DRUG SUBSTANCE NAME MANUFACTURER药物物质名称制造商.docx
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DRUG SUBSTANCE NAME MANUFACTURER药物物质名称制造商.docx
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DRUGSUBSTANCENAMEMANUFACTURER药物物质名称制造商
3.2.SDRUGSUBSTANCE[NAME,MANUFACTURER]
3.2.S.1GeneralInformation[name,manufacturer]
3.2.S.1.1Nomenclature[name,manufacturer]
∙USAN:
ibuprofen
∙Compendialname:
ibuprofen
∙Chemicalname(s):
α-Methyl-4-(2-methylpropyl)benzeneaceticacid
∙Companynamesorlaboratorycode:
ShandongXinhuaPharmaceuticalCompanyLimited
∙Othernonproprietaryname:
ibuprofen
∙ChemicalAbstractsService(CAS)registrynumber:
15687-27-1
3.2.S.1.2Structure[name,manufacturer]
∙Chemicalstructure
∙Molecularformula:
C13H18O2
∙Molecularweight:
206.28.
3.2.S.1.3GeneralProperties[name,manufacturer]
∙Generaldescription:
white,crystallinepowderorcolorlesscrystals
∙Meltingorboilingpoints:
mp75-77℃
∙Opticalrotation
∙Solubilityprofile:
practicallyinsolubleinwater,freelysolubleinacetone,inmethanolandinmethylenechloride.Itdissolvesindilutesolutionsofalkalihydroxidesandcarbonates.
∙SolutionpH:
∙Partitioncoefficients
∙Dissociationconstants
∙ParticleSize
Medianparticlediameter(µm):
30~45
Particles18~78µmindiameter(%):
≥70
Particlesmorethan120µmindiameter(%):
0
∙TappedDensity
TappedDensity:
0.46~0.65g/mL
∙Purity
DegradationProductsProfile
IbuprofenisstableunderUVlight,inacidoralkaline,anddegradesinhightemperatureorunderoxidizingcondition.
ProcessImpuritiesProfile
Thepossibleprocessimpuritiesofibuprofenare:
2-(4-n-butylphenyl)propionicacid.
∙Biologicalactivities
3.2.S.2Manufacture[name,manufacturer]
3.2.S.2.1Manufacturers[name,manufacturer]
ManufactureSite
Name:
ShandongXinhuaPharmaceuticalCompanyLimited
Address:
No.14DongyiRoad,ZhangdianBorough,255005,
Zibo,Shandong,
China
PackagingSite
Name:
ShangdongXinhuaZiboPackagingandUpholsterCompanyLimited
Address:
ZhangdianBorough,255028
Zibo,Shangdong,
China
3.2.S.2.2DescriptionofManufacturingProcessandProcessControls[name,manufacturer]
Followingistheflowchartthatillustratesthemanufacturingprocessofibuprofen.
RefertoDMF15511forfulldetailsregardingchemistrymanufacturingandcontrolsusedintheproduction.DMFholderforIbuprofenhasproposedvalidatedmethodsthataresuitableforstability-indicatingpurposes,andhasdocumentedstabilitydataforthedrugsubstance.
3.2.S.2.3ControlofMaterials
RefertoDMF15511forinformationregardingmaterialsandcontrolsusedintheproductionofibuprofen.
3.2.S.2.4ControlsofCriticalStepsandIntermediates[name,manufacturer]
RefertoDMF15511forinformationregardingcontrolsofcriticalstepsidentifiedin3.2.S.2.2ofthemanufacturingprocessandqualityandcontroloftheintermediates.
3.2.S.2.5ProcessValidationand/orEvaluation[name,manufacturer]
RefertoDMF15511forinformationregardingprocessvalidation.
3.2.S.2.6ManufacturingProcessDevelopment[name,manufacturer]
RefertoDMF15511forinformationregardingmanufacturingprocessdevelopmentusedinproducingpilotandproductionscalebatches.
3.2.S.3Characterization[name,manufacturer]
3.2.S.3.1ElucidationofStructureandotherCharacteristics[name,manufacturer]
Forfulldetailsregardingproofofibuprofenstructure,baseduponspectroscopy,analyticaltesting,andinferencefromsyntheticrouterefertoDMF15511.
3.2.S.3.2Impurities[name,manufacturer]
ForfulldetailsregardingthecharacterizationandidentificationofimpuritiesrefertoDMF15511.
3.2.S.4ControlofDrugSubstance[name,manufacturer]
3.2.S.4.1Specification[name,manufacturer]
Asummaryofdrugsubstancetests,analyticalprocedures,acceptancelimitsandresultsforthedrugsubstancebatch(Lot#15531)(COAslocatedin3.2.S.4.4)usedforthemanufacturingofthesubmissionbatch(Lot#9A)isgiveninthetablebelow.
Tests
Acceptancecriteria
Analyticalprocedure
Appearance
White,crystallinepowderorcolorlesscrystals
Visual
IdentificationTest
A:
IR
B:
UV
C:
HPLC
A.IR:
CorrespondstoRS
B.UV:
Absorptivitiesat264nmand273nm,calculatedontheanhydrousbasis,donotdifferbymorethan3.0%
C.HPLC:
CorrespondstoRS
USP<197M>
USP<197U>
USPmethod
Water
NMT1.0%
USP<921>
MethodΙa
Residueonignition
NMT0.5%
USP<281>
Heavymetals
NMT0.002%
USP<231>
MethodΠ
Relatedsubstances
Individualimpurity:
NMT0.3%
Totalimpurities:
NMT1.0%
Organicvolatileimpurities
Meetrequirements
USP<467>
MethodV
ResidualSolvents
Ethanol:
NMT0.5%
1,2-Dichloroethane:
NMT5ppm
USP<467>
Limitof4-isobutylacetophenone
NMT0.1%
USPmethod
Assay
97.0%-103.0%(driedsubstance)
USPmethod
Microbialcontamination
Totalaerobicmicrobialcount:
NMT1000cfu/g
Totalcombinedmoldsandyeastscount:
NMT100cfu/g
Escherichiacoli.:
0
USP<61>
Meltingpoint
Opticalrotation
ThereisanofficialmonographinUSPforIbuprofendrugsubstance.USPtestsareshadedinthetable.Limitsforthesetestsarethosefoundinthepharmacopoeia.
Thespecificationincludesallthecriticaldrugsubstanceattributesthataffectthemanufacturingandqualityofthedrugproduct.InadditiontothetestsfoundintheUSPmonograph,weincludespecificationsforappearance.Thedrugsubstanceisnon-sterileactiveingredientwithoutmicrobialstaticproperty.Thesynthesisandprocessingofthedrugsubstancedoesn’tinvolvestepsinherentlyreducemicroorganismsaccordingtothesupplier’sstatement.Therefore,microorganismlevelswillalsobemonitoredbasedonICHQ6ADecisionTree#6.
3.2.S.4.2AnalyticalProcedures[name,manufacturer]
Appearance
Thedrugsubstanceisvisuallyinspectedtoverifythatitiswhite,crystallinepowderorcolorlesscrystals.
Identification
Theidentificationtests,aspecificIRtest,aUVtest,andHPLCmethod,areperUSPmonograph.
IRmethod
TheIRabsorptionspectrumofamineraloildispersionofthefinepowderofthetablet(notdried)exhibitsmaximaonlyatthesamewavelengthsasthatofastandardpreparation.
UVmethod
PrepareasolutionofIbuprofeninthemediumcontainingabout5mgperml.
Respectiveabsorptionsat264nmand273nm,calculatedontheanhydrousbasis,donotdifferbymorethan3.0%.
HPLCmethod
Ibuprofenisidentifiedbycomparingtherelativeretentiontimeofthemajorpeakintheassaychromatogramtothatofthereferencestandard.
Water
Weighaccurately100mgofgrindedfinepowderandtestasdirectedinUSPWaterDetermination<921>MethodIa,usingKarlFishertitratorandanhydratemethanolassolvent.Thetestisconductedtwiceinparalleltogettheaveragewatercontent.
Residueonignition
Theresidueonignitionofthedrugsubstanceistestedon2gsamplesasperUSPmonograph,usingUSPResidueonignition<281>.
Heavymetals
Theheavymetalstestisconductedon1gsamplesasperUSPmonograph,usingUSPHeavyMetalsTest<231>MethodΠ.
Assay
AssayisdeterminedbytheUSPmethod.Thechromatographicsystemislistedbelow.
Parameter
Value
Column
C18,packing5um,4.6mm×250mm
Mobilephase
Acetonitrile-buffersolution(60:
40)
Flowrate
2mL/min
Injectionvolume
5µL
Detector
UVdetector
Wavelength
254nm
Recordingtime
10minutes
Mobilephase,internalstandardsolution,Ibuprofenstandardsolution,4-Isobutylacetophenonestandardsolutionandthetestsolutionarepreparedasdirectedinthemonograph.
InjecttwicefollowingProcedurespecifiedinthepharmacopoeiaandcalculatethecontent,inmg,ofC13H18O2inindividualtabletsusingtheformulabelow.
f:
calibrationfactor
Ar:
averagepeakresponseofIbuprofeninthereferencestandard1
mr:
theweight,inmg,ofthereferencestandard1
And
M:
contentofIbuprofeninthefilm-coatedtablet
As:
peakresponseofIbuprofeninthetestsolution
Vs:
volumeofthetestsolution,100ml
Wst:
contentofthereferencestandard,%,ifthestandardizationresultofthereferencestandardisabove100%,Wstis100%;ifbelow100%,Wstistheactualvalue
ms:
weightoftabletpowdertakentopreparethetestsolution,inmg
Vr:
volumeofthestandardsolution,10ml
Ci,Ci′:
concentration,inmg/mL,ofvalerophenoneinthestandardsolutionandthetestsolution
Ai,Ai′:
valerophenonepeakresponseobtainedfromthestandardsolutionandthetestsolution
Chromatographicpurity
ChromatographicpurityistestedasperUSPmonograph.Thechromatographicsystemislistedbelow.
Parameter
Value
Column
C18,packing5μmL1,4.6mm×15cm
Mobilephase
Acetonitrile-buffersolution(60:
40)
Temperature
30±0.2℃
Flowrate
2mL/min
Injectionvolume
5µL
Wavelength
214nm
Recordingtime
60minutes
Mobilephase,testsolutionandresolutionsolutionarepreparedasdirectedinthemonograph.
Accuratelyinject5µLoftheresolutionsolutionfor5timesinparallelafterthebaselineisstable,recordthechromatogram.ThesystemissuitableforuseifRSDofinjectionsisnotmorethan2.0%,therelativeretentiontimesareabout0.8forvalerophenoneand1.0foribuprofen,andtheresolution,R,betweenthevalerophenonepeakandtheibuprofenpeakisnotlessthan2.0.
PerformthetestasdirectedinProcedureinthemonograph.Calculatethepercentageofeachimpuritytakenbytheformula:
100ri/rt
ri:
theresponseofanindividualpeak,otherthanthesolventpeakandthemainibuprofenpeak
rt:
thesumoftheresponsesofallthepeaks,excludingthatofthesolventpeak
Impurities(OrganicVolatileImpurities)
OrganicvolatileimpuritiesaretestedasdirectedunderUSPOrganicVolatileImpurities<467>MethodV,using6890GCchromatographer.Thechromatographicsystemislistedbelow.
Parameter
Value
Detector
flame-ionizationdetector
Column
0.53mm×30mfusedsilicaanalyticalcolumncoatedwitha3.0µmG43stationaryphase,anda
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