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Effervescenttabletsandinstantdrinksareattractivedosageformsforhealthcare

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companieslookingtomeettheneedsofmodernpatientsandconsumers

Choosing effective granulation strategies for effervescent formulations

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Effervescent tabletsand instantdrinks offeravery versatile approachtooral administration

Comparison of a conventional wet granulation method (1 & 2) and TOPO granulation (3 & 4) to manufacture an effervescent painkiller Figure 1

Designedtodissolverapidlyinaglassof water,theseuserfriendlyformulationshelpto overcometheunpleasanteffectsthatmany individualsexperiencewhenswallowing conventionaltabletsandcapsules.Arecentstudy revealedthatdependingontabletorcapsule size,shapeandsurfacetexturealmosthalfofus findswallowingtraditionaloraldosageforms difficultoruncomfortable.1 Theunpleasanttaste andodourthatpatientsandconsumersoften experiencecanalsobeafactorthatcontributesto pooradherencetotreatmentregimens. Effervescenttabletsandinstantdrinks,by

contrast,offeraneasyandmorepleasantoral experience.Thesedosageformsundergo effervescenceuponexposuretowater,allowingthe activepharmaceuticalingredient(API)ornutrient toberapidlyreleasedintoasolutionforthe patienttodrinkasabeverage.Theapplicationof tastemaskingandflavouringtechnologiesin formulationdevelopmentmakesitpossibleto designproductsthattastepleasantandcaneven beenjoyed.Inaddition,thefactthatthese formulationsallowlargeamountsorevenmultiple APIstobedeliveredinasingledosemeans effervescenttabletsandinstantdrinksofferavery versatileapproachtooraladministration. Owingtothemoisturesensitivenatureofthese

formulations,specialistgranulationexpertiseis requiredtocreatehighqualityandstable productswithashelflifeofupto3yearsand usabilityinhotandhumidclimates(climatezones

IIIIV).Inthisarticle,welookatthegranulation technologiesthatareavailablewhendeveloping effervescenttabletandinstantdrinkformulations andhighlightthefactorsthatshouldbe consideredwhenmakingthischoice.

Theimportanceofgranulation Granulationisakeystepinthedevelopmentand latermanufactureofeffervescentdosageforms (Figure1).Pharmaceuticalpowders,suchas activeingredientsandexcipients,typicallycontain abroaddistributionofparticlesizesthatcan makeprocessingdifficult.Granulationisusedto transformthesefinepowdersintolargergranules ofaconsistentsize,whichcanbemoreeasily processedinsubsequentproductionsteps. Theformationofdustfreegranulesenhances

theflowabilityofmaterialsafactorthatis necessarytocontrolAPIdosageanddelivera homogenousdistributionofactiveswithin products.Thisisimportanttoensurethatthey performasintendedwhentakenbypatients. Granulationisalsoimportanttoachieveanarrow particlesizedistribution,whichisbeneficialfor reliableandcosteffectiveproductmanufacture. Granulationbreaksdownawkwardlyshaped needlelikeparticles,whichwouldotherwisebe impossibletofurtherprocess.Adjustinggranule morphologyalsoaffectsAPIbioavailability, allowingthereleaseprofileoftheactiveingredient tobetunedaccordingtotherequirementsofthe finishedproduct.

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Importantly for moisturesensitive effervescent formulations, granulation can be used to reduce the accessible surface area of the reactive components. As the stability of effervescent products is related to the contact area of the active ingredients, granulation results in the manufacture of more stable products as the active ingredients cannot interact through surface interactions. Whenitcomestothetechnologiesthatareused

forgranulation,twoapproachesarecommonly adopted:drygranulation,wherebyprimary powderparticlesarebondedtogetherbyphysical compaction,orwetgranulation,achievedthrough theadditionofasolventtoformlarger, multiparticulargranules.

Drygranulation Formanynoneffervescentformulationsandsome lessreactiveeffervescents,drygranulationisan efficientmanufacturingoption.Themostcommon methodofdrygranulationisrollercompaction, wherebyapowderiscompactedbetweentwo counterrotatingrollersandthencompressed into aribbon.Thisribbonisfurtherprocessedvia millingtogenerateparticlesofthedesiredsize. Rollercompactionisahighthroughputmethod thatcanbeoperatedcontinuouslywith minimalsupervision. Asnoliquidsareused,themethoddoesnot

involvecostlyandtimeconsumingdryingsteps. Furthermore,anymaterialthatdoesnotmeetthe requiredparticlesizecanberecycledbackinthe process,minimisingwaste.Asaresult,this approachtogranulationcanbeverycosteffective incaseswhenprocessabilityandthemorphology ofparticlesneedtobeimproved.However,whenit comestothemanufactureofmorereactive effervescentproducts,drygranulationisoftennot suitableastheeffervescentcomponentsare compactedwithoutpassivation.Thispassivation stepisimportanttostabilisethereactive ingredientsandmaintainproductqualityduring manufacture,shippingandstorage.Asaresult, moreadvancedtechnologiesarerequired.

TOPOgranulation TOPOvacuumgranulationisapatentedwet granulationtechnologydesignedtostabilisethe moisturesensitivecomponentsofeffervescent dosage forms in air, whilst ensuring they react rapidly and completely in water. TOPO granulation modifies the surface of the reactive acidic components within effervescent mixtures (most commonly citric acid) causing a layer of less reactive citrate to form on the surface of the acid particles, passivating them. The vacuum allows manufacturers to achieve

lower drying temperatures and shorter drying times, decreasing the likelihood of any thermal degradation occurring to the effervescent components or the APIs and resulting in a more costeffective production process. It also prevents uncontrolled effervescent chain reactions from occurring a factor that is important for the creation of consistent, highquality products. The use of TOPO granulation offers a very

effective means of producing effervescent tablets

Granulationisakeystepinthe developmentandlatermanufacture ofeffervescentdosageforms

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Using TOPO granulation to develop an effervescent painkiller

AtHERMESPHARMA,werecentlydevelopedananalgesicandantipyreticproduct,containing500mgof acetylsalicylicacidand50mgofcaffeine,forpatientssufferingwithheadachesandflulikesymptoms.Because ourcustomersoughtauserfriendlyoraldosageformwithafastonsetofaction,weoptedforaneffervescent tabletformulation. ThiswasidealastheAPIscouldbefullydissolvedinaglassofwater,offeringamore convenientwayforpatientstotakethemedicationandalsoenablingrapidabsorptiononceinthebody. AcetylsalicylicacidcanbeaparticularlychallengingAPItoformulateandpresenteduswithanumberof

factorstoconsider.Forexample,withrepeateddoses,thecompoundcanirritatethestomach,andeffortshadto bemadetominimiseoreliminatethissideeffect.Effervescentformulationsareaconvenientsolutiontothis challengeastheyenabletheuseofabufferingsystemthatfavoursAPItransitfromthestomachintothe intestine...whereabsorptionoccurs. Acetylsalicylicacidisaverymoisturesensitivecompound.Inthepresenceofwater,itbreaksdowntosalicylic

acidandaceticacid. Aceticacidhasastrongandunpleasantvinegaryodour.Moreover,smallamountsof salicylicacidandaceticacidcanleadtovisiblediscolourationoftheproduct.Giventhateffervescentsare particularlysensitivetowater,averystableformulationhadtobedeveloped. Ahighlyeffectivegranulationtechnologywasrequiredtoensurethattheeffervescentformulationwould

remainstableforextendedperiodsoftimeandtheproductwouldperformasintended. Afterconsideringthe options,theclearsolutionthatwouldallowustoachieveahighquality,stableproductwastheuseofTOPO granulation. TheTOPOprocessresultedinaneffervescentgranulatethatcouldbepassivatedtoreducemoisture sensitivity.Italsoofferedverygoodcompressionpropertiesthatensuredtheproductwasdurableandcould withstandshippingandstorage. Thankstothistechnology,wedevelopedaverystableproductwithalongshelflife. Theproductwasableto

maintainitsperformancefor36monthswithoutanyadditionalstoragerequirements. Theresultinghighproduct stabilityalsoensuredthattherewasnodiscolourationorunpleasantodourortastederivedfromtheformation ofaceticacid,evenunderhotandhumidconditions(climatezoneIVb).

that remain stable even when packaged in tubes that are repeatedly opened and exposed to air and humidity, such as in bathrooms. As a result, the technology is ideal for the production of medicinal products and food/dietary supplements designed for tropical and highhumidity regions. Moreover, because TOPO allows the manufacture of effervescents under conditions of up to 30% humidity, the technology can help to minimise the costs associated with air conditioning in manufacturing plants.

TOPOgranulatesalsohaveexcellent compressibilitycharacteristics,leadingto effervescenttabletswithhighphysicalstability. Thisavoidsthetabletsbreakingduringtransport orwhenatabletisremovedfromthetube,while maintainingtheirrapiddissolvability. Furthermore,theparticlesizedistributionof granulescanbemodifiedsothattheycanbeeasily blendedwithotherexcipients.

Unlikeothermethods,thepurewaterusedin TOPOgranulationensuresthatthereareno solvent residues left in the finished product. TOPO granulation also minimises or avoids the need for insoluble excipients, which can lead to unattractive foamsorfilmswhenthetabletisdissolvedin water.Inaddition,asTOPOtechnologyrequires onlyasmallamountofwaterandnoorganic solvents,itisamoreenvironmentallyfriendly, sustainableandcostefficientmethodof manufacturingeffervescentproducts.

Continuous flow Continuous flow (CF) technology is a further development of TOPO granulation thats specifically designed for the highthroughput manufacturing of effervescent products. The process is performed within an inclined drum, with the primary particle powder being fed in at one

end and the granules collected from the other. CF allows the manufacture of up to 10 tons of granules every day and is a very economical approach for the production of highly stable effervescent tablets and granules. As such, CF is often the most appropriate solutionwhenlargevolumesofproductare required,especiallywhentheycontainsensitive APIs,suchascalciumandvitaminD3.

Conclusion Effervescenttabletsandinstantdrinksareuserfriendlyalternativestotraditionaloraldosage formsandhelptoovercometheunpleasanteffects thatmanypatientsandconsumersexperience whenswallowingconventionaltabletsand capsules.Granulationplaysanimportantrolein thedevelopmentandmanufactureofthese products,helpingtoturnfinepowdersintofreeflowing,dustfreegranules,whichcanbe processedmoreeasily.

Althoughtraditionaldrygranulationstrategies canbeusedfortheproductionofsome effervescentproducts,whenmoresensitiveactive ingredientsareinvolved,theseapproaches performlesseffectively.Advancedtechnologies, suchasTOPOandCFgranulation,enable effectivepassivationofthereactiveeffervescent components,ensuringoptimalstability,usability andoverallqualityofthefinalproduct.

REFERENCE 1.www.swallowingtablets.com.

FORMOREINFORMATION DrMartinKoeberle HeadofAnalyticalDevelopmentandStabilityTesting HERMESPHARMA www.hermespharma.com

TOPO granulateshave excellent compressibility characteristics, leadingto effervescent tabletswith highphysical stability

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http:www.hermespharma.comhttp:www.swallowingtablets.com

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