采用多功能單沖孔壓片機預(yù)測沖孔形狀對平板失效的影響外文文獻翻譯、中英文翻譯
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asianjournalofpharmaceuticalsciences12(2017)412–417 Availableonlineatwww.sciencedirect.com ScienceDirect journalhomepage:www.elsevier.com/locate/ajps OriginalResearchPaper Predictionofeffectsofpunchshapeson tabletingfailurebyusingamulti-functional single-punchtabletpress TakashiOsamuraa,b,YoshikoTakeuchia,RisakoOnoderaa,MasahiroKitamurab, YoshiteruTakahashib,KoheiTaharaa,HirofumiTakeuchia,* a b LaboratoryofPharmaceuticalEngineering,GifuPharmaceuticalUniversity,1-25-4Daigaku-Nishi,Gifu501-1196,Japan PharmaceuticalTechnologyDepartment,SawaiPharmaceuticalCo.Ltd,12-34,Hiroshibacho,Suita-Shi,Osaka564-0052,Japan ARTICLE INFO ABSTRACT Articlehistory: Received11April2017 Accepted4May2017 Availableonline17May2017 Keywords: Tableting Formulationdesign Lubricant Punchshape Single-punchtabletpress Losartanpotassium Wepreviouslydetermined“Tabletingproperties”byusingamulti-functionalsingle-punch tabletpress(GTP-1).Weproposedplotting“Compactability”onthex-axisagainst “Manufacturability”onthey-axistoallowvisualevaluationof“Tabletingproperties”.Various typesoftabletingfailureoccurincommercialdrugproductionandarein?uencedbythe amountoflubricantusedandtheshapeofthepunch.WeusedtheGTP-1tomeasure “Tabletingproperties”withdifferentamountsoflubricantandcomparedtheresultswith thoseoftabletingonacommercialrotarytabletingmachine.Tabletscompressedwithasmall amountoflubricantshowedbad“Manufacturability”,leadingtostickingofpowderonpunches. Wealsotestedvariouspunchshapes.TheGTP-1correctlypredictedtheactualtabletingresults forallpunchshapes.Withpunchesthatweremorelikelytocausetabletingfailure,oursystem predictedtheeffectsoflubricantquantityinthetabletformulationandtheoccurrenceof stickingintherotarytabletingmachine. 2017ProductionandhostingbyElsevierB.V.onbehalfofShenyangPharmaceutical University.ThisisanopenaccessarticleundertheCCBY-NC-NDlicense(http:// creativecommons.org/licenses/by-nc-nd/4.0/). 1. Introduction powdershavebeeninvestigatedbyusingtheequationsof KawakitaandLudde[1],Heckel[2,3],andKlevanetal.[4].Some constantsintheseequationsarefrequentlyusedasindica- Indevelopingatabletformulation,itisnecessarytounder- stand“Tabletingproperties”andtodeterminetheoptimum type,grade,andamountofingredients.“Compressibility”is evaluatedbyloadingpressureontoapowderbedwhilemea- suringthebulkdensityofthebed.Thepropertiesofformulated torsof“Compressibility”.“Compactability”istypicallyevaluated bymeasuringthetensilefracturestress(TFS)oftabletsasa functionofcompactionpressure[5,6].“Manufacturability”con- cernstabletingfailure(e.g.,sticking,capping,andbinding). Sugimorietal.proposedthatcappingcouldbepredictedfrom *Correspondingauthor.GifuPharmaceuticalUniversity,1-25-4Daigaku-nishi,Gifu501-1196,Japan.Tel.:+81582308100. E-mailaddress:takeuchi@gifu-pu.ac.jp(H.Takeuchi). PeerreviewunderresponsibilityofShenyangPharmaceuticalUniversity. http://dx.doi.org/10.1016/j.ajps.2017.05.001 1818-0876/2017ProductionandhostingbyElsevierB.V.onbehalfofShenyangPharmaceuticalUniversity.Thisisanopenaccess articleundertheCCBY-NC-NDlicense(http://creativecommons.org/licenses/by-nc-nd/4.0/). asianjournalofpharmaceuticalsciences12(2017)412–417 413 residualdiewallpressure[7].Urabeetal.suggestedthates- timationofgeneraltabletingpropertiesandfailureswaspossible byusingamicro-powdercharacterizerwithin?nitesimalquan- titiesofpowdersample[8,9]. 2. 2.1. Materialsandmethods Materials Combiningtheseseparatetests,theGamlenTabletPress (GTP-1;GamlenTabletingLtd.,Nottingham,UK),abenchtop single-punchtabletpress,measurespressureanddisplace- mentduringcompression,thefrictionbetweendieandtablet duringejection(ejectionstress),andthestrengthofthetablet (TFS)inasingledevice.Inourpreviousstudy,wesuggested theuseofTFSasanindicatorof“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”,asdiewall frictioncanbeproblematicwhenthetabletisejectedfrom 2.2. Methods thedie[10].Weevaluated“Compressibility”,“Compactability”, and“Manufacturability”withaGTP-1andplottedTFS(i.e., “Compactability”)onthex-axisagainstejectionstress(i.e., “Manufacturability”)onthey-axistoallowvisualevaluation ofthequantitative“Tabletingproperties”offormulations.This methodmakesitpossibletoreachanoptimumtabletformu- lationquickly.Wedemonstratedtheusefulnessofthemethod byusinglosartanpotassiumasanactivepharmaceuticalin- gredient,microcrystallinecelluloseasanexcipient,and magnesiumstearate(MgSt)asalubricantinamodelformu- lation.Wecon?rmedquantitativelythatthemicrocrystalline celluloseincreasedthe“Compactability”,andthattheamount ofMgStandmixingtimeaffectedboth“Compactability”and “Manufacturability”. Commercialdrugproductionusesrotarytabletingma- chineswithmuchmoredynamictabletingconditionsthanthe GTP-1.Wethereforeneedtodeterminetherelationshipbetween theresultsobtainedwitheachapparatus.Pittetal.reported that“Compactability”determinedbytheGTP-1agreedwiththat producedbyanindustrialtabletingmachine(Fette;FetteCom- pacting,Germany)[11].Theyfoundthatmeasurementofthe ejectionstressusingtheGTP-1wasusefulinpredictingthe occurrenceofcappingduringcommercial-scaletabletingoffor- mulationswithdifferentlevelsofmicrocrystallinecellulose. Ingeneral,tabletingfailuresarestronglyaffectedbytheamount oflubricantintheformulationandtheshapeofthetablet(i.e., thepunchshape).Alackoflubricantlowers“Manufacturability” andleadstotabletingfailure[12,13].Ontheotherhand,too muchlubricantreduces“Compactability”andthustablet strength[14].Inaddition,somepunchshapesaremoreprone totabletingfailure,notablypunchesthathavesecantlines,em- bossedmarks,andlargecurvesontheirsurfaces[15,16].When thesetypesofpunchesareused,morelubricantisneededin theformulationtopreventtabletingfailure.Whenpredicting “Tabletingproperties”attheproductionscalebyusingthe GTP-1,both“Compactability”and“Manufacturability”needto besatisfactory,andtheshapeofthepunchmustbechosen tominimizetabletingfailure. Here,wepreparedfourformulationswithdifferent amountsoflubricant.Wemeasuredthe“Compactability”and 2.2.1. Samplepreparation TabletswiththeformulationslistedinTable1wereprepared bydirectcompression.Inallcasesthequantitywas450g,which isenoughtomake3000tabletsof150mgeachatthemanu- facturingscale.LP,DilactoseR,MCC,andStarch1500weremixed inaplasticbagandsievedthrougha12-meshsieve.Thesieved powderwasmixedfor10minat10rpminarotarymixer(CB1- 5/10;10L;PicksTechnica,Japan).MgStwasaddedtothemixture at0,0.5,1,or3mgpertablet(Table1)andthensamplesB(MgSt 0.5),C(MgSt1),andD(MgSt3)weremixedforafurther60min. 2.2.2. EvaluationofformulationsontheGTP-1 TheGTP-1measurestheupperpunchpressureanddisplace- mentduringcompression,theejectionforce(thefriction betweenthediewallandthetabletduringejection),andthe strengthofthetablet(TFS)afterejection.Tomakeatablet, 100mgofpowderisplacedinthedieoftheGTP-1andcom- pressedat4.9kNbytheupperpunch(a?atpunch6mmin diameter)ata?xed30mm/min.Allformulationswerepressed andmeasuredthreetimes.Themethodsofcalculationandplot- tingaredescribedinourpreviousreport[10]. 2.2.3. Evaluationofformulationsontherotarytableting machine Fourtypesofformulation(AtoD,Table1)withvariousamounts oflubricantwerecompressedonarotarytabletingmachine (Virgo-512,KikusuiSeisakusho,Japan).About600tablets(150mg each,90gtotal)werecontinuouslycompressedataround6.0 kNand30rpm.Fourdifferenttypesofpunchwereused: Type1,?atpunchwithasecantline;Type2,convexcuppunch (R[majorcupradius]=11mm);Type3,compoundcuppunch (R=9mm,r[minorcupradius]=3mm);andType4,convex cuppunchwithasecantlineandembossedmarks(R=9)mm (7.5mmeach;Fig.1).Thecupradiuswastakenasasingle arcgeneratedfromthetablet’scenterline(midpoint)acrossthe tablet’sdiameter,minoraxis,ormajoraxis.InTypes2and4, Table1–Formulations. “Manufacturability”oftheseformulationswiththeGTP-1, plottedtheresults,andcomparedthemwiththeresultsof production-scaletableting.Wealsocompared“Tabletingprop- erties”usingpunchesofvariousshapes.Theaimofthisstudy wastoexaminetheusefulnessofmeasuring“Tabletingprop- erties”withtheGTP-1forthedevelopmentofformulationsin commercialdrugproduction. Sample Losartanpotassium(LP)(mg) DilactoseR(mg) CeolusPH302(MCC)(mg) Starch1500(mg) Magnesiumstearate(MgSt)(mg) Total A 50 26 59 15 0 150 B 50 25.5 59 15 0.5 150 C 50 25 59 15 1 150 D 50 23 59 15 3 150 414 asianjournalofpharmaceuticalsciences12(2017)412–417 Upperpunch Lowerpunch Upperpunch Lowerpunch Type1:flatpunchwithsecantline Type2:convexcuppunch(R=11) Upperpunch Lowerpunch Upperpunch Lowerpunch Type3:compoundcuppunch(R=9,r=3) Type4:convexcuppunchwithsecantline andembossedmarks(R=9) Fig.1–Fourtypesofpunchestested. theconvexcuppuncheshadasingleradius,whereasinType 3,theconvexcuppunchhadtworadii.Thesurfaceofevery tabletwasvisuallyinspected.Tabletingwasterminatedwhen failureoccurred.Tablethardnesswasmeasured?vetimeswith ahardnesstester(PortableCheckerPC-30,OkadaSeiko,Japan). placementofsamplesBandCinrange(I)indicatednoprob- lemswith“Compactability”or“Manufacturability”.Incontrast, theplacementofsampleAinrange(III)indicatedproblems with“Manufacturability”(stickingandbinding);andtheplace- mentofsampleDinrange(II)indicatedpotentiallylowtablet hardness.Optimizationofformulationssothatthedatafall inrange(I)willachievedurablephysicalpropertiesduring 3. Resultsanddiscussion distributionanduse[17,18]. 3.1. “Tabletingproperties”ofmodelformulationswith differentamountsoflubricant Ourmethodforvisuallyassessing“Tabletingproperties” plotsTFS(hardness)onthex-axisandejectionstress (“Manufacturability”)onthey-axis[10].Thegraphisdivided intofourranges(Fig.2).Ifapointisplottedinrange(I)(lower right),theformulationhassuperior“Compactability”and “Manufacturability”.Conversely,ifapointisplottedin 3.2. Comparisonof“tabletingproperties”predictedby usingeachapparatus Wetestedtheabilityofthemethoddescribedinsection3.1 topredicttheresultsoftabletingonacommercialrotary “Manufacturability”10 Ejectionstress (MPa) range(IV)(upperleft),thetabletissoftanddiewallfriction ishigh,indicatingproblemswithboth“Compactability”and “Manufacturability”. Fourtypesofformulation(samplesAtoDinTable1)with IV A(MgSt0) differentlevelsoflubricantwereprepared,andthencom- pressedbyusingtheGTP-1(Table2).SampleA(MgSt0)had “Compactability” TFS(MPa) good“Compactability”(TFS≥2MPa),butbad“Manufacturability” (ejectionstress≥5MPa),andsowasplottedinrange(III). 0 1 5 2 3 4 5 SamplesBandC,withincreasingamountsofMgSt,wereplotted inrange(I),indicatingmuchbetter“Manufacturability”.Samples withinsuf?cientlubricant,whichlowers“Manufacturability”, areplottedinrange(III)or(IV)[12,13]. SampleD(MgSt3)hadreduced“Compactability” (TFS=1.83MPa),butgood“Manufacturability”(ejection II B(MgSt0.5) C(MgSt1) D(MgSt3) I stress=1.01MPa),andwasplottedinrange(II).Toomuchlu- bricantdecreases“Compactability”andthustablethardness (ShahandMlodozeniec,1977).Thiscorrespondstoplottingin range(II)or(IV).Ourmethodmakesitpossibletovisualizethe effectsoflubricantquantityon“Tabletingproperties”.The 0 Fig.2–“Tabletingproperties”offourformulations evaluatedbyusingthebenchtopsingle-punchtabletpress (means,n=3). asianjournalofpharmaceuticalsciences12(2017)412–417 415 Table2–“Tabletingproperties”ofmodelformulationswithdifferentamountsoflubricantevaluatedwiththebenchtop single-punchtabletpress. Sample A(MgSt0) B(MgSt0.5) C(MgSt1) D(MgSt3) “Compactability”: TFS(MPa) 2.880.10 2.660.16 2.270.07 1.830.04 “Manufacturability”: ejectionstress(MPa) 8.210.78 3.250.77 1.540.00 1.010.09 “Compressibility”: elasticrecovery(%) 32.970.56 35.031.03 36.640.26 38.780.38 Plotrange III I I II tabletingmachineusingaType1punch(?atpunchwitha secantline;Fig.3A).SamplesB(MgSt0.5),C(MgSt1),andD (MgSt3)weretabletedwithoutanyproblems.SampleA(MgSt 0)leftmaterialsstucktothesurfaceofthepunch(Fig.3B),which interferedwiththetabletingprocessafter130to140presses (Fig.3;Table3).Thisresultwasconsistentwiththeplotting ofsampleAinrange(III)insection3.1.Thepredictionfor sampleD(MgSt3)placeditinrange(II),indicatingpoor “Compactability”,becausetablethardnessdecreasesasthe amountoflubricantisincreased.Aspredicted,thetablet (A) Initial hardnessofsampleDwaslowerthanthoseofsamplesA,B, andC(Table4,Type1). 3.3. Evaluationof“tabletingproperties”ontherotary Upperpunch Lowerpunch tabletingmachinewithvariouspunches (B) After130–140presses Theresultsinsection3.2agreedwiththoseinsection3.1when a?atpunchwithasecantlinewasused.Wealsotesteddif- ferentpuncheswithcurvedsurfaces(withdifferentcurvatures), secantlines,andembossedmarks(Fig.1).WhenaType3com- poundcuppunchwasused,theparticlesatthecenterofthe tabletdidnotdeformasmuchasthoseattheperiphery(Fig.4). Upperpunch Lowerpunch Thisdifferenceindicatesthatuseofacompoundcuppunch maymakeitdif?culttocompresstabletsevenlyacrossthe Fig.3–Stickingofpowderto?atpunchsurfaces(Type1). (A)Beforetableting;(B)after130to140presses.SampleA (50%activepharmaceuticalingredient,50%excipients,no magnesiumstearate). surface.Ontheotherhand,theuseofa?atpunchisnotprone tostickingonthepunchsurfaces.Therefore,puncheswitha suitableshapehavetobechosencarefully,dependingonthe powderformulation. Table3–NumbersoftabletssuccessfullyproducedwithpunchesofeachtypeinGTP-1. Sample A(MgSt0) B(MgSt0.5) C(MgSt1) D(MgSt3) Plotrange III I I II “Manufacturability” Bad Good Good Good Type1 130–140 600a 600a 600a Type2 165–175 600a 600a 600a Type3 5–15 5–15 105–115 600a Type4 20–30 95–105 600a 600a Type1:?atpunchwithasecantline;Type2:convexcuppunch(R=11);Type3:compoundcuppunch(R=9,r=3);Type4:convexcuppunch withasecantlineandembossedmarks(R=9). a Thetabletsweremanufacturedwithoutanyfailureusingthetotalamountofformulatedpowders. Table4–Hardness(N)oftabletsmanufacturedonarotarytabletingmachine. Sample A(MgSt0) B(MgSt0.5) C(MgSt1) D(MgSt3) Plotrange III I I II “Compactability” Good Good Good Bad Type1 61.02.3 53.23.3 49.24.7 34.61.8 Type2 54.25.4 44.42.9 42.64.3 29.81.6 Type3 42.02.6a 35.82.0a 35.62.5 28.00.7 Type4 51.44.8a 39.02.2 35.81.9 26.81.3 Type1:?atpunchwithasecantline;Type2:convexcuppunch(R=11);Type3:compoundcuppunch(R=9,r=3);Type4:convexcuppunch withasecantlineandembossedmarks(R=9). a Tabletscouldnotbeformedwiththeseformulations.Therefore,thesurfaceofthepuncheswaslubricatedwithmagnesiumstearateand tabletingwasperformedagain. 416 asianjournalofpharmaceuticalsciences12(2017)412–417 Fig.4–Electronmicrographsofatabletcompressedwithacompoundcuppunch. WhentheType2convexcuppunch(R=11)wasused,samples B(MgSt0.5),C(MgSt1),andD(MgSt3)weretabletedwithout anyfailures(Table3).However,afteronly165to175tabletswere compressed,tabletsofsampleA(MgSt0)wouldnotseparate fromthesurfaceofthepunchandwerecaughtonthescraper andbrokeapart.Thesurfaceofthepunchwascoveredwith powder.Thisresultcorrespondedwiththeplottingofsample Ainrange(III)(Fig.2),indicatingpoor“Manufacturability”. WhentheType3compoundcuppunch(R=9,r=3)wasused, sampleD(MgSt3)wastabletedwithoutanyfailures(Table3). Incontrast,sampleA(MgSt0)adheredtothepunchimme- diately,andthecupbeganto?llwithpowder.SampleB(MgSt 0.5)coveredthesurfaceofthepunchassoonascompression began:only5to15tabletswerepressedbeforethetablets becamedif?culttoseparatefromthepunchandbrokeapart. SampleC(MgSt1)begantoadheretothecenterofthecup after105to115tabletshadbeenpressed,andadimple-like indentationappearedinthecenterofthetablet.Ejectionstress (onthey-axis),whichwasassociatedwiththeoccurrenceof tabletingfailure,increasedintheorderofsamplesD下載提示(請認真閱讀)
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