicarbonate (MW = 84) of sodium bicarbonate (MW = 84)
210
1==
843X
XX = 1.2 gX = 1.2 g
Tartaric AcidTartaric Acid
2 NaHC02 NaHC033 + C + C44HH660066 2 H 2 H220 + 2C00 + 2C022 -+ Na -+ Na22CC44HH44OO66
2 x 84 1502 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) tartaric acid, two grams of tartaric acid (MW = 150)
reacts with 2.24 g of sodium bicarbonate. reacts with 2.24 g of sodium bicarbonate.
150
2==
842X
XX = 2.24 gX = 2.24 g
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 2.24 g of sodium bicarbonate is required to react
with 1 + 2 g of the citric : tartaric acid combination.with 1 + 2 g of the citric : tartaric acid combination.
Since it is desired to leave a small amount of the Since it is desired to leave a small amount of the
acids unreacted to enhance palatability and taste, acids unreacted to enhance palatability and taste,
2.24 g + 1.2 g= 3.44 g, only 3.4 g of sodium 2.24 g + 1.2 g= 3.44 g, only 3.4 g of sodium
bicarbonate will be utilized. Therefore, the ratio of bicarbonate will be utilized. Therefore, the ratio of
the effervescent ingredients is the effervescent ingredients is
1 : 2 : 3.4 for the citric acid : tartaric acid : sodium 1 : 2 : 3.4 for the citric acid : tartaric acid : sodium
bicarbonate. bicarbonate.
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