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pharmaceuticalguide
Friday,January14,2011

Tablet:Manufacturing
methods/Granulation

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Introduction
Granulationmaybedefinedasasizeenlargementprocesswhichconvertssmall
particlesintophysicallystronger&largeragglomerates.
Granulationmethodcanbebroadlyclassifiedintotwotypes:Wetgranulationand
Drygranulation
Idealcharacteristicsofgranules
Theidealcharacteristicsofgranulesincludesphericalshape,smallerparticlesize
distributionwithsufficientfinestofillvoidspacesbetweengranules,adequate
moisture(between12%),goodflow,goodcompressibilityandsufficienthardness.
Theeffectivenessofgranulationdependsonthefollowingproperties
i)Particlesizeofthedrugandexcipients
ii)Typeofbinder(strongorweak)
iii)Volumeofbinder(lessormore)
iv)Wetmassingtime(lessormore)
v)Amountofshearapplied
vi)Dryingrate(Hydrateformationandpolymorphism)

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Introduction

InjectionMoldMaking

Themostwidelyusedprocessofagglomerationinpharmaceuticalindustryiswet
granulation.Wetgranulationprocesssimplyinvolveswetmassingofthepowder
blendwithagranulatingliquid,wetsizinganddrying.

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Importantstepsinvolvedinthewetgranulation
i)Mixingofthedrug(s)andexcipients
ii)Preparationofbindersolution
iii)Mixingofbindersolutionwithpowdermixturetoformwetmass.
iv)Coarsescreeningofwetmassusingasuitablesieve(612 screens).
v)Dryingofmoistgranules.
vi)Screeningofdrygranulesthroughasuitablesieve(1420 screen).
vii)Mixingofscreenedgranuleswithdisintegrant,glidant,andlubricant.

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Tablet:Manufacturing
methods/Granulation
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AboutMe
ImranAli

Limitationofwetgranulation
i)Thegreatestdisadvantageofwetgranulationisitscost.Itisanexpensive
processbecauseoflabor,time,equipment,energyandspacerequirements.
ii)Lossofmaterialduringvariousstagesofprocessing
iii)Stabilitymaybemajorconcernformoisturesensitiveorthermolabiledrugs
iv)Multipleprocessingstepsaddcomplexityandmakevalidationandcontrol
difficult
v)Aninherentlimitationofwetgranulationisthatanyincompatibilitybetween
formulationcomponentsisaggravated.

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Specialwetgranulationtechniques
i)Highshearmixturegranulation
ii)Fluidbedgranulation
iii)Extrusionspheronization
iv)Spraydrying

Highshearmixturegranulation
HighshearmixturehasbeenwidelyusedinPharmaceuticalindustriesfor
blendingandgranulation.Blendingandwetmassingisaccompaniedbyhigh
mechanicalagitationbyanimpellerandachopper.Mixing,densificationand
agglomerationareachievedthroughshearandcompactionforceexertedbythe
impeller.
Advantages:
i)Shortprocessingtime
ii)Lessamountofliquidbindersrequiredcomparedwithfluidbed.
iii)Highlycohesivematerialcanbegranulated.

Fluidbedgranulation
Fluidizationistheoperationbywhichfinesolidsaretransformedintoafluidlike
statethroughcontactwithagas.Atcertaingasvelocitythefluidwillsupportthe
particlesgivingthemfreemobilitywithoutentrapment.
Fluidbedgranulationisaprocessbywhichgranulesareproducedinasingle
equipmentbysprayingabindersolutionontoafluidizedpowderbed.Thematerial
processedbyfluidbedgranulationarefiner,freeflowingandhomogeneous.
ExtrusionandSpheronization
Itisamultiplestepprocesscapableofmakinguniformsizedsphericalparticles.It
isprimarilyusedasamethodtoproducemultiparticulatesforcontrolledrelease
application.
Advantages:
i)Abilitytoincorporatehigherlevelsofactivecomponentswithoutproducing
excessivelylargerparticles.
ii)Applicabletobothimmediateandcontrolledreleasedosageform.

Spraydryinggranulation
Itisauniquegranulationtechniquethatdirectlyconvertsliquidsintodrypowderin
asinglestep.Thismethodremovesmoistureinstantlyandconvertspumpable
liquidsintoadrypowder.
Advantages:
i)Rapidprocess
ii)Abilitytobeoperatedcontinuously
iii)Suitableforheatsensitiveproduct

Listsofequipmentsforwetgranulation
HighSheargranulation:
i)LittlefordLodgiegranulator
ii)LittlefordMGTgranulator
iii)Diosnagranulator
iv)Gralmixer
Granulatorwithdryingfacility:
i)Fluidizedbedgranulator
ii)Daynautamixerprocessor
iii)Doubleconeortwinshellprocessor
iv)Topogranulator
Specialgranulator:
i)Rotogranulator
ii)Marumerizer

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Currenttopicsrelatedtowetgranulation
I.Hydrateformation
Forexample,theophyllineanhydrousduringhighshearwetgranulationtransfers
totheophyllinemonohydrate.Themidpointconversionoccursinthreeminutes
afterthebindersolutionisadded.
Foronlinemonitoringofthetransformationfromoneformtoanother,Raman
spectroscopyismostwidelyused.
II.Polymorphictransformation
Thedryingphaseofwetgranulationplaysavitalroleforconversionofoneform
toanother.
Forexample,glycinewhichexistinthreepolymorphsthatis.isthemost
stableformandisthemetastableform.ThestableGlycinepolymorph()
convertstometastableform()whenwetgranulatedwithmicrocrystalline
cellulose.

Drygranulation
Introduction
Indrygranulationprocessthepowdermixtureiscompressedwithouttheuseof
heatandsolvent.Itistheleastdesirableofallmethodsofgranulation.Thetwo
basicproceduresaretoformacompactofmaterialbycompressionandthento
millthecompacttoobtainagranules.Twomethodsareusedfordrygranulation.
Themorewidelyusedmethodisslugging,wherethepowderisprecompressed
andtheresultingtabletorslugaremilledtoyieldthegranules.Theothermethod
istoprecompressthepowderwithpressurerollsusingamachinesuchas
Chilosonator.

Advantages
Themainadvantagesofdrygranulationorsluggingarethatitusesless
equipmentsandspace.Iteliminatestheneedforbindersolution,heavymixing
equipmentandthecostlyandtimeconsumingdryingsteprequiredforwet
granulation.Sluggingcanbeusedforadvantagesinthefollowingsituations:
i)Formoisturesensitivematerial
ii)Forheatsensitivematerial
iii)Forimproveddisintegrationsincepowderparticlesarenotbondedtogetherby
abinder

Disadvantages
i)Itrequiresaspecializedheavydutytabletpresstoformslug
ii)Itdoesnotpermituniformcolourdistributionascanbe
iii)Achievedwithwetgranulationwherethedyecanbeincorporatedintobinder
liquid.
iv)Theprocesstendstocreatemoredustthanwetgranulation,increasingthe
potentialcontamination.

Stepsindrygranulation
i)Millingofdrugsandexcipients
ii)Mixingofmilledpowders
iii)Compressionintolarge,hardtabletstomakeslug
iv)Screeningofslugs
v)Mixingwithlubricantanddisintegratingagent
vi)Tabletcompression

Twomaindrygranulationprocesses
Sluggingprocess
Granulationbysluggingistheprocessofcompressingdrypowderoftablet
formulationwithtabletpresshavingdiecavitylargeenoughindiametertofill
quickly.Theaccuracyorconditionofslugisnottooimportant.Onlysufficient
pressuretocompactthepowderintouniformslugsshouldbeused.Onceslugs
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areproducedtheyarereducedtoappropriategranulesizeforfinalcompression
byscreeningandmilling.
Factorswhichdeterminehowwellamaterialmayslug
i)Compressibilityorcohesivenessofthemater
ii)Compressionratioofpowder
iii)Densityofthepowder
iv)Machinetype
v)Punchanddiesize
vi)Slugthickness
vii)Speedofcompression
viii)Pressureusedtoproduceslug

Rollercompaction
Thecompactionofpowderbymeansofpressurerollcanalsobeaccomplishedby
amachinecalledchilsonator.Unliketabletmachine,thechilsonatorturnsouta
compactedmassinasteadycontinuousflow.Thepowderisfeddownbetween
therollersfromthehopperwhichcontainsaspiralaugertofeedthepowderinto
thecompactionzone.Likeslugs,theaggregatesarescreenedormilledfor
productionintogranules.

Formulationfordrygranulation
Theexcipientsusedfordrygranulationarebasicallysameasthatofwet
granulationorthatofdirectcompression.Withdrygranulationitisoftenpossible
tocompacttheactiveingredientwithaminoradditionoflubricantand
disintegratingagent.Fillersthatareusedindrygranulationincludethefollowing
examples:Lactose,dextrose,sucrose,MCC,calciumsulphate,StaRxetc.
Examplesofsometablet
formulationpreparedbydry
granulation

AdvancementinGranulations
SteamGranulation
Itismodificationofwetgranulation.Heresteamisusedasabinderinsteadof
water.Itsseveralbenefitsincludeshigherdistributionuniformity,higherdiffusion
rateintopowders,morefavourablethermalbalanceduringdryingstep,steam
granulesaremorespherical,havelargesurfaceareahenceincreaseddissolution
rateofthedrugfromgranules,processingtimeisshorterthereforemorenumber
oftabletsareproducedperbatch,comparedtotheuseoforganicsolventwater
vapourisenvironmentallyfriendly,nohealthhazardstooperators,norestriction
byICHontracesleftinthegranules,freshlydistilledsteamissterileandtherefore
thetotalcountcanbekeptundercontrol,lowersdissolutionratesocanbeused
forpreparationoftastemaskedgranuleswithoutmodifyingavailabilityofthedrug.
Butthelimitationisthatitisunsuitableforthermolabiledrugs.Moreoverspecial
equipmentsarerequiredandareunsuitableforbindersthatcannotbelater
activatedbycontactwithwatervapour.

MeltGranulation/ThermoplasticGranulation
(24)
Heregranulationisachievedbytheadditionofmeltablebinder.Thatisbinderisin
solidstateatroomtemperaturebutmeltsinthetemperaturerangeof5080C.
Meltedbinderthenactslikeabindingliquid.Thereisnoneedofdryingphase
sincedriedgranulesareobtainedbycoolingittoroomtemperature.Moreover,
amountofliquidbindercanbecontrolledpreciselyandtheproductionand
equipmentcostsarereduced.Itisusefulforgranulatingwatersensitivematerial
andproducingSRgranulationorsoliddispersion.Butthismethodisnotsuitable
forthermolabilesubstances.Whenwatersolublebindersareneeded,
PolyethyleneGlycol(PEG)isusedasmeltingbinders.Whenwaterinsoluble
bindersareneeded,Stearicacid,cetylorstearylalcohol,variouswaxesand

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mono,di,&triglyceridesareusedasmeltingbinders.

MoistureActivatedDryGranulation(MADG)
(58)
Itinvolvesmoisturedistributionandagglomeration.TabletspreparedusingMADG
methodhasbettercontentuniformity.Thismethodutilizesverylittlegranulating
fluid.Itdecreasesdryingtimeandproducesgranuleswithexcellentflowability.

MoistGranulationTechnique(MGT)
(59)
Asmallamountgranulatingfluidisaddedtoactivatedrybinderandtofacilitate
agglomeration.ThenamoistureabsorbingmateriallikeMicrocrystallineCellulose
(MCC)isaddedtoabsorbanyexcessmoisture.ByaddingMCCinthiswaydrying
stepisnotnecessary.Itisapplicablefordevelopingacontrolledrelease
formulation.

ThermalAdhesionGranulationProcess(TAGP)
(60)
Itisapplicableforpreparingdirecttabletingformulations.TAGPisperformed
underlowmoisturecontentorlowcontentofpharmaceuticallyacceptablesolvent
bysubjectingamixturecontainingexcipientstoheatingatatemperatureinthe
rangefromabout30Ctoabout130Cinaclosedsystemundermixingbytumble
rotationuntiltheformationofgranules.Thismethodutilizeslesswaterorsolvent
thantraditionalwetgranulationmethod.Itprovidesgranuleswithgoodflow
propertiesandbindingcapacitytoformtabletsoflowfriability,adequatehardness
andhaveahighuptakecapacityforactivesubstanceswhosetabletingispoor.

FoamGranulation
(61)
Hereliquidbindersareaddedasaqueousfoam.Ithasseveralbenefitsover
spray(wet)granulationsuchasitrequireslessbinderthanSprayGranulation,
requireslesswatertowetgranulate,rateofadditionoffoamisgreaterthanrate
ofadditionofsprayedliquids,nodetrimentaleffectsongranulate,tablet,orinvitro
drugdissolutionproperties,nopluggingproblemssinceuseofspraynozzlesis
eliminated,nooverwetting,usefulforgranulatingwatersensitiveformulations,
reducesdryingtime,uniformdistributionofbinderthroughoutthepowderbed,
reducemanufacturingtime,lessbinderrequiredforImmediateRelease(IR)and
ControlledRelease(CR)formulations
PostedbyImranAliat3:12AM
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Labels:Tablet:Manufacturingmethods/Granulation

8comments:
shivabizconn March26,2012at11:14PM
nice posting.STELLAR PHARMATECH Pvt. Ltd is a renowned manufacturer,
exporter and supplier of Pharmaceutical medicines.Pharmaceutical Tablets
manufacturers.
Reply

DavidBrandon March22,2013at3:54AM
So tablet compression comes in the last, i thought the process of tablet
manufacturingiseasybutafterreadingtheabovepostmyviewsarechanged.
Reply

MattHamonz April15,2013at9:34PM
Pharmaceutical packaging is more than just filling the content into a colorfully
designedandlabeledcontainer.Itdemandsanextremedegreeofsafetyuntilthe

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pharmaceuticalguide:Tablet:Manufacturingmethods/Granulation
productreachestheendusersandbroughttouse.Clickhereformoredetails.
Reply

LJ July7,2014at3:46AM
This is a great article. I love finding out about new stuff, and this sort of thing is
importanttoeverydaylife,eventhoughwemaynotknowit.Iwonderwhichwayis
best,wetordryoverallforpharmaceuticalgranulation?
Reply

asifpasha April30,2015at9:47PM
It'sreallyverymuchhelpfulformypreparations...
Reply

PRIYADARSHINIDUTTA October1,2015at7:35AM
thishelpedmetowritesomequestionsformypracticalmanual.
Reply

July18,2016at9:53PM
Youmightbeinterestedinthevideotoo:
https://youtu.be/YUFHfu2osH0
Reply

July18,2016at9:53PM
Youmightbeinterestedinthevideotoo:
https://youtu.be/YUFHfu2osH0
Reply

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