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【溫馨提示】壓縮包內(nèi)含CAD圖有下方大圖片預(yù)覽，下拉即可直觀呈現(xiàn)眼前查看、盡收眼底縱觀。打包內(nèi)容里dwg后綴的文件為CAD圖，可編輯，無(wú)水印，高清圖，壓縮包內(nèi)文檔可直接點(diǎn)開(kāi)預(yù)覽，需要原稿請(qǐng)自助充值下載，所見(jiàn)才能所得，請(qǐng)見(jiàn)壓縮包內(nèi)的文件及下方預(yù)覽，請(qǐng)細(xì)心查看有疑問(wèn)可以咨詢QQ：11970985或197216396 畢業(yè)設(shè)計(jì)（論文）外文翻譯學(xué)生姓名班 級(jí)學(xué) 號(hào)學(xué)院名稱專業(yè)名稱指導(dǎo)教師 年5月26日asianjournalofpharmaceuticalsciences12(2017)412417Availableonlineatwww.sciencedirect.comScienceDirectjournalhomepage:www.elsevier.com/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:/creativecommons.org/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).Sugimorietal.proposedthatcappingcouldbepredictedfrom*Correspondingauthor.GifuPharmaceuticalUniversity,1-25-4Daigaku-nishi,Gifu501-1196,Japan.Tel.:+81582308100.E-mailaddress:takeuchigifu-pu.ac.jp(H.Takeuchi).PeerreviewunderresponsibilityofShenyangPharmaceuticalUniversity.http:/dx.doi.org/10.1016/j.ajps.2017.05.0011818-0876/2017ProductionandhostingbyElsevierB.V.onbehalfofShenyangPharmaceuticalUniversity.ThisisanopenaccessarticleundertheCCBY-NC-NDlicense(http:/creativecommons.org/licenses/by-nc-nd/4.0/).asianjournalofpharmaceuticalsciences12(2017)412417413residualdiewallpressure7.Urabeetal.suggestedthates-timationofgeneraltabletingpropertiesandfailureswaspossiblebyusingamicro-powdercharacterizerwithinnitesimalquan-titiesofpowdersample8,9.2.2.1.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-tingaredescribedinourpreviousreport10.2.2.3.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”GoodGoodGoodBadType161.02.353.23.349.24.734.61.8Type254.25.444.42.942.64.329.81.6Type342.02.6a35.82.0a35.62.528.00.7Type451.44.8a39.02.235.81.926.81.3Type1: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-pre