2017618 IndianPharmacopoeia1996

DILTIAZEMHYDROCHLORIDE

C22H26N2O4S,HClMol.Wt.
450.98

DiltiazemHydrochlorideis(+)cis2,3,4,5tetrahydro5(2
dimethylaminoethyl)2(4methoxyphenyl)4oxobenzo[b]
thiazepin3ylacetatemonohydrochloride.

Category:Antianginalcalciumchannelblocker.

Dose:Initially,30to60mgthricedailymaximum,480mg
daily.

Description:White,crystallinepowderorsmallcrystals.

Solubility:Freelysolubleinchloroform,inmethanol,inwater
andinformicacidsparinglysolubleinethanolinsolublein
ether.

Storage:Storeinwellclosed,lightresistantcontainers.

STANDARDS

DiltiazemHydrochloridecontainsnotlessthan98.5percent
andnotmorethan101.5percentofC22H26N2O4S,HCl,
calculatedwithreferencetothedriedsubstance.

Identification:A:Theinfraredabsorptionspectrum,
Appendix5.4,isconcordantwiththereferencespectrumof
diltiazemhydrochlorideorwiththespectrumobtainedfrom
diltiazemhydrochlorideRS.

B:InthetestforRelatedsubstances,theprincipalpeakinthe
chromatogram obtained with solution (1) has the same
retention time as that of the peak due to diltiazem
hydrochlorideinthechromatogramobtainedwithsolution(2).

C: A 5% w/v solution gives the reactions of chlorides,

Appendix3.1.

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D:Meltsatabout210owithdecomposition,Appendix8.8.

Specific optical rotation: Between +110o and +116o,

determinedina1%w/vsolution,Appendix8.9.

Heavymetals:Notmore than 20 ppm, determined on 1 g by

MethodA,Appendix3.12.

Relatedsubstances,theprincipalpeakinthechromatogram
obtainedwithsolution(1)hasthesameretentiontimeasthat
ofthepeakduetodiltiazemhydrochlorideinthechromatogram
obtainedwithsolution(2)0.0012%w/veachofdiltiazem
hydrochlorideRSanddesacetyldiltiazemhydrochlorideRS.

Thechromatographicproceduremaybecarriedoutusing(a)a
stainlesssteelcolumn(30cmx3.9mm)packedwithstationary
phaseLCI,(b)asthemobilephasewithaflowrateofabout1.6
mlperminuteasolutionpreparedasdescribedbelowand(c)a
detectionwavelengthofabout240nm.Forthemobilephase,
prepareabuffersolutioncontaining0.116%w/vofd10
camphorsulphonicacidin0.1Msodiumacetate,butadjustthe
pHofthesolutionto6.2bytheadditionof0.1Msodium
hydroxide,mix50volumesofthisbuffersolutionto6.2bythe
additionof0.1Msodiumhydroxide,mix50volumesofthis
buffersolutionwith25volumesofacetonitrileand25volumes
ofmethanol,filteranddegas.

Inject10plofsolution(2)andrecordthepeakresponses.The
retentiontimesfordesacetyldiltiazemanddiltiazemareabout
0.65and1.0,respectively.Theresolution,R,between
desacetyldiltiazemanddiltiazemisnotlessthan3,andthe
numberoftheoreticalplates,n,forthediltiazempeakisnot
lessthan1200.Therelativestandarddeviationofthepeak
responseforreplicateinjectionsduetodiltiazemanddesacetyl
diltiazempeaksisnotmorethan10.0%.Inject10mlof
solution(1)andmeasuretheresponsesofallpeaks.

Calculatethepercentagecontentofdesacetyldiltiazem
hydrochlorideinthesubstancebeingexaminedcomparingthe
areaofpeaksduetodesacetyldiltiazeminthechromatograms
ofsolutions(1)and(2)andfromthecontentofdesacetyl
diltiazemhydrochlorideinsolution(2).Similarly,calculatethe
percentagecontentofeachimpuritypeakotherthanthepeaks
duetodiltiazemanddesacetyldiltiazemwiththatofthepeak
duetodesaceyldiltiazeminthechromatogramobtainedwith
solution(1)andfromthecontentofdesacetyldiltiazem
hydrochlorideinsolution(2).Desacetyldiltiazemhydrochloride
contentisnotmorethan0.%w/vandthetotalimpurities
includingdesacetyldiltiazemhydrochloridecontentisnotmore
than1.0%w/vwithnootherindividualimpuritybeingmorethan
0.5%w/v.

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Relatedsubstances:Carryoutthemethodforhigh
performanceliquidchromatography,Appendix4.3,usingthe
followingsolutionsinmethanolcontaining(1)0.12%w/v
solutionofthesubstancebeingexaminedand(2)0.12%w/v
eachofdiltiazemhydrochlorideRSanddesacetyldiltiazem
hydrochlorideRS.

Thechromatographicproceduremaybecarriedoutusing(a)a
stainlesssteelcolumn(30cmx3.9mm)packedwithstationary
phaseLC1,(b)asthemobilephasewithaflowrateofabout
1.6mlperminuteasolutionpreparedasdescribedbelowand
(c)adetectionwavelengthofabout240nm.Forthemobile
phase,prepareabuffersolutioncontaining0.116%w/vofd10
camphorsulphonicacidin0.1Msodiumacetate,adjustthepH
ofthesolutionto6.2bytheadditionof0.1Msodiumhydroxide,
mix50volumesofthisbuffersolutionwith25volumesof
acetonitrileand25volumesofmethanol,filteranddegas.

Injectsolution(2)sixtimes.Thetestisnotvalidunlessthe
relativestandarddeviationoftheareaofthepeakresponsefor
replicateinjectionsduetodiltiazemhydrochlorideislessthan
10.0%.Makeadjustments,ifnecessary.

Inject10lofsolution(1)and(2)separatelyandmeasurethe
peakresponsesofallthepeaks.Therelativeretentiontimesfor
desacetyldiltiazemanddiltiazemareabout0.65and1.0
respectively.Calculatethepercentagecontentofdesacetyl
diltiazemhydrochlorideinthesubstancebeingexaminedby
comparingtheratiooftheareaofthepeakduetodesacetyl
diltiazemobtainedwithsolutions(2)and(1)respectively.
Similarly,calculatethepercentagecontentofeachimpurity
peakotherthantheprincipalpeakandthepeakdueto
desacetyldiltiazembycomparingtheratiosoftheindividual
areasofeachimpuritypeakobtainedwithsolution(1)withthat
obtainedwithsolution(2).Desacetyldiltiazemhydrochloride
contentisnotmorethan0.5%w/v,thetotalimpuritiesincluding
desacetyldiltiazemhydrochloridecontentisnotmorethan1%
w/vwithnoindividualimpuritymorethan0.5%w/v.
(Ammendment6)

Lossondrying:Notmorethan0.5%,determinedon1gby
dryinginanovenat105ofor2hours,Appendix8.6.

Assay:
CarryoutthemethoddescribedinthetestforRelated
substances.Injectsolutions(1)and(2)alternately.Thetestis
notvalidunlesstherelativestandarddeviationforreplicate
injectionsislessthan2.0%.Calculatethecontentof
C22H26N2O4S,HClfromthedeclaredcontentof
C22H26N2O4S,HClindiltiazemhydrochlorideRS.
CarryoutthemethoddescribedinthetestforRelated
substancesusingthefollowingsolutionsinmethanolcontaining
(1)0.12%w/vofthesubstancebeingexamined,(2)0.0012%
w/veachofdiltiazemhydrochlorideRSanddesacetyl
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diltiazemmhydrochlorideRSand(3)0.12%w/vsolutionof
diltiazemhydrochlorideRS.

Injectsolution(2)andcheckthesystemsuitabilityparameters
liketherelativeretentiontimes,theresolution,R,andcolumn
efficiencyintermsoftheoreticalplates.Injectsolution(3)six
timesandrecordthepeakresponses.Therelativestandard
deviationforreplicateinjectionsisnotmorethan2.0%.

Injectseparately10mlofeachofsolutions(1)and(2),record
thechromatogramsandmeasuretheresponsesforthemajor
peaks.CalculatethecontentofC22H26N2O4S,HClby
comparingtheareaofresponsesduetothediltiazempeaksin
thechromatogramsofsolutions(1)and(3)andfromthe
declaredcontentofC22H26N2O4S,HClindiltiazem
hydrochlorideRS.
(Ammendment6)

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