盐酸氟桂利嗪EP8

EUROPEANPHARMACOPOEIA8.0FlunarizinedihydrochlorideLimits:–impuritiesA,B,C,D:foreachimpurity,notmorethan0.75timestheareaoftheprincipalpeakinthechromatogramobtainedwithreferencesolution(b)(1.5percent);–total:notmorethantheareaoftheprincipalpeakinthechromatogramobtainedwithreferencesolution(b)(2percent);–disregardlimit:0.025timestheareaoftheprincipalpeakinthechromatogramobtainedwithreferencesolution(b)(0.05percent).Lossondrying(2.2.32):maximum1.0percent,determinedon0.500gbydryinginanovenat105°Cfor4h.ASSAYDissolve50.0mginethanol(96percent)Randdiluteto100.0mLwiththesamesolvent.Dilute2.0mLofthissolutionto100.0mLwithethanol(96percent)R.Measuretheabsorbance(2.2.25)attheabsorptionmaximumat239nm.CalculatethecontentofC27H36F2O6takingthespecificabsorbancetobe336.STORAGEProtectedfromlight.IMPURITIESSpecifiedimpurities:A,B,C,D.A.R1=H,R2=F:6α,9-difluoro-11β,17,21-trihydroxy-16α-methylpregna-1,4-diene-3,20-dione(flumetasone),B.R1=CO-CH3,R2=F:6α,9-difluoro-11β,17-dihydroxy-16α-methyl-3,20-dioxopregna-1,4-dien-21-ylacetate(flumetasoneacetate),C.R1=CO-C(CH3)3,R2=H:9-fluoro-11β,17-dihydroxy-16α-methyl-3,20-dioxopregna-1,4-dien-21-yl2,2-dimethylpropanoate(dexamethasonepivalate),D.R1=CO-C(CH3)3,R2=Cl:6α-chloro-9-fluoro-11β,17-dihydroxy-16α-methyl-3,20-dioxopregna-1,4-dien-21-yl2,2-dimethylpropanoate(chlordexamethasonepivalate).01/2008:1722corrected7.0FLUNARIZINEDIHYDROCHLORIDEFlunarizinidihydrochloridumC26H28Cl2F2N2Mr477.4[30484-77-6]DEFINITION1-[Bis(4-fluorophenyl)methyl]-4-[(2E)-3-phenylprop-2-enyl]piperazinedihydrochloride.Content:99.0percentto101.5percent(driedsubstance).CHARACTERSAppearance:whiteoralmostwhitepowder,hygroscopic.Solubility:slightlysolubleinwater,sparinglysolubleinmethanol,slightlysolubleinalcoholandinmethylenechloride.mp:about208°C,withdecomposition.IDENTIFICATIONA.Infraredabsorptionspectrophotometry(2.2.24).Comparison:Ph.Eur.referencespectrumofflunarizinedihydrochloride.B.Dissolve25mgin2mLofmethanolRandadd0.5mLofwaterR.Thesolutiongivesreaction(a)ofchlorides(2.3.1).TESTSRelatedsubstances.Liquidchromatography(2.2.29).Preparethesolutionsimmediatelybeforeuseandprotectfromlight.Testsolution.Dissolve0.100gofthesubstancetobeexaminedinmethanolRanddiluteto10.0mLwiththesamesolvent.Referencesolution(a).Dissolve10mgofflunarizinedihydrochlorideforsystemsuitabilityCRSinmethanolRanddiluteto1.0mLwiththesamesolvent.Referencesolution(b).Dilute1.0mLofthetestsolutionto100.0mLwithmethanolR.Dilute5.0mLofthissolutionto20.0mLwithmethanolR.Column:–size:l=0.10m,Ø=4.6mm,–stationaryphase:base-deactivatedoctadecylsilylsilicagelforchromatographyR(3μm).Mobilephase:–mobilephaseA:solutioncontaining23.8g/LoftetrabutylammoniumhydrogensulfateRand7g/LofammoniumacetateR,–mobilephaseB:acetonitrileR,Time(min)MobilephaseA(percentV/V)MobilephaseB(percentV/V)0-1280→4020→6012-154060Flowrate:1.5mL/min.Detection:spectrophotometerat230nm.Injection:10μL.Systemsuitability:referencesolution(a):–peak-to-valleyratio:minimum1.5,whereHp=heightabovethebaselineofthepeakduetoimpurityCandHv=heightabovethebaselineofthelowestpointofthecurveseparatingthispeakfromthepeakduetoflunarizine,–thechromatogramobtainedisconcordantwiththechromatogramsuppliedwithflunarizinedihydrochlorideforsystemsuitabilityCRS.Limits:–correctionfactor:forthecalculationofcontent,multiplythepeakareaofimpurityAby1.5,–impuritiesA,D:foreachimpurity,notmorethan0.4timestheareaoftheprincipalpeakinthechromatogramobtainedwithreferencesolution(b)(0.1percent),–impurityB:notmorethantwicetheareaoftheprincipalpeakinthechromatogramobtainedwithreferencesolution(b)(0.5percent),–impurityC:notmorethantheareaoftheprincipalpeakinthechromatogramobtainedwithreferencesolution(b)(0.25percent),–anyotherimpurity:foreachimpurity,notmorethan0.4timestheareaoftheprincipalpeakinthechromatogramobtainedwithreferencesolution(b)(0.1percent),GeneralNotices(1)applytoallmonographsandothertexts2255FlunitrazepamEUROPEANPHARMACOPOEIA8.0–total:notmorethan4timestheareaoftheprincipalpeakinthechromatogramobtainedwithreferencesolution(b)(1.0percent),–disregardlimit:0.2timestheareaoftheprincipalpeakinthechromatogramobtainedwithreferencesolution(b)(0.05percent).Lossondrying(2.2.32):maximum5.0percent,determinedon1.000gbydryinginanovenat105°Cfor4h.Sulfatedash(2.4.14):maximum0.1percent,determinedon1.0ginaplatinumcrucible.ASSAYDissolve0.200gin70mLofalcoholR.Carryoutapotentiometrictitration(2.2.20),using0.1Msodiumhydroxide.Readthevolumeaddedatthesecondpointofinflexion.Carryoutablanktitration.1mLof0.1Msodiumhydroxideisequivalentto23.87mgofC26H28Cl2F2N2.STORAGEInanairtightcontainer,protectedfromlight.IMPURITIESSpecifiedimpurities:A,B,C,D.A.1-[bis(4-fluorophenyl)methyl]piperazine,B.R1=R2=R3=H,R4=C6H5:1-[(RS)-(4-fluorophenyl)phenylmethyl]-4-[(2E)-3-phenylprop-2-enyl]piperazine,C.R1=F,R2=R3=H,R4=C6H5:1-[(RS)-(2-fluorophenyl)(4-fluorophenyl)methyl]-4-[(2E)-3-phenylprop-2-enyl]piperazine,D.R1=R4=H,R2=F,R3=C6H5:1-[bis(4-fluorophenyl)methyl]-4-[(2Z)-3-phenylprop-2-enyl]piperazine.01/2008:0717corrected6.0FLUNITRAZEPAMFlunitrazepamumC16H12FN3O3Mr313.3[1622-62-4]DEFINITION5-(2-Fluorophenyl)-1-methyl-7-nitro-1,3-dihydro-2H-1,4-benzodiazepin-2-one.Content:99.0percentto101.0percent(driedsubstance).CHARACTERSAppearance:whiteoryellowish,crystallinepowder.Solubility:practicallyinsolubleinwater,solubleinacetone,slightlysolubleinalcohol.IDENTIFICATIONInfraredabsorptionspectrophotometry(2.2.24).Comparison:Ph.Eur.referencespectrumofflunitrazepam.TESTSRelatedsubstances.Liquidchromatography(2.2.29).Preparethesolutionsimmediatelybeforeuse.Testsolution.Dissolve100.0mgofthesubstancetobeexaminedin10mLofacetonitrileRanddiluteto50.0mLwiththemobilephase.Referencesolution(a).Dilute1.0mLofthetestsolutionto100.0mLwiththemobilephase.Dilute5.0mLofthissolutionto50.0mLwiththemobilephase.Referencesolution(b).Dissolve4mgofthesubstancetobeexaminedand4mgofnitrazepamRin5mLofacetonitrileRanddiluteto20.0mLwiththemobilephase.Dilute1.0mLofthesolutionto20.0mLwiththemobilephase.Column:–size:l=0.15m,Ø=4.6mm,–stationaryphase:octadecylsilylsilicagelforchromatographyR(5μm).Mobilephase:methanolR,acetonitrileR,waterR(50:305:645V/V/V).Flowrate:1.0mL/min.Detection:spectrophotometerat254nm.Injection:20μL.Runtime:6timestheretentiontimeofflunitrazepam.Relativeretentionwithreferencetoflunitrazepam(retentiontime=about11min):impurityA=about0.2;impurityB=about0.6;impurityC=about2.3;impurityD=about4.0.Systemsuitability:referencesolution(b):–resolution:minimum4.0betweenthepeaksduetonitrazepamandflunitrazepam.Limits:–correctionfactor:forthecalculationofcontent,multiplythepeakareaofimpurityCby2.44,–anyimpurity:notmorethantheareaoftheprincipalpeakinthechromatogramobtainedwithreferencesolution(a)(0.1percent),–total:notmorethan3timestheareaoftheprincipalpeakinthechromatogramobtainedwithreferencesolution(a)(0.3percent),–disregardlimit:0.5timestheareaoftheprincipalpeakinthechromatogramobtainedwithreferencesolution(a)(0.05percent).Lossondrying(2.2.32):maximum0.5percent,determinedon1.000gbydryinginanovenat105°C.Sulfatedash(2.4.14):maximum0.1percent,determinedon1.0g.ASSAYDissolve0.250gin20mLofanhydrousaceticacidRandadd50mLofaceticanhydrideR.Titratewith0.1Mperchloricacid,determiningtheend-pointpotentiometrically(2.2.20).1mLof0.1Mperchloricacidisequivalentto31.33mgofC16H12FN3O3.2256Seetheinformationsectionongeneralmonographs(coverpages)