Granulation is a process that involves sticking small particles together to form larger, multiparticle structures called granules. This is commonly done in the pharmaceutical industry to produce granules that will later be used in tablet or capsule manufacturing. There are two main types of granulation - wet granulation, which uses a liquid to bind particles together, and dry granulation, which uses pressure without a liquid. Wet granulation is more common and involves mixing powder particles with a liquid and then forcing the wet mass through a sieve to form wet granules that are then dried. Shear granulators are a common type of granulator used for wet granulation that uses rotating blades to force the wet mass through a sieve to produce granules of a

2. Granulation is the process in which primary powderGranulation 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 betweenPharmaceutical 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 ofIn the majority of cases this will be in the production of
tablets or capsules, when granules will be made as antablets or capsules, when granules will be made as an
intermediate product and have a typical size range betweenintermediate product and have a typical size range between
0.2 and 0.5 mm,0.2 and 0.5 mm,
GranulationGranulation

3. reasons for Granulationreasons for Granulation
To prevent segregation of the constituents of the powder mixTo prevent segregation of the constituents of the powder mix
Segregation is due to differences in the size or density of theSegregation is due to differences in the size or density of the
components of the mix, the smaller and/or denser particlescomponents of the mix, the smaller and/or denser particles
concentrating at the base of a container with the largerconcentrating 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 theAn ideal granulation will contain all the constituents of the
mix in the correct proportion in each granule, andmix in the correct proportion in each granule, and
segregation of the ingredients will not occursegregation of the ingredients will not occur

4. PowderPowder GranulesGranules
GranulationGranulation
sievingsieving
Segregated PowderSegregated Powder MonosizedMonosized
GranulesGranules

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

6. Many powders, because of their small size, irregularMany powders, because of their small size, irregular
shape or surface characteristics, are cohesive and do notshape or surface characteristics, are cohesive and do not
flow well.flow well.
Poor flow will often result in a wide weight variation withinPoor 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 beGranules produced from such a cohesive system will be
larger and more isodiametric, both factors contributing tolarger and more isodiametric, both factors contributing to
improved flow properties.improved flow properties.
To improve the flow properties of the mixTo improve the flow properties of the mix

7. Some powders are difficult to compact even if a readilySome powders are difficult to compact even if a readily
compactable adhesive is included in the mix, but granulescompactable adhesive is included in the mix, but granules
of the same formulation are often more easily compactedof the same formulation are often more easily compacted
and produce stronger tablets. This is associated with theand produce stronger tablets. This is associated with the
distribution of the adhesive within the granule. Oftendistribution of the adhesive within the granule. Often
solutesolute
migration occurring during the postgranulation dryingmigration 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, whichThis 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 theTo improve the compaction characteristics of the
mixturemixture

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

9. Materials which are slightly hygroscopic may adhere andMaterials 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 willGranulation may reduce this hazard, as the granules will
be able to absorb some moisture and yet retain theirbe able to absorb some moisture and yet retain their
flowability because of their size.flowability because of their size.
More convenient for storageMore convenient for storage
Because granules are denser than the powder mix, theyBecause granules are denser than the powder mix, they
occupy less volume per unit weight. They are thereforeoccupy 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 adhesionReduce 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 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 excipientsIn a suitable formulation a number of different excipients
will be needed inwill be needed in addition to the druG.addition to the druG.
DiluentsDiluents, to produce a unit dose weight of suitable size,, to produce a unit dose weight of suitable size,
Disintegrating agentsDisintegrating 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. onof the granule when it reaches a liquid medium, e.g. on
ingestion by the patient.ingestion by the patient.
AdhesivesAdhesives 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 powderIn the dry methods of granulation the primary powder
particles areparticles are
 Granulation: (aggregation) under high pressure withoutGranulation: (aggregation) under high pressure without
the use ofthe use of a liquida liquid using one of the following processes.using one of the following processes.
 UsingUsing SluggersSluggers: large tablet compacts (known as a: large tablet compacts (known as a slugslug))
isis
produced in a heavy-duty tabletting press (a processproduced in a heavy-duty tabletting press (a process
known asknown as slugginsluggin’)’)
 or usingor using Roller compactorsRoller compactors the powder is squeezedthe powder is squeezed
between two rollers to produce a sheet of materialbetween two rollers to produce a sheet of material
((rollerroller
compactioncompaction).).
 Milling: the intermediate products are broken using aMilling: the intermediate products are broken using a
suitable milling technique to produce granular material,suitable milling technique to produce granular material,
dry Granulationdry Granulation

12. roller coMpactorsroller coMpactors
AlexanderwerkAlexanderwerk
Roller compactorRoller compactor

13. Hutt RollerHutt Roller
compactorcompactor

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

15. Wet granulationWet granulation
 Wet granulation involves the massing of a mix of dry primaryWet 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 itThe 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 aas a
solvent containing a dissolved adhesive (binding agent)solvent containing a dissolved adhesive (binding agent)
whichwhich
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 isIn the traditional wet granulation method the wet mass is
forced through a sieve to produce wet granules which areforced through a sieve to produce wet granules which are
thenthen
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 granulEEffEct of granulation mEthod on granulE
structurEstructurE
The properties of the granules are influenced by theThe properties of the granules are influenced by the
manufacturing process.manufacturing process.
The method and conditions of granulation affect intergranular andThe method and conditions of granulation affect intergranular and
intragranular pore structure by changing the degree of packingintragranular pore structure by changing the degree of packing
within the granules.within the granules.
Precompressed granules (dry granulation),Precompressed granules (dry granulation), consisting ofconsisting of
compressed drug and binder particles, are held together bycompressed 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 ofconsist of
intact drug particles held together in a sponge-like matrix ofintact drug particles held together in a sponge-like matrix of
binder.binder.
Fluidized-bed granulesFluidized-bed granules are similar to those prepared by the wetare similar to those prepared by the wet
granulation, but possess greater porosity and the granulegranulation, 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.
WithWith spray-dried systemsspray-dried systems the granules consist of sphericalthe granules consist of spherical
particles composed of an outer shell and an inner core ofparticles composed of an outer shell and an inner core of
particles.particles.

18. There are many types of granulator used in theThere 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

19. Powder mixing in a separatePowder mixing in a separate
operationoperation
using suitable mixing equipment.using suitable mixing equipment.
A planetary mixer is used for wetA planetary mixer is used for wet
massing of the powdersmassing of the powders
With some formulations, such asWith some formulations, such as
those containing two or threethose containing two or three
ingredients in equal quantities, itingredients in equal quantities, it
isis
suitable to mix powder in thesuitable to mix powder in the
planetary mixer.planetary mixer.
The mixed powders are fed into theThe mixed powders are fed into the
bowl of the planetary mixer andbowl of the planetary mixer and
granulating liquid is added as thegranulating liquid is added as the
Shear granulatorsShear granulators
Planetary MixerPlanetary Mixer
MixingMixing
bowlbowl
MixingMixing
armarm

20. The moist mass has beenThe moist mass has been
transferredtransferred
to a granulator, as oscillatingto a granulator, as oscillating
granulator.granulator.
The rotor bars of the granulatorThe rotor bars of the granulator
oscillate and force the moist massoscillate and force the moist mass
through the sieve screen, the sizethrough the sieve screen, the size
ofof
which determines the granule size.which determines the granule size.
The mass should be sufficiently moist to form discreteThe mass should be sufficiently moist to form discrete
granulesgranules
when sieved. If excess liquid is added, string (filament) ofwhen sieved. If excess liquid is added, string (filament) of
material will be formed and if the mix is too dry the mass willmaterial will be formed and if the mix is too dry the mass will
OscillatingOscillating
GranulatorGranulator
RotorRotor
SievSiev
ee

21. The granules can be collected on trays and transferred to aThe granules can be collected on trays and transferred to a
dryingdrying
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 to2. Dissolved material can migrate to
thethe
upper surface of granules’ bed, asupper surface of granules’ bed, as
thethe
solvent is only removed from thesolvent is only removed from the
upper surface of the bed on theupper surface of the bed on the
tray.tray.
3. Granules may aggregate owing to3. Granules may aggregate owing to
bridge formation at the points ofbridge formation at the points of
To deaggregate the granules and remix them, a sieving stageTo 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 granulesThis is quicker and, as it keeps the individual granules
separated during drying, it reduces the problems of aggregationseparated during drying, it reduces the problems of aggregation
and intergranular solute migration, thereby reducing the needand 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 theThe process is not very sensitive to changes in the
characteristics of the granule ingredients (e.g. surfacecharacteristics 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 beThe 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 equipmentthe need for several pieces of equipment
 The high material losses because of the transferThe high material losses because of the transfer
stages.stages.

24. High-speed mixer/granulatorsHigh-speed mixer/granulators
The granulator has a stainlessThe granulator has a stainless
steel mixing bowl containing asteel mixing bowl containing a
three-bladed main impellerthree-bladed main impeller ,,
which revolves in the horizontalwhich revolves in the horizontal
plane,plane,
and aand a three-bladed auxiliarythree-bladed auxiliary
chopperchopper (breaker blade) which(breaker blade) which
revolves either in the vertical orrevolves either in the vertical or
the horizontal plane.the horizontal plane.
chopper
chopper

25. The unmixed dry powders are placed in the bowl andThe unmixed dry powders are placed in the bowl and
mixedmixed
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 ofGranulating liquid is then added via a port in the lid of
thethe
granulator while the impeller is turning.granulator while the impeller is turning.
The granulating fluid is mixed into the powders by theThe granulating fluid is mixed into the powders by the
impeller.impeller.
The chopper is usually switched on when the moist massThe chopper is usually switched on when the moist mass
isis
formed, as its function is to break up the wet mass toformed, 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 whichpassing through a wire mesh which
breaks up any large aggregates,breaks up any large aggregates,
into the bowl of a fluidized-bedinto 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 fewMixing 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 theThe process needs to be controlled with care as the
granulation progresses so rapidly that a usablegranulation progresses so rapidly that a usable
granulegranule
can be transformed very quickly into an unusable,can be transformed very quickly into an unusable,
overmassed system. Thus it is often necessary to useovermassed system. Thus it is often necessary to use
aa
suitable monitoring system to indicate the end of thesuitable monitoring system to indicate the end of the
granulation process, i.e. when a granule of the desiredgranulation 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 rawThe process is also sensitive to variations in raw

27. glattglatt
Air inletAir inlet
Air filterAir filter
Air outletAir outlet
SpraySpray
nozzlenozzleProductProduct
containercontainer
GranulatingGranulating
liquidliquid
ExhaustExhaust
filterfilter
Fluidized-bed granulatorFluidized-bed granulator

28. The powder particles areThe powder particles are
fluidized in a stream of air.fluidized in a stream of air.
Granulation fluid is pumpedGranulation fluid is pumped
from a reservoir andfrom a reservoir and
sprayedsprayed
from a nozzle on to the bedfrom a nozzle on to the bed
of powders.of powders.
Heated and filtered air isHeated and filtered air is
blown through the bed ofblown through the bed of
unmixed powders to fluidizeunmixed powders to fluidize
fluidizEd-bEd granulator (glatt)fluidizEd-bEd granulator (glatt)
Air inletAir inlet
Air filterAir filter
Air outletAir outlet
SpraySpray
nozzlenozzle
ProductProduct
containercontainer
GranulatingGranulating
liquidliquid
ExhaustExhaust
filterfilter

29. The fluid causes the primaryThe fluid causes the primary
powder particles to adhere whenpowder particles to adhere when
the droplets and powders collide.the droplets and powders collide.
Escape of material from theEscape of material from the
granulation chamber is preventedgranulation chamber is prevented
by exhaust filters, which areby exhaust filters, which are
periodically agitated toperiodically agitated to
reintroduce the collected materialreintroduce the collected material
into the fluidized bed.into the fluidized bed.
Sufficient liquid is sprayed toSufficient liquid is sprayed to
produce granules of the requiredproduce granules of the required
size, at which point the spray issize, at which point the spray is
turned off but the fluidizing airturned off but the fluidizing air
continued.continued.
The wet granules are then driedThe wet granules are then dried
in the heated fluidizing airin the heated fluidizing air
Air inletAir inlet
Air filterAir filter
Air outletAir outlet
SpraySpray
nozzlenozzle
ProductProduct
containercontainer
GranulatingGranulating
liquidliquid
ExhaustExhaust
filterfilter

30. All the granulation processes, which require separateAll the granulation processes, which require separate
equipment in the conventional method, are performedequipment in the conventional method, are performed
inin
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 conditionsThe 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 affectingOptimization of process parameters affecting
granulationgranulation
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

31. Spray-driersSpray-driers
Granular product is madeGranular product is made
from a solution or afrom a solution or a
suspension rather thansuspension rather than
initially dry primary powderinitially dry primary powder
particles.particles.
The resultant granules areThe resultant granules are
free-flowing hollow spheresfree-flowing hollow spheres
and the distribution of theand the distribution of the
binder in such granulesbinder in such granules
results in good compactionresults in good compaction
properties.properties.
suspensionsuspension
Fluidization airFluidization air
screenscreen

32. Spray-drying can convert hardSpray-drying can convert hard
elastic materials into more ductileelastic materials into more ductile
ones.ones.
The primary advantages of theThe primary advantages of the
process are the short drying timeprocess are the short drying time
and the minimal exposure of theand the minimal exposure of the
product to heat owing to the shortproduct to heat owing to the short
residence time in the dryingresidence time in the drying
chamber.chamber.
This means that littleThis means that little
deteriorationdeterioration
of heat-sensitive materials takesof heat-sensitive materials takes
suspensionsuspension
Fluidization airFluidization air
screenscreen

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

34. Extrusion/spheronization process is used to make uniformlyExtrusion/spheronization process is used to make uniformly
sized spherical particles.sized spherical particles.
It is used primarily to produce multiparticulates for controlledIt is used primarily to produce multiparticulates for controlled
drug release applications.drug release applications.
The major advantage over other methods of producing drugThe major advantage over other methods of producing drug
loaded spheres or pellets is the ability to incorporat highloaded spheres or pellets is the ability to incorporat high
levelslevels
of active ingredients without producing excessively largeof active ingredients without producing excessively large
particles (minimal excipients).particles (minimal excipients).
Ideal flow behaviour and dosabilityIdeal flow behaviour and dosability
Compact structureCompact structure
Low hygroscopicityLow hygroscopicity
Advantages of granulation using Extrusion/spheronizationAdvantages 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 powderDry mixing of ingredients to achieve a homogenous powder
dispersiondispersion
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 diameter3. Extrusion to form rod-shaped particles of uniform diameter
4. Spheronization to round off these rods into spherical particles4. Spheronization to round off these rods into spherical particles
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 distribution.6. Screening to achieve the desired narrow size distribution.

36. Schematic representation of production extruderSchematic representation of production extruder
ExtrusionExtrusion

37. SpheronizationSpheronization
• The function of spheronization is to round off the rodsThe function of spheronization is to round off the rods
producedproduced
by extrusion into spherical particles.by extrusion into spherical particles.
• This is carried out inThis is carried out in SpheronizerSpheronizer which consists of a bowl withwhich 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 onThe rounding of the extrudate into spheres is dependent on
frictional forces generated by particle–particle and particlefrictional forces generated by particle–particle and particle
equipment collisions.equipment collisions.

38. Rotor granulationRotor granulation
In theIn the Freund granulatorFreund granulator ,,
the powder mixture isthe powder mixture is
addedadded
to the bowl and wetted withto the bowl and wetted with
granulating liquid from agranulating liquid from a
spray.spray.
The base plate rotates atThe base plate rotates at
high speed and centrifugalhigh speed and centrifugal
force keeps the moist massforce keeps the moist mass

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

40. Process principleProcess principle
Powder is mixed and moistened and the powder bed set intoPowder 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 processThe impact and acceleration forces that occur in this process
result in the formation of agglomerates, which become roundedresult 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 processPrinciple of the powder layering process
Using this technique it is possible to continue the processUsing this technique it is possible to continue the process
and coat the pellets by spraying coating solution on to theand 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 pelletsIn layered pellets can be produced by using uncoated pellets
as nuclei in a second granulation with a powder mix of aas 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 formedTo form granules, sufficiently strong bonds must be formed
between powder particles so that they adhere and preventbetween 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 betweenThere are four primary bonding mechanisms between
particles:particles:1.1. Adhesion and cohesion forces in the immobile liquid filmsAdhesion 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 stepsThe 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 conditionsof granulating equipment and processing conditions
employed) can affect the characteristics of theemployed) can affect the characteristics of the
granulations produced.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.

44. PARTICLE SIzE ANd SHAPEPARTICLE SIzE ANd SHAPE..
The particle size of a granulation is known to affectThe 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 dinggranule 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 uponThe surface area of the drug has a significant effect upon
dissolution rate. An inverse relationship normally existsdissolution 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 areMethods for determining surface area of solid particles are
gas adsorption and air permeability.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 isadsorbed onto the powder to form a monolayer is
measured and then used to calculate the surface area ofmeasured and then used to calculate the surface area of
the powder sample.the powder sample.
Air permeabilityAir 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 thepowder, is used to calculate the surface area of the
powder sample.powder sample.

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

47.  Methods used to determine granule density involve theMethods 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,
itit
is a solvent of low surface tension (e.g., benzene) inis 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 ofThese pycnometer methods depends on the ability of
thethe
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 fluidDensity is calculated from the volume of intrusion fluid
displaced in the pycnometer by a given mass ofdisplaced in the pycnometer by a given mass of

48. strength anD Friability.strength anD Friability.
A granule is an aggregation of component particles thatA 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 surfaceThe 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 agglomerationThese forces are responsible for initial agglomeration
of the wet powder.of the wet powder.
Upon drying, the granule has strong bonds resultingUpon drying, the granule has strong bonds resulting
from fusion or recrystallization of particles and curingfrom fusion or recrystallization of particles and curing
of the adhesive or binder.of the adhesive or binder.

49. Measurements of granule strength estimate theMeasurements of granule strength estimate the
magnitude of attractive forces that hold the granulemagnitude of attractive forces that hold the granule
together.together.
The resultant strength of a granule depends on baseThe resultant strength of a granule depends on base
material, the kind and amount of granulating agent usedmaterial, 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 theyGranule strength and friability are important, as they
affect changes in particle size distribution ofaffect 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 strengthCompression strength . Where a granule is placed. Where a granule is placed
between anvils, and the force required to break thebetween anvils, and the force required to break the
granule is measured.granule is measured.
Friability measurementsFriability measurements . measuring the tendency of. measuring the tendency of
granules to break into smaller pieces when subjected togranules to break into smaller pieces when subjected to
disturbing forces.disturbing forces.

51. Flow ProPertiesFlow ProPerties..
Flow properties of a material result from many surfaceFlow 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: particleThey can affect granule properties such as: particle
size,size,
particle size distribution, particle shape, surfaceparticle size distribution, particle shape, surface
texture or roughness, surface energy, and surfacetexture or roughness, surface energy, and surface

52. With fine powders (<150µm), the magnitude of theWith 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 granulesFor larger particles (>150µm) such as granules
produced by a wet granulation, frictional forces areproduced 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 interparticulateFlow measur the effect of all the interparticulate
forcesforces
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. ComPaCtionComPaCtionThe process of compacting powder or granule materialsThe process of compacting powder or granule materials
toto
form a tablet is complex, owing to the numerousform a tablet is complex, owing to the numerous
internalinternal
events that act simultaneously.events that act simultaneously.
The basic tool that has been developed for studying theThe 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 transducersTablet presses are instrumented by affixing transducers
to measure the forces applied during the compressionto measure the forces applied during the compression
process. The signals produced by the transducerprocess. The signals produced by the transducer
systemsystem

54. Effervescent salts are granules or coarseEffervescent salts are granules or coarse
to very coarse powders containing a medicinal agent in ato 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 toWhen 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 usuallyThe resulting carbonated solution masks the usually
saline or undesirable taste of the medicinal agentsaline or undesirable taste of the medicinal agent
present.present.

55. A good effervescent blend consists of both citric acid andA good effervescent blend consists of both citric acid and
tartaric acid (1 :2 ratio), since the former is rather sticky totartaric acid (1 :2 ratio), since the former is rather sticky to
manipulate and the latter produces a chalky, friablemanipulate and the latter produces a chalky, friable
granule.granule.
Citric AcidCitric Acid
3 NaHC03 NaHC033 + C+ C66 HH88 OO77 .H.H22 O 4 HO 4 H22 0 + 3C00 + 3C022 + Na+ Na33 CC66 HH55 OO77
3 x 843 x 84 210210
One gram of citric acid (MW = 210) reacts with 1.2 g ofOne gram of citric acid (MW = 210) reacts with 1.2 g of
sodium bicarbonate (MW = 84)sodium bicarbonate (MW = 84)
210
1
==
843X
X
X = 1.2 gX = 1.2 g

56. Tartaric AcidTartaric Acid
2 NaHC02 NaHC033 + C+ C44 HH66 0066 2 H2 H22 0 + 2C00 + 2C022 -+ Na-+ Na22 CC44 HH44 OO66
2 x 84 1502 x 84 150
Since it is desired to use a 1:2 ratio of critic acid toSince it is desired to use a 1:2 ratio of critic acid to
tartaric acid, two grams of tartaric acid (MW = 150) reactstartaric 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
==
842X
X
X = 2.24 gX = 2.24 g

57. From the above, it has been calculated that 1.2 g andFrom 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 acidsSince it is desired to leave a small amount of the acids
unreacted to enhance palatability and taste, 2.24 g + 1.2unreacted to enhance palatability and taste, 2.24 g + 1.2
g= 3.44 g, only 3.4 g of sodium bicarbonate will beg= 3.44 g, only 3.4 g of sodium bicarbonate will be
utilized. Therefore, the ratio of the effervescentutilized. Therefore, the ratio of the effervescent
ingredients isingredients 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