European pharmacopoeia 7.0, Vol. 2

1951 Pages·41.255 MB·English

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EUROPEANPHARMACOPOEIA7.0 Acamprosatecalcium
01/2009:0308 Thechromatogramobtainedwiththetestsolutionshows
corrected6.8 nogreyzoneandnogreyish-greenzonebetweenthezones
correspondingtogalactoseandarabinoseinthechromatogram
ACACIA, SPRAY-DRIED obtainedwiththereferencesolution.
Starch,dextrinandagar. To10mLofsolutionSpreviously
Acaciae gummi dispersione desiccatum boiledandcooledadd0.1mLof0.05Miodine. Noblueor
reddish-browncolourdevelops.
DEFINITION
Sterculiagum
Spray-driedacaciaisobtainedfromasolutionofacacia.
A. Place0.2gina10mLground-glass-stopperedcylinder
CHARACTERS graduatedin0.1mL.Add10mLofethanol(60per
Itdissolvescompletelyandrapidly,afterabout20min,in centV/V)Randshake. Anygelformedoccupiesnotmore
twiceitsmassofwater. Theliquidobtainediscolourlessor than1.5mL.
yellowish,dense,viscous,adhesive,translucentandweaklyacid B. To1.0gadd100mLofwaterRandshake. Add0.1mL
tobluelitmuspaper. Spray-driedacaciaispracticallyinsoluble ofmethylredsolutionR.Notmorethan5.0mLof
inethanol(96percent). 0.01Msodiumhydroxideisrequiredtochangethecolour
oftheindicator.
IDENTIFICATION
Tannins. To10mLofsolutionSadd0.1mLofferricchloride
A. Examinedunderamicroscope,inethanol(96percent)R,
solutionR1. Agelatinousprecipitateisformed,butneitherthe
thepowderisseentoconsistpredominantlyofspheroidal
precipitatenortheliquidshowsadarkbluecolour.
particlesabout4-40μmindiameter,withacentralcavity
containing1orseveralair-bubbles;afewminuteflat Tragacanth. Examinethechromatogramsobtainedinthetest
fragmentsarepresent. Onlytracesofstarchgranulesare forGlucoseandfructose.
visible. Novegetabletissueisseen. Results:thechromatogramobtainedwiththetestsolution
B. Examinethechromatogramsobtainedinthetestforglucose showsnogreenish-greyoryellowish-greyzonecorresponding
andfructose. tothezoneofxyloseinthechromatogramobtainedwiththe
referencesolution.
Results:thechromatogramobtainedwiththetestsolution
shows3zonesduetogalactose,arabinoseandrhamnose. Lossondrying(2.2.32):maximum10.0percent,determined
Nootherimportantzonesarevisible,particularlyinthe on1.000gbydryinginanovenat105°C.
upperpartofthechromatogram. Totalash(2.4.16).:maximum4.0percent.
C. Dissolve1gofthedrugtobeexaminedin2mLofwaterR
Microbialcontamination
bystirringfrequentlyfor20min. Add2mLofethanol
TAMC:acceptancecriterion104CFU/g(2.6.12).
(96percent)R.Aftershakingawhitegelatinousmucilageis
formedwhichbecomesfluidonadding10mLofwaterR. TYMC:acceptancecriterion102CFU/g(2.6.12).
AbsenceofEscherichiacoli(2.6.13).
TESTS
AbsenceofSalmonella(2.6.13).
SolutionS.Dissolve3.0gofthedrugtobeexaminedin25mL
ofwaterRbystirringfor10min. Allowtostandfor20minand FUNCTIONALITY-RELATEDCHARACTERISTICS
diluteto30mLwithwaterR. Thissectionprovidesinformationoncharacteristicsthatare
Glucoseandfructose. Thin-layerchromatography(2.2.27). recognisedasbeingrelevantcontrolparametersforoneor
morefunctionsofthesubstancewhenusedasanexcipient
Testsolution. To0.100ginathick-walledcentrifugetubeadd
(seechapter5.15). Thissectionisanon-mandatorypartofthe
2mLofa100g/LsolutionoftrifluoroaceticacidR,shake
monographanditisnotnecessarytoverifythecharacteristics
vigorouslytodissolvetheforminggel,stopperthetubeand
todemonstratecompliance. Controlofthesecharacteristics
heatthemixtureat120°Cfor1h. Centrifugethehydrolysate,
canhowevercontributetothequalityofamedicinalproduct
transfertheclearsupernatantcarefullyintoa50mLflask,add
byimprovingtheconsistencyofthemanufacturingprocess
10mLofwaterRandevaporatetodrynessunderreduced
andtheperformanceofthemedicinalproductduringuse.
pressure. Totheresultingclearfilmadd0.1mLofwaterRand
Wherecontrolmethodsarecited,theyarerecognisedasbeing
0.9mLofmethanolR.Centrifugetoseparatetheamorphous
suitableforthepurpose,butothermethodscanalsobeused.
precipitate. Dilutethesupernatant,ifnecessary,to1mLwith
Whereverresultsforaparticularcharacteristicarereported,
methanolR.
thecontrolmethodmustbeindicated.
Referencesolution. Dissolve10mgofarabinoseR,10mgof
Thefollowingcharacteristicmayberelevantforspray-dried
galactoseR,10mgofglucoseR,10mgofrhamnoseRand
acaciausedasaviscosity-increasingagentand/orsuspending
10mgofxyloseRin1mLofwaterRanddiluteto10mLwith
agentinaqueouspreparations.
methanolR.
Plate:TLCsilicagelplateR. Apparentviscosity. Determinethedynamicviscosityusinga
capillaryviscometer(2.2.9)orarotatingviscometer(2.2.10)on
Mobilephase:16g/Lsolutionofsodiumdihydrogen
a100g/Lsolutionofspray-driedacacia(driedsubstance).
phosphateR,butanolR,acetoneR(10:40:50V/V/V).
Application:10μLasbands.
01/2008:1585
DevelopmentA:overapathof10cm. corrected6.0
DryingA:inacurrentofwarmairforafewminutes.
DevelopmentB:overapathof15cmusingthesamemobile ACAMPROSATE CALCIUM
phase.
DryingB:at110°Cfor10min. Acamprosatum calcicum
Detection:spraywithanisaldehydesolutionRandheatat
110°Cfor10min.
Results:thechromatogramobtainedwiththereference
solutionshows5clearlyseparatedcolouredzonesdueto
galactose(greyish-greenorgreen),glucose(grey),arabinose
(yellowish-green),xylose(greenish-greyoryellowish-grey)and C H CaNOS M 400.5
10 20 2 8 2 r
rhamnose(yellowish-green),inorderofincreasingR value. [77337-73-6]
F
GeneralNotices(1)applytoallmonographsandothertexts 1301
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Acarbose EUROPEANPHARMACOPOEIA7.0
DEFINITION internaldiameter,equippedwithapolytetrafluoroethyleneflow
Calciumbis[3-(acetylamino)propane-1-sulfonate]. capcoveredbyaglass-woolplug. Allowafewmillilitresofthis
solutiontoflow,thenplaceaplugofglasswoolovertheresin.
Content:98.0percentto102.0percent(driedsubstance).
Pass50mLof1Mhydrochloricacidthroughthecolumn. The
CHARACTERS pHoftheeluateiscloseto1. Washwith3quantities,each
Appearance:whiteoralmostwhitepowder. of200mL,ofdistilledwaterRtoobtainaneluateatpH6.
Dissolve0.100gofthesubstancetobeexaminedin15mL
Solubility:freelysolubleinwater,practicallyinsolublein
ofdistilledwaterR.Passthroughthecolumnandwashwith
ethanol(96percent)andinmethylenechloride.
3quantities,eachof25mL,ofdistilledwaterR,collecting
IDENTIFICATION theeluate. AllowtoeluteuntilaneluateatpH6isobtained.
Titratethesolutionobtainedwith0.1Msodiumhydroxide,
A. Infraredabsorptionspectrophotometry(2.2.24).
determiningtheend-pointpotentiometrically(2.2.20).
Comparison:Ph.Eur. referencespectrumofacamprosate
1mLof0.1Msodiumhydroxidecorrespondsto20.02mgof
calcium.
C H CaNOS.
B. Itgivesreaction(a)ofcalcium(2.3.1). 10 20 2 8 2
IMPURITIES
TESTS
SolutionS.Dissolve5.0gincarbondioxide-freewaterR and
diluteto100mLwiththesamesolvent. A. 3-aminopropane-1-sulfonicacid(homotaurine).
Appearanceofsolution. SolutionSisclear(2.2.1)and
colourless(2.2.2,MethodII). 01/2008:2089
pH(2.2.3):5.5to7.0forsolutionS.
ACARBOSE
ImpurityA.Liquidchromatography(2.2.29).
Testsolution. Dissolve0.40gofthesubstancetobeexamined Acarbosum
indistilledwaterRanddiluteto20.0mLwiththesame
solvent. Dilute10.0mLofthissolutionto100.0mLwith
boratebuffersolutionpH10.4R.Place3.0mLofthesolution
obtainedina25mLground-glass-stopperedtube. Add0.15mL
ofafreshlyprepared5g/LsolutionoffluorescamineRin
acetonitrileR.Shakeimmediatelyandvigorouslyfor30s.
Placeinawater-bathat50°Cfor30min. Coolunderastream
ofcoldwater. Centrifugeandfilterthesupernatantthrougha
C H NO M 646
suitablemembranefilter(nominalporesize0.45μm),25mmin 25 43 18 r
[56180-94-0]
diameter.
Referencesolution. Dissolve50mgofacamprosate DEFINITION
impurityACRSindistilledwaterRanddiluteto200.0mLwith O-4,6-Dideoxy-4-[[(1S,4R,5S,6S)-4,5,6-trihydroxy-3-
thesamesolvent. Dilute0.4mLofthesolutionto100.0mL (hydroxymethyl)cyclohex-2-enyl]amino]-α-D-glucopyranosyl-
withboratebuffersolutionpH10.4R.Treat3.0mLofthis (1→4)-O-α-D-glucopyranosyl-(1→4)-D-glucopyranose,whichis
solutioninthesamewayasthetestsolution producedbycertainstrainsofActinoplanesutahensis.
Column: Content:95.0percentto102.0percent(anhydroussubstance).
— size:l=0.15m,Ø=4.6mm;
CHARACTERS
— stationaryphase:sphericaloctadecylsilylsilicagelfor
Appearance:whiteoryellowish,amorphouspowder,
chromatographyR(5μm)withaspecificsurfaceareaof
170m2/gandaporesizeof12nm. hygroscopic.
Solubility:verysolubleinwater,solubleinmethanol,practically
Mobilephase:acetonitrileR,methanolR,0.1Mphosphate
insolubleinmethylenechloride.
buffersolutionpH6.5R(10:10:80V/V/V).
Flowrate:1mL/min. IDENTIFICATION
Detection:spectrophotometerat261nm. A. Infraredabsorptionspectrophotometry(2.2.24).
Injection:20μL. Comparison:acarboseforidentificationCRS.
Runtime:6timestheretentiontimeofimpurityA B. Examinethechromatogramsobtainedintheassay.
Retentiontimes:fluorescamine=about4min; Results:theprincipalpeakinthechromatogramobtained
impurityA=about8min;acamprosateisnotdetectedbythis withthetestsolutionissimilarinretentiontimeandsize
system. totheprincipalpeakinthechromatogramobtainedwith
Limits: referencesolution(a).
— impurityA:notmorethantheareaofthecorresponding
TESTS
peakinthechromatogramobtainedwiththereference
solution(0.05percent). SolutionS.Dissolve1.00gincarbondioxide-freewaterRand
diluteto20.0mLwiththesamesolvent.
Heavymetals(2.4.8):maximum10ppm.
pH(2.2.3):5.5to7.5forsolutionS.
Dissolve2.0gindistilledwaterRanddiluteto20mLwith
thesamesolvent. 12mLofthesolutioncomplieswithtestA. Specificopticalrotation(2.2.7):+168to+183(anhydrous
Preparethereferencesolutionusing10mLofleadstandard substance).
solution(1ppmPb)R. Dilute2.0mLofsolutionSto10.0mLwithwaterR.
Lossondrying(2.2.32):maximum0.4percent,determinedon Absorbance(2.2.25):maximum0.15at425nmforsolutionS.
1.000gbydryinginanovenat105°C.
Relatedsubstances. Liquidchromatography(2.2.29).
ASSAY Testsolution. Dissolve0.200gofthesubstancetobeexamined
To4gofcationexchangeresinR(75-150μm)add20mLof inwaterRanddiluteto10.0mLwiththesamesolvent.
distilledwaterRandstirmagneticallyfor10min. Introduce Referencesolution(a). Dissolvethecontentsofavialof
thissuspensionintoaglasscolumn,45cmlongand2.2cmin acarboseCRSin5.0mLofwaterR.
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EUROPEANPHARMACOPOEIA7.0 Acarbose
Referencesolution(b). Dissolve20mgofacarboseforpeak — anyotherimpurities:foreachimpurity,notmorethan
identificationCRS(acarbosecontainingimpuritiesA,B,C,D, 0.2timestheareaoftheprincipalpeakinthechromatogram
E,F,GandH)in1mLofwaterR. obtainedwithreferencesolution(c)(0.2percent);
Referencesolution(c). Dilute1.0mLofthetestsolutionto — total:notmorethan3timestheareaoftheprincipalpeak
100.0mLwithwaterR. inthechromatogramobtainedwithreferencesolution(c)
(3.0percent);
Column:
— disregardlimit:0.1timestheareaoftheprincipalpeak
— size:l=0.25m,Ø=4mm,
inthechromatogramobtainedwithreferencesolution(c)
— stationaryphase:aminopropylsilylsilicagelfor (0.1percent).
chromatographyR(5μm),
Heavymetals(2.4.8):maximum20ppm.
— temperature:35°C. Dissolve1.5ginwaterRanddiluteto15mLwiththesame
Mobilephase:mix750volumesofacetonitrileR1and solvent. Ifthesolutionisnotclear,carryoutprefiltrationand
250volumesofasolutioncontaining0.60g/Lofpotassium usethefiltrate. 10mLcomplieswithlimittestE.Preparethe
dihydrogenphosphateRand0.35g/Lofdisodiumhydrogen referencesolutionusing20mLofleadstandardsolution
phosphatedihydrateR. (1ppmPb)R.
Flowrate:2.0mL/min. Water(2.5.12):maximum4.0percent,determinedon0.300g.
Detection:spectrophotometerat210nm. Sulfatedash(2.4.14):maximum0.2percent,determinedon
1.0g.
Injection:10μLofthetestsolutionandreferencesolutions(b)
and(c). ASSAY
Runtime:2.5timestheretentiontimeofacarbose. Liquidchromatography(2.2.29)asdescribedinthetestfor
Identificationofimpurities:usethechromatogram relatedsubstanceswiththefollowingmodification.
suppliedwithacarboseforpeakidentificationCRSandthe Injection:testsolutionandreferencesolution(a).
chromatogramobtainedwithreferencesolution(b)toidentify
CalculatethepercentagecontentofC H NO fromtheareas
thepeaksduetoimpuritiesA,B,C,D,E,F,GandH. 25 43 18
ofthepeaksandthedeclaredcontentofacarboseCRS.
Relativeretentionwithreferencetoacarbose(retention
time=about16min):impurityD=about0.5; STORAGE
impurityH=about0.6;impurityB=about0.8; Inanairtightcontainer.
impurityA=about0.9;impurityC=about1.2;
impurityE=about1.7;impurityF=about1.9; IMPURITIES
impurityG=about2.2.
Specifiedimpurities:A,B,C,D,E,F,G,H.
Systemsuitability:referencesolution(b):
— peak-to-valleyratio:minimum1.2,whereH =heightabove
p
thebaselineofthepeakduetoimpurityAandH =height
v
abovethebaselineofthelowestpointofthecurveseparating
thispeakfromthepeakduetoacarbose,
— thechromatogramobtainedissimilartothechromatogram
suppliedwithacarboseforpeakidentificationCRS.
Limits:
— correctionfactors:forthecalculationofcontents,
multiplythepeakareasofthefollowingimpuritiesby
thecorrespondingcorrectionfactor:impurityB=0.63;
impurityD=0.75;impurityE=1.25;impurityF=1.25; A. O-4,6-dideoxy-4-[[(1S,4R,5S,6S)-4,5,6-trihydroxy-3-
impurityG=1.25; (hydroxymethyl)cyclohex-2-enyl]amino]-α-D-glucopyranosyl-
(1→4)-O-α-D-glucopyranosyl-(1→4)-D-arabino-hex-2-
— impurityA:notmorethan0.6timestheareaofthe
ulopyranose,
principalpeakinthechromatogramobtainedwithreference
solution(c)(0.6percent);
— impurityB:notmorethan0.5timestheareaofthe
principalpeakinthechromatogramobtainedwithreference
solution(c)(0.5percent);
— impurityC:notmorethan1.5timestheareaofthe
principalpeakinthechromatogramobtainedwithreference
solution(c)(1.5percent); B. (1R,4R,5S,6R)-4,5,6-trihydroxy-2-(hydroxymethyl)cyclohex-
2-enyl4-O-[4,6-dideoxy-4-[[(1S,4R,5S,6S)-4,5,6-trihydroxy-3-
— impurityD:notmorethantheareaoftheprincipalpeak
inthechromatogramobtainedwithreferencesolution(c) (hydroxymethyl)cyclohex-2-enyl]amino]-α-D-glucopyranosyl]-
(1.0percent); α-D-glucopyranoside,
— impurityE:notmorethan0.2timestheareaofthe
principalpeakinthechromatogramobtainedwithreference
solution(c)(0.2percent);
— impuritiesF,G:foreachimpurity,notmorethan0.3times
theareaoftheprincipalpeakinthechromatogramobtained
withreferencesolution(c)(0.3percent);
— impurityH:notmorethan0.2timestheareaofthe C. α-D-glucopyranosyl4-O-[4,6-dideoxy-4-[[(1S,4R,5S,6S)-4,5,
principalpeakinthechromatogramobtainedwithreference 6-trihydroxy-3-(hydroxymethyl)cyclohex-2-enyl]amino]-α-D-
solution(c)(0.2percent); glucopyranosyl]-α-D-glucopyranoside,
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Acebutololhydrochloride EUROPEANPHARMACOPOEIA7.0
01/2008:0871
corrected7.0
ACEBUTOLOL HYDROCHLORIDE
Acebutololi hydrochloridum
D. 4-O-[4,6-dideoxy-4-[[(1S,4R,5S,6S)-4,5,6-trihydroxy-3-
(hydroxymethyl)cyclohex-2-enyl]amino]-α-D-glucopyranosyl]-
D-glucopyranose,
C H ClNO M 372.9
18 29 2 4 r
[34381-68-5]
DEFINITION
N-[3-Acetyl-4-[(2RS)-2-hydroxy-3-[(1-methylethyl)amino]pro-
poxy]phenyl]butanamidehydrochloride.
Content:99.0percentto101.0percent(driedsubstance).
CHARACTERS
E. O-4,6-dideoxy-4-[[(1S,4R,5S,6S)-4,5,6-trihydroxy-
3-(hydroxymethyl)cyclohex-2-enyl]amino]-α-D- Appearance:whiteoralmostwhite,crystallinepowder.
glucopyranosyl-(1→4)-O-α-D-glucopyranosyl-(1→4)- Solubility:freelysolubleinwaterandinethanol(96percent),
O-α-D-glucopyranosyl-(1→4)-D-arabino-hex-2-ulopyranose veryslightlysolubleinacetoneandinmethylenechloride.
(4-O-α-acarbosyl-D-fructopyranose), mp:about143°C.
IDENTIFICATION
Firstidentification:B,D.
Secondidentification:A,C,D.
A. Ultravioletandvisibleabsorptionspectrophotometry
(2.2.25).
Testsolution. Dissolve20.0mgina0.1percentV/Vsolution
ofhydrochloricacidRanddiluteto100.0mLwiththesame
acidsolution. Dilute5.0mLofthissolutionto100.0mL
witha0.1percentV/VsolutionofhydrochloricacidR.
F. O-4,6-dideoxy-4-[[(1S,4R,5S,6S)-4,5,6-trihydroxy-3-
(hydroxymethyl)cyclohex-2-enyl]amino]-α-D-glucopyranosyl- Spectralrange:220-350nm.
(1→4)-O-α-D-glucopyranosyl-(1→4)-O-α-D-glucopyranosyl- Absorptionmaxima:at233nmand322nm.
(1→4)-D-glucopyranose(4-O-α-acarbosyl-D-glucopyranose), Specificabsorbanceattheabsorptionmaximum:555to
605at233nm.
B. Infraredabsorptionspectrophotometry(2.2.24).
Preparation:discs.
Comparison:acebutololhydrochlorideCRS.
C. Thin-layerchromatography(2.2.27).
Testsolution. Dissolve20mgofthesubstancetobe
examinedinmethanolRanddiluteto20mLwiththesame
solvent.
Referencesolution(a). Dissolve20mgofacebutolol
hydrochlorideCRSinmethanolRanddiluteto20mLwith
thesamesolvent.
Referencesolution(b). Dissolve20mgofpindololCRSin
methanolRanddiluteto20mLwiththesamesolvent. To
G. α-D-glucopyranosylO-4,6-dideoxy-4-[[(1S,4R,5S,6S)-4,5,6- 1mLofthissolutionadd1mLofreferencesolution(a).
trihydroxy-3-(hydroxymethyl)cyclohex-2-enyl]amino]-α-D- Plate:TLCsilicagelF254plateR.
glucopyranosyl-(1→4)-O-α-D-glucopyranosyl-(1→4)-O-α-D- Mobilephase:perchloricacidR,methanolR,waterR
glucopyranoside(α-D-glucopyranosylα-acarboside), (5:395:600V/V/V).
Application:10μL.
Development:over3/4oftheplate.
Drying:inair.
Detection:examineinultravioletlightat254nm.
Systemsuitability:thechromatogramobtainedwith
referencesolution(b)shows2clearlyseparatedprincipal
spots.
Results:theprincipalspotinthechromatogramobtained
withthetestsolutionissimilarinpositionandsizetothe
H.O-4,6-dideoxy-4-[[(1S,4R,5S,6S)-4,5,6-trihydroxy-3- principalspotinthechromatogramobtainedwithreference
(hydroxymethyl)cyclohex-2-enyl]amino]-α-D-glucopyranosyl- solution(a).
(1→4)-O-6-deoxy-α-D-glucopyranosyl-(1→4)-D-glucopyranose. D. Itgivesreaction(a)ofchlorides(2.3.1).
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EUROPEANPHARMACOPOEIA7.0 Acebutololhydrochloride
TESTS — anyotherimpurity:foreachimpurity,notmorethanthe
areaoftheprincipalpeakinthechromatogramobtained
Appearanceofsolution. Thesolutionisnotmoreopalescent
withreferencesolution(a)(0.1percent);
thanreferencesuspensionII(2.2.1)andnotmoreintensely
colouredthanreferencesolutionBY (2.2.2,MethodII). — total:notmorethan5timestheareaoftheprincipalpeak
5
inthechromatogramobtainedwithreferencesolution(a)
Dissolve0.5ginwaterRanddiluteto10mLwiththesame
(0.5percent);
solvent.
— disregardlimit:0.5timestheareaoftheprincipalpeak
pH(2.2.3):5.0to7.0.
inthechromatogramobtainedwithreferencesolution(a)
Dissolve0.20gincarbondioxide-freewaterRanddiluteto
(0.05percent).
20mLwiththesamesolvent.
Heavymetals(2.4.8):maximum20ppm.
Relatedsubstances. Liquidchromatography(2.2.29).
Dissolve0.50gin20.0mLofwaterR.Thesolutioncomplies
Testsolution. Dissolve0.100gofthesubstancetobeexamined
withtestE.Preparethereferencesolutionbydiluting10.0mLof
inmobilephaseAanddiluteto50.0mLwithmobilephaseA.
leadstandardsolution(1ppmPb)Rto20.0mLwithwaterR.
Referencesolution(a). Dissolve20.0mgofthesubstanceto
Lossondrying(2.2.32):maximum0.5percent,determinedon
beexaminedinmobilephaseAanddiluteto100.0mLwith
1.000gbydryinginanovenat105°Cfor3h.
mobilephaseA.Dilute0.5mLofthissolutionto50.0mLwith
mobilephaseA. Sulfatedash(2.4.14):maximum0.1percent,determinedon
1.0g.
Referencesolution(b). Dissolvethecontentsofavialof
acebutololimpurityICRSin1.0mLofmobilephaseA.
ASSAY
Referencesolution(c). Mix2.0mLofreferencesolution(a)
Dissolve0.300gin50mLofethanol(96percent)Randadd
and1.0mLofreferencesolution(b)anddiluteto10.0mLwith
1mLof0.1Mhydrochloricacid. Carryoutapotentiometric
mobilephaseA.
titration(2.2.20),using0.1Msodiumhydroxide. Readthe
Referencesolution(d). Dissolve5.0mgofacebutolol volumeaddedbetweenthe2pointsofinflexion.
impurityCCRSin10mLofacetonitrileRanddiluteto
1mLof0.1Msodiumhydroxideisequivalentto37.29mgof
25.0mLwithmobilephaseA.Dilute0.5mLofthissolutionto
C H ClNO.
50.0mLwithmobilephaseA. 18 29 2 4
Referencesolution(e). Dissolve5.0mgofacebutolol STORAGE
impurityBCRSin10.0mLofacetonitrileRanddiluteto
Protectedfromlight.
25.0mLwithmobilephaseA.Dilute1.0mLofthissolutionto
50.0mLwithmobilephaseA.
IMPURITIES
Column:
Specifiedimpurities:A,B,C,D,E,F,G,H,I,J,K.
— size:l=0.125m,Ø=4mm,
— stationaryphase:end-cappedoctadecylsilylsilicagelfor
chromatographyR(5μm),
— temperature:40°C.
Mobilephase:
— mobilephaseA:mix2.0mLofphosphoricacidR,and
3.0mLoftriethylamineRanddiluteto1000mLwith A. N-[3-acetyl-4-[(2RS)-oxiran-2-ylmethoxy]phenyl]butanamide,
waterR;
— mobilephaseB:mixequalvolumesofacetonitrileRand
mobilephaseA;
Time MobilephaseA MobilephaseB
(min) (percentV/V) (percentV/V)
0-2 98 2
B. R1=R2=CO-CH :N-[3-acetyl-4-[(2RS)-2-hydroxy-3-[(1-
2-30.5 98→10 2→90 methylethyl)amino3]propoxy]phenyl]acetamide(diacetolol),
30.5-41 10 90
D. R1=H,R2=CO-CH :1-[5-amino-2-[(2RS)-2-hydroxy-3-[(1-
3
methylethyl)amino]propoxy]phenyl]ethanone,
Flowrate:1.2mL/min.
E. R1=CO-CH-CH-CH,R2=H:N-[4-[(2RS)-2-hydroxy-3-[(1-
Detection:spectrophotometerat240nm. 2 2 3
methylethyl)amino]propoxy]phenyl]butanamide,
Injection:25μL.
Systemsuitability:referencesolution(c): J. R1=CO-CH-CH,R2=CO-CH :N-[3-acetyl-4-[(2RS)-
2 3 3
— resolution:minimum7.0betweenthepeaksduetoimpurityI 2-hydroxy-3-[(1-methylethyl)amino]propoxy]phenyl]-
andacebutolol. propanamide,
Limits:
K. R1=R2=CO-CH-CH-CH :N-[3-butanoyl-4-[(2RS)-2-hydroxy-
— impurityB:notmorethantheareaoftheprincipalpeak 2 2 3
3-[(1-methylethyl)amino]propoxy]phenyl]butanamide,
inthechromatogramobtainedwithreferencesolution(e)
(0.2percent);
— impurityC:notmorethantheareaoftheprincipalpeak
inthechromatogramobtainedwithreferencesolution(d)
(0.1percent);
— impurityI:notmorethantwicetheareaoftheprincipalpeak
inthechromatogramobtainedwithreferencesolution(a)
(0.2percent); C. N-(3-acetyl-4-hydroxyphenyl)butanamide,
GeneralNotices(1)applytoallmonographsandothertexts 1305
www.uapf.com.ua
Aceclofenac EUROPEANPHARMACOPOEIA7.0
Add3mLofa10.0g/LsolutionofhydrochloricacidR.
Allowtostandprotectedfromlightfor15min. Abluecolour
developsandaprecipitateisformed.
TESTS
Relatedsubstances. Liquidchromatography(2.2.29). Prepare
F. R=OH:N-[3-acetyl-4-[(2RS)-2,3-dihydroxypropoxy]phenyl]-
thesolutionsimmediatelybeforeuse.
butanamide,
Testsolution. Dissolve50.0mgofthesubstancetobeexamined
I. R=NH-CH-CH :N-[3-acetyl-4-[(2RS)-3-(ethylamino)-2- inamixtureof30volumesofmobilephaseAand70volumes
2 3
hydroxypropoxy]phenyl]butanamide, ofmobilephaseBanddiluteto25.0mLwiththesamemixture
ofsolvents.
Referencesolution(a). Dissolve21.6mgofdiclofenac
sodiumCRS(impurityA)inamixtureof30volumesofmobile
phaseAand70volumesofmobilephaseBanddiluteto
50.0mLwiththesamemixtureofsolvents.
Referencesolution(b). Dilute2.0mLofthetestsolutionto
10.0mLwithamixtureof30volumesofmobilephaseAand
G. N,N′-[[(1-methylethyl)imino]bis[(2-hydroxypropane-1,3- 70volumesofmobilephaseB.
diyl)oxy(3-acetyl-1,4-phenylene)]]dibutanamide(biamine), Referencesolution(c). Mix1.0mLofreferencesolution(a)and
1.0mLofreferencesolution(b)anddiluteto100.0mLwitha
mixtureof30volumesofmobilephaseAand70volumesof
mobilephaseB.
Referencesolution(d). Dissolve4.0mgofaceclofenac
impurityFCRSand2.0mgofaceclofenacimpurityHCRSin
amixtureof30volumesofmobilephaseAand70volumesof
mobilephaseBthendiluteto10.0mLwiththesamemixture
ofsolvents.
H.N,N′-[(2-hydroxypropane-1,3-diyl)bis[oxy(3-acetyl-1,4-
Referencesolution(e). Mix1.0mLofreferencesolution(b)and
phenylene)]]dibutanamide.
1.0mLofreferencesolution(d)anddiluteto100.0mLwitha
mixtureof30volumesofmobilephaseAand70volumesof
07/2009:1281 mobilephaseB.
Referencesolution(f). Dissolvethecontentsofavialof
ACECLOFENAC
diclofenacimpurityACRS(aceclofenacimpurityI)in1.0mL
ofamixtureof30volumesofmobilephaseAand70volumes
Aceclofenacum ofmobilephaseB,add1.5mLofthesamemixtureofsolvents
andmix.
Referencesolution(g). Dissolve4mgofaceclofenacforpeak
identificationCRS(containingimpuritiesB,C,D,EandG)
in2.0mLofamixtureof30volumesofmobilephaseAand
70volumesofmobilephaseB.
Column:
— size:l=0.25m,Ø=4.6mm;
C H ClNO M 354.2
16 13 2 4 r — stationaryphase:sphericalend-cappedoctadecylsilylsilica
[89796-99-6]
gelforchromatographyR(5μm)withaporesizeof10nm
andacarbonloadingof19percent;
DEFINITION
— temperature:40°C.
[[[2-[(2,6-Dichlorophenyl)amino]phenyl]acetyl]oxy]aceticacid.
Mobilephase:
Content:99.0percentto101.0percent(driedsubstance).
— mobilephaseA:1.12g/LsolutionofphosphoricacidR
CHARACTERS adjustedtopH7.0usinga42g/Lsolutionofsodium
Appearance:whiteoralmostwhite,crystallinepowder. hydroxideR;
Solubility:practicallyinsolubleinwater,freelysolublein — mobilephaseB:waterR,acetonitrileR(1:9V/V);
acetone,solubleinethanol(96percent).
Time MobilephaseA MobilephaseB
IDENTIFICATION (min) (percentV/V) (percentV/V)
0-25 70→50 30→50
Firstidentification:B.
Secondidentification:A,C. 25-30 50→20 50→80
A. Dissolve50.0mginmethanolRanddiluteto100.0mLwith 30-50 20 80
thesamesolvent. Dilute2.0mLofthesolutionto50.0mL
withmethanolR.Examinedbetween220nmand370nm Flowrate:1.0mL/min.
(2.2.25),thesolutionshowsanabsorptionmaximumat Detection:spectrophotometerat275nm.
275nm. Thespecificabsorbanceattheabsorptionmaximum Injection:10μLofthetestsolutionandreferencesolutions(c),
is320to350. (e),(f)and(g).
B. Infraredabsorptionspectrophotometry(2.2.24). Identificationofimpurities:usethechromatogramsupplied
Comparison:Ph.Eur. referencespectrumofaceclofenac. withaceclofenacforpeakidentificationCRSandthe
C. Dissolveabout10mgin10mLofethanol(96percent)R. chromatogramobtainedwithreferencesolution(g)toidentify
To1mLofthesolution,add0.2mLofamixture,prepared thepeaksduetoimpuritiesB,C,D,EandG.
immediatelybeforeuse,ofequalvolumesofa6g/Lsolution Relativeretentionwithreferencetoaceclofenac
ofpotassiumferricyanideRanda9g/Lsolutionofferric (retentiontime=about11min):impurityA=about0.8;
chlorideR.Allowtostandprotectedfromlightfor5min. impurityG=about1.3;impurityH=about1.5;
1306 Seetheinformationsectionongeneralmonographs(coverpages)
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EUROPEANPHARMACOPOEIA7.0 Acemetacin
impurityI=about2.3;impurityD=about3.1; B. R=CH :methyl[2-[(2,6-dichlorophenyl)amino]phenyl]-
3
impurityB=about3.2;impurityE=about3.3; acetate(methylesterofdiclofenac),
impurityC=about3.5;impurityF=about3.7.
C. R=CH :ethyl[2-[(2,6-dichlorophenyl)amino]phenyl]acetate
Systemsuitability:referencesolution(c): 2 5
(ethylesterofdiclofenac),
— resolution:minimum5.0betweenthepeaksdueto
impurityAandaceclofenac.
Limits:
— impurityA:notmorethantheareaofthecorresponding
peakinthechromatogramobtainedwithreference
solution(c)(0.2percent);
— impuritiesB,C,D,E,G:foreachimpurity,notmorethan
theareaofthepeakduetoaceclofenacinthechromatogram
obtainedwithreferencesolution(e)(0.2percent); D. R= CH :methyl[[[2-[(2,6-dichlorophenyl)-
3
— impurityF:notmorethantheareaofthecorresponding amino]phenyl]acetyl]oxy]acetate(methylesterof
peakinthechromatogramobtainedwithreference aceclofenac),
solution(e)(0.2percent);
E. R = CH : ethyl[[[2-[(2,6-dichlorophenyl)-
— impurityH:notmorethantheareaofthecorresponding amino2]ph5enyl]acetyl]oxy]acetate(ethylesterof
peakinthechromatogramobtainedwithreference aceclofenac),
solution(e)(0.1percent);
F. R=CH-CH :benzyl[[[2-[(2,6-dichlorophenyl)-
— impurityI:notmorethantheareaofthecorrespondingpeak 2 6 5
amino]phenyl]acetyl]oxy]acetate(benzylesterof
inthechromatogramobtainedwithreferencesolution(f)
aceclofenac),
(0.1percent);
— unspecifiedimpurities:notmorethan0.5timestheareaof G. R =CH-COH:[[[[[2-[(2,6-dichlorophenyl)-
2 2
thepeakduetoaceclofenacinthechromatogramobtained amino]phenyl]acetyl]oxy]acetyl]oxy]aceticacid(acetic
withreferencesolution(e)(0.10percent); aceclofenac),
— total:notmorethan0.7percent;
H.R=CH-CO-O-CH-COH:[[[[[[[2-[(2,6-dichlorophenyl)-
2 2 2
— disregardlimit:0.1timestheareaofthepeakdueto amino]phenyl]acetyl]oxy]acetyl]oxy]acetyl]oxy]aceticacid
aceclofenacinthechromatogramobtainedwithreference (diaceticaceclofenac),
solution(e)(0.02percent).
Heavymetals(2.4.8):maximum10ppm.
To2.0ginasilicacrucible,add2mLofsulfuricacidRtowet
thesubstance. Heatprogressivelytoignitionandcontinue
heatinguntilanalmostwhiteoratmostagreyishresidueis
obtained. Carryouttheignitionatatemperaturenotexceeding
800°C.Allowtocool. Add3mLofhydrochloricacidRand
I. 1-(2,6-dichlorophenyl)-1,3-dihydro-2H-indol-2-one.
1mLofnitricacidR.Heatandevaporateslowlytodryness.
Coolandadd1mLofa100g/LsolutionofhydrochloricacidR
and10.0mLofdistilledwaterR.Neutralisewitha1.0g/L
04/2008:1686
solutionofammoniaRusing0.1mLofphenolphthalein
corrected7.0
solutionRasindicator. Add2.0mLofa60g/Lsolutionof
anhydrousaceticacidRanddiluteto20mLwithdistilled
ACEMETACIN
waterR.12mLofthesolutioncomplieswithtestA.Preparethe
referencesolutionusingleadstandardsolution(1ppmPb)R.
Acemetacinum
Lossondrying(2.2.32):maximum0.5percent,determinedon
1.000gbydryinginanovenat105°C.
Sulfatedash(2.4.14):maximum0.1percent,determinedon
1.0g.
ASSAY
Dissolve0.300gin40mLofmethanolR.Titratewith0.1M
sodiumhydroxide,determiningtheend-pointpotentiometrically
(2.2.20).
C H ClNO M 415.8
1mLof0.1Msodiumhydroxideisequivalentto35.42mgof 21 18 6 r
[53164-05-9]
C H ClNO.
16 13 2 4
DEFINITION
STORAGE
[[[1-(4-Chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-
Inanairtightcontainer,protectedfromlight.
yl]acetyl]oxy]aceticacid.
IMPURITIES Content:99.0percentto101.0percent(driedsubstance).
Specifiedimpurities:A,B,C,D,E,F,G,H,I.
CHARACTERS
Appearance:yelloworgreenish-yellow,crystallinepowder.
Solubility:practicallyinsolubleinwater,solubleinacetone,
slightlysolubleinanhydrousethanol.
Itshowspolymorphism(5.9).
IDENTIFICATION
A. R=H:[2-[(2,6-dichlorophenyl)amino]phenyl]aceticacid Infraredabsorptionspectrophotometry(2.2.24).
(diclofenac), Comparison:acemetacinCRS.
GeneralNotices(1)applytoallmonographsandothertexts 1307
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Acemetacin EUROPEANPHARMACOPOEIA7.0
Ifthespectraobtainedinthesolidstateshowdifferences, Systemsuitability:referencesolution(d):
dissolvethesubstancetobeexaminedandthereference
— peak-to-valleyratio:minimum15,whereH =heightabove
substanceseparatelyinacetoneR,evaporatetodrynessand p
thebaselineofthepeakduetoimpurityBandH =height
recordnewspectrausingtheresidues. v
abovethebaselineofthelowestpointofthecurveseparating
thispeakfromthepeakduetoacemetacin.
TESTS
Limits:
Relatedsubstances. Liquidchromatography(2.2.29).
— correctionfactors:forthecalculationofcontent,multiplythe
Testsolution. Dissolve0.100gofthesubstancetobeexamined peakareasofthefollowingimpuritiesbythecorresponding
inacetonitrileforchromatographyRanddiluteto20.0mL correctionfactor:impurityC=1.3;impurityD=1.4;
withthesamesolvent. impurityF=1.3;
Referencesolution(a). Dilute5.0mLofthetestsolution — impurityE:notmorethan3timestheareaoftheprincipal
to50.0mLwithacetonitrileforchromatographyR.Dilute peakinthechromatogramobtainedwithreference
1.0mLofthissolutionto100.0mLwithacetonitrilefor solution(a)(0.3percent);
chromatographyR.
— impurityB:notmorethantheareaofthecorresponding
Referencesolution(b). Dissolve5.0mgofacemetacin peakinthechromatogramobtainedwithreference
impurityACRSand10.0mgofindometacinCRS(impurityB) solution(c)(0.2percent);
inacetonitrileforchromatographyR,anddiluteto50.0mL
withthesamesolvent. — impurityA:notmorethantheareaofthecorresponding
peakinthechromatogramobtainedwithreference
Referencesolution(c). Dilute1.0mLofreferencesolution(b) solution(c)(0.1percent);
to20.0mLwithacetonitrileforchromatographyR.
— impuritiesC,D,F:foreachimpurity,notmorethanthearea
Referencesolution(d). To1mLofreferencesolution(b),add oftheprincipalpeakinthechromatogramobtainedwith
10mLofthetestsolutionanddiluteto20mLwithacetonitrile referencesolution(a)(0.1percent);
forchromatographyR.
— unspecifiedimpurities:foreachimpurity,notmorethanthe
Referencesolution(e). Dissolvethecontentsofavialof areaoftheprincipalpeakinthechromatogramobtained
acemetacinimpuritymixtureCRS(containingimpuritiesC,D, withreferencesolution(a)(0.10percent);
EandF)in1.0mLofthetestsolution.
— total:notmorethan4timestheareaoftheprincipalpeak
Column: inthechromatogramobtainedwithreferencesolution(a)
— size:l=0.25m,Ø=4mm; (0.4percent);
— stationaryphase:sphericalend-cappedoctadecylsilylsilica — disregardlimit:0.5timestheareaoftheprincipalpeak
gelforchromatographyR(5μm); inthechromatogramobtainedwithreferencesolution(a)
(0.05percent).
— temperature:40°C.
Heavymetals(2.4.8):maximum20ppm.
Mobilephase:
Solventmixture:methanolR,acetoneR(10:90V/V).
— mobilephaseA:dissolve1.0gofpotassiumdihydrogen
0.250gcomplieswithtestH.Preparethereferencesolution
phosphateRin900mLofwaterR,adjusttopH6.5with
using0.5mLofleadstandardsolution(10ppmPb)R.
1Msodiumhydroxideanddiluteto1000mLwithwaterR;
Lossondrying(2.2.32):maximum0.5percent,determinedon
— mobilephaseB:acetonitrileforchromatographyR;
1.000gbydryinginanovenat105°C.
Time MobilephaseA MobilephaseB Sulfatedash(2.4.14):maximum0.1percent,determinedon
(min) (percentV/V) (percentV/V) 1.0g.
0-5 95 5
5-9 95→65 5→35 ASSAY
9-16 65 35
Dissolve0.350gin20mLofacetoneRandadd10mLof
16-28 65→20 35→80 waterR.Titratewith0.1Msodiumhydroxide,determiningthe
end-pointpotentiometrically(2.2.20).
28-34 20 80
1mLof0.1Msodiumhydroxide isequivalentto41.58mg
Flowrate:1.0mL/min. ofC H ClNO.
21 18 6
Detection:spectrophotometerat235nm.
STORAGE
Injection:20μL.
Protectedfromlight.
Identificationofimpurities:
— usethechromatogramsuppliedwithacemetacinimpurity IMPURITIES
mixtureCRSandthechromatogramobtainedwithreference
solution(e)toidentifythepeaksduetoimpuritiesC,D,E Specifiedimpurities:A,B,C,D,E,F.
andF;
— usethechromatogramobtainedwithreferencesolution(b)
toidentifythepeakduetoimpurityB.
Relativeretentionwithreferencetoacemetacin
(retentiontime=about15min):impurityA=about0.7;
impurityB=about0.9;impurityF=about1.2;
impurityC=about1.3;impurityD=about1.5;
impurityE=about2.2. A. 4-chlorobenzoicacid,
1308 Seetheinformationsectionongeneralmonographs(coverpages)
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EUROPEANPHARMACOPOEIA7.0 Acesulfamepotassium
Systemsuitability:referencesolution(b):
— thechromatogramshows2clearlyseparatedbands.
Results:theprincipalbandinthechromatogramobtained
withthetestsolutionissimilarinpositionandsizetothe
principalbandinthechromatogramobtainedwithreference
solution(a).
C. 0.5mLofsolutionS(seeTests)givesreaction(b)of
B. R1=R2=R3=H:[1-(4-chlorobenzoyl)-5-methoxy-2-
potassium(2.3.1).
methylindol-3-yl]aceticacid(indometacin),
C. R1=Cl,R2=H,R3=CH-COH:[[[1-(3,4-dichlorobenzoyl)- TESTS
2 2
5-methoxy-2-methyl-1H-indol-3-yl]acetyl]oxy]aceticacid, SolutionS.Dissolve10.0gincarbondioxide-freewaterRand
D. R1=H,R2=C(CH),R3=CH-COH:[[[1-(4-chlorobenzoyl)- diluteto50mLwiththesamesolvent.
33 2 2
6-(1,1-dimethylethyl)-5-methoxy-2-methyl-1H-indol-3- Appearanceofsolution. SolutionSisclear(2.2.1)and
yl]acetyl]oxy]aceticacid, colourless(2.2.2,MethodII).
E. R1=R2=H,R3=CH-CO-O-C(CH) :1,1-dimethylethyl Acidityoralkalinity. To20mLofsolutionSadd0.1mLof
2 33
[[[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3- bromothymolbluesolutionR1. Notmorethan0.2mLof0.01M
yl]acetyl]oxy]acetate, hydrochloricacidor0.01Msodiumhydroxideisrequiredto
changethecolouroftheindicator.
F. R1=R2=H,R3=CH-CO-O-CH-COH:[[[[[1-
2 2 2
(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3- ImpurityA.Thin-layerchromatography(2.2.27).
yl]acetyl]oxy]acetyl]oxy]aceticacid. Testsolution. Dissolve0.80gofthesubstancetobeexamined
inwaterRanddiluteto10mLwiththesamesolvent.
01/2008:1282
Referencesolution(a). Dissolve50mgofacetylacetamideR
corrected6.0
(impurityA)inwaterRanddiluteto25mLwiththesame
solvent. To5mLofthesolutionadd45mLofwaterRand
ACESULFAME POTASSIUM
diluteto100mLwithmethanolR.
Referencesolution(b). To10mLofreferencesolution(a)add
Acesulfamum kalicum
1mLofthetestsolutionanddiluteto20mLwithmethanolR.
Plate:TLCsilicagelplateR.
Mobilephase:waterR,ethanol(96percent)R,ethylacetateR
(2:15:74V/V/V).
Application:5μL.
Development:overapathof15cm.
CHKNOS M 201.2 Drying:inairuntilthesolventsarecompletelyremoved.
4 4 4 r
[55589-62-3] Detection:spraywithphosphoricvanillinsolutionRandheat
at120°Cforabout10min;examineindaylight.
DEFINITION
Systemsuitability:thechromatogramobtainedwithreference
Potassium6-methyl-1,2,3-oxathiazin-4-olate2,2-dioxide.
solution(a)showsaclearlyvisiblespotandthechromatogram
Content:99.0percentto101.0percent(driedsubstance).
obtainedwithreferencesolution(b)shows2clearlyseparated
spots.
CHARACTERS
Limit:
Appearance:whiteoralmostwhite,crystallinepowderor
colourlesscrystals. — impurityA:anyspotduetoimpurityAisnotmoreintense
Solubility:solubleinwater,veryslightlysolubleinacetoneand thanthespotinthechromatogramobtainedwithreference
inethanol(96percent). solution(a)(0.125percent).
Relatedsubstances. Liquidchromatography(2.2.29).
IDENTIFICATION
Testsolution. Dissolve0.100gofthesubstancetobeexamined
Firstidentification:A,C.
inwaterRanddiluteto10.0mLwiththesamesolvent.
Secondidentification:B,C.
Referencesolution(a). Dissolve4.0mgofacesulfame
A. Infraredabsorptionspectrophotometry(2.2.24). potassiumimpurityBCRSinwaterRanddiluteto100.0mL
Comparison:acesulfamepotassiumCRS. withthesamesolvent. Dilute1.0mLofthissolutionto
B. Thin-layerchromatography(2.2.27). 200.0mLwithwaterR.
Testsolution. Dissolve5mgofthesubstancetobeexamined Referencesolution(b). Dissolve0.100gofthesubstancetobe
inwaterRanddiluteto5mLwiththesamesolvent. examinedinreferencesolution(a)anddiluteto10.0mLwith
thesamesolution.
Referencesolution(a). Dissolve5mgofacesulfame
potassiumCRSinwaterRanddiluteto5mLwiththesame Referencesolution(c). Dilute1.0mLofthetestsolution
solvent. to100.0mLwithwaterR.Dilute1.0mLofthissolutionto
10.0mLwithwaterR.
Referencesolution(b). Dissolve5mgofacesulfame
potassiumCRSand5mgofsaccharinsodiumRinwaterR Column:
anddiluteto5mLwiththesamesolvent. — size:l=0.25m,Ø=4.6mm,
Plate:celluloseforchromatographyRasthecoating — stationaryphase:octadecylsilylsilicagelfor
substance. chromatographyR(3μm).
Mobilephase:concentratedammoniaR,acetoneR,ethyl Mobilephase:mix40volumesofacetonitrileR and60volumes
acetateR(10:60:60V/V/V). ofa3.3g/Lsolutionoftetrabutylammoniumhydrogen
Application:5μLasbands. sulfateR.
Development:twiceoverapathof15cm. Flowrate:1mL/min.
Drying:inacurrentofwarmair. Detection:spectrophotometerat234nm.
Detection:examineinultravioletlightat254nm. Injection:20μL.
GeneralNotices(1)applytoallmonographsandothertexts 1309
www.uapf.com.ua
Acetazolamide EUROPEANPHARMACOPOEIA7.0
Runtime:3timestheretentiontimeofacesulfame. 04/2009:0454
Relativeretentionwithreferencetoacesulfame(retention
time=about5.3min):impurityB=about1.6. ACETAZOLAMIDE
Systemsuitability:
Acetazolamidum
— peak-to-valleyratio:minimum1.2,whereH =height
p
abovethebaselineofthepeakduetoimpurityBand
H =heightabovethebaselineofthelowestpointofthe
v
curveseparatingthispeakfromthepeakduetoacesulfame
inthechromatogramobtainedwithreferencesolution(b).
Limits: CHNOS M 222.2
4 6 4 3 2 r
[59-66-5]
— impurityB:notmorethantheareaoftheprincipalpeak
inthechromatogramobtainedwithreferencesolution(a)
DEFINITION
(20ppm),
N-(5-Sulfamoyl-1,3,4-thiadiazol-2-yl)acetamide.
— unspecifiedimpurities:foreachimpurity,notmorethanthe
Content:98.5percentto101.0percent(driedsubstance).
areaoftheprincipalpeakinthechromatogramobtained
withreferencesolution(c)(0.1percent),
CHARACTERS
— total:notmorethantheareaoftheprincipalpeakinthe
Appearance:whiteoralmostwhite,crystallinepowder.
chromatogramobtainedwithreferencesolution(c)(0.1per
Solubility:veryslightlysolubleinwater,slightlysolublein
cent),
ethanol(96percent). Itdissolvesindilutesolutionsofalkali
— disregardlimit:0.5timestheareaoftheprincipalpeak hydroxides.
inthechromatogramobtainedwithreferencesolution(c)
Itshowspolymorphism(5.9).
exceptforthepeakduetoimpurityB(0.05percent).
Fluorides:maximum3ppm. IDENTIFICATION
Firstidentification:A,B.
Potentiometry(2.2.36,MethodI).
Secondidentification:A,C,D.
Testsolution. Dissolve3.000gofthesubstanceto
beexaminedindistilledwaterR,add15.0mLof A. Ultravioletandvisibleabsorptionspectrophotometry
total-ionic-strength-adjustmentbufferR1anddiluteto50.0mL (2.2.25).
withdistilledwaterR. SolutionA.Dissolve30.0mgin0.01Msodiumhydroxide
anddiluteto100.0mLwiththesamesolvent. Dilute10.0mL
Referencesolutions. To0.5mL,1.0mL,1.5mLand3.0mL
ofthesolutionto100.0mLwith0.01Msodiumhydroxide.
offluoridestandardsolution(10ppmF)Radd15.0mLof
total-ionic-strength-adjustmentbufferR1anddiluteto50.0mL SolutionB.Dilute25.0mLofsolutionAto100.0mLwith
withdistilledwaterR. 0.01Msodiumhydroxide.
Indicatorelectrode:fluoride-selective. Spectralrange:230-260nmforsolutionA;260-350nmfor
solutionB.
Referenceelectrode:silver-silverchloride.
Absorptionmaximum:at240nmforsolutionA;at292nm
Heavymetals(2.4.8):maximum5ppm. forsolutionB.
12mLofsolutionScomplieswithtestA.Preparethereference Specificabsorbanceattheabsorptionmaximum:162to
solutionusingleadstandardsolution(1ppmPb)R. 176forsolutionA;570to620forsolutionB.
Lossondrying(2.2.32):maximum1.0percent,determinedon B. Infraredabsorptionspectrophotometry(2.2.24).
1.000gbydryinginanovenat105°Cfor3h. Comparison:acetazolamideCRS.
Ifthespectraobtainedinthesolidstateshowdifferences,
ASSAY
dissolvethesubstancetobeexaminedandthereference
Dissolve0.150gin50mLofanhydrousaceticacidR. substanceseparatelyinethanol(96percent)R,evaporate
Titratewith0.1Mperchloricacid,determiningtheend-point todrynessandrecordnewspectrausingtheresidues.
potentiometrically(2.2.20). C. Introduceabout20mgintoatest-tubeandadd4mLof
1mLof0.1Mperchloricacidisequivalentto20.12mg dilutehydrochloricacidRand0.2gofzincpowderR.
ofCHKNOS. ImmediatelyplaceapieceofleadacetatepaperRoverthe
4 4 4 mouthofthetube. Thepapershowsabrownish-blackcolour.
IMPURITIES D. Dissolveabout25mginamixtureof0.1mLofdilutesodium
hydroxidesolutionRand5mLofwaterR.Add0.1mLof
Specifiedimpurities:A,B.
coppersulfatesolutionR.Agreenish-blueprecipitateis
formed.
TESTS
Appearanceofsolution. Thesolutionisnotmoreopalescent
thanreferencesuspensionII(2.2.1)andnotmoreintensely
colouredthanreferencesolutionY orBY (2.2.2,MethodII).
5 5
A. 3-oxobutanamide(acetylacetamide), Dissolve1.0gin10mLof1Msodiumhydroxide.
Relatedsubstances. Liquidchromatography(2.2.29).
Testsolution. Dissolve40mgofthesubstancetobeexamined
inthemobilephaseanddiluteto100.0mLwiththemobile
phase.
Referencesolution(a). Dilute1.0mLofthetestsolutionto
100.0mLwiththemobilephase. Dilute1.0mLofthissolution
B. 5-chloro-6-methyl-1,2,3-oxathiazin-4(3H)-one2,2-dioxide. to10.0mLwiththemobilephase.
1310 Seetheinformationsectionongeneralmonographs(coverpages)