輔料功能性指標(biāo)對(duì)制劑質(zhì)量的影響默克

輔料功能性指標(biāo)對(duì)制劑質(zhì)量的影響默克第1頁(yè)/共57頁(yè)HighFunctionalExcipients2第2頁(yè)/共57頁(yè)FunctionalParticleEngineeringPhysicalcharacteristicsinadditiontochemistrydeterminethequalityofyourproducts.3第3頁(yè)/共57頁(yè)FlowabilityParticlesizedistributionfortheactive(s)intheformulationHygroscopicityCompressibilityDrugloadingcapacityFriabilityStabilityMouthfeelContentuniformityoffinisheddosageDisintegrationtimeoffinaldosageDissolutionofdrugsubstanceFunctionalParticleEngineeringKeyPhysicalCharacteristicsofanSolidFormulationExcipient4第4頁(yè)/共57頁(yè)Filler/matrixpolymerGlidantBinderDisintegrantAPILubricantFunctionalExcipientsofTablets5第5頁(yè)/共57頁(yè)GlidantMultifunctionalDC-excipientAPILubricantMultifunctionalDC-Excipients6第6頁(yè)/共57頁(yè)P(yáng)ropertiesofanidealDC-excipient...ItshouldhaveaoutstandingflowabilityItshouldhaveaparticlesizedistributionappropriatefortheactive(s)intheformulationItshouldbenot/littlehygroscopicItshouldhaveahighcompressibilityItsholdhaveahighdrugloadingcapacity

Itshouldhaveanexcellentpressure-hardnessprofileItshouldresultintabletswithlowfriabilityItshouldformtabletswithshortdisintegrationtimeandfastdrugdissolutionItshouldresultintabletswithexcellentcontentuniformityItshouldbeunsusceptibletolubricantsItshouldbephysiologicallyinert

ItshouldbecompatiblewithalltypesofingredientsItshouldbestabletoair,moistureandheatItmustnotshowanyphysicalorchemicalchangeonagingItshouldbecolourlessandtastelessItshouldacceptcolourantsuniformlyItshouldbeinexpensiveItshouldpocessapropermouthfeelItshouldnotinterferewiththebiologicalavailabilityofactivesItshouldbereworkablewithoutlossofflowandcompressibilityItshouldmakethevalidationofthetablettingprocesseasy7第7頁(yè)/共57頁(yè)ExcipientsforDirectCompression8第8頁(yè)/共57頁(yè)TabletManufacturingbyDirectCompression

ProcessFlowChartDC-ExcipientsTabletsMixingDirectCompressionAPI(s)MixtureMixingLubricant9第9頁(yè)/共57頁(yè)WetgranulationPotentialreductionof6additionalstepsTotalcostreductionupto3timesCompressiontotablets1.Weighingofingredients2.Blendingofingredients3.4.5.-6.-7.-8.-TOTALDirectCompression0.4–1.00€/kg0.2–1.50€/kg0.5–0.75€/kg1.0–2.00€/kg0.3–0.70€/kg1.5–3.00€/kg0.3–0.70€/kg0.3–0.70€/kg4.7–10.35€/kgProcesscost(€/kg)0.4–1.00€/kg0.2–1.50€/kg

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1.6–4.50€/kgProcesscost(Estimative)1.Weighingofingredients2.Blendingofingredients3.Prep.granulationfluid4.Granulation5.Wetsieving6.Dryingprocess7.Drysievingprocess8.Add.ofexternalphaseTOTAL

CostBreakDown10第10頁(yè)/共57頁(yè)IdealRequirementsAdvantagesLimitationsFlowabilityCosteffectiveproductionsSegregationCompressibilityBetterstabilityofAPIVariationinfunctionalityDilutionpotentialFasterdissolutionLowdilutionpotentialReworkabilityLesswear&tearofpunchesReworkabilityStabilitySimplifiedvalidationPoorcompressibilityofAPIControlledparticlesizeLowermicrobialcontaminationLubricantsensitivityWhatarethebestExcipientsforDC?11第11頁(yè)/共57頁(yè)12MannitolforDC:Parteck?M第12頁(yè)/共57頁(yè)MannitolPositioningLessreactivethanlactoses(noMaillard-reaction:threattoAPI)LesshygroscopicthanlactosesandMCCRecommendedforpeoplewithlactoseintoleranceVegetarian:NoBSE/TSEsafetyriskDerivedfrominexhaustibleresources(sugarorstarch)?Sugar“-freesoidealfordiabeticpatientsParteck?M:MannitolforDC13第13頁(yè)/共57頁(yè)P(yáng)arteck?M:AuniqueproductUniquecharacteristicsDirectlycompressibleMannitolUniqueparticlepropertiesHighcompactibilityatlowcompressionforcesRapiddisintegrationanddissolutionHighdilutionpotentialExcellentflowExceptionallylowspecifiedlevelofreducingsugarsTwogradesavailableGuaranteedMerckKGaAquality14第14頁(yè)/共57頁(yè)GranularMannitolSpraydriedMannitol(Parteck?M)DifferentTypesofMannitol15第15頁(yè)/共57頁(yè)P(yáng)olymorphandBET-surfaceProductPolymorphappr.BET(m2/g)QualityParteck?M200beta3SpraydriedParteck?M300beta3SpraydriedPearlitolSD100alpha0,6SpraydriedPearlitolSD200alpha0,5SpraydriedPearlitol300DCbeta0,5GranulatedPearlitol400DCbeta0,4GranulatedPearlitol500DCbeta0,3GranulatedMannogemEZalpha0,5SpraydriedMannogemGranularbeta0,3GranulatedMannogem2080beta0,5GranulatedMannogem3215beta0,4Granulated16SupplierASupplierB第16頁(yè)/共57頁(yè)P(yáng)arteck?M:Compressibilitytablethardness[N]010020030040005101520253035compressionforce[kN]Parteck?M200MannitolSDGran.MannitolMethodFormulation:99%testmaterial+1%magnesiumstearate;5min.mixingCompression:singlepunchpress(KorschEK0DMS,rpm:54,punch:11mm,flat,facetted)Tabletweight:500mg(rel.S.D.:0.5)17第17頁(yè)/共57頁(yè)5010015020025051525Compressionforce[kN]tablethardness[N]Parteck?M200MannitolSDGran.mannitolMethodFormulation:25%Ascorbicacid,74%testmaterial,1%MgstearateTabletpress:

KilianLX28A,30rpm,Punch:

9/16''diameterconcavebeveledgeTabletweight:1000mg,MannitolSDiscommerciallyavailablespray-driedmannitolGranularmannitoliscommerciallyavailablepre-granulatedmannitolParteck?M:Highdilutionpotential

18第18頁(yè)/共57頁(yè)020406080Parteck?MDC-MannitolLactose/starch-granulesTablettosetablethardness(N)Parteck?M:FastDisintegrationFormulation:98,5%Mannit;1,5%Mg-Stearat,Compr.Force15KN|99%Lactose,1%Mg-Stearat,Compr.Force15KN19第19頁(yè)/共57頁(yè)0102030Parteck?MDC-MannitolLactose/starch-granulesTablettoseDisintegrationtime(min)Parteck?M:FastDisintegrationFormulation:98,5%Mannit;1,5%Mg-Stearat,Compr.Force15KN|99%Lactose,1%Mg-Stearat,Compr.Force15KN20第20頁(yè)/共57頁(yè)P(yáng)arteck?M:ExcellentflowabilityMaterialAngleofreposeQualityParteck?M20025.3°SpraydriedCompetitorBGR30.0°GranulatedCompetitorBGR28.4°GranulatedCompetitorBGR30.7°GranulatedCompetitorASD27.0°Spraydried21第21頁(yè)/共57頁(yè)00,511,522,533,544,55Parteck?M200Parteck?M300DC-Lactose(anhydrous)DC-SucroseDC-DextroseWatercontent[%]55%68%76%86%rel.humidityx1x2x31=7.22=9.33=12.5Parteck?M:Nowater-uptake22第22頁(yè)/共57頁(yè)NosignificantdeviationsintabletweightandhardnesseswereobservedThegoodflowandcompressibilityofParteck?Misidealforhigh-throughputproductiononfastrotarypressesContentuniformitywasindefinedrange(+/-1,8%)Parteck?M:DCwithlowdoseactives40.000/h80.000/hTabletweight120.1mg(rel.sd.:0.6%)118.8(rel.sd.:0,9%)Hardness178N(rel.sd.4.1%)173N(rel.sd:4.1)Disintegration3'25''3'22''Scaleup23第23頁(yè)/共57頁(yè)P(yáng)arteck?M:ReducingsugarsCommercialstandard

Ph.Eur.0,20%

USP0,30%Parteck?M

Limit<0,05%(actualvalues~50%oflimit)

Additionallyspecified:totalresidualsugar<0,4%Causeforinstabilityandbrowning24第24頁(yè)/共57頁(yè)ExcipientforWetGranulation:Parteck?DeltaM25第25頁(yè)/共57頁(yè)TabletManufacturingbyWetGranulation

ProcessFlowChartExcipientsMixingAPI(s)AdditionofBinderSolutionWetGranulationDryingTabletsCompression26第26頁(yè)/共57頁(yè)TabletManufacturingbyWetGranulation

ProcessFlowChartExcipientsMixingAPI(s)AdditionofBinderSolutionWetGranulationDryingTabletsCompressionWithParteckDeltaMyoudonotneedadditionalbinder!!!27第27頁(yè)/共57頁(yè)P(yáng)ropertiesofParteck?DeltaMUniqueMannitolcrystals90%deltapolymorphicLargesurfaceaftergranulationExcellentbindingpropertiesAccelerateddisintegrationDMFavailableMerckKGaAquality28第28頁(yè)/共57頁(yè)P(yáng)arteck?DeltaM:UniqueMannitolCrystalsSeveralpolymorphicformsofMannitolhavebeenclassified(Walter-Levy1968)CommerciallyavailablecrystallineMannitolisinbetaformBetacrystalsarethemoststableformParteck?DeltaMhasdelta(δ)crystalsDuringwetgranulationthedelta-polymorphtransformsintobetaThesebetacrystalsareaggregatesoffinecrystallineprimaryparticleswithalargesurfaceareaThisconversionisconnectedwithaconsiderableincreaseinsurfaceareaandporevolume29第29頁(yè)/共57頁(yè)P(yáng)arteck?DeltaM:UniqueMannitolCrystals(continued…)IncustomerspecificformulationsthisconversionresultedinEnhancementofcompressionpropertiesShorteningofdisintegrationtimeShorteningofin-vitrodrugreleaseHardertabletsareachievedbyDecreaseinelasticdeformationIncreaseinparticlebindingsites30第30頁(yè)/共57頁(yè)SEMsofbeta-mannitolBeforewetgranulationAfterwetgranulation31第31頁(yè)/共57頁(yè)SEMsofdelta-mannitolBeforewetgranulationAfterwetgranulation32第32頁(yè)/共57頁(yè)P(yáng)arteck?DeltaM:Surface-areaBET-Method33第33頁(yè)/共57頁(yè)P(yáng)arteck?DeltaM:CompressionprofileMannitolwasgranulatedwith15%wateranddriedinafluidizedbed.Granuleslargerthan1mmwereremoved.Granulesweremixedfor5minwith1.5%MSTandcompressedonasinglepunchpressatvariouscompressionforces(KorschEKODMS)Punch Tabletweight11mm,flat,facetted 400mg34第34頁(yè)/共57頁(yè)P(yáng)arteck?DeltaM:AcceleratedDisintegration35第35頁(yè)/共57頁(yè)36DirectlyCompressibleMg:Parteck?MgDC第36頁(yè)/共57頁(yè)P(yáng)arteck?MgDCDirectCompressibleExcipientParteck?MgDC100%MagnesiumcarbonateWithoutanyadditivesDeclarationofPharmacopoeia’sPHEUR,BP,USP,E504availablePurityrequirementsofthefoodandpharmaindustryarefulfilledAhighBETsurface37第37頁(yè)/共57頁(yè)

Parteck?MgDC:BenefitsfortheCustomerDirectcompressibility:facilitatesformulationworkandreducesproductioncostsHighcompactibilityevenatlowcompressionforces:reducesstressontablettingpressesandtoolingNoneedforextrabinder:simplifiesformulationworkandtheregulatoryeffortHighmineralcontent:duetolackofbinderallowsforsmallertabletsizesand/ormoreadditionalformulationcomponentsNolicenseagreementorpaymentrequired:savestimeFastdisintegrationtime:leadstofastdissolutionandfastaction38第38頁(yè)/共57頁(yè)

Parteck?MgDC:SolidDoseApplicationsSwallowedtabletsODTformulationsEffervescenttabletsChewabletabletsCombinationwithotheringredientslikevitaminsmineralsmicromineralsfunctionaladditivesAPIs39第39頁(yè)/共57頁(yè)

Parteck?MgDC:Unique,FunctionalParticleSEMofParteck?MgDC

2500xSEMofParteck?MgDC

25000x40第40頁(yè)/共57頁(yè)

Parteck?MgDC:BETSurfaceArea41第41頁(yè)/共57頁(yè)

Parteck?MgDC:CompressionProfile(I)Parteck?MgDCissuperiorinhardnesstoallotherpureDCMg-Carbonates

42KorschEKDMSTablettingmachine,ParteckMgDC/Competitors+1%MgStearate,500mgTablets,diameter11mm,facetted,HardnessbyERWEKATBH30MD第42頁(yè)/共57頁(yè)P(yáng)arteck?MgDC:CompressionProfile(II)Parteck?MgDCisashardasthebeststarchcontainingDCMg-Carbonates

43KorschEKDMSTablettingmachine,ParteckMgDC/Competitors+1%MgStearate,500mgTablets,diameter11mm,facetted,HardnessbyERWEKATBH30MD第43頁(yè)/共57頁(yè)

Parteck?MgDC:FriabilityParteck?MgDCleadstolowerfriabilitythanallotherpureDCMg-Carbonates44KorschEKDMSTablettingmachine,ParteckMgDCtablets/Competitors+1%MgStearate,500mgTablets,diameter11mm,facetted,FriabilitybyERWEKATA420第44頁(yè)/共57頁(yè)ExcipientforOrallyDisintegratingTablets:

Parteck?ODT45第45頁(yè)/共57頁(yè)WhatisODT?ODT=OrallyDisintegratingTabletsDefinitionsDefinitionbyUSFoodandDrugAdministrationCenterforDrugEvaluationandResearch(CDER)

Asoliddosageformcontainingmedicinalsubstances,whichdisintegratesrapidly(USP<30s)DefinitionEP

Orodisperse=atabletthatcanbeplacedinthemouthwhereisdispersedrapidlybeforeswallowing.

(Ph.Eur.<180s)46第46頁(yè)/共57頁(yè)BenefitsofODTProductsPatientvaluesConvenienceandeaseofusemakesODT`sbeneficialforchildren,elderlyanddisabledpeopleEffectiveincaseofdiseasesthatcanrestrictswallowing(Parkinson,AID`sandcancer)Convenientfortravellers(nowaternecessary)MarketingvaluesCost-effectivedevelopment(directcompression)Creationofbranded,differentiatedlineextensions(protectionof

marketshare)Usingnew(ODT)technologytoextentpatentlifeofanestablisheddrug47第47頁(yè)/共57頁(yè)P(yáng)arteck?ODT

Introduction–composition,production,regulatoryEP,USP,JPsuper-disintegrant5%CroscarmellosesodiumEP,USP,JPFiller,binder,slightlysweettaste95%Mannitol(spraydried,BET>2m2/g)Reg.StatusFunctionQuantityExcipientTheuniquesurfacestructureleadstoexceptionalcompressionbehaviourandfastdisintegration48第48頁(yè)/共57頁(yè)P(yáng)arteck?ODTormechanicalmixture?ParteckODTDCMannitolA+5%Na-CMCDCMannitolB+5%Na-CMCDCMannitolC+5%Na-CMCDCMannitolD+5%Na-CMCParteckODTshowsbettercompressibility&fasterdisintegrationthanmechanicalmixtureswithDC-Mannitols!!!49第49頁(yè)/共57頁(yè)P(yáng)arteck?ODT:DirectCompressionProfileParteck?ODTshowsexcellenttablettingbehaviourGoodtabletqualitycouldbeachievedbyverylowcompressionforcesFriabilityofParteck?

ODTtablets<0,4%Angleofrepose:33°-38°

->goodflow99%testmaterialand1%magnesiumstearate,mixedandcompressedon500mgtablets,diameter11mm,facetted,singlepunchEK0DMSHardnessbyERWEKATBH30MDPlaceboCompressionProfileofParteck?ODTvs.Competitors+1%Mg-stearateKorschEK0DMS,500mgtablets,diameter11mm,flat,facetted,tablethardnessbyERWEKATBH30MD50第50頁(yè)/共57頁(yè)P(yáng)arteck?ODT:DisintegrationtimeParteck?ODTtabletsdisintegrateinlessthan40secIncreasedphysicalstabilityofthetabletsdoesnotcompromisedisintegrationtime313mgParteck?ODTwith80mgascorbicacid,1%magnesiumstearate,0.5%orangeflavor,0.2%sucraloseon400mgtablets,diameter11mm,facetted,singlepunchEK0DMSHardnessbyERWEKATBH30MD,DisintegrationProfileofAPIFormulationwithParteck?ODTvs.Competitors+200mgIbuprofen+1%SiO2+1%Mg-stearateKorschEK0DMS,500mgtablets,diameter11mm,flat,facetted,USPdisintegrationinwaterat37°C51第51頁(yè)/共57頁(yè)FeaturesofParteck?ODTParteck?O