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BindersinTabletManufacturingWhatYouNeedtoKnow
BYARNISAISTARS,PH.D. Bindersserveseveralcriticalfunctionsintabletmanufacturing.Asthenameofthisclassofexcipientssuggests, theprimaryfunctionistocausethevariouscomponentsintheformulationtobindtogethertoformahard tablet.Inaddition,agoodbindershouldminimizefriability(thetendencytocrumble)ofboththeintermediate granulesformedduringwetcompressionprocessingaswellasinthefinishedtablets.Finally,theadhesive propertiesofabindershouldnotbesogoodastopreventadequatedissolution.Inthisregard,selectingan appropriatebinderbecomesdifficultbecausedissolutionandbindingpropertiesopposeeachotheranda balancemustbefound.Furthermore,theeffectivenessofthebinderisnotintrinsic,butisinfluencedbymany othervariablesintheformulationcomponentsandprocess.Thispaperprovidesanoverviewofthepopular choicesavailable,aswellassomeconsiderationsforoptimalbinderselection.

RoleinTableting
DirectCompression
Directcompressionisthemoststraightforwardtabletingprocess,consistingonlyofcompressingblendedtablet ingredients.Becauseofitssimplicityitofferscostadvantagesintermsofbothcapitalequipmentexpenditureas wellasoperationalworkflow. Bindersusedindirectcompressiontabletingrequireasmallparticlesizewithanarrowparticlesizedistribution. Thisensuresevenblendingthroughoutthedrypowder.Becausedirectcompressiondoesnotinvolvesolvent use,solubilityconsiderationsareeliminated.Instead,goodcompressibilityisarequirement.Themore deformable(compressible)abinderis,thebetteritwillabsorbtheenergyofcompressiontoyieldatabletwith highcrushstrengthandlowfriability. Inpractice,manyactiveingredientsaredifficulttoprocessusingthismethodbecauseofpoorcompressibility. Especiallyinsomenutritionalsupplementsthatcontainalargerportionofactivesthantypicalpharmaceutical preparations,directcompressionoftenfailstoproducesufficienttabletstrength.

WetGranulation
Becauseofthepracticallimitationsofdirectcompression,wetgranulationtendstobeusedforthemajorityof tabletmanufacturing.Itisamoretimeandcapitalintensiveprocess,butovercomesmanyoftheshortcomings ofdirectcompression.Inwetgranulation,binderscausetheagglomerationoftheblendedformulapowder intogranules.Theyaredissolvedordispersedinthegranulationfluid(usuallywateroralcohol),orblendeddry withtheotherformulationcomponentsbeforethesolventisadded.Thismixturethenundergoesaninitial pelletizingprocess,afterwhichtheliquidisevaporatedandtheresultingparticlesarefurthersizedand compressedintotablets.Bindersmaintainthedriedgranulesintheappropriatesizeandallowforproper tableting. 1

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Duringwetgranulation,theformulaingredientsdissolveinthegranulationfluid,andthenrecrystallize.The binderformsamatrixofinterparticulatebridgeswithothercomponentsintheformulaasthesolventis evaporated.Complexinteractionsofpropertiesincludingbindersolubility,mechanicalandfilmforming characteristics,andsurfacetensionandviscosityoftheliquidmixtureinfluencegranuleformationandstructure, aswellastheproperties(hardness,friability,anddissolution)ofthefinaltabletproduct.Becausethese interactionsdependonmanyparametersatonce,optimalbinderselectioninwetgranulationprocessesisoften determinedempirically.Thereare,however,someguidelinesusefulinstreamliningthisprocess.

TypesofBinders
NaturalPolymers
Polymericcarbohydratessuchasstarchandrelatedproductsaretypicallyusedinwetgranulationprocesses. ThesebindersarelistedinTable1.Starchisoneoftheoldestandmostwidelyusedbinders.Ittendsto producesoftandfriablegranuleswhichleadtotabletsthatdisintegraterapidly,butalsosufferfrompoor hardnesscharacteristicsandincreasedfriability.Acaciaproducessomeofthehardesttablets,whichalsotend todisintegrateslowly.Thispropertyissharedbyalginicacidandsodiumalginate.Thiscanmakethesebinders usefulforpreparationsrequiringslowreleaseofactiveingredients.Becauseoftheirsugarlikeproperties,many ofthesebindersalsosufferfromsusceptibilitytomicrobialcontamination.

Sugars
Sugarssuchasglucoseandsucrosearecommonformulationbinders.Theyareincorporatedinmuchhigher proportionsthanstarches,andcanconsistofupto25%ofthefinalformula.Likethenaturalpolymers mentionedabove,theyarealsomorecommoninwetgranulationprocessingthandirectcompression,andthe principalonesaresummarizedinTable1.Sugarstendtoproducehard,brittletablets.Thiscanbeusefulin makingchewabletablets,aroleforwhichsugarsareparticularlydesirableduetotheirinherentsweetness.In wetcompressiontableting,sugarsareoftenaddedasasyrupsratherthandrypowders.Sorbitol(asugar alcohol)hastheadditionalpropertyofbeinghighlyhygroscopic,andthereforeoftenfindsuseasahumectantin manyformulations.Ifmoisturecontrolisarequiredpropertyinaparticulartabletformulation,sorbitolisa goodselection.

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Table1.NaturalPolymersandSugarsusedasBinders.*
Binder Formul. % 25 13 35 310 15 13 225 225 210 Comments NaturalPolymers Soft,friablegranules;fast disintegratingtablets Requiresheatforprocessing Tabletsofmoderateharness;raw materialconsistencyissues Difficultprocessing;rawmaterial consistencyissues Hardtablets;slowdisintegration Goodforslowrelease;hygroscopic Sugars Formsveryhardtablets Moderatelyhard,brittletablets Hygroscopic;humectantproperties RepresentativeExamples Spectrum Cat.No. S1552 GE105 GU115 GU117 TR105 AL172 S1118 C3167 DE145 SY105 SU103 SO219 ProductDescription

Starch Gelatin Acacia Tragacanth AlginicAcid SodiumAlginate Glucose Sucrose Sorbitol

CornStarch,powder,NF Gelatin,powder,NF Acacia,spraydriedpowder,NF Acacia,milledpowder,NF Tragacanth,powder,NF AlginicAcid,NF SodiumAlginate,NF GlucoseSyrup,FCC Dextrose,hydrous,powder,USP Syrup,NF Sucrose,crystal,NF Sorbitol,Powder,NF

*adaptedfromRefs[1]and[2].

SyntheticPolymers
Syntheticpolymericbindershavebecomeincreasinglypopular.Someofthemostpopularonesarelistedin Table2.Theycanbesynthesizedveryreproduciblyandcleanly,therebyavoidingsomeofthevariabilitythat mightexistinnaturalsourcesforexcipientssuchasstarchesandgums.Whereasnaturalsugarderivativesare almostalwaysusedinaqueousvehicles(inwetcompression),polymershavegreaterutilityinbothpurewater andwateralcoholmixtures.Usingalcoholsometimeshasprocessingadvantagessuchasreducingdryingtime, anditisessentialforwatersensitiveformulations.Polymericbindersalsotendtoimpartverydesirablebinding characteristicsforavarietyofformulationsandtabletingparameters. Table2.SyntheticPolymersusedasBinders.*
Binder Methylcellulose Formul. % 15 510 25 510 Process (solvent) wet(water) Dry Wet(water oralc.) Dry Comments Easycompression;moderate tabletstrengthwithgoodshelf life Incompatiblewithsomeoxidizers HY122 HY123 HY124 H1393 ET110 Hypromellose,2910,50MPaS,USP Hypromellose,2208,100MPaS,USP Hypromellose,2208,4,000MPaS,USP Hypromellose,2208,100,000MPaS,USP Ethylcellulose,NF RepresentativeExamples Spectrum ProductDescription Cat.No. ME137 Methylcellulose,4,000cps,USP

Hydroxypropyl methylcellulose (Hypromellose, HPMC) Ethylcellulose

15 510

Wet(EtOH) Dry Wet(water oralc.) Dry

Polyvinyl pyrrolidone (PVP,povidone)

0.55 510

Softgranules;easydisintegrating tablets;slowdissolution(goodfor slowreleaseformulations) Easyprocessing;good compression;tabletshardenwith age;usedineffervescent& chewabletablets

P1416 P1454

PovidoneK90,USP PovidoneK30,USP

*adaptedfromRefs[1]and[2]. 3

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BinderSelection
Becauseabindersutilityinagivenformulationcannotbedefinedbyasinglecharacteristic,manufacturers spendconsiderabletimeevaluatingtheperformanceofvariousbindersacrossmultipleparametersintheir formulas.Selectionoftheoptimalbinderforaformuladependsonmanyvariables,andformulatorstypically mustevaluatemultiplebindersinseveralformulastoarriveatanacceptableformula.Theyseekeaseof processing,goodcompressibility,andtabletsthatarehardandnonfriable,butthathavereasonabledissolution propertiesaswell.Thecostofpolymericbinderstendstobesignificantlygreaterthannaturalpolymersand sugars,butbecausebinderrawmaterialcostsrepresentonlyasmallfractionofthetotaltabletcost,thisis generallynotafactorinbinderselection. DowChemicalhaspublishedaseriesofpapersthatcomparetheperformanceofvariousbindersinseveral formulaswithdifferentwetgranulationprocessingmethods(fluidbed,highshear,andlowsheargranulation).35 Severalmodelsoftabletformulationswereused,includinghighdose,highsolubility(VitaminC);highdose,low solubility(Acetaminophen);andlowdose,lowsolubility(methazolamide).Thesestudiesareusefulbecause theydidnotseektooptimizetheperformanceofanyparticularformula,butrathercompareperformance acrossvariousparametersforanumberofbinders.TheDowresearchersevaluatedHydroxypropylcellulose (HPC),Polyvinylpyrrolidone(PVP),Methylcellulose,Acacia,andPregelatinizedStarch.Inthesestudiessynthetic polymersconsistentlyoutperformedtheacaciaandstarchacrossmostproducttypesandgranulationmethods. Whilethisworkisnotconclusiveforalltabletformulations,itdoessupportthenotionamongmanyformulators thatsyntheticpolymersarecomparativelyeasytouseasbinders,andmanyoftheseproductscanbereadily optimizedrelativelyquicklyforuseinawidevarietyofformulationtypes. Certainlynaturalpolymersandsugarswillstillfinduseasbindersintabletformulations;especiallyforthesome ofthefunctionsnotedinTable1(chewabletablets,slowreleaseformulations,humectantproperties).For formulationsthatseektobeallnatural,thecarbohydratebinderswillcontinuetobeindispensible. Optimalselectionanduseofbindersintabletsisstillapainstakingprocessinvolvingarduoustrialanderror evaluationandextensivedatacollection.Everyformulationchemistbecomesanexpertintherequirementsof theirownformulatypes.Butwhenaformulatorneedstodevelopanewtabletproduct,therequirementsfor theoptimizationprocesscanbereducedusingthebroadguidelinespresentedheretoarriveatagoodinitial selectionforevaluation.

References
1. 2. 3. 4. 5. 6. Parikh,DM.Handbookofpharmaceuticalgranulationtechnology,NewYork:MarcelDekker;1997,pp5972. Lieberman,HA.Pharmaceuticaldosageformstablets,NewYork:MarcelDekker;1989,pp105108 DowChemicalCompany,GranulationwithDowCellulosicPolymersI.FluidBedGranulation,FormNo.19801151 0702AMS,July2002 DowChemicalCompany,GranulationwithDowCellulosicPolymersII.HighShearGranulation,FormNo.198 011700702AMS,July2002 DowChemicalCompany,GranulationwithDowCellulosicPolymersIII.LowShearGranulation,FormNo.198 011810602AMS,June2002 MuraliD.DurigT.Binderselectionintableting.NaturalProductsInsider;May2008.Availablefrom: http://www.naturalproductsinsider.com/articles/2008/05/binderselectionintableting.aspx