一种药品单冲压片机的结构设计【机械类毕业-含CAD图纸】.zip
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asianjournalofpharmaceuticalsciences12(2017)412417AvailableonlineatScienceDirectjournalhomepage:/locate/ajpsOriginalResearchPaperPredictionofeffectsofpunchshapesontabletingfailurebyusingamulti-functionalsingle-punchtabletpressTakashiOsamuraa,b,YoshikoTakeuchia,RisakoOnoderaa,MasahiroKitamurab,YoshiteruTakahashib,KoheiTaharaa,HirofumiTakeuchia,*abLaboratoryofPharmaceuticalEngineering,GifuPharmaceuticalUniversity,1-25-4Daigaku-Nishi,Gifu501-1196,JapanPharmaceuticalTechnologyDepartment,SawaiPharmaceuticalCo.Ltd,12-34,Hiroshibacho,Suita-Shi,Osaka564-0052,JapanARTICLEINFOABSTRACTArticlehistory:Received11April2017Accepted4May2017Availableonline17May2017Keywords:TabletingFormulationdesignLubricantPunchshapeSingle-punchtabletpressLosartanpotassiumWepreviouslydetermined“Tabletingproperties”byusingamulti-functionalsingle-punchtabletpress(GTP-1).Weproposedplotting“Compactability”onthex-axisagainst“Manufacturability”onthey-axistoallowvisualevaluationof“Tabletingproperties”.Varioustypesoftabletingfailureoccurincommercialdrugproductionandareinuencedbytheamountoflubricantusedandtheshapeofthepunch.WeusedtheGTP-1tomeasure“Tabletingproperties”withdifferentamountsoflubricantandcomparedtheresultswiththoseoftabletingonacommercialrotarytabletingmachine.Tabletscompressedwithasmallamountoflubricantshowedbad“Manufacturability”,leadingtostickingofpowderonpunches.Wealsotestedvariouspunchshapes.TheGTP-1correctlypredictedtheactualtabletingresultsforallpunchshapes.Withpunchesthatweremorelikelytocausetabletingfailure,oursystempredictedtheeffectsoflubricantquantityinthetabletformulationandtheoccurrenceofstickingintherotarytabletingmachine.2017ProductionandhostingbyElsevierB.V.onbehalfofShenyangPharmaceuticalUniversity.ThisisanopenaccessarticleundertheCCBY-NC-NDlicense(http:/licenses/by-nc-nd/4.0/).1.IntroductionpowdershavebeeninvestigatedbyusingtheequationsofKawakitaandLudde1,Heckel2,3,andKlevanetal.4.Someconstantsintheseequationsarefrequentlyusedasindica-Indevelopingatabletformulation,itisnecessarytounder-stand“Tabletingproperties”andtodeterminetheoptimumtype,grade,andamountofingredients.“Compressibility”isevaluatedbyloadingpressureontoapowderbedwhilemea-suringthebulkdensityofthebed.Thepropertiesofformulatedtorsof“Compressibility”.“Compactability”istypicallyevaluatedbymeasuringthetensilefracturestress(TFS)oftabletsasafunctionofcompactionpressure5,6.“Manufacturability”con-cernstabletingfailure(e.g.,sticking,capping,andbinding).Sposedthatcappingcouldbepredictedfrom*Correspondingauthor.GifuPharmaceuticalUniversity,1-25-4Daigaku-nishi,Gifu501-1196,Japan.Tel.:+81582308100.E-mailaddress:takeuchigifu-pu.ac.jp(H.Takeuchi).PeerreviewunderresponsibilityofShenyangPharmaceuticalUniversity./10.1016/j.ajps.2017.05.0011818-0876/2017ProductionandhostingbyElsevierB.V.onbehalfofShenyangPharmaceuticalUniversity.ThisisanopenaccessarticleundertheCCBY-NC-NDlicense(/licenses/by-nc-nd/4.0/).asianjournalofpharmaceuticalsciences12(2017)412417413residualdiewallpressure7.Urabeetal.suggestedthates-timationofgeneraltabletingpropertiesandfailureswaspossiblebyusingamicro-powdercharacterizerwithinnitesimalquan-titiesofpowdersample8,.MaterialsandmethodsMaterialsCombiningtheseseparatetests,theGamlenTabletPress(GTP-1;GamlenTabletingLtd.,Nottingham,UK),abenchtopsingle-punchtabletpress,measurespressureanddisplace-mentduringcompression,thefrictionbetweendieandtabletduringejection(ejectionstress),andthestrengthofthetablet(TFS)inasingledevice.Inourpreviousstudy,wesuggestedtheuseofTFSasanindicatorof“Compactability”andejec-Wepurchasedgranulatedlactose(DilactoseR;FreundCorpo-ration,Japan),microcrystallinecellulose(MCC:CeolusPH302,AsahiKaseiChemicals,Japan),partlypregelatinizedstarch(Starch1500;NipponCalorcon,Japan),magnesiumstearate(MgSt;TaiheiChemical,Japan),andlosartanpotassium(LP;Kolon,Korea).tionstressasanindicatorof“Manufacturability”,asdiewallfrictioncanbeproblematicwhenthetabletisejectedfrom2.2.Methodsthedie10.Weevaluated“Compressibility”,“Compactability”,and“Manufacturability”withaGTP-1andplottedTFS(i.e.,“Compactability”)onthex-axisagainstejectionstress(i.e.,“Manufacturability”)onthey-axistoallowvisualevaluationofthequantitative“Tabletingproperties”offormulations.Thismethodmakesitpossibletoreachanoptimumtabletformu-lationquickly.Wedemonstratedtheusefulnessofthemethodbyusinglosartanpotassiumasanactivepharmaceuticalin-gredient,microcrystallinecelluloseasanexcipient,andmagnesiumstearate(MgSt)asalubricantinamodelformu-lation.Weconrmedquantitativelythatthemicrocrystallinecelluloseincreasedthe“Compactability”,andthattheamountofMgStandmixingtimeaffectedboth“Compactability”and“Manufacturability”.Commercialdrugproductionusesrotarytabletingma-chineswithmuchmoredynamictabletingconditionsthantheGTP-1.Wethereforeneedtodeterminetherelationshipbetweentheresultsobtainedwitheachapparatus.Pittetal.reportedthat“Compactability”determinedbytheGTP-1agreedwiththatproducedbyanindustrialtabletingmachine(Fette;FetteCom-pacting,Germany)11.TheyfoundthatmeasurementoftheejectionstressusingtheGTP-1wasusefulinpredictingtheoccurrenceofcappingduringcommercial-scaletabletingoffor-mulationswithdifferentlevelsofmicrocrystallinecellulose.Ingeneral,tabletingfailuresarestronglyaffectedbytheamountoflubricantintheformulationandtheshapeofthetablet(i.e.,thepunchshape).Alackoflubricantlowers“Manufacturability”andleadstotabletingfailure12,13.Ontheotherhand,toomuchlubricantreduces“Compactability”andthustabletstrength14.Inaddition,somepunchshapesaremorepronetotabletingfailure,notablypunchesthathavesecantlines,em-bossedmarks,andlargecurvesontheirsurfaces15,16.Whenthesetypesofpunchesareused,morelubricantisneededintheformulationtopreventtabletingfailure.Whenpredicting“Tabletingproperties”attheproductionscalebyusingtheGTP-1,both“Compactability”and“Manufacturability”needtobesatisfactory,andtheshapeofthepunchmustbechosentominimizetabletingfailure.Here,wepreparedfourformulationswithdifferentamountsoflubricant.Wemeasuredthe“Compactability”and2.2.1.SamplepreparationTabletswiththeformulationslistedinTable1werepreparedbydirectcompression.Inallcasesthequantitywas450g,whichisenoughtomake3000tabletsof150mgeachatthemanu-facturingscale.LP,DilactoseR,MCC,andStarch1500weremixedinaplasticbagandsievedthrougha12-meshsieve.Thesievedpowderwasmixedfor10minat10rpminarotarymixer(CB1-5/10;10L;PicksTechnica,Japan).MgStwasaddedtothemixtureat0,0.5,1,or3mgpertablet(Table1)andthensamplesB(MgSt0.5),C(MgSt1),andD(MgSt3)weremixedforafurther60min.2.2.2.EvaluationofformulationsontheGTP-1TheGTP-1measurestheupperpunchpressureanddisplace-mentduringcompression,theejectionforce(thefrictionbetweenthediewallandthetabletduringejection),andthestrengthofthetablet(TFS)afterejection.Tomakeatablet,100mgofpowderisplacedinthedieoftheGTP-1andcom-pressedat4.9kNbytheupperpunch(aatpunch6mmindiameter)ataxed30mm/min.Allformulationswerepressedandmeasuredthreetimes.Themethodsofcalculationandplot-tingaredescribedinourpreviousreport.EvaluationofformulationsontherotarytabletingmachineFourtypesofformulation(AtoD,Table1)withvariousamountsoflubricantwerecompressedonarotarytabletingmachine(Virgo-512,KikusuiSeisakusho,Japan).About600tablets(150mgeach,90gtotal)werecontinuouslycompressedataround6.0kNand30rpm.Fourdifferenttypesofpunchwereused:Type1,atpunchwithasecantline;Type2,convexcuppunch(Rmajorcupradius=11mm);Type3,compoundcuppunch(R=9mm,rminorcupradius=3mm);andType4,convexcuppunchwithasecantlineandembossedmarks(R=9)mm(7.5mmeach;Fig.1).Thecupradiuswastakenasasinglearcgeneratedfromthetabletscenterline(midpoint)acrossthetabletsdiameter,minoraxis,ormajoraxis.InTypes2and4,Table1Formulations.“Manufacturability”oftheseformulationswiththeGTP-1,plottedtheresults,andcomparedthemwiththeresultsofproduction-scaletableting.Wealsocompared“Tabletingprop-erties”usingpunchesofvariousshapes.Theaimofthisstudywastoexaminetheusefulnessofmeasuring“Tabletingprop-erties”withtheGTP-1forthedevelopmentofformulationsincommercialdrugproduction.SampleLosartanpotassium(LP)(mg)DilactoseR(mg)CeolusPH302(MCC)(mg)Starch1500(mg)Magnesiumstearate(MgSt)(mg)TotalA502659150150B5025.559150.5150C502559151150D502359153150414asianjournalofpharmaceuticalsciences12(2017)412417UpperpunchLowerpunchUpperpunchLowerpunchType1:flatpunchwithsecantlineType2:convexcuppunch(R=11)UpperpunchLowerpunchUpperpunchLowerpunchType3:compoundcuppunch(R=9,r=3)Type4:convexcuppunchwithsecantlineandembossedmarks(R=9)Fig.1Fourtypesofpunchestested.theconvexcuppuncheshadasingleradius,whereasinType3,theconvexcuppunchhadtworadii.Thesurfaceofeverytabletwasvisuallyinspected.Tabletingwasterminatedwhenfailureoccurred.Tablethardnesswasmeasuredvetimeswithahardnesstester(PortableCheckerPC-30,OkadaSeiko,Japan).placementofsamplesBandCinrange(I)indicatednoprob-lemswith“Compactability”or“Manufacturability”.Incontrast,theplacementofsampleAinrange(III)indicatedproblemswith“Manufacturability”(stickingandbinding);andtheplace-mentofsampleDinrange(II)indicatedpotentiallylowtablethardness.Optimizationofformulationssothatthedatafallinrange(I)willachievedurablephysicalpropertiesduring3.Resultsanddiscussiondistributionanduse17,18.3.1.“Tabletingproperties”ofmodelformulationswithdifferentamountsoflubricantOurmethodforvisuallyassessing“Tabletingproperties”plotsTFS(hardness)onthex-axisandejectionstress(“Manufacturability”)onthey-axis10.Thegraphisdividedintofourranges(Fig.2).Ifapointisplottedinrange(I)(lowerright),theformulationhassuperior“Compactability”and“Manufacturability”.Conversely,ifapointisplottedin3.2.Comparisonof“tabletingproperties”predictedbyusingeachapparatusWetestedtheabilityofthemethoddescribedinsection3.1topredicttheresultsoftabletingonacommercialrotary“Manufacturability”10Ejectionstress(MPa)range(IV)(upperleft),thetabletissoftanddiewallfrictionishigh,indicatingproblemswithboth“Compactability”and“Manufacturability”.Fourtypesofformulation(samplesAtoDinTable1)withIVA(MgSt0)differentlevelsoflubricantwereprepared,andthencom-pressedbyusingtheGTP-1(Table2).SampleA(MgSt0)had“Compactability”TFS(MPa)good“Compactability”(TFS2MPa),butbad“Manufacturability”(ejectionstress5MPa),andsowasplottedinrange(III).0152345SamplesBandC,withincreasingamountsofMgSt,wereplottedinrange(I),indicatingmuchbetter“Manufacturability”.Sampleswithinsufcientlubricant,whichlowers“Manufacturability”,areplottedinrange(III)or(IV)12,13.SampleD(MgSt3)hadreduced“Compactability”(TFS=1.83MPa),butgood“Manufacturability”(ejectionIIB(MgSt0.5)C(MgSt1)D(MgSt3)Istress=1.01MPa),andwasplottedinrange(II).Toomuchlu-bricantdecreases“Compactability”andthustablethardness(ShahandMlodozeniec,1977).Thiscorrespondstoplottinginrange(II)or(IV).Ourmethodmakesitpossibletovisualizetheeffectsoflubricantquantityon“Tabletingproperties”.The0Fig.2“Tabletingproperties”offourformulationsevaluatedbyusingthebenchtopsingle-punchtabletpress(means,n=3).asianjournalofpharmaceuticalsciences12(2017)412417415Table2“Tabletingproperties”ofmodelformulationswithdifferentamountsoflubricantevaluatedwiththebenchtopsingle-punchtabletpress.SampleA(MgSt0)B(MgSt0.5)C(MgSt1)D(MgSt3)“Compactability”:TFS(MPa)2.880.102.660.162.270.071.830.04“Manufacturability”:ejectionstress(MPa)8.210.783.250.771.540.001.010.09“Compressibility”:elasticrecovery(%)32.970.5635.031.0336.640.2638.780.38PlotrangeIIIIIIItabletingmachineusingaType1punch(atpunchwithasecantline;Fig.3A).SamplesB(MgSt0.5),C(MgSt1),andD(MgSt3)weretabletedwithoutanyproblems.SampleA(MgSt0)leftmaterialsstucktothesurfaceofthepunch(Fig.3B),whichinterferedwiththetabletingprocessafter130to140presses(Fig.3;Table3).ThisresultwasconsistentwiththeplottingofsampleAinrange(III)insection3.1.ThepredictionforsampleD(MgSt3)placeditinrange(II),indicatingpoor“Compactability”,becausetablethardnessdecreasesastheamountoflubricantisincreased.Aspredicted,thetablet(A)InitialhardnessofsampleDwaslowerthanthoseofsamplesA,B,andC(Table4,Type1).3.3.Evaluationof“tabletingproperties”ontherotaryUpperpunchLowerpunchtabletingmachinewithvariouspunches(B)After130140pressesTheresultsinsection3.2agreedwiththoseinsection3.1whenaatpunchwithasecantlinewasused.Wealsotesteddif-ferentpuncheswithcurvedsurfaces(withdifferentcurvatures),secantlines,andembossedmarks(Fig.1).WhenaType3com-poundcuppunchwasused,theparticlesatthecenterofthetabletdidnotdeformasmuchasthoseattheperiphery(Fig.4).UpperpunchLowerpunchThisdifferenceindicatesthatuseofacompoundcuppunchmaymakeitdifculttocompresstabletsevenlyacrosstheFig.3Stickingofpowdertoatpunchsurfaces(Type1).(A)Beforetableting;(B)after130to140presses.SampleA(50%activepharmaceuticalingredient,50%excipients,nomagnesiumstearate).surface.Ontheotherhand,theuseofaatpunchisnotpronetostickingonthepunchsurfaces.Therefore,puncheswithasuitableshapehavetobechosencarefully,dependingonthepowderformulation.Table3NumbersoftabletssuccessfullyproducedwithpunchesofeachtypeinGTP-1.SampleA(MgSt0)B(MgSt0.5)C(MgSt1)D(MgSt3)PlotrangeIIIIIII“Manufacturability”BadGoodGoodGoodType1130140600a600a600aType2165175600a600a600aType3515515105115600aType4203095105600a600aType1:atpunchwithasecantline;Type2:convexcuppunch(R=11);Type3:compoundcuppunch(R=9,r=3);Type4:convexcuppunchwithasecantlineandembossedmarks(R=9).aThetabletsweremanufacturedwithoutanyfailureusingthetotalamountofformulatedpowders.Table4Hardness(N)oftabletsmanufacturedonarotarytabletingmachine.SampleA(MgSt0)B(MgSt0.5)C(MgSt1)D(MgSt3)PlotrangeIIIIIII“Compactability”GoodGoodGoodBadType161.02.353.23.349.24.734.61.8Type254.25.444.42.942.64.329.81.6Type342.02.6a35.82.0a35.62.528.00.7Type451.44.8a39.026.81.3Type1:atpunchwithasecantline;Type2:convexcuppunch(R=11);Type3:compoundcuppunch(R=9,r=3);Type4:convexcuppunchwithasecantlineandembossedmarks(R=9).aTabletscouldnotbeformedwiththeseformulations.Therefore,thesurfaceofthepuncheswaslubricatedwithmagnesiumstearateandtabletingwasperformedagain.416asianjournalofpharmaceuticalsciences12(2017)412417Fig.4Electronmicrographsofatabletcompressedwithacompoundcuppunch.WhentheType2convexcuppunch(R=11)wasused,samplesB(MgSt0.5),C(MgSt1),andD(MgSt3)weretabletedwithoutanyfailures(Table3).However,afteronly165to175tabletswerecompressed,tabletsofsampleA(MgSt0)wouldnotseparatefromthesurfaceofthepunchandwerecaughtonthescraperandbrokeapart.Thesurfaceofthepunchwascoveredwithpowder.ThisresultcorrespondedwiththeplottingofsampleAinrange(III)(Fig.2),indicatingpoor“Manufacturability”.WhentheType3compoundcuppunch(R=9,r=3)wasused,sampleD(MgSt3)wastabletedwithoutanyfailures(Table3).Incontrast,sampleA(MgSt0)adheredtothepunchimme-diately,andthecupbegantollwithpowder.SampleB(MgSt0.5)coveredthesurfaceofthepunchassoonascompressionbegan:only5to15tabletswerepressedbeforethetabletsbecamedifculttoseparatefromthepunchandbrokeapart.SampleC(MgSt1)begantoadheretothecenterofthecupafter105to115tabletshadbeenpressed,andadimple-likeindentationappearedinthecenterofthetablet.Ejectionstress(onthey-axis),whichwasassociatedwiththeoccurrenceoftabletingfailure,increasedintheorderofsamplesDCBA.Therefore,theresultsobtainedwiththeGTP-1correctlypre-dictedthetabletingsuccessontherotarypress.Manytabletshavebothsecantlinesandembossedmarks.PunchessuchasType4,withacomplexsurfaceshape,areoftenusedincommercialtabletproduction.Whensuchpunchesareused,tabletingfailures,suchassticking,tendtooccuraroundsecantlinesandembossedmarks.WhentheType4punchwasused,samplesC(MgSt1)andD(MgSt3)weretabletedwithoutanyproblems(Table3).Incontrast,sampleB(MgSt0.5)coveredthesurfaceofthepunchafter95to105tabletswerepressed,andbecamedifculttoseparatefromthepunchandbrokeapart.SampleC(MgSt1)didnotstick,butbothBandCwereplottedinrange(I)(Table3).TheGTP-1experimentcorrectlypredictedtheincreasedpossibilityoffailurebythedistancebetweensamplesBandCintheplot.SampleA(MgSt0)lledthecupsofallpunches(Fig.5),forcingustostopthecom-pression.Nevertheless,thenumberoftabletssuccessfullycompressedbeforesticking(Table3)wasassociatedwiththedegreeofejectionstress,conrmingtheplacementofsampleAinrange(III)(Fig.2).Wemeasuredthehardnessoftabletsmanufacturedontherotarytabletingmachinewitheachtypeofpunch(Table4).WecouldnotpresssampleA(MgSt0)intheTypes3and4punches,orsampleB(MgSt0.5)intheType3punch,becauseofseverestickingduringcompression,sowecoatedthepunchsur-faceswithMgStbyhandandthenpressedthesamples.Theeffectsoflubricantcontentontablet“Compactability”intheGTP-1(Table2)paralleledtheeffectsontablethardnessintherotarytabletingmachine(Table4).SampleD(MgSt3)wasplottedinrange(II)(Fig.2).AlthoughsampleDavoidedtabletingfailureinallpunches,itshardnesswasthelowestofall.SampleA(MgSt0),whichplottedinrange(III),producedtabletingfailureinallpunches,butitshardnesswasthehighestofall.Thesedifferencesindicatethatindesigningaformulation,itisnec-essarytocomprehensivelyevaluateboth“Compactability”and“Manufacturability”.asianjournalofpharmaceuticalsciences12(2017)412417417A(MgSt0mg)after2030pressesB(MgSt0.5mg)after95105pressesC(MgSt1mg)aftercompressionofallpowderD(MgSt3mg)aftercompressionofallpowder4.ConclusionFig.5Stickingofpowdertoconvexpunchsurfaces(Type4,R=9).itseffectontabletstrength.JPharmSci1977;66:155159.6TesfaiS,GoranA.RelationshipsbetweentheeffectiveForallpunchshapes,thepropertiesoftabletspressedontheGTP-1reectedtheresultsoftabletingonarotarymachine.SampleA,plottedinrange(III)(poor“Manufacturability”),re-sultedintabletingfailure(sticking)atthemanufacturingscale.SampleD,plottedinrange(II)(good“Manufacturability”)wascompressedwithouttabletingfailureontherotarymachine.Powdersplottedinrange(II)(poor“Compactability”)wereweakest.AlthoughsamplesBandCwerebothplottedinrange(I)(idealconditions),sampleCspositionindicatedbetter“Manufacturability”.Withcomplexpunchshapes(Types3and4),aspredicted,sampleCgavebetter“Manufacturability”andhadlesstabletingfailureontherotarymachinethansampleB.Ourevaluationmethodreliablypredictedboththe“Manufacturability”and“Compactability”oftabletspreparedonarotarytabletingmachine,conrmingitscapacitytoevalu-ateformulationsthatavoidtabletingfailurewithanypunchshape,usingonlysmallsampleamounts.ConictsofinterestTheauthorsdeclarethatthereisnoconictsofinterest.REFERENCES1KawakitaK,LuddeK-H.Someconsiderationsonpowdercompressionequations.PowderTechnol1969;11:6168.2HeckelRW.Densitypressurerelationshipsinpowdercompaction.TransMetallSocAIME1961;221:671675.3HeckelRW.Ananalysisofpowdercompactionphenomena.TransMetallSocAIME1961;221:10011008.4KlevanI,NordstromJ,ThoI,etal.Astatisticalapproachtoevaluatethepotentialcompressionparametersforclassicationofpharmaceuticalpowdermaterials.EurJPharmBiopharm2010;75:425435.5DavidST,AugsburgerLL.Plasticowduringcompressionofdirectlycompressiblellersand789101112131415161718interparticulatecontactareaandthetensilestrengthoftabletsofamorphousandcrystallinelactoseofvaryingparticlesize.EurJPharmSci1999;8:235242.SugimoriK,MoriS,KawashimaY.Introductionofanewindexforthepredictionofcappingtendencyoftablets.ChemPharmBull1989;37:458462.UrabeM,ItoS,ItaiS,etal.Assessmentoftabletingpropertiesusinginnitesimalquantitiesofpowderedmedicine.IntJPharm2003;263:183187.UrabeM,ItoS,ItaiS,etal.AssessmentoftabletingpropertiesusinginnitesimalquantitiesofpowderedmedicineII.JDrugDelivSciTechnol2006;16:357361.OsamuraT,TakeuchiY,OnoderaR,etal.Characterizationoftabletingpropertiesmeasuredwithamulti-functionalcompactioninstrumentforseveralpharmaceuticalexcipientsandactualtabletformulations.IntJPharm2016;510:195202.PittKG,WebberRJ,HillKA,etal.Compressionpredictionaccuracyfromsmallscalecompactionstudiestoproductionpresses.PowderTechnol2015;270:490493.KikutaJ,KitamoriN.Frictionalpropertiesoftabletlubricants.DrugDevIndPharm1985;11:845854.DelacourteA,GuyotJC,ColomboP,etal.Effectivenessoflubricantsandlubricationmechanismintablettechnology.DrugDevIndPharm1995;21:21872199.ShahAC,MlodozeniecAR.Mechanismofsurfacelubrication:inuenceofdurationoflubricant-excipientmixingonprocessingcharacteristicsofpowdersandpropertiesofcompressedtablets.JPharmSci1977;10:13771382.EiliazadehB,PittK,BriscoeB.Effectsofpunchgeometryonpowdermovementduringpharmaceuticaltabletingprocesses.IntJSolidsStruct2004;41:59675977.RobertsM,FordJM,MacleodGS,etal.Effectofpunchtipgeometryandembossmentonthepunchtipadherenceofamodelibuprofenformulation.JPharmPharmacol2004;56:947950.CaiL,FarberL,ZhangD,etal.Anewmethodologyforhighdrugloadingwetgranulationformulationdevelopment.IntJPharm2013;441:790800.SohJLP,GrachetM,WhitlockM,etal.Characterization,optimizationandprocessrobustnessofaco-processedmannitolforthedevelopmentoforallydisintegratingtablets.PharmDevTechnol2013;18:172185.原始研究论文采用多功能单冲孔压片机预测冲孔形状对平板失效的影响。Takashi Osamura a,b, Yoshiko Takeuchi a, Risako Onodera a, Masahiro Kitamura b, Yoshiteru Takahashi b, Kohei Tahara a, Hirofumi Takeuchi。日本制药工业大学制药工程实验室1-25-4号，Gifu 501-1196，日本b制药技术部，Sawai药业股份有限公司，12-34,Hiroshibacho, Suita-Shi，大阪564-0052，日本。R T I C L E I N F O。文章历史:2017年4月11日收到接受了2017年5月42017年5月17日上线。2017年由爱思唯尔公司代表沈阳药学院生产和托管。这是一个在CC BY-NC-ND许可下的开放访问文章。文摘我们之前通过使用多功能单冲孔压片机(GTP-1)来确定“Tableting属性”。我们建议在x轴上绘制“紧实性”，以“可制造性”在y轴上，以允许视觉评价“Tableting属性”。在商业药物生产中出现了各种类型的平板失效，并受到使用的润滑剂数量和冲孔形状的影响。我们使用GTP-1来测量不同数量的润滑剂的“Tableting属性”，并将结果与在商用旋转平板电脑上的结果进行比较。平板电脑以一种“可制造性”的小缺陷被压缩，导致了粘性物质的产生。我们的系统预测了润滑剂数量对平板电脑配方的影响，以及粘在旋转平板电脑上的发生。关键词: 制锭；配方设计；润滑剂；穿孔形状；单冲压片机；洛沙坦钾1.介绍在开发一种片剂配方时，有必要了解“平板的特性”，并确定最佳的种类、等级和配料量。“压缩性”是指在测量床体密度时，将压力加载到粉末床上。制定的属性用Kawakita和Ludde1、Heckel2、3和Klevan等4的方程对粉体进行了研究。这些方程中的一些常数常被用作“压缩性”的指标。“压实性”是通过测量片剂的拉伸断裂应力(TFS)作为压实压力的函数5,6。“可制造性”涉及到表的失败(例如，粘贴、封盖和绑定)。Sugimori等人提出，可以从残余的模壁压力7中预测上限。Urabe等人提出了一种用微量粉体样品的微粉特性来估计一般型和失败型的可能性。结合这些单独的测试，Gamlen平板压机(GTP-1;一种台式单孔压片机，在压缩过程中测量压力和位移，在弹射过程中模具和平板之间的摩擦(弹射应力)，以及在单个设备中平板的强度。在我们之前的研究中，我们建议使用TFS作为“可压性”和弹射应力作为“可制造性”的指标，因为当平板被从模具中弹射出来时，模壁摩擦可能会产生问题10。我们用GTP-1评估了“可压缩性”、“可压缩性”和“可制造性”，并绘制了TFS(即:“压紧性”)在x轴上与弹射应力(即“可制造性”)在y轴上，允许对配方的定量“Tableting特性”进行视觉评价。这种方法可以快速达到最佳的片剂配方。我们用losartan钾作为一种活性药物成分，微晶纤维素为辅料，并将硬脂酸镁(MgSt)作为模型配方中的润滑剂，证明了该方法的有效性。我们定量地确认微晶纤维素增加了“压实性”，而MgSt和混合时间的量同时影响了“紧致性”和“可制造性”。商业药品生产使用的是旋转的平板电脑，它具有比GTP-1更动态的tableting条件。在每一种装置所得到的结果之间，我们有确定的关系。皮特等人报道称，“紧致性”是由一种工业用平板电脑产生的。Fette压实、德国)11。他们发现，利用GTP-1测定弹射应力，在预测不同水平的微晶纤维素配方的商业规模时，可以很好地预测出上限的发生。在配方和片剂的形状上，都有大量的润滑剂。thepunchshape)。alackoflubricant降低了“可制造性”，导致了tableting失败12,13。另一方面，过多的润滑剂会降低“紧致性”，从而降低了平板的强度14。此外，一些冲孔形状更容易出现在平板上的失败，尤其是那些有割线、凸纹和表面上的大曲线的冲孔15,16。当使用这些类型的冲孔时，在配方中需要更多的润滑剂以防止表的失败。当使用GTP-1预测生产规模的“Tableting properties”时，“可压缩性”和“可制造性”都需要令人满意，因此必须选择punch的形状，以尽量减少Tableting的失败。在这里，我们准备了四种不同数量润滑剂的配方。我们用GTP-1测量了这些配方的“紧致性”和“可制造性”，并将其与生产规模表的结果进行了比较。我们还用各种形状的冲孔来比较“Tableting properties”。本研究的目的是研究用GTP-1测量“Tableting属性”在商业药物生产中的应用的有效性。2 材料和方法2.1 材料我们购买了粒状乳糖(二乳糖R;日本Freund Corporation，微晶纤维素(MCC: Ceolus PH302, Asahi Kasei化学品，日本)，部分预糊化淀粉(淀粉1500;日本卡乐康(日本)，硬脂酸镁(MgSt;泰和化学，日本)，和洛沙坦钾(LP;Kolon、韩国)。2.2 方法2.2.1 样品制备表1所列配方的片剂是直接压缩的。该产品的数量为450g，足以在生产规模上生产3000片每片150毫克。LP,DilactoseR,MCC，和starch1500weremixed在一个塑料袋，通过一个12目筛网筛。在旋转搅拌机(CB15/10;10L;PicksTechnica，日本)10分钟内，将筛子粉混合10分钟。MgStwasaddedtothemixture在0,0.5,1，或3 mg /片(表1)，然后样本B (MgSt 0.5)，C (MgSt 1)， D (MgSt 3)混合，再进一步60分钟。2.2.2。GTP-1对GTP-1的计算公式GTP-1测量在压缩时的上冲孔压力和位移，弹射力(在弹射过程中，模壁与平板之间的摩擦)，以及弹射后的平板(TFS)的强度。为了制造出一种药片，100毫克的粉末被放置在GTP-1的模具中，并在一个固定的30毫米/分钟内被上冲孔(直径为6毫米的扁穿孔)压缩到4.9 kN。所有的公式都被压缩和测量了三次。在我们之前的报告10中描述了它的计算和绘图。2.2.3。在旋转的平板电脑上用旋转的平板电脑(Virgo-512,KikusuiSeisakusho,Japan)压缩了不同数量的润滑剂，对其配方进行了评估。大约600片(每台150毫克，90克)持续压缩在6.0 kN和30 rpm。使用四种不同类型的冲床:1型，平冲头，割线;2型，凸杯冲头(R主要杯半径= 11 mm); 3型，复合杯冲头(R = 9 mm, R小杯半径= 3 mm);和4型、凸杯穿孔割线和压花标志(R = 9)毫米(7.5毫米;如图1所示，杯子的半径是由平板的中心线(中点)在平板的直径、小轴或主轴上产生的一个弧。在类型2和4中，凸杯冲孔有一个单一半径，而inType 3，凸杯冲头有两个半径。每一款平板电脑的表面都经过了视觉检查。当失败发生时，Tableting被终止。用硬度计(便携式检查器PC-30，日本Okada Seiko)测量了五次平板硬度。图1 -四种类型的冲孔测试3所示结果与讨论3.1。用不同数量的润滑剂进行模型配方的“Tableting properties”我们的视觉评估“Tableting properties”的方法是在y轴10上绘制x轴和弹射应力(“可制造性”)。图被划分为4个范围(图2)。如果一个点在range (I)(右下方)绘制，则该公式具有优越的“紧性”和“可制造性”。相反，如果一个点在range (IV)(上左)绘制，平板是软的，而死壁摩擦是高的，表明存在“紧性”和“可制造性”的问题。四种配方(样表1 D)与不同级别的润滑剂做好准备,然后压缩使用GTP-1(表2),样品(MgSt 0)有很好的“压实性”(TFS2 MPa),butbad“制造”(喷射压力5 MPa),所以在范围(3)策划,SamplesBandC withincreasingamountsofMgSt,wereplottedinrange(我),indicatingmuchbetter“制造”。润滑不足的样品，降低了“可制造性”，绘制在范围(III)或(IV)12,13。样品D (MgSt 3)降低了“压紧性”(TFS = 1.83 MPa)，但良好的“可制造性”(ejection stress = 1.01 MPa)，并在range (II)中绘制。过多的润滑剂降低了“压紧性”，从而降低了片剂的硬度(Shah和Mlodozeniec,1977)。这对应于范围(II)或(IV)的绘图。我们的方法可以想象润滑剂数量对“平板性能”的影响。的样品B和C在范围(I)的位置表明没有“可压性”或“可制造性”的问题。与此相反，样本A在范围(III)的位置显示出了“可制造性”(stickingandbinding)的问题;而样本D在range (II)中的放置表明了潜在的低片剂硬度。优化公式，使数据在范围内(I)在分配和使用过程中实现耐用的物理特性17,18。3.2 使用各装置预测的“平板性能”的比较。我们测试了第3.1节中所述方法的能力，以预测一种商用旋转平板电脑上的tableting的结果，使用一种1型冲头(用割线冲头;图3 a)。样品B (MgSt 0.5)、C (MgSt 1)和D (MgSt 3)无任何问题。(图3b)，在130 - 140压机(图3)后，干扰了平板的制作过程(图3)。表3).这一结果与第3.1节中样本A在范围(III)中的标绘一致。对样品D (MgSt 3)的预测将其放置在range (II)中，表明“压紧性”较差，因为随着润滑油用量的增加，片剂硬度降低。如预测，D试样的片剂硬度低于A、B、C样品(表4、1型)。图2 - 4个公式的“Tableting属性”图3 -将粉末粘贴到平冲孔表面(1型)。3.3。用各种冲头对旋转平板电脑上的“压片特性”进行评价。第3.2节的结果与第3.1节的结果一致，当使用割线时使用割线。此外，我们还测试了不同的弯曲面(有不同的曲率)、割线和浮雕的痕迹(图1)。当使用非典型3复合杯冲头时，平板中心的颗粒不像周围的颗粒那样变形(图4)。这种差异表明，使用复合杯冲头可能会使压片在表面上均匀地压缩。另一方面，平冲头的使用不容易粘在冲孔表面上。因此，根据粉末配方，选择合适形状的冲孔必须小心选择。图4 -用复合杯冲压机压缩的平板电脑的电子显微图当使用type2convexcuppunch (R=11)时，样本B (MgSt 0.5)、C (MgSt 1)和D (MgSt 3
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