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UpdatedPh.Eur.9.0,effective01/01/2017
Nifedipine
GeneralNotices
(Ph.Eur.monograph0627)
C17H18N2O6346.321829254
Actionanduse
Calciumchannelblocker.
Preparations
NifedipineCapsules
ProlongedreleaseNifedipineCapsules
ProlongedreleaseNifedipineTablets
PhEur
DEFINITION
Dimethyl2,6dimethyl4(2nitrophenyl)1,4dihydropyridine3,5dicarboxylate.
Content
98.0percentto102.0percent(driedsubstance).
CHARACTERS
Appearance
Yellow,crystallinepowder.
Solubility
Practicallyinsolubleinwater,freelysolubleinacetone,sparinglysolubleinethanol.
Whenexposedtodaylightandtoartificiallightofcertainwavelengths,itreadilyconvertstoanitrosophenylpyridinederivative.Exposuretoultraviolet
lightleadstotheformationofanitrophenylpyridinederivative.
Preparesolutionsimmediatelybeforeuseinthedarkorunderlongwavelengthlight(>420nm)andprotectthemfromlight.
IDENTIFICATION
Firstidentification:B
Secondidentification:A,C,D
A.Meltingpoint(2.2.14):171Cto175C.
B.Infraredabsorptionspectrophotometry(2.2.24).
Comparison nifedipineCRS.
C.Thinlayerchromatography(2.2.27).
Testsolution Dissolve10mgofthesubstancetobeexaminedinmethanolRanddiluteto10mLwiththesamesolvent.
Referencesolution Dissolve10mgofnifedipineCRSinmethanolRanddiluteto10mLwiththesamesolvent.
Mobilephase ethylacetateR,cyclohexaneR(40:60V/V).
Application 5L.
Development Over3/4oftheplate.
Drying Inair.
Detection Examineinultravioletlightat254nm.
Results Theprincipalspotinthechromatogramobtainedwiththetestsolutionissimilarinposition,appearanceat254nmandsizetotheprincipal
spotinthechromatogramobtainedwiththereferencesolution.
D.To25mginatesttube,add10mLofamixtureof1.5volumesofhydrochloricacidR,3.5volumesofwaterRand5volumesofalcoholRand
dissolvewithgentleheating.Add0.5gofzincRingranulesandallowtostandfor5minwithoccasionalswirling.Filterintoasecondtesttube,add
5mLofa10g/LsolutionofsodiumnitriteRtothefiltrateandallowtostandfor2min.Add2mLofa50g/LsolutionofammoniumsulfamateR,shake
vigorouslywithcareandadd2mLofa5g/LsolutionofnaphthylethylenediaminedihydrochlorideR.Anintenseredcolourdevelopswhichpersistsfor
notlessthan5min.
TESTS
ImpurityDandotherbasicimpurities
Transfer4gtoa250mLconicalflaskanddissolvein160mLofglacialaceticacidRusinganultrasonicbath.Titratewith0.1Mperchloricacidusing
0.25mLofnaphtholbenzeinsolutionRasindicatoruntilthecolourchangesfrombrownishyellowtogreen.Notmorethan0.48mLof0.1Mperchloric
acidisrequired(0.14percent).
Relatedsubstances
Liquidchromatography(2.2.29).
Testsolution Dissolve0.200gofthesubstancetobeexaminedin20mLofmethanolRanddiluteto50.0mLwiththemobilephase.
Referencesolution(a) Dissolve10mgofnifedipineimpurityACRSinmethanolRanddiluteto25.0mLwiththesamesolvent.
Referencesolution(b) Dissolve10mgofnifedipineimpurityBCRSinmethanolRanddiluteto25.0mLwiththesamesolvent.
Referencesolution(c) Mix1.0mLofreferencesolution(a),1.0mLofreferencesolution(b)and0.1mLofthetestsolutionanddiluteto20.0mLwith
themobilephase.Dilute2.0mLofthissolutionto10.0mLwiththemobilephase.
Column:
size:l=0.15m,=4.6mm,
stationaryphase:octadecylsilylsilicagelforchromatographyR(5m).
Mobilephase acetonitrileR,methanolR,waterR(9:36:55V/V/V).
Flowrate 1.0mL/min.
Detection Spectrophotometerat235nm.
Injection 20Linjectthetestsolutionandreferencesolution(c).
Runtime Twicetheretentiontimeofnifedipine.
Elutionorder ImpurityA,impurityB,nifedipine.
Retentiontime Nifedipine=about15.5min.
Systemsuitability:referencesolution(c):
resolution:minimum1.5betweenthepeaksduetoimpurityAandimpurityBandminimum1.5betweenthepeaksduetoimpurityBand
nifedipine.
Limits:
impurityA:notmorethantheareaofthecorrespondingpeakinthechromatogramobtainedwithreferencesolution(c)(0.1percent),
impurityB:notmorethantheareaofthecorrespondingpeakinthechromatogramobtainedwithreferencesolution(c)(0.1percent),
anyotherimpurity:notmorethantheareaofthepeakduetonifedipineinthechromatogramobtainedwithreferencesolution(c)(0.1percent),
total:notmorethan0.3percent,
disregardlimit:0.1timestheareaofthepeakduetonifedipineinthechromatogramobtainedwithreferencesolution(c)(0.01percent).
Lossondrying(2.2.32)
Maximum0.5percent,determinedon1.000gbydryinginanovenat105Cfor2h.
Sulfatedash(2.4.14)
Maximum0.1percent,determinedon1.0g.
ASSAY
Dissolve0.1300ginamixtureof25mLof2methyl2propanolRand25mLofperchloricacidsolutionR.Titratewith0.1Mceriumsulfateusing
0.1mLofferroinRasindicator,untilthepinkcolourdisappears.Titrateslowlytowardstheendofthetitration.Carryoutablanktitration.
1mLof0.1Mceriumsulfateisequivalentto17.32mgofC17H18N2O6.
STORAGE
Protectedfromlight.
IMPURITIES
Specifiedimpurities:A,B,C,D.
A.dimethyl2,6dimethyl4(2nitrophenyl)pyridine3,5dicarboxylate(nitrophenylpyridineanalogue),
B.dimethyl2,6dimethyl4(2nitrosophenyl)pyridine3,5dicarboxylate(nitrosophenylpyridineanalogue),
C.methyl2(2nitrobenzylidene)3oxobutanoate,
D.methyl3aminobut2enoate.
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