Review Article An Overview of Analytical Determination of

Hindawi Publishing CorporationJournal of ChemistryVolume 2013 Article ID 184948 16 pageshttpdxdoiorg1011552013184948

Review ArticleAn Overview of Analytical Determination ofDiltiazem Cimetidine Ranitidine and Famotidine byUV Spectrophotometry and HPLC Technique

Nighat Shafi1 Farhan Ahmed Siddiqui1 Huma Naseem2 Nawab Sher3 Arif Zubair4

Azhar Hussain5 Ali Akbar Sial1 and Mirza Tasawer Baig1

1 Faculty of Pharmacy Federal Urdu University Arts Science and Technology Karachi 75300 Pakistan2Department of Pharmaceutical Chemistry Faculty of Pharmacy University of Karachi Karachi 75270 Pakistan3Department of Chemistry University of Karachi Karachi 75270 Pakistan4Department of Environmental Sciences Faculty of Science Federal Urdu University Arts Science and TechnologyKarachi 75300 Pakistan

5 Department of Pharmaceutics Faculty of Pharmacy University of Karachi Karachi 75270 Pakistan

Correspondence should be addressed to Farhan Ahmed Siddiqui farhanchemistgmailcom

Received 5 May 2013 Revised 8 July 2013 Accepted 9 July 2013

Academic Editor Ghada M Hadad

Copyright copy 2013 Nighat Shafi et al This is an open access article distributed under the Creative Commons Attribution Licensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

This review article recapitulates the analytical methods for the quantitative determinations of diltiazem and three H2receptor

antagonists (cimetidine ranitidine and famotidine) by one of the spectroscopic technique (UV spectrophotometery) andseparation technique such as high-performance liquid chromatography (HPLC) The clinical and pharmaceutical analysis of thesedrugs requires effective analytical procedures for quality control pharmaceutical dosage formulations and biological fluids Anextensive survey of the literature published in various analytical and pharmaceutical chemistry-related journals has been compiledin its review A synopsis of reported spectrophotometric and high-performance liquid chromatographic methods for individualdrug is integrated This appraisal illustrates that majority of the HPLC methods reviewed are based on the quantitative analysis ofdrugs in biological fluids and they are appropriate for therapeutic drug monitoring purpose

1 Introduction

11 Diltiazem Hydrochloride Diltiazem hydrochloride(DLZ) d-cis diltiazem d-cis-3-acetyloxy-5-[2-(dimethylam-ino) ethyl]-23-dihydro-2-(4-methoxyphenyl)-15-benzothi-azepin-4(5H)one)hydrochloride (Figure 1) are one of thewidely used benzothiazepine Ca2+-blocking drugs (calciumchannel blockers) Clinically it is used to treat cardiovasculardiseases such as angina pectoris hypertension and cardiacarrhythmias [1 2]

12 Histamine H2Receptor Antagonists Histamine H

2recep-

tor antagonists cimetidine (CIM) ranitidine (RAN) andfamotidine (FAM) classified as class III drugs (high solubilitylow permeability) according to the Biopharmaceutics Classi-fication System (BCS) [3 4] are used in the treatment of

gastrooesophageal reflux disease and gastric and duodenalulceration [5]

13 Cimetidine Cimetidine is N-Cyano-N-methyl-N-[2-[[(5-methyl-1H-imidazol-4-yl)methyl]thio]ethyl]guanidinecontains imidazole ring (Figure 2) and inhibits hepatic cyto-chrome P450 (CYP) 1A2 2C9 2D6 and 3A4 P450 isoforms[6]

14 Ranitidine Hydrochloride Ranitidine hydrochloride isN-2-[[[5-[(dimethylamino)methyl]-2 furanyl]methyl]thio]ethyl-N1015840-methyl-2-nitro-11-ethenediamine (Figure 3) ahistamine H

2receptor antagonist with a furan ring structure

that increases its potency to inhibit gastric acid secretioninduced by various stimuli while lacking the antiandrogenicand hepatic microsomal enzyme-inhibiting effects [7]

2 Journal of Chemistry

N

S

O O

CH3

O

NH3C CH3

OCH3

Figure 1 Diltiazem

15 Famotidine Famotidine 3-[[[2-[(aminoiminomethyl)amino]-4-thiazolyl]methyl]thio]-N (aminosulfonyl) (Figure4) is highly selective histamine H

2receptor antagonist indi-

cated for the treatment of duodenal ulcer gastric ulcer gas-troesophageal reflux disease and Zollinger-Ellison syndrome[8] in the treatment of Parkinsonrsquos and inhibits basal andnoc-turnal gastric secretion as well as secretion stimulated by foodand pentagastrin [9]

The present review article deals with the analytical meth-ods that are useful for pure form pharmaceutical formula-tions and biological specimens of diltiazem and H

2receptor

antagonists (cimetidine ranitidine and famotidine) werefocused and summarized

2 Analytical Methods

Assay method development is very significant for pharma-ceutical industries and pathological laboratories and thisis always desirable to select and develop simple accurateprecise and economical method for the determination ofdrugs in pharmaceutical dosage forms and pathologicalsamples Analytical data are used to screen potential drugs inbiological samples aid in the development of drug synthesessupport formulation studies monitor the stability of bulkpharmaceuticals and formulated products and test finalproducts for release [10]

3 Official and Compendial Methodsof Analysis

Monographs in the ldquoAnalytical Profile of Drug Substancesrdquoseries were also published for diltiazem [11] cimetidine [12]and ranitidine [13] Eur Ph 2002 [14] recommends an HPLCassay for diltiazem in its dosage forms Stability-indicatingmethod for the determination of diltiazem hydrochloride informulated oral preparations by the HPLC technique hasbeen recommended in USP 29 [15] High-performance liquidchromatographic methods are prescribed according to BP2011 and USP 34 for quantitative analysis of pharmaceuticalscontaining cimetidine ranitidine hydrochloride and famoti-dine [16ndash20] Chromatographic conditions of official meth-ods are presented in Table 1 However British Pharmacopeia[21] recommended potentiometric titration method with01M NaOH for ranitidine hydrochloride

NH

N

H3C

H3C

S N

CN

NH

NH

Figure 2 Cimetidine

4 Reported Methods of Analysis

41 Diltiazem Literature survey revealed that a number ofassaymethods have been used for analysis of diltiazem in bulkdrug pharmaceutical preparations and serumusing differenttechniques including LC-MSMS [22ndash24] gas chromatogra-phy [25ndash28] and electron capture gas chromatography [29]

411 Spectrophotometric Methods Many research papershave described the spectrophotometric methods for thedetection of diltiazem in rawmaterials and different pharma-ceutical formulations Recently Ayad et al [30] established amethod by kinetic spectrophotometric and spectrofluorimet-ric technique using NBD-Cl (4-Chloro-7-nitrobenzene-2-oxa-13-diazole) The reported method has many advantagesin contrast with other methods in terms of sensitivity andselectivity by way of high-quality precision and accuracyHosny [31] reported an ion-pair complex formation methodfor the assaying of diltiazem in its formulation by usingchromotrope 2R and rose bengal reagents Another spectro-photometric determination of diltiazem by ternary complexformation reaction with cobalt thiocyanate at acidic pH (3ndash5) After extraction complex was deliberated at 627 nm [32]Pietras et al [33] compare the classical and derivative spec-trophotometric method for the quantitations of diltiazemin bulk and formulation Assay was performed by the first-and second-order method with the application of ldquopeak-zerordquo and ldquopeak-peakrdquo techniques with excellent correlationcoefficient (1199032 lt 09999) Sabino et al [34] presented a verysensitive determination of diltiazem by the reduction ofCu(II) in buffer (pH 7) and micellar medium be full of 44-dicarboxy-22 biquinoline acid Cu(I) produced as a result ofreduction of Cu(II) reacts with 44-dicarboxy-22 biquinolineacid-formed complexes which was quantitatively detectedat 558 nm Similarly chloro drug derivative of diltiazemwas formed by means of reaction involving tertiary aminogroup of diltiazem and sodium hypochlorite Newly formedderivative then reacted with starch and potassium iodidein sodium bicarbonate solution given blue color complexquantitatively read out at 540 nm [35] Leitaoa and Esteves daSilva reported a spectrophotometricmethod based on kineticstudy by factorial analysis Drug was reacted in two stageswith hydroxylamine and a ferric salt as a result hydrox-amic acid and ferric hydroxamate were formed respectively[36] Diltiazem was quantitatively investigated in capsuleand tablet dosage form by means of reaction with sodiummetavanadate in acidic medium (sulfuric acid) and spectro-photometrically measured at 750 nm [37] Ayad et al [38]describe an analytical method bymeans of oxidation reactionof diltiazem with iron(III) in acidic environment while

Journal of Chemistry 3

Table 1 Official methods of analysis

Drug Column Mobile phase nm Ref

Diltiazem Column L1 46 times 300mm Buffer MeOH ACN (50 25 25) 240 [15]USP

Cimetidine Column L1 46 times 250mm MeOH H3PO4 (Sod Hex sulphonate) (240mL 03mL 940mg)make up to 1 L 220 USP

[16]

Column C18 46 times 250mm Buffer (11 g Sod Hex sulphonate in 780mL water + 04mL diethylamine pH 28 by H3PO4) + 250mL MeOH 220 BP

[17]

Ranitidine Column L1 46 times 200mm MeOH buffer (85 15)buffer 01M ammonium cyanate 322 USP

[18]

Famotidine Column L1 46 times 250mm Water MeOH buffer (32 5 3) buffer 138 g NaH2PO4 in watermdash1 L 254 USP[19]

Column C18 46 times 250mmtemp 50∘C

MeOH ACN buffer (6 94 900) buffer (188 g Sod Hex sulphonate)in 900mL watermdashph 35 by acetic acid 265 BP

[20]

ON

H3CS

HNH

N

CH3 NO2

CH3

Figure 3 Ranitidine

S

N NH2N NH2

SN

NH2

S

NH2

OO

Figure 4 Famotidine

iron(III) is converted into iron(II) which reacted with the110-phenanthroline or 22-bipyridyl in the direction of stablecomplexes deliberated at 510 and 520 nm respectively In thesame way another oxidation-reduction reaction of diltiazemwas established by the El-DidamonywithN-bromosuccinim-ide (NBS) Remaining NBS was thenmeasured by the declinein absorbance of amaranth dye or by ceric ammonium sulfatewhereas remaining oxidant was deliberated by diminish inthe shade of chromotrope 2R or rhodamine 6G [39]

A simple and reproducible method based on the forma-tion of hydroxamic acid which reacts with iron(III) forminga complex with a maximum absorption at 525 nm [40]coloured complex of the drug with cobalt thiocyanate andmethyl orange [41] showed linearity in the range 60ndash600and 5ndash60120583gmLminus1 with the absorption maxima at 630 and420 nm respectively Indirect determination of diltiazem inpure form and pharmaceutical formulations presented byKamath and Shivram [42] Kamath also developed a selectivemethod using the ferric hydroxamatemethod and detected at500 nm in the range of 50ndash800120583gmLminus1 [43] Spectrophoto-metric method in pharmaceuticals was based on the reactionof hydrolyzed diltiazem with folin-Ciocalteu reagent andmeasurement of the coloured compound at 750 nm [44]Formulations of diltiazem were also determined by extrac-tive spectrophotometric methods using bromothymol bluebromophenol blue and bromocresol green [45] Abu-Shadiet al [46] established two accurate and selectivemethods that

comprise the reaction of 23 dichloro-56-dicyanoquinoneDDQwith dipyridamole celiprolol and diltiazem to develophighly coloured radical anions In the secondmethod Fe(III)hydroxamate reacts with diltiazem to produce red complexesIn vitro dissolution study was performed for 240 minutes andmeasured spectrophotometrically at 240 nm Parameters ofmean dissolution time and time for 70 dissolution (119879

70)

were also determined [47]

412 HPLC Methods At present HPLC is the most widelyused technique for the analysis of bulk drugs and their for-mulations [48] Derivatization of the drugs prior to analysisis normally not requiredThe sample preparation is extremelysimple and the errors associated with it are generally kept toa minimum by using HPLC [49] Several examinations usingHPLC for determination of diltiazem (Table 2) in bulk drugsubstances and their formulations have been reported Indianauthors Cumar et al [50] documented an analytical methodas per ICH guidelines for bulk and tablet dosage form onZorbax-SB Phenyl column by using UV detector Linearitywas performed on 50ndash150 120583gmLminus1 range while correlationof coefficient was fitted at 09987 Sultana et al [51] providesa well-organized and reproducible separation of the com-ponents with UV detection A reliable and simple methodwas presented with a binary solvent system Standardizedextraction procedures for drugs in various dosage forms were


Table 2 Application of HPLC to the determination of diltiazem

Column Mobile phase nm Ref

50 times 46mm 18 120583m Zorbax SB-Phenyl ACN water (60 40) + 1MlTrifluoroacetic acid 238 [50]

Hypersil ODS C-18 (150 times 46mm 5 micron) Methanol water (80 20 vv pH 31) 236 [51]C18 Bondapak RP column MeCN and 005M KH2PO4 237 [52]Spherisorb S5W MeOH-CH2Cl2-hexane 237 [58]Short alkyl chain silanol-deactivated column Methanol buffer (50 50) 237 [59]C18-bonded silica gel Methanol phosphate buffer-diethyl amine 237 [60]Stainless steel Bondapak-C1810m column Methanol TEMED (08 pH 54) 60 40 (volvol) 238 [61]Spherisorb C18 column Methanol-water triethylamine 239 [67]C18-reversed phase column Bondapak 10m silica 300(39mm ID)

Methanol-acetonitrile-004M ammoniumBromide-triethyl ammine (40 24 36 006) pH lt 64 237 [68]

5 120583m Lichrocart Lichrospher 60 RP-select B Acetonitrile 0025molLminus1 KH2PO4 35 64 (vv) 55 pH 215 [74]A 15 cm times 41mm pH-stable (pH 1ndash13) polymeric reversephase column

MeCN-001M tetrabutyl-ammonium hydroxide (60 40vv) 254 [75]

Hiber 250-46 RP-18 column ACN water (85 15 vv pH 26 plusmn 002) 230 [80]Kromasil C18 column (300mm times 4mm id 10 120583m particlesize) Methanol water (90 10 vv) 237 [81]

Hiber 250-46 RP-18 column ACN methanol water (30 20 50 vv pH 259 plusmn 002) 230 [82]Hiber RT 250-46 Purospher Star RP-18 column Methanol water 80 20 (vv pH 31 plusmn 002) 240 [83]Hiber RP-18 column ACN methanol water (30 20 50 vv pH 36) 230 [84]Nuclosil 100-10 C-18 (250 times 46mm) ACN methanol water (10 55 35 vv pH 265 plusmn 002) 240 [85]Purospher STAR RP-18 end capped (5120583m) Methanol water (60 40 vv) with pH 39 230 [86]Spherisorb S5W silica column 10mM ammonium perchlorate in MeOH pH 76 240 [97]Radial-PAK CN column 006M KH2PO4-MeOH-Et3N (55 45 0 25) 237 [98]Nucleosil C-18 column Acetonitrile-01M NH4H2PO4 (37 63) 237 [100]Cyanopropylsilane RP column Acetonitrile-phosphate buffer triethylamine (pH 35) 237 [101]Supelcosil LC-8-DB column MeOH-005M phosphate buffer pH 50 (1 1) 237 [102]

120583-Bondapak CN RP column 001M Na phosphate buffer (pH 50)-MeOH-diethylamine(55 45 05) 254 [109]

also developed and successfully applied to a wide range ofcurrent pharmaceutical formulations [52] Trans-Diltiazem7 known and several unknown related compounds wereseparated from diltiazem-HCl Minimum detectable amountand the relative standard deviation of the assay procedurewere 01 and 015 respectively [53]

413 Bioanalytical Methods by HPLC Several investigationsperformed [54ndash56] on development of HPLC methods fordetermination of drugs in biological fluids Li et al [57] pre-sented an HPLC method and applied in pharmacokineticstudies Drug was extracted in mixture of hexane chloro-form and isopropanol (60 40 5 vvv) and separated withisocratic mode Method was linear over the clinical range of0ndash300 ngmLminus1 with 3 ngmLminus1 of LOD Spiked extractionrecoveries of diltiazem were found to be 914ndash1040

Kinney andKelly reported [58] an estimation of diltiazemin plasma using normal-phase column liquid chromatogra-phy with ultraviolet detection Chaudhary et al [59] devel-oped a liquid chromatographic method in human seruminvolving one-step deproteinization of serum by usingacetonitrile A sensitive method was developed by using

an end-capped reversed-phase column with a regressioncoefficient of 09998 [60] Several writers have carried out thedetermination of diltiazem in biological samples after liquid-liquid extraction by means of ethyl acetate [61] methyl tert-butyl ether [62ndash66] a mixture of n-hexane-methylethanol-dichloromethane-mmonia [67] and hexane and isopropanol[68] A few of these schemes engage extraction of diltiazemwith organic solvents and back-extraction into phosphoricacid [64] hydrochloric acid [61 63 65] and sulfuric acid[62 68] However these attempts are reported to be ade-quately sensitive the drug has been deliberated using eithera large plasma sample volume or the suggested extractionprocedures give rise to poor separation of the investigateddrug from endogenous interferences in biological specimensand recovery of about 80ndash85 Ascalone and Dal Bo [69]and Mangani et al [70] have projected an automated HPLCestimation of diltiazem in human plasma by means of acolumn-switching technique for online cleanupThese inves-tigations have a very low limit of detection while somedrawbacks are their high reagent consumption and the needof two pumps Hubert et al [71] described an automatedmethod for the quantitation of diltiazem in human plasma


via liquid-solid extraction on a disposable cartridge coupledto HPLC Christensen et al [72] and Ascalone et al [73] haveexecuted the partition of diltiazem from plasma with solid-phase extraction on C18 cartridges however this type ofcartridge gave relatively low recovery values (75ndash80)Theseinvestigations overcome problems caused by endogenouscompounds Zendelovska et al [74] propose a newmethod inplasma samples using solid-phase extraction on RP-select Bcartridges and liquid-liquid extractionwith diethyl etherTherewards of thesemethods are low reagent consumption shortanalysis time ease of operation no matrix interferences andsatisfactory limit of quantification to enable pharmacokineticstudies of diltiazem Rustum [75] utilized a salting-out extrac-tion procedure and polymeric reversed-phase column for thedetermination of diltiazem in human whole blood

HPLC analysis of diltiazem in plasma for pharmacoki-netic study in a healthy man also has been reported [76]Pharmacokinetic parameters of diltiazem were determinedusing a sensitive and reproducible HPLC method which fol-lowed international standards in validation of the analyticalassay [77] Anothermethod consists of extraction of the drugsby using hexane-isopropanol (98 2) followed by solventevaporation and redissolution of the residue in MeCN-05MKH2PO4(pH 25 30 70) [78] Synchronized detection of

diltiazem and six of its metabolites is known to occur inhumans The assay was successfully applied to detect thekinetics of these drugs in healthy volunteers [79]

414 Simultaneous Determination Diltiazem was alsosimultaneously determined by HPLC technique in bulkdosage form and successfully applied in human serum withother classes of drugs due to their coadministration Priorto determination method was optimized and validatedaccording to respective ICH guidelines For the first time inthe literature diltizem and statins (simvastatin rosuvastatinand atorvastatin) were separated on isocratic eluation byRP-HPLC with UV detection Method was optimized withdifferent ratios of mobile phase C18 columns organicmodifier and pH of mobile phase Method was found to belinear (0625ndash20mgmLminus1) accurate (979ndash102) precise(CV lt 2) and also robust with short time of analysis(lt10min) [80] In the same way diltiazem and lovastatinwere simultaneously estimated by Kulkarni et al [81] and forthe first the time reported in writing style Both the drugswere separated on Kromasil C18 column with UV detector inthe presence of propranolol as an internal standard Simulta-neous determination of diltiazem and three hypoglycaemicdrugs type II (non-insulin-dependent) diabetes mellitusare reported in 2011 Method was optimized and validatedisocratically mode and no significant meddlings were foundfrom tablet excipients Intraday (056 to 131) and interday(056 to 139) precision and accuracyrecovery (98ndash102)were within limits All the analytes were eluated within 6minwhich is important for quality control analysis) [82] RP-HPLC method of diltiazem with four commonly prescribednon steroidal anti-inflammatory drugs (NSAIDs) is alsodocumented by Sultana et al in accordance with the ICHguidelines Separation was achieved on C18 column at

ambient temperature Method was linear in the desired range125ndash50120583gmLminus1 with the best resolution and recovery inserum (9897ndash1004) [83] Another simple reproducibleand economically cost-effective HPLC method for quanti-tative determination diltiazem and quinolones is reportedby Sultana et al in 2009 Diltiazem and quinolones wereefficiently separated on Hiber 250-46 STAR RP-18 columnin the presence of internal standard The developed methodwas verified by later in vitro interaction studies of diltiazemwith fluoroquinolones [84] Shabana et al describe a simpleRP-HPLC method for simultaneous separation of diltiazemprazosin hydrochloride and two other calcium channelblockers on 10-micron particle size column The developedmethod has advantages over other reported methods due totheir short time of analysis (within 7 minutes) and for theirsensitivity that is LOD and LOQ were achieved at 00542and 01642 120583gmLminus1 respectively [85] Diltiazem cimetidineranitidine and famotidine were simultaneously separatedon Purospher STAR RP-18 end capped (5120583m) with isocraticeluation Calibration curves were linear within the range of2ndash12120583gmLminus1 with excellent correlation coefficients le0999The developed method was competent with high precision(le19) and accuracy (961ndash1025) and successfully appliedfor the in vitro interaction studies of diltiazem and H

2

antagonists [86] However several analytical procedures havealso been described for simultaneous separation and enantio-separation of diltiazem its analogs possible degradationproducts and metabolites Simultaneous identification andquantification of six commonly prescribed calcium channelblocking drugs by single-step extraction method wasestablished by Jianchun from alkaline samples [87] TheHPLC modes show adequate sensitivity and reproducibilityto cover the concentration range 10ndash400 ngmLminus1 requiredas therapeutic levels in plasma for these drugs [88] Li et al[89] developed a common method for the detection ofdiltiazem verapamil nifedipine nitrendipine and theiractive metabolites using a C18 columnThe detection limit ofthe assay was 8 ngmLminus1 for all compounds over the concen-tration range 1ndash1000 ngmLminus1 The optical isomers of dL-cis-diltiazem were detected by hydrolysis of and esterificationwith the chiral reagent d-2-(2-naphthyl) propionyl chlorideRP HPLC separation was achieved with 001M NH

4OAC-

MeCN (1 9) pH 66 and detection was performed at 254 nm[90] Direct enantiomeric seperation of cis-(plusmn)diltiazem inplasma was achieved on ovomucoid [91] and topical 2diltiazem formulations [92] column The former involves adeproteinization of serum and acetonitrile used for samplecleanup The degree of extraction of the enantiomers was86 in the later method Packed column subcritical andsupercritical fluid chromatography (p-sub or pSFC) hasbeen used as a powerful chiral separation technique for theresolution of optical isomers of diltiazem P-sub- or p-SFCtends to obtain higher column efficiency than normal-phaseHPLC [93] Direct resolution of four optical isomers wascompletely resolved on both normal- and reversed-phasechiralcel of columns This chiral resolution was applied todetermine 3 optical impurities that might be present indiltiazem and its tablets [94] The enantiomers separations


the 8-chloro derivative of diltiazem (clentiazem maleate)and their deacetyl forms were resolved on ovomucoid-bonded chiral stationary phase with a mobile phase of ace-tonitrile-002M phosphate buffer (pH 60) [95] S(-)N-1-(2-naphthylsulfonyl)-2-pyrrolidinecarbonyl chloride (a highlyoptically pure derivatization reagent) was developed forconverting enantiomers into diastereomers for subsequentresolution by high-performance liquid chromatography [96]HPLC measurements of diltiazem and its metabolites werealso investigated in biological fluids [97ndash104] Diltiazem wasdetected in the presence of desacetyldiltiazem on LichrosorbRP 18 column with acetate-MeCN-MeOH (50 40 10) andalso purified by preparative HPLC on LiChroprep Si60 withpetroleum ether-EtOAc-MeOH (50 50 5) as mobile phase[105] Simultaneous analysis of diltiazem N-monodemeth-yldiltiazem and desactyldiltiazem were identified with theextraction efficiency of 95ndash100 and the limit of detectionwas 5 ngmLminus1 [106] Different C18 columns are comparedwith the influences of organic cosolvent pH ionic strengthand the addition of various amines for the detection ofdiltiazem and its 5 metabolites [107] Goebel and Koelledescribed a very sensitive method for the determinationof diltiazem and four of its metabolites in plasma samplesCalibration curves were linear between 1 and 800 ngmLminus1and the lower limit of detection was 01-02 ngmLminus1 [108]HPLC combined with mass spectrometry was used for theanalysis of diltiazem and its 3 metabolites in blood plasma ofpatients treated for ischemic heart disease [109] A sensitiveand automatic method for the analysis of diltiazem and itsmain metabolites in acidified serum is described using solid-liquid extraction on disposable extraction cartridges Thismethod avoids the in vitro degradation and eliminates thenumerousmanipulations involved in liquid-liquid extraction[110] Tracqui et al [111] developed an automated methodby using liquid-solid extraction on disposable extractioncartridges in combination with HPLC Lee et al established[112] amethod that involves the use of two 5120583mBDS silica gelcolumns 15 cm (46mm ID) in series for increased resolutionand sensitivity and organic mobile phase for both extractionand elution of diltiazem Dasandi and his coworkers [113]have described a high-throughput and specific methodusing ultraperformance liquid chromatography tandemmass spectrometry (UPLC-MSMS) Compared with thepublished methods the narrow peaks produced by UPLC areof particular advantage when coupled to electrospray massspectrometry and offering superior sensitivity Total runtime was 20min only therefore the method is particularlysuitable for routine assay Zoest and his companions [114]developed a sensitive specific and reproducible assay for thepharmacokinetic study of diltiazem primary and secondarymetabolites of diltiazem

42 Cimetidine

421 Spectrophotometric Methods Sensitive spectrophoto-metric method based on the reaction of CIM RAN FAMand NIZ with N-bromosuccinimide (NBS) and subsequentmeasurement of the excess NBS by its reaction with p-aminophenol to give a violet-colored product Decrease in

the absorption intensity (Δ119860) of the colored product due tothe presence of the drug was correlated with its concentra-tion in the sample solution (120582max at 552 nm) [115] Anothersensitive method presented by Darwish et al [116] for deter-mination of H

2receptor antagonists based on the oxidation

of these drugs with cerium(IV) in presence of perchloricacid and subsequent measurement of the excess Ce(IV) by itsreaction with p-dimethylaminobenzaldehyde to give a red-colored product (120582max at 464 nm) Fast spectrophotometricmethods for the analysis of CIM in pharmaceuticals andhuman urine using batch and flow-injection proceduresbased on the formation of a green complex drug and Cu(II)in aceticacetate medium measured at 330 nm [117] Two fastmethods developed by Garcia et al [118] using batch andflow-injection procedures for CIM based on the formationof a green complex with Cu(II) in aceticacetate mediummeasured at 330 nm Kelani et al [119] described threesensitive stability indicating spectrophotometric methodsusing sodium nitro prusside 3-methyl-2-benzo-thiazolinonehydrazine and cobalt(II) respectively

422 HPLC Methods CIM is highly polar drug thereforeseveral RP-HPLC methods reported on the analysis in pureform tablet and biological fluids (Table 3) using either a C

8

[120] C18 [121ndash127] or polymeric column [128] Determina-tion of CIM in human plasma and urine samples has beeninvestigated by the solid-phase or liquid-phase extractiontechniques [121ndash124 129ndash143] and extrelut extraction [144]These methods have some drawbacks including the needof large volume plasma extraction [133ndash135] poor recovery[136 137] utilization of an internal standard that is not com-mercially available [135 138] requirement of an additionalprotonation step [139] low capabilities of urine analysis [133139 140] and triple extraction [142 143]whichwere time con-suming HPLC method presented by Jantratid et al [145] forthe estimation of CIM in human plasma involves a simplifiedsample preparation by protein precipitation with perchloricacid

Iqbal et al [146] reported an HPLC method for CIM inbiological fluids Plasma sample preparation needs liquidextraction with water-saturated ethyl acetate After extrac-tion extracts were evaporated under nitrogen and reconsti-tuted with mobile phase Advantages of this validated assayover other reported methods include a simple plasma extrac-tion and urine dilution procedures and willingly availableinternal standard and applicability to clinical studies Samplecleanup and analysis of CIM in urine and blood weredescribed by Apffel and his friends [147] sample preparationswere achieved by adsorption technique on Waters Sep-pakC18 disposable precolumns and the separation was per-formed on a RP column Dong-Sun et al [148] presentedan analytical work saving online-column switching HPLCmethod with UV detection for cleanup and analysis Gomitaet al [149] established an HPLC method for microdetermi-nation of CIM in rat plasma Betto et al [121] developed anHPLC method with diode-array detector in order to assayCIM and its related impurities in pharmaceutical formula-tions


Table 3 Application of HPLC to the determination of H2 receptor antagonists

Column Mobile phase Detection Ref

250 times 46mm ID Nucleosil C18 (5 120583m) packed by Chromex ACN phosphate buffer pH 62 (25 75 vv) 228 nm [137]

Phenomenex (Torrance CA) C18 (46 times 250mm)Prodigy5 m ODS (3) 100

ACN heptanesulfonic acid 20mM sodium acetatebuffer (23 77)

228 nm [146]

120583-Bondapak C18 column21mM disodium hydrogenphosphate triethylamine ACN (1000 60 150 vv)pH 35

320 nm [160]

Supelcosil LC-CN column (5 120583m 250 times 46mm ID) 005M potassium dihydrogen phosphate ACN (88 12vv) pH 65

229 nm [162]

Spherisorb phenyl cartridge column 10 cm times 046 cm ID5 120583m particle diameter

88-89 of 002M phosphate buffer pH 3 and 11-12 ofmethanol

228 nm [167]

Cation-exchange column 01M sodium acetate buffer(pH5) CAN tetrahydrofuran (565 36 75 vv)

230 nm [172]

5-120583mODS silica ACN-7mM triethylammonium ion in phosphoric acidpH 30 (30 70 vv)

315 nm [173]

Nucleosil C18 column Ammonium acetate solution (05M) acetonitrile andmethanol

254 nm [176]

Phenomenex (Torrance CA USA) Prodigy ODS (3) (5mmparticle size 25 cm times 39mm ID) reversed-phase HPLCcolumn

ACN and heptanesulfonic acid (25 gLminus1) in 20mMsodium acetate buffer (23 77)

267 nm [191]

Supelcosil LC18 column ACN 01 M dihydrogen phosphate buffer containing02 triethylamine (13 87 vv) pH 30

265 nm [206]

Octadecyl silane-bonded silica column Methanol 002M sodium acetate (pH 45) (1 4) 254 nm [209]

Porous graphitic carbon (PGC) column ACN water containing 05 pentane sulphonic acid(50 50 vv)

265 nm [210]

43 Ranitidine

431 Spectrophotometric Methods Three spectrophotomet-ric methods for the determination of RAN involve forma-tion and solving of simultaneous equations making useof first-order derivative spectroscopy and two wavelengthcalculations presented by Pillai and Singhvi [150] Kineticspectrophotometric method involves the reaction of thedrugswith alkaline potassiumpermanganate and green coloris produced peaking at 610 nm The reaction is monitored bymeasuring the rate of change of absorbance of the resultingmanganate species [151] Another kinetic method describedby Walash et al [152] for RAN and NIZ based on the reac-tion of the compounds with 7-chloro-4-nitrobenz-2-oxa-13-diazole in borate buffer (pH 74) at 60∘C for 25min andthe reaction product is measured at 495 nm The protolyticconstants of RAN and NIZ were studied using a spectro-photometric method [153] Four newmethods established byBasavaiah and Nagegowda [154] using titrimetry and visi-ble spectrophotometry with potassium bromate as the oxi-dimetric reagent and acid dyes methyl orange indigo car-mine and metanil yellow Determination of RAN and NIZthrough charge transfer complex formation with either p-chloranilic acid or 23 dichloro-56-dicyanoquinone (DDQ)and the colored products are quantified at 515 and 467 nmin chloranilic acid and DDQ methods respectively [155]Charge-transfer complexation method for RAN FAM and

NIZ is based on interaction of these drugs with 7788-tetra-cyanoquinodimethane to give green-colored radical anionsthat are deliberate at 840 nm [156]

432 HPLC Methods Literature showed that a variety ofHPLCmethods have been reported for the estimation of RAN(Table 3) in biological fluids by using a short polymeric chain[157] silica-based column [158] polymeric base reversed-phase column [159] without solvent extraction or one-stepsample preparation [158 160ndash162] two-step extraction [163]two solvents combination for extraction [164] protein pre-cipitation and salting out procedures [157] solid-phaseextraction [165ndash167] liquid-liquid extraction with organicsolvents [168ndash170] and ion-pair high-performance liquidchromatography [161 163] Farthing et al [171] reported aHPLC method for RAN in human plasma by solid-phaseextraction and midbore chromatographic technique

Prueksaritanont et al [172] Rahman et al [173] andVinas et al [174] established sensitive methods for the con-current determination of RAN and its metabolites (RAN N-oxide RAN S-oxide and desmethylranitidine) in humanplasma and urine Lant et al [175] developed an assay forRAN and all the above metabolites in biological fluids by apostcolumn fluorimetric derivatization Quantitative as wellas qualitative analysis of RAN and its metabolites weredetermined by a direct liquid introduction-RP HPLC-massspectrometry system [176]


Kokoletsi and his companions [176] presented a methodfor the simultaneous determination of RAN methylparabenand propylparaben in oral liquids Purifications of sampleswere carried out by solid-phase extraction using a copoly-meric sorbent

44 Famotidine

441 Spectrophotometric Methods Amin and his compan-ions [177] reported three selective spectrophotometric meth-ods for the determination of FAM through oxidation withn-bromosuccinimide and ceric sulphate by measuring theabsorbance at 521 and (528 526) nm respectively Dissolutiontest for FAM tablets was optimized using a simple direct spec-trophotometric flow injection assay (120582max 265 nm) that hasalso been fully validated in terms of linearity limit of detec-tion precision selectivity and accuracy [178] Different UVspectrophotometric methods have been reported for thedetermination of FAM in pharmaceutical formulations basedon the reaction of FAM with 14-benzoquinone [179] andsodium nitroprusside [180] interaction of FAM with ninhy-drin [181] and p-chloranilic acid [182] charge transfer com-plexation with chloranil 23-dichloro 56-dicyano 14-benzo-quinone and dichloronitrophenol [183] measuring the peakheight of the second derivative [184] ion-pair complex for-mation with bromocresol green and bromothymol blue [185186] and difference spectrophotometric and quadratic poly-nomial coefficient methods [187]

442 HPLC Methods Literature survey showed that a num-ber of HPLC methods have been reported for the individualand simultaneous determination of FMT [188ndash192] and of allrelated compounds (Table 3) [193ndash199] Majority of methodsutilized either solid phase or liquid-liquid extraction tech-niques [200ndash203] Extensive methods were reported [204205] for FAM in which HPLC separation with column-switching technique was applied RP-HPLC method for thedetermination of FAM and its potential impurities in dosageforms were performed on a Supelcosil C18 column with anisocratic mobile phase Response was linearly dependent onconcentration 1ndash80 120583gmLminus1 (regression coefficient 1198772 from09981ndash09999) [206] Carlucci et al [207] established an RP-HPLC and second-derivative ultraviolet spectra in finishedproduct by utilizing the linear relationship between concen-tration and derivative peak amplitude Campanero et al [190]presented a liquid chromatography-electrospray ionizationmass spectrometric detectionwith a rapid andwell-organizedsample refine method for the estimation of FAM in humanplasma Assay method using a monolithic column has beendeveloped for quantification of FAM in plasma and enablesthe measurement of FAM for therapeutic drug monitoringwith a minimum detectable limit of 5 ngmLminus1 [208]

Stability-indicative liquid chromatographic analysis anddegradation kinetics of FAM in tablets are described byKamath and friends [209] Another stability-indicating assaywas demonstrated for the simultaneous determination ofFAM and related impurities in pharmaceuticals using porousgraphitic carbon column [210]

45 Simultaneous Determination of H2Receptor Antagonists

Literature shows several articles published for the simulta-neous determination of H

2receptor antagonists (cimitedine

ranitidine and famotidine) with other categories of drugclasses (Table 4) An HPLC method on fourth-generationfluoroquinolones that is gemifloxacin and cimetidine ran-itidine and famotidine was established the presence of geti-floxacin as an internal standard by the Pakistani authorsMobile phase was delivered isocratically at ambient tempera-ture Quantitation was performed at three different wave-lengths that is 221 256 and 267 nm as well as statistical anal-ysis such that Studentrsquos 119905-test and Friedmanrsquos were also func-tional to compare these outcomes [211] Naveed et al [212]presented a RP-HPLC method for the simultaneous deter-mination of lisinopril and all three H

2receptor antagonists

Separation was performed isocratically with 10mLminminus1flow rate over the concentration range of 25ndash100 and 07ndash1250 120583gmLminus1 for H

2receptor antagonists and lisinopril

respectively with regression value of plusmn0999 In the same waycaptopril a specific ACE inhibitor was quantitatively deter-mined by theRP-HPLC techniquewithCIMRAN andFAMFor method optimization different mixtures of mobile phasewere tried and retention time resolution and peak symmetrywere also taken into consideration for system suitabilityLater on the validated method was efficiently verified forin vitro interaction studies [213] Arayne et al [214] alsodeveloped and validated a high-performance liquid chro-matographic method for metformin ranitidine famotidineand cimetidine in their synthetic mixtures and dosage formsCalibration curve was constructed in the concentrationrange of 5ndash25 120583gmLminus1 with 0997ndash09998 1199032 values Inter-andintraday precision and accuracy were less than 2 and 986ndash1024 respectively Another sensitive and selective liquidchromatographic method was published for the prazosinCIM RAN and FAM by Najma et al [215] as per (ICH)guidelines Mobile phase was pumped in column throughisocratic mode Total run time of analysis was less than fiveminutes that is important for quality control analysis and clin-ical laboratories Similarly an HPLC method for the simul-taneous estimation of a fluoroquinolone sparfloxacin andabove H

2receptor antagonists was also reported in bulk

dosage form and human serum The demonstrated methodwas specific as there is no interference found from the spikematrix and serum Accuracy and precision of the methodwere found in acceptable boundary 9802ndash102136 and 05ndash22 respectively Statistical Paired 119905-test was applied for theverification of the collected data [216] HPLC simultaneousdetermination of CIM RAN FAM and NIZ was establishedusing a two-level full-factorial design with three variables(volume of methanol percentage of triethylamine and con-centration of phosphate buffer) None of the commercialsamples was found to be outside the compendial limits of90ndash1100 of the claim amount [217] HPLC method forCIM and RAN in plasma sample was investigated by cleanupprocedure that used solid-phase extraction and separated ona Lichrocart Lichrospher 60 RP-select B column The effectsof organic modifiers mobile phase composition pH andbuffer concentration on retention time of analytes were alsoinvestigated [218]


Table 4 Application of HPLC to the simultaneous determination of H2 receptor antagonists

Column Mobile phase Detection (nm) Ref

RP-mediterranea column C18 (250times 46mm 5 120583m) ACN methanol water (20 28 52 vvv) pH 28adjusted by phosphoric acid 221 256 and 267 [211]

Hypersil ODS C18 (150 9 46mm 5 lm) andPurospher STAR RP-18 column

ACN water (70 25 vv) pH adjusted to 30 byphosphoric acid 225 [212]

Purospher star C18 (5 120583m 25times 046 cm) column methanol water (60 40 vv) pH adjusted to 30 plusmn 002by phosphoric acid 225 [213]

Purospher Star RP18 endcapped (250mmtimes 46mm ID)column packed with 5-120583m particles

Methanol-water-triethylamine(20 80 005) whose pH was adjusted to 30 withphosphoric acid

229 [214]

Nucleosil 100-10 C-18 column (250times 46mm 10 micron) Methanol water acetonitrile (60 45 5 vv pH 383) 240 [215]

Purospher STAR C18 (250times 46mm 5 120583m) column Methanol water ACN (54 41 5 vvv) pH 27adjusted by phosphoric acid 232 and 250 [216]

(15 cmtimes 46mm ID) of Inertsil ODS-2 (5 120583m) column004M aqueous sodium dihydrogenphosphate ACN methanol TEA (345 20 35 07vvvv)

230 nm [217]

5 Conclusion

In this paperUVandHPLCmethods for the determination ofdiltiazem and three H

2-receptor antagonists in bulk material

pharmaceutical formulations and biological specimens arereviewed Spectrophotometric techniques provided practical(less-time-consuming simpler and more convenient) andsignificant economic advantages over other methods there-fore they are a frequent choice for pharmaceutical analysesHPLC methods generally required complex and expensiveequipment provision for use and disposal of solvents labor-intensive sample preparation procedure and personal skillsin chromatographic techniques In addition most of theHPLC methods reviewed have the potential application toclinical research of drug combination multidrug pharma-cokinetics and interactions

References

[1] D Colin Therapeutic Drug Churchill Livingstone Division ofLongman Group London UK 2nd edition 1999

[2] S C SweetmanMartindale the Complete Drug Reference Phar-maceutical Press 33rd edition 2002

[3] E Jantratid S Prakongpan J B Dressman et al ldquoBiowaivermonographs for immediate release solid oral dosage formscimetidinerdquo Journal of Pharmaceutical Sciences vol 95 no 5pp 974ndash984 2006

[4] B AHendriksenMV S Felix andM B Bolger ldquoThe compos-ite solubility versus pH profile and its role in intestinal absorp-tion predictionrdquo AAPS PharmSci vol 5 no 1 article E4 2003

[5] J G Hardman L E Limbird and A G Gilman EdsGoodmanampGilmanrsquosThe Pharmacological Basis ofTherapeutics McGraw-Hill New York NY USA 10th edition 2001

[6] C Martınez C Albet J A G Agundez et al ldquoComparativein vitro and in vivo inhibition of cytochrome P450 CYP1A2CYP2D6 and CYP3A by H

2-receptor antagonistsrdquo Clinical

Pharmacology ampTherapeutics vol 65 no 4 pp 369ndash376 1999[7] N R Peden J H B Saunders and K G Wormsley ldquoInhibition

of pentagastrin-stimulated and nocturnal gastric secretion by

ranitidine a newH2-receptor antagonistrdquoThe Lancet vol 1 no

8118 pp 690ndash692 1979[8] C W Howden and G N J Tytgat ldquoThe tolerability and safety

profile of famotidinerdquo Clinical Therapeutics vol 18 no 1 pp36ndash54 1996

[9] H D Maples L P James C D Stowe et al ldquoFamotidine dis-position in children and adolescents with chronic renal insuffi-ciencyrdquo Journal of Clinical Pharmacology vol 43 no 1 pp 7ndash142003

[10] United States Pharmacopeia 30 National Formulary 25 OfficialMonographs The United States Pharmacopeial ConventionRockville Md USA 2007

[11] D J Mazzo C L Obetz and J Shuster ldquoDiltiazem hydrochlo-riderdquo Analytical Profiles of Drug Substances and Excipients vol23 pp 53ndash98 1994

[12] P M G Bavin A Post J E Zarembo et al ldquoCimetidinerdquo inAnalytical Profiles of Drug Substances K Florey Ed vol 13 pp127ndash183 Academic Press Orlando Fla USA 30th edition 1984

[13] M Hohnjec J Kuftinec M Malnar et al ldquoRanitidinerdquo inAnalytical Profiles of Drug Substances K Florey Ed vol 15 pp533ndash561 Academic Press New York NY USA 1986

[14] European Pharmacopoeia Council of Europe StrasbourgFrance 4th edition 2002

[15] ldquoThe United State Pharmacopoeardquo vol 34 pp 2581ndash2586 2011[16] ldquoThe United State Pharmacopoeardquo vol 34 pp 2337ndash2340 2011[17] ldquoThe Birtish Pharmacopoeardquo 6th edition pp 2602ndash2605 2011[18] ldquoThe United State Pharmacopoeardquo vol 34 pp 3258ndash3261 2011[19] ldquoThe United State Pharmacopoeardquo vol 34 pp 2792ndash2796 2011[20] ldquoThe Birtish Pharmacopoeardquo 6th edition pp 2805ndash2806 2011[21] ldquoThe Birtish Pharmacopoeardquo 6th edition pp 3258ndash3261 2011[22] C Georgita F Albu V David and A Medvedovici ldquoNonlinear

calibrations on the assay of dilitiazem and two of its metabolitesfrom plasma samples by means of liquid chromatographyand ESIMS2 detection application to a bioequivalence studyrdquoBiomedical Chromatography vol 22 no 3 pp 289ndash297 2008

[23] B K Matuszewski M L Constanzer and C M Chavez-EngldquoStrategies for the assessment of matrix effect in quantitativebioanalytical methods based on HPLC-MSMSrdquo AnalyticalChemistry vol 75 no 13 pp 3019ndash3030 2003


[24] R Dams M A Huestis W E Lambert and C M MurphyldquoMatrix effect in bio-analysis of illicit drugs with LC-MSMSinfluence of ionization type sample preparation and biofluidrdquoJournal of the American Society for Mass Spectrometry vol 14no 11 pp 1290ndash1294 2003

[25] J P Clozel G Caille Y Taeymans P Theroux P Biron andJ G Besner ldquoImproved gas chromatographic determination ofdiltiazem and deacetyldiltiazem in human plasmardquo Journal ofPharmaceutical Sciences vol 73 no 2 pp 207ndash209 1984

[26] O Grech-Belanger E Leboeuf and S Langlois ldquoA gas chromat-ographic method for the analysis of diltiazem in plasmardquo Jour-nal of Chromatography vol 417 no 1 pp 89ndash98 1987

[27] RT Sane M Purandare G Nayak et al ldquoGas chromatographicdetermination of diltiazem hydrochloride in pharmaceuticalsrdquoIndian Drugs vol 26 no 11 pp 623ndash625 1989

[28] M Nishikawa A Ishii K Watanabe H Seno T KumazawaandO Suzuki ldquoDetermination of diltiazem in bodyfluids by gaschromatography with surface ionization detectionrdquo JapaneseJournal of Forensic Toxicology vol 12 no 3 pp 247ndash251 1994

[29] H R Ochs and M Knuchel ldquoPharmacokinetics and absolutebioavailability of diltiazem in humansrdquoKlinischeWochenschriftvol 62 no 7 pp 303ndash306 1984

[30] M M Ayad H E Abdellatef M M Hosny Y A Sharaf et alldquoApplication of 4-chloro-7-nitrobenzofurazan for the analysis ofpropafenone and diltiazem hydrochlorides using kinetic spec-trophotometric and spectrofluorimetric methodsrdquo EuropeanJournal of Chemistry vol 4 no 1 pp 35ndash43 2013

[31] MM Hosny ldquoSpectrophotometric determination of diltiazemfluphenazine and dothiepin hydrochlorides using chromotrope2R and rose bengalrdquo Mansoura Journal of PharmaceuticalSciences vol 20 pp 64ndash77 2004

[32] R Bindu and A K Chandrasekharan ldquoColorimetric determi-nation of diltiazem hydrochloride in pharmaceutical formula-tionsrdquo Indian Drugs vol 31 no 4 pp 168ndash169 1994

[33] R Pietras D Kowalczuk andHHopkała ldquoComparison of clas-sical and derivative UV-spectrophotometric methods for thequantification of diltiazem andmexiletinerdquoActa Poloniae Phar-maceutica vol 61 no 5 pp 315ndash320 2004

[34] L Z L Sabino D C Marino and H D Moya ldquoDeterminationof diltiazem based on the reduction of Cu(II)-BCA complexesinmicellarmediumrdquoCanadian Journal of Chemistry vol 88 no6 pp 533ndash539 2010

[35] N Rahman S N H Azmi and Y Ahmad ldquoQuantitation ofdiltiazem hydrochloride in commercial dosage forms by visiblespectrophotometryrdquo Journal of the Chinese Chemical Societyvol 54 pp 419ndash430 2007

[36] J M M Leitaoa and J C G Esteves da Silva ldquoFactorial analysisoptimization of a Diltiazem kinetic spectrophotometric quan-tification methodrdquo Analytica Chimica Acta vol 609 no 1 pp1ndash12 2008

[37] N Rahman and S N H Azmi ldquoSpectrophotometric determi-nation of diltiazem hydrochloride with sodium metavanadaterdquoMicrochemical Journal vol 65 no 1 pp 39ndash43 2000

[38] M M Ayad A Shalaby H E Abdellatef and M M HosnyldquoNew colorimetric methods for the determination of trazodoneHCl famotidine and diltiazem HCl in their pharmaceuticaldosage formsrdquo Analytical and Bioanalytical Chemistry vol 376no 5 pp 710ndash714 2003

[39] A M El-Didamony ldquoIndirect spectrophotometric determina-tion of diltiazem hydrochloride in pure form and pharmaceu-tical formulationsrdquo Central European Journal of Chemistry vol3 no 3 pp 520ndash536 2005

[40] D Zivanov-Stakic D Agbaba S Vladimirov and L J CiricldquoSpectrophotometric determination of diltiazem in dosageformsrdquo Farmaco vol 47 no 3 pp 393ndash396 1992

[41] Y K Agrawal K Shivramachandra andB E Rao ldquoSpectropho-tometric methods for the determination of diltiazem in phar-maceutical preparationsrdquo Indian Journal of Pharmaceutical Sci-ences vol 54 no 6 pp 218ndash221 1992

[42] B V Kamath and K Shivram ldquoExtractive spectrophotometricmethod for the determination of diltiazem hydrochloride in itsdosage formsrdquo Indian Drugs vol 29 no 1 pp 50ndash52 1991

[43] B V Kamath K Shivram and A C Shah ldquoSelective spectro-photometric determination of diltiazem hydrochloride in tab-letsrdquo Journal of Pharmaceutical and Biomedical Analysis vol 11no 4-5 pp 407ndash409 1993

[44] K Sreedhar C S P Sastry M Narayana Reddy and D GSankar ldquoExtractive spectrophotometric determinations of dil-tiazem hydrochloriderdquo Indian Drugs vol 32 no 2 pp 90ndash921995

[45] N Rahman and S N Hejaz-Azmi ldquoExtractive spectrophoto-metric methods for determination of diltiazemHCl in pharma-ceutical formulations using bromothymol blue bromophenolblue and bromocresol greenrdquo Journal of Pharmaceutical andBiomedical Analysis vol 24 no 1 pp 33ndash41 2000

[46] H A Abu-Shadi S T Hasib H H Hassanein and A AbadildquoSpectrophotometric determination of some cardiovasculardrugsrdquo Egyptian Journal of Pharmaceutical Sciences vol 36 no1ndash6 pp 393ndash405 1995

[47] S Dadashzadeh A Zarghi andA J Ebrahimian ldquoPharmacoki-netics and comparative bioavailability of two diltiazem tabletformulations in healthy volunteersrdquo Daru vol 11 no 1 pp 14ndash18 2003

[48] R K Gilpin and L A Pachla ldquoPharmaceuticals and relateddrugsrdquoAnalytical Chemistry vol 73 no 12 pp 2805ndash2816 2001

[49] A M Krstulovic and C R Lee ldquoDefining drug purity throughchromatographic and related methods current status andperspectivesrdquo Journal of Chromatography B vol 689 no 1 pp137ndash153 1997

[50] R Pravin Cumar M Vasudevan and D Raman ldquoRP-HPLCmethod development and validation for the estimation ofdiltiazem in bulk and tablet dosage formsrdquo Asian Journal ofPharmaceutical and Clinical Research vol 5 no 3 pp 62ndash642012

[51] N Sultana M S Arayne N Shafi et al ldquoA validatedmethod forthe analysis of diltiazem in raw materials and pharmaceuticalformulations by RP-HPLCrdquo Pakistan Journal of PharmaceuticalSciences vol 20 no 4 pp 279ndash284 2007

[52] A S Sidhu J M Kennedy and S Deeble ldquoGeneral method forthe analysis of pharmaceutical dosage forms by high-perform-ance liquid chromatographyrdquo Journal of Chromatography vol391 no 1 pp 233ndash242 1987

[53] PM Lacroix N Beaulieu T D Cyr and E G Lovering ldquoHigh-performance liquid chromatography method for assay of dilti-azem hydrochloride and its related compounds in bulk drugand finished tabletsrdquo Journal of Pharmaceutical Sciences vol 78no 3 pp 243ndash246 1989

[54] D Zendelovska S Simeska S Petrov and P Milosevski ldquoAsensitive method for determination of famotidine in humanplasma byHPLC and its application for bioequivalence studiesrdquoActa Pharmaceutica vol 52 no 2 pp 113ndash120 2002

[55] D Zendelovska T Stafilov and S Petrov ldquoSimultaneous quan-tification of cefaclor and cephalexine in blood plasma using


high-performance liquid chromatography with UV detectionrdquoActa Pharmaceutica vol 52 no 4 pp 243ndash250 2002

[56] D Zendelovska T Stafilov and M Stefova ldquoOptimization of asolid-phase extraction method for determination of indapam-ide in biological fluids using high-performance liquid chromat-ographyrdquo Journal of Chromatography B vol 788 no 1 pp 199ndash206 2003

[57] K Li X Zhang and F Zhao ldquoHPLC determination of diltiazemin human plasma and its application to pharmacokinetics inhumansrdquo Biomedical Chromatography vol 17 no 8 pp 522ndash525 2003

[58] C D Kinney and J G Kelly ldquoEstimation of concentrations ofdiltiazem in plasma using normal-phase column liquid chro-matography with ultraviolet detectionrdquo Journal of Chromatog-raphy B vol 382 pp 377ndash381 1986

[59] R S Chaudhary S S Gangwal M K Avachat Y N Shahand K C Jindal ldquoDetermination of diltiazem hydrochloridein human serum by high-performance liquid chromatographyrdquoJournal of Chromatography B vol 614 no 2 pp 261ndash266 1993

[60] BH Jensen andC Larsen ldquoQuantitation of diltiazem in humanplasma byHPLC using an end-capped reversed-phase columnrdquoActa Pharmaceutica Nordica vol 3 no 3 pp 179ndash180 1991

[61] M Delwar Hussain Y K Tam B A Finegan and R T CouttsldquoSimple and sensitive high-performance liquid chromato-graphic method for the determination of diltiazem and six ofits metabolites in human plasmardquo Journal of ChromatographyB vol 582 no 1-2 pp 203ndash209 1992

[62] C VergheseM S Smith L Aanonsen E L Pritchett andD GShand ldquoHigh-performance liquid chromatographic analysis ofdiltiazem and its metabolite in plasmardquo Journal of Chromatog-raphy vol 272 no 1 pp 149ndash155 1983

[63] K-J Goebel and E U Kolle ldquoHigh-performance liquid chro-matographic determination of diltiazem and four of its metabo-lites in plasma Application to pharmacokineticsrdquo Journal ofChromatography B vol 345 no 2 pp 355ndash363 1985

[64] L M Dube NMousseau and I J McGilveray ldquoHigh-perform-ance liquid chromatographic determination of diltiazem andfour of its metabolites in plasma evaluation of their stabilityrdquoJournal of Chromatography B vol 430 no 1 pp 103ndash111 1988

[65] D Paczkowski R Dabrowski D Sitkiewicz and Z SadowskildquoAnalysis of diltiazem and desacetyldiltiazem in serum by high-performance liquid chromatographyrdquo Polish Journal of Pharma-cology vol 47 no 5 pp 429ndash434 1995

[66] G Carignan K Carrier S Laganiere and M Lessard ldquoSimul-taneous determination of diltiazem and quinidine in humanplasma by liquid chromatographyrdquo Journal of ChromatographyB vol 672 no 2 pp 261ndash269 1995

[67] P Scully E Meehan and J G Kelly ldquoHigh-performance liquidchromatographic assay for diltiazem in small-volume bloodspecimens and application to pharmacokinetic studies in ratsrdquoJournal of Chromatography A vol 729 no 1-2 pp 297ndash3001996

[68] D R Rutledge A H Abadi L M Lopez and C A BeaudreauldquoHigh-performance liquid chromatographic determination ofdiltiazemand twoof itsmetabolites in plasmausing a short alkylchain silanol deactivated columnrdquo Journal of ChromatographyB vol 615 no 1 pp 111ndash116 1993

[69] V Ascalone and L Dal Bo ldquoAutomated high-performance liq-uid chromatographic and column-switching technique for on-line clean-up and analysis of diltiazem in human plasmardquoJournal of Chromatography B vol 423 pp 239ndash249 1987

[70] F Mangani G Luck C Fraudeau and E Verette ldquoOn-line col-umn-switching high-performance liquid chromatography anal-ysis of cardiovascular drugs in serum with automated sampleclean-up and zone-cutting technique to perform chiral separa-tionrdquo Journal of Chromatography A vol 762 no 1-2 pp 235ndash241 1997

[71] P Hubert P Chiap and J Crommen ldquoAutomatic determinationof diltiazem and desacetyldiltiazem in human plasma usingliquid-solid extraction on disposable cartridges coupled toHPLCmdashPart I optimization of the HPLC system and methodvalidationrdquo Journal of Pharmaceutical and Biomedical Analysisvol 9 no 10ndash12 pp 877ndash882 1991

[72] H Christensen E Carlson A Asberg L Schram and K JBerg ldquoA simple and sensitive high-performance liquid chro-matography assay of diltiazem and main metabolites in renaltransplanted patientsrdquo Clinica Chimica Acta vol 283 no 1-2pp 63ndash75 1999

[73] V Ascalone M Locatelli and B Malavasi ldquoDetermination ofdiltiazem and its main metabolites in human plasma by auto-mated solid-phase extraction and high-performance liquidchromatography a new method overcoming instability of thecompounds and interference problemsrdquo Journal of Chromatog-raphy B vol 657 no 1 pp 133ndash140 1994

[74] D Zendelovska T Stafilov M Stefova et al ldquoHigh-perform-ance liquid chromatographic determination of diltiazem inhuman plasma after solid-phase and liquid-liquid extractionrdquoAnalytical and Bioanalytical Chemistry vol 376 no 6 pp 848ndash853 2003

[75] A M Rustum ldquoDetermination of diltiazem in human wholeblood and plasma by high-performance liquid chromatographyusing a polymeric reversed-phase column and utilizing a salt-ing-out extraction procedurerdquo Journal of Chromatography Bvol 490 no 2 pp 365ndash375 1989

[76] R Boulieu J L Bonnefous and S Ferry ldquoDetermination ofdiltiazem and its metabolites in plasma by high performanceliquid chromatographyrdquo Journal of Liquid Chromatography vol13 no 2 pp 291ndash301 1990

[77] A Zarghi S Dadashzadeh and A J Ebrahimian ldquoHPLC quan-tification of diltiazem in plasma from manrdquo Pharmacy andPharmacology Communications vol 6 no 8 pp 341ndash343 2000

[78] M Parissi-Poulou G Ismailos and P Macheras ldquoModifiedHPLC analysis of diltiazem in plasma for pharmacokineticstudiesrdquo International Journal of Pharmaceutics vol 62 no 2-3 pp R13ndashR16 1990

[79] P K F Yeung T J Montague B Tsui and C McGregor ldquoHigh-performance liquid chromatographic assay of diltiazem and sixof its metabolites in plasma application to a pharmacokineticstudy in healthy volunteersrdquo Journal of Pharmaceutical Sciencesvol 78 no 7 pp 592ndash597 1989

[80] N Sultana M S Arayne N Shafi F A Siddiqui and A Hus-sain ldquoDevelopment of a RP-HPLCmethod for the simultaneousanalysis of diltiazem and statin application in pharmaceuticalsand human serumrdquo Analytical Methods vol 2 no 10 pp 1571ndash1576 2010

[81] A S Kulkarni S D Jadhav S S Khetmar and M S BhatialdquoDevelopment of chromatographic technique for simultaneousestimation of lovastatin and diltiazem hydrochloriderdquoMahidolUniversity Journal of Pharmaceutical Sciences vol 39 no 3-4pp 17ndash23 2012

[82] N Sultana M S Arayne N Shafi F A Siddiqui and A Hus-sain ldquoDevelopment and validation of new assay method for thesimultaneous analysis of diltiazem metformin pioglitazone


and rosiglitazone by RP-HPLC and its applications in pharma-ceuticals and human serumrdquo Journal of Chromatographic Sci-ence vol 49 no 10 pp 774ndash779 2011

[83] N Sultana M S Arayne N Shafi and F A Siddiqui ldquoSimul-taneous RP-LC analysis of diltiazem and non-steroidal anti-inflammatory drugs in pharmaceutical formulations andhuman serumrdquo Chromatographia vol 71 no 1-2 pp 71ndash772010

[84] N SultanaM S Arayne N Shafi N Asia S Naz andH Sham-shad ldquoA RP-HPLCmethod for the simultaneous determinationof diltiazem and quinolones in bulk formulations and humanserumrdquo Journal of the Chilean Chemical Society vol 54 no 4pp 358ndash362 2009

[85] S Naz N Sultana M S Arayne and N Shafi ldquoSimultaneousdetermination of prazosin and calcium chanel blockers in rawmaterials pharmaceutical formulations and human serum byRP-HPLCrdquo International Journal of Pharma research and Devel-opment vol 2 no 9 pp 6ndash10 2010

[86] N Sultana M S Arayne and N Shafi ldquoIn vitro interactionstudies of diltiazem with H

2receptor antagonistsrdquo Medicinal

Chemistry Research vol 19 no 7 pp 698ndash716 2010[87] L Jianchun ldquoRP-HPLC determination of diltiazem in plasma

and pharmacokinetic parameterrdquo pp 12ndash15 1992[88] C Giachetti P Poletti and G Zanolo ldquoAnalysis of calcium

blocker drugs in plasma HRGC and HPLC analytical condi-tions for pharmacokinetic studiesrdquo Journal of High ResolutionChromatography vol 10 no 12 pp 654ndash658 1987

[89] K Li X Zhang Y Yuan N Luo and L Tan ldquoHPLC determi-nation of diltiazem in human serum and its pharmacokineticparametersrdquo Chinese Journal of Chromatography vol 15 no 5pp 451ndash453 1997

[90] R Shimizu K Ishii N Tsumagari M Tanigawa M Matsu-moto and I T Harrison ldquoDetermination of optical isomers indiltiazem hydrochloride by high-performance liquid chromat-ographyrdquo Journal of Chromatography A vol 253 no 1 pp 101ndash108 1982

[91] G Rosell A Camacho and P Parra ldquoDirect enantiomeric sepa-ration of cis-(plusmn)diltiazem in plasma by high-performance liquidchromatography with ovomucoid columnrdquo Journal of Chromat-ography B vol 619 no 1 pp 87ndash92 1993

[92] M Shah L Sandler V Rai C Sharma and L Raghavan ldquoQual-ity of compounded topical 2 diltiazem hydrochloride formu-lations for anal fissurerdquo World Journal of Gastroenterology vol19 no 34 pp 5645ndash5650 2013

[93] K Yaku A Keiichi N Nishimura S Tadashi and F MorishitaSupercritical Fluid Methods and Protocols vol 13 ofMethods inBiotechnology Humana Press New York NY USA 2000

[94] I Kazuhiro M Kenjirou N Noriyuki M Takaaki and S Tada-shi ldquoDirect chromatographic resolution of four optical isomersof diltiazem hydrochloride on a chiralcel of columnrdquo Journal ofChromatography A vol 686 no 1 pp 93ndash100 1994

[95] HNishi N Fujimura H Yamaguchi and T Fukuyama ldquoDirecthigh-performance liquid chromatographic separation of theenantiomers of diltiazemhydrochloride and its 8-chloro deriva-tive on a chiral ovomucoid columnrdquo Journal of Chromatographyvol 633 no 1-2 pp 89ndash96 1993

[96] R Shimizu T Kakimoto I Kazuhiro Y Fujimoto HNishi andN Tsumagari ldquoNew derivatization reagent for the resolutionof optical isomers in diltiazem hydrochloride by high-perform-ance liquid chromatographyrdquo Journal of Chromatography A vol357 no 1 pp 119ndash125 1986

[97] R K Bhamra A EWard andWHolt ldquoHPLCmeasurement ofdiltiazem and desacetyldiltiazem in serum or plasmardquo Biomed-ical Chromatography vol 2 no 4 pp 180ndash182 1987

[98] H Zhao and M S Chow ldquoAnalysis of diltiazem and desacet-yldiltiazem in plasma using modified high-performance liq-uid chromatography improved sensitivity and reproducibilityrdquoPharmaceutical Research vol 6 no 5 pp 428ndash430 1989

[99] VAscalone andL Flaminio ldquoAutomated high-performance liq-uid chromatography with column switching for on-line clean-up and analysis of diltiazem andmetabolites in human plasmardquoJournal of Chromatography B vol 495 pp 358ndash360 1989

[100] R Boulieu J L Bonnefous and S Ferry ldquoSolid-phase extrac-tion of diltiazem and its metabolites from plasma prior to high-performance liquid chromatographyrdquo Journal of Chromatogra-phy B vol 528 no 2 pp 542ndash546 1990

[101] K E Johnsona and J A Piepera ldquoAn HPLC method for thedetermination of diltiazem and three of its metabolites inserumrdquo Journal of Liquid Chromatography vol 13 no 5 pp 951ndash960 1990

[102] A Leneveu A Stheneur A Bousquet and A Roux ldquoAuto-mated high-performance liquid chromatographic technique fordetermining diltiazem and its threemainmetabolites in serumrdquoJournal of Liquid Chromatography vol 14 no 19 pp 3519ndash35301991

[103] R E Wiens D J Runser J P Lacz and D C Dimmitt ldquoQuan-titation of diltiazem and desacetyldiltiazem in dog plasma byhigh-performance liquid chromatographyrdquo Journal of Pharma-ceutical Sciences vol 73 no 5 pp 688ndash689 1984

[104] D R Abernethy J B Schwartz and E L Todd ldquoDiltiazemand desacetyldiltiazem analysis in human plasma using high-performance liquid chromatography improved sensitivitywithout derivatizationrdquo Journal of Chromatography B vol 342no 1 pp 216ndash220 1985

[105] D Marini G Pollino and F Balestrieri ldquoDitiazem purificationfrom related substances and HPLC determinationrdquo BollettinoChimico Farmaceutico vol 124 no 3 pp 138ndash145 1985

[106] S CMontamat D R Abernethy J RMitchell et al ldquoHigh-per-formance liquid chromatographic determination of diltiazemand its major metabolites N-monodemethyldiltiazem and des-acetyldiltiazem in plasmardquo Journal of Chromatography B vol415 no 1 pp 203ndash207 1987

[107] P Hoglund and L G Nilsson ldquoLiquid chromatographic deter-mination of diltiazem and its metabolites using trans isomersas internal standards with dynamic modification of the solidphase by addition of an amine to the mobile phaserdquo Journal ofChromatography B vol 414 no 1 pp 109ndash120 1987

[108] K J Goebel and E U Koelle ldquoHigh-performance liquid chro-matographic determination of diltiazem and four of its metabo-lites in plasma application to pharmacokineticsrdquo Journal ofChromatography B vol 345 no 2 pp 355ndash363 1985

[109] L T Malaya VM Brovkovich and G V Andrievskii ldquoAnalysisof diltiazem and its metabolites by HPLC and mass spectrom-etryrdquo Pharmaceutical Chemistry Journal vol 24 no 8 pp 535ndash537 1990

[110] F F T Ververs H G Schaefer J F Lefeevre LM Lopez andHDerendorf ldquoSimultaneous assay of propranolol diltiazem andmetabolites of diltiazem in human plasma by liquid chromatog-raphyrdquo Journal of Pharmaceutical and Biomedical Analysis vol8 no 6 pp 535ndash539 1990

[111] A Tracqui P Kintz and P Mangin ldquoHPLCMS determinationof buprenorphine and norbuprenorphine in biological fluids


and hair samplesrdquo Journal of Forensic Sciences vol 42 no 1 pp111ndash114 1997

[112] YH Lee C K ShimMH Lee and S K Kim ldquoHPLCdetermi-nation of diltiazemanddeacetyldiltiazem in rat plasmardquo Journalof Korean Pharmaceutical Sciences vol 22 no 4 pp 317ndash3211992

[113] B Dasandi S Shah and S Shivprakash ldquoDevelopment andvalidation of a high throughput and robust LC-MSMS withelectrospray ionization method for simultaneous quantitationof diltiazem and its two metabolites in human plasma applica-tion to a bioequivalence studyrdquo Journal of Chromatography Bvol 877 no 8-9 pp 791ndash798 2009

[114] A R Zoest C THung and SWanwimolruk ldquoDiltiazem a sen-sitive HPLC assay and application to pharmacokinetic studyrdquoJournal of Liquid Chromatography vol 15 no 8 pp 1277ndash12871992

[115] I A Darwish S A Hussein AMMahmoud and A I HassanldquoA sensitive spectrophotometric method for the determinationof H2-receptor antagonists by means of N-bromosuccinimide

and p-aminophenolrdquo Acta Pharmaceutica vol 58 no 1 pp 87ndash97 2008

[116] I A Darwish S A Hussein A M Mahmoud and AI HassanldquoSpectrophotometric determination of H

2-receptor antagonists

via their oxidationwith cerium(IV)rdquo SpectrochimicaActaA vol69 no 1 pp 33ndash40 2008

[117] M S Garcia M I Albero C Sanchez-Pedreno and M SAbuherba ldquoSpectrophotometric determination of cimetidine inpharmaceuticals and urine using batch and flow-injectionmethodsrdquo Journal of Pharmaceutical and Biomedical Analysisvol 32 no 4-5 pp 1003ndash1010 2003

[118] M S Garcia M I Albero C Sanchez-Pedreno andM S Abu-herba ldquoSpectrophotometric determination of cimetidine inpharmaceuticals and urine using batch and flow-injectionmethodsrdquo Journal of Pharmaceutical and Biomedical Analysisvol 32 no 4-5 pp 1003ndash1010 2003

[119] K M Kelani A M Aziz M A Hegazy and L A Fattah ldquoDif-ferent spectrophotometric methods for the determination ofcimetidine ranitidine hydrochloride and famotidinerdquo Spectro-scopy Letters vol 35 no 4 pp 543ndash563 2002

[120] T Imamura T Nagata K Kuddo K Kimura and M NodaldquoSensitive detection and determination of cimetidine in humantissues with high-performance liquid chromatographyrdquo Journalof Chromatography B vol 534 pp 253ndash259 1990

[121] P Betto E Ciranni-Signoretti and R Di Fava ldquoDeterminationof cimetidine and related impurities in pharmaceutical formu-lations by high-performance liquid chromatographyrdquo Journal ofChromatography vol 586 no 1 pp 149ndash152 1991

[122] R Chiou R J Stubbs and W F Bayne ldquoDetermination ofcimetidine in plasma and urine by high-performance liquidchromatographyrdquo Journal of Chromatography B vol 377 pp441ndash446 1986

[123] D R P Guay H N Bockbrader and G R Matzke ldquoHigh-performance liquid chromatographic analysis of cimetidine inserum and urinerdquo Journal of Chromatography vol 228 pp 398ndash403 1982

[124] M G Kunitani D A Johnson R A Upton and S RiegelmanldquoConvenient and sensitive high-performance liquid chromat-ography assay for cimetidine in plasma or urinerdquo Journal ofChromatography vol 224 no 1 pp 156ndash161 1981

[125] V Nitsche andHMascher Journal of Chromatography vol 237pp 449ndash452 1983

[126] J S Kaka ldquoRapid method for cimetidine and ranitidine deter-mination in human and rat plasma by HPLCrdquo Journal of LiquidChromatography vol 11 no 16 pp 3447ndash3456 1988

[127] A M Rustam ldquoEstimation of cyclosporin-A in whole blood bysimple and rapid reversed-phase HPLC utilizing a salting-outextraction procedurerdquo Journal of Chromatographic Science vol28 no 11 pp 594ndash598 1990

[128] A M Rustum and N E Hoffman ldquoLiquid chromatographicdetermination of cimetidine in whole blood and plasma byusing short polymeric reverse phase columnrdquo Journal of theAssociation of Official Analytical Chemists vol 71 no 3 pp 519ndash522 1988

[129] E G Lovering and N M Curran ldquoHigh-performance liquidchromatographic determination of cimetidine and related com-pounds (raw material and tablets)rdquo Journal of Chromatographyvol 319 no 2 pp 235ndash240 1985

[130] H A Strong and M Spino ldquoHighly sensitive determination ofcimetidine and its metabolites in serum and urine by high-per-formance liquid chromatographyrdquo Journal of ChromatographyB vol 422 pp 301ndash308 1987

[131] W C Randolph V L Osborne S S Walkenstein and A PIntoccia ldquoHigh pressure liquid chromatographic analysis ofcimetidine a histamine H

2receptor antagonist in blood and

urinerdquo Journal of Pharmaceutical Sciences vol 66 no 8 pp1148ndash1150 1977

[132] G W Mihaly S Cockbain D B Jones R G Hanson and RA Smallwood ldquoHigh-pressure liquid chromatographic deter-mination of cimetidine in plasma and urinerdquo Journal of Phar-maceutical Sciences vol 71 no 5 pp 590ndash592 1982

[133] J A Ziemniak D A Chiarmonte and J J Schentag ldquoLiquid-chromatographic determination of cimetidine its knownmeta-bolites and creatinine in serum and urinerdquo Clinical Chemistryvol 27 no 2 pp 272ndash275 1981

[134] Q Lin G L Lensmeyer and F C Larson ldquoQuantitationof cimetidine and cimetidine sulfoxide in serum by solid-phase extraction and solvent-recycled liquid chromatographyrdquoJournal of Analytical Toxicology vol 9 no 4 pp 161ndash166 1985

[135] B Lorenzo and D E Drayer ldquoImproved method for the meas-urement of cimetidine in human serum by reverse-phase high-pressure liquid chromatographyrdquo Journal of Laboratory andClinical Medicine vol 97 no 4 pp 545ndash550 1981

[136] S J Soldin D R Fingold P C Fenje and W A Mahon ldquoHighperformance liquid chromatographic analysis of cimetidine inserumrdquoTherapeutic Drug Monitoring vol 1 no 3 pp 371ndash3791979

[137] M T Kelly D McGuirk and F J Bloomfield ldquoDeterminationof cimetidine inhuman plasma by high-performance liquidchromatography following liquid-liquid extractionrdquo Journal ofChromatography B vol 668 no 1 pp 117ndash123 1995

[138] K XuVKArora A K Chaudhary R B Cotton and I A BlairldquoQuantitative analysis of cimetidine in human plasma usingLCAPCISRMMSrdquo Biomedical Chromatography vol 13 no 7pp 455ndash461 1999

[139] M Abdel-Rahim D Ezra C Peck and J Lazar ldquoLiquid-chro-matographic assay of cimetidine in plasma and gastric fluidrdquoClinical Chemistry vol 31 no 4 pp 621ndash623 1985

[140] J Hempenius J Wieling J P G Brakenhoff F A Maris and JH G Jonkman ldquoHigh-throughput solid-phase extraction forthe determination of cimetidine in human plasmardquo Journal ofChromatography B vol 714 no 2 pp 361ndash368 1998



[142] W C Randolph R C Heel T M Speight and G S AveryldquoHigh-pressure liquid chromatographie analysis of cimetidinea histamineH

2-receptor antagonist in blood andurinerdquo Journal

of Pharmaceutical Sciences vol 66 no 8 pp 1148ndash1150 1977[143] N E Larsen P Hesselfeldt S J Rune and E F Havidberg

ldquoCimetidine assay in human plasma by liquid chromatographyrdquoJournal of Chromatography B vol 163 no 1 pp 57ndash63 1979

[144] M Kozma and L Vereczkey ldquoRapid method for determinationof cimetidine in biological fluids by high-performance liquidchromatography using extrelut extractionrdquo Journal of Chro-matography B vol 273 no 1 pp 223ndash227 1983

[145] E Jantratid S Prakongpan J P Foley J B Dressman and JB Dressman ldquoConvenient and rapid determination of cimeti-dine in human plasma using perchloric acid-mediated plasmaprotein precipitation and high-performance liquid chromatog-raphyrdquo Biomedical Chromatography vol 21 no 9 pp 949ndash9572007

[146] T Iqbal C S Karyekar M Kinjo G C Ngan and T C Dowl-ing ldquoValidation of a simplified method for determination ofcimetidine in human plasma and urine by liquid chromatog-raphy with ultraviolet detectionrdquo Journal of Chromatography Bvol 799 no 2 pp 337ndash341 2004

[147] J A Apffel U A Th Brinkman R W Frei et al ldquoAnalysis ofcimetidine in biological fluids by high performance liquid chro-matographyrdquo Journal of Liquid Chromatography and RelatedTechnologies vol 5 no 12 pp 2413ndash2422 1982

[148] L Dong-Sun K Kyung-Hee and S Hee-Soo ldquoDeterminationof cimetidine in human urine by column switching HPLC withUV-detectionrdquo Bulletin of the Korean Society vol 16 no 2 pp77ndash196 1995

[149] Y Gomita M Nanba K Furono K Eto and Y Araki ldquoMicro-determination of cimetidine in rat plasma by high-performanceliquid chromatographyrdquo International Journal of Pharmaceuticsvol 54 no 2 pp 89ndash93 1989

[150] S Pillai and I Singhvi ldquoSpectrophotometric simultaneousestimation of ranitidine hydrochloride and ondansetron hydro-chloride from tablet formulationrdquo Indian Journal of Pharmaceu-tical Sciences vol 69 no 4 pp 601ndash604 2007

[151] E M Hassan and F Belal ldquoKinetic spectrophotometric deter-mination of nizatidine and ranitidine in pharmaceutical prepa-rationsrdquo Journal of Pharmaceutical and Biomedical Analysis vol27 no 1-2 pp 31ndash38 2002

[152] M I Walash F Belal F Ibrahim M Hefnawy and M EidldquoKinetic spectrophotometric method for the determination ofranitidine and nizatidine in pharmaceuticalsrdquo Journal of AOACInternational vol 85 no 6 pp 1316ndash1323 2002

[153] D Dumanovic I Juranic D Dzeletovic V M Vasic and JJovanovic ldquoProtolytic constants of nizatidine ranitidine andNN1015840-dimethyl-2-nitro-11-ethenediamine spectrophotometricand theoretical investigationrdquo Journal of Pharmaceutical andBiomedical Analysis vol 15 no 11 pp 1667ndash1678 1997

[154] K Basavaiah and P Nagegowda ldquoDetermination of ranitidinehydrochloride in pharmaceutical preparations by titrimetry andvisible spectrophotometry using bromate and acid dyesrdquo Far-maco vol 59 no 2 pp 147ndash153 2004

[155] M Walash M Sharaf-El Din M E-S Metwalli and M Reda-Shabana ldquoSpectrophotometric determination of nizatidine and

ranitidine through charge transfer complex formationrdquoArchivesof Pharmacal Research vol 27 no 7 pp 720ndash726 2004

[156] S Al-Ghannam and F Belal ldquoSpectrophotometric determina-tion of three anti-ulcer drugs through charge-transfer complex-ationrdquo Journal of AOAC International vol 85 no 5 pp 1003ndash1008 2002

[157] A M Rustum A Rahman and N E Hoffman ldquoHigh-per-formance liquid chromatographic determination of ranitidinein whole blood and plasma by using a short polymeric columnrdquoJournal of Chromatography B vol 421 no 2 pp 418ndash424 1987

[158] G W Mihaly O H Drummer A Marshall R A Smallwoodand W J Louis ldquoHigh-pressure liquid chromatographic deter-mination of ranitidine a newH

2-receptor antagonist in plasma

and urinerdquo Journal of Pharmaceutical Sciences vol 69 no 8 pp1155ndash1157 1980

[159] AM RustumA Rahman andN EHoffman ldquoHigh-perform-ance liquid chromatographic determination of ranitidine inwhole blood and plasma by using a short polymeric columnrdquoJournal of Chromatography B vol 421 no 2 pp 418ndash424 1987

[160] A Ahmadiani and H Amini ldquoRapid determination of raniti-dine in human plasma by high-performance liquid chromatog-raphywithout solvent extractionrdquo Journal of Chromatography Bvol 751 no 2 pp 291ndash296 2001

[161] G Mullersman and H Derendorf ldquoRapid analysis of ranitidinein biological fluids and determination of its erythrocyte parti-tioningrdquo Journal of Chromatography B vol 381 no 2 pp 385ndash391 1986

[162] C F Wong K K Peh and K H Yuen ldquoSimple high-perform-ance liquid chromatographic method for the determination ofranitidine in human plasmardquo Journal of Chromatography B vol718 no 1 pp 205ndash210 1998

[163] P F Carey L E Martin and P E Owen ldquoDetermination ofranitidine and itsmetabolites in humanurine by reversed-phaseion-pair high-performance liquid chromatographyrdquo Journal ofChromatography B vol 225 no 1 pp 161ndash168 1981

[164] T Prueksaritanont N Sittichai S Prueksaritanont and RVongsaroj ldquoSimultaneous determination of ranitidine and itsmetabolites in human plasma and urine by high-performanceliquid chromatographyrdquo Journal of Chromatography B vol 490no 1 pp 175ndash185 1989

[165] D Farthing K L R Brouwer I Fakhry and D Sica ldquoSolid-phase extraction and determination of ranitidine in humanplasma by a high-performance liquid chromatographic methodutilizing midbore chromatographyrdquo Journal of ChromatographyB vol 688 no 2 pp 350ndash353 1997

[166] T L Lloyd T B Perschy A E Gooding and J J TomlinsonldquoRobotic solid phase extraction and high performance liquidchromatographic analysis of ranitidine in serum or plasmardquoBiomedical Chromatography vol 6 no 6 pp 311ndash316 1992

[167] H T Karnes K Opong-Mensah D Farthing and L ABeightol ldquoAutomated solid-phase extraction and high-per-formance liquid chromatographic determination of ranitidinefrom urine plasma and peritoneal dialysaterdquo Journal of Chro-matography B vol 422 pp 165ndash173 1987


[169] C Lopez-Calull L Garcıa-Capdevila C Arroyo and J BonalldquoSimple and robust high-performance liquid chromatographicmethod for the determination of ranitidine in microvolumes of


human serumrdquo Journal of Chromatography B vol 693 no 1 pp228ndash232 1997

[170] M S Salem A M Gharaiebeh H N Alkaysi and A BadwanldquoHigh-performance liquid chromatographic analysis of raniti-dine in plasma and urinerdquo Journal of Clinical Pharmacy andTherapeutics vol 13 no 5 pp 351ndash357 1988



[173] A Rahman N E Hoffman and AM Rustum ldquoDeterminationof ranitidine in plasma by high-performance liquid chromatog-raphyrdquo Journal of Pharmaceutical and Biomedical Analysis vol7 no 6 pp 747ndash753 1989

[174] P Vinas N Campillo C Lopez-Erroz and M Hernandez-Cordoba ldquoUse of post-column fluorescence derivatization todevelop a liquid chromatographic assay for ranitidine and itsmetabolites in biological fluidsrdquo Journal of Chromatography Bvol 693 no 2 pp 443ndash449 1997

[175] M S Lant L E Martin and J Oxford ldquoQualitative and quan-titative analysis of ranitidine and its metabolites by high-per-formance liquid chromatography-mass spectrometryrdquo Journalof Chromatography vol 323 no 1 pp 143ndash152 1985

[176] M X Kokoletsi S Kafkala and M Tsiaganis ldquoA novel gradientHPLC method for simultaneous determination of ranitidinemethylparaben and propylparaben in oral liquid pharmaceu-tical formulationrdquo Journal of Pharmaceutical and BiomedicalAnalysis vol 38 no 4 pp 763ndash767 2005

[177] A S Amin S A Shama I S Ahmed and E A Gouda ldquoSpec-trophotometric determination of famotidine through oxidationwith N-bromosuccinimide and cerric sulphaterdquo Analytical Let-ters vol 35 no 11 pp 1851ndash1862 2002

[178] P D Tzanavaras A Verdoukas and T Balloma ldquoOptimizationand validation of a dissolution test for famotidine tablets usingflow injection analysisrdquo Journal of Pharmaceutical and Biomed-ical Analysis vol 41 no 2 pp 437ndash441 2006

[179] A K S Ahmad M A Kawy and M Nebsen ldquoSpectrophoto-metric and spectrofluorimetric determination of famotidineand ranitidine using 14-benzoquinone reagentrdquo Analytical Let-ters vol 32 no 7 pp 1403ndash1419 1999

[180] Y K Agrawal K Shivramchandra G N Singh and B E RaoldquoSpectrophotometric determination of famotidine in pharma-ceutical preparationsrdquo Journal of Pharmaceutical and Biomedi-cal Analysis vol 10 no 7 pp 521ndash523 1992

[181] N Rahman and M Kashif ldquoApplication of ninhydrin to spec-trophotometric determination of famotidine in drug formula-tionsrdquo Farmaco vol 58 no 10 pp 1045ndash1050 2003

[182] H A Mohamad ldquoSpectrophotometric determination of famo-tidine using p-chloranilic acidrdquo Bulletin of Pharmaceutical Sci-ences (Assiut University) vol 23 no 223 pp 157ndash163 2000

[183] B V Kamath K Shivram and S Vangani ldquoSpectrophotometrydetermination of famotidine by charge transfer complexationrdquoAnalytical Letters vol 25 no 12 pp 2239ndash2247 1992

[184] El-Yazbi and A Fawzy ldquoSecond-derivative spectrophotometricdetermination of famotidinerdquo Spectroscopy Letters vol 25 no7 pp 1011ndash1021 1992

[185] A Z Abu Zuhri R M Shubietah and G M Badah ldquoExtrac-tional-spectrophotometric determination of famotidine inpharmaceutical formulationsrdquo Journal of Pharmaceutical andBiomedical Analysis vol 21 no 2 pp 459ndash465 1999

[186] SM Blaih F A El-Yazbi and EMHassan ldquoSpectrophotomet-ric and titrimetric methods for the determination of famotidinein dosage formrdquo STP Pharma Sciences vol 4 no 6 pp 492ndash494 1994

[187] S Raghuveer CM R Srivastava andD K Vatsa ldquoSpectropho-tometric determination of famotidine in its dosage formsrdquoIndian Drugs vol 29 no 7 pp 320ndash322 1992

[188] HMaurer ldquoChromatography of histamineH1- andH

2-receptor

blockers in biosamplesrdquo Journal of Chromatography B vol 531pp 369ndash405 1990

[189] B Carkir A Tosun and M Sahin Journal of PharmaceuticalSciences vol 3 pp 493ndash496 1997

[190] M Campanero I BuenoM Arangoa et al ldquoImproved selectiv-ity in detection of polar basic drugs by liquid chromatography-electrospray ionizationmass spectrometry illustration using anassay method for the determination of famotidine in humanplasmardquo Journal of Chromatography B vol 763 no 1-2 pp 21ndash33 2001

[191] T C Dowling and R F Frye ldquoDetermination of famotidinein human plasma and urine by high-performance liquid chro-matographyrdquo Journal of Chromatography B vol 732 no 1 pp239ndash243 1999

[192] A Zoest S Wanwimoluk and C Hung ldquoSensitive high-performance liquid chromatographic determination of famoti-dine in plasma application to pharmacokinetic studyrdquo Journalof Chromatography B vol 572 no 1-2 pp 227ndash238 1991

[193] S Singh S Kumar N Sharda and A K Chakraborti ldquoNewfindings on degradation of famotidine under basic conditionsIdentification of a hitherto unknown degradation product andthe condition for obtaining the propionamide intermediate inpure formrdquo Journal of Pharmaceutical Sciences vol 91 no 1 pp253ndash257 2002

[194] Z Degim and I Agabeyoglu ldquoNonisothermal stability tests offamotidine and nizatidinerdquo Il Farmaco vol 729 no 9 pp 729ndash735 2002

[195] M S Suleiman H Y Muti M E Abdel-Hamid M Hassan YM El-Sayed and N M Najib ldquoA stability-indicating HPLCanalysis of famotidine and its application to kinetic studiesrdquoAnalytical Letters vol 22 no 6 pp 1499ndash1512 1989

[196] G Junnarkar and S Stavchansky ldquoThermal degradation offamotidine in aqueous solution stability indicating assayrdquo Ana-lytical Letters vol 25 no 10 pp 1907ndash1913 1992

[197] S E Biffar and D J Mazzo ldquoReversed-phase determination offamotidine potential degradates and preservatives in pharma-ceutical formulations by high-performance liquid chromatog-raphy using silica as a stationary phaserdquo Journal of Chromatog-raphy A vol 363 no 2 pp 243ndash249 1986

[198] S Husain S Khalid V Nagaraju and N R Rao ldquoHigh-per-formance liquid chromatographic separation and determina-tion of small amounts of process impurities of famotidine inbulk drugs and formulationsrdquo Journal of ChromatographyA vol743 no 2 pp 328ndash334 1996

[199] X-Z Qin D P Ip K H-C Chang P M Dradransky M ABrooks and T Sakuma ldquoPharmaceutical application of LC-MS 1mdashcharacterization of a famotidine degradates in a packagescreening study by LC-APCI MSrdquo Journal of Pharmaceuticaland Biomedical Analysis vol 12 no 2 pp 221ndash233 1994


[200] W C Vincek M L Constanzer G A Hessey II and W FBayne ldquoAnalytical method for the quantification of famotidinean H2-receptor blocker in plasma and urinerdquo Journal of Chro-

matography B vol 338 pp 438ndash443 1985[201] L Cvitkovic L Zupancic-Kralj and J Marsel ldquoDetermination

of famotidine in human plasma and urine by high-performanceliquid chromatographyrdquo Journal of Pharmaceutical and Biomed-ical Analysis vol 9 no 2 pp 207ndash210 1991

[202] S Wanwimolruk A R Zoest S Z Wanwimolruk and C THung ldquoSensitive high-performance liquid chromatographicdetermination of famotidine in plasma Application to pharma-cokinetic studyrdquo Journal of Chromatography B vol 572 no 1-2pp 227ndash238 1991

[203] Y Imai and S-I Kobayashi ldquoA simple method for the quantifi-cation of famotidine in human plasma and urine by paired-ionhigh performance liquid chromatographyrdquo Biomedical Chro-matography vol 6 no 5 pp 222ndash223 1992

[204] P Guo L M Ye B Lu Y J He and ZW Li ldquoDirect injection ofplasma to determine famotidine in plasma usingHPLC columnswitching techniquerdquo Acta Pharmaceutica Sinica vol 25 no 8pp 622ndash625 1990

[205] L Zhong and K C Yeh ldquoDetermination of famotidine inhuman plasma by high performance liquid chromatographywith column switchingrdquo Journal of Pharmaceutical and Biomed-ical Analysis vol 16 no 6 pp 1051ndash1057 1998

[206] N Helali F Darghouth and L Monser ldquoRP-HPLC determina-tion of famotidine and its potential impurities in pharmaceuti-calsrdquo Chromatographia vol 60 no 7-8 pp 455ndash460 2004

[207] G Carlucci P Mazzeo C Vetuschi and E Di GiuseppeldquoReversed-phase high-performance liquid chromatographicand derivative UV spectrophotometric determination of famo-tidine in pharmaceutical preparationsrdquo International Journal ofPharmaceutics vol 102 no 1ndash3 pp 271ndash274 1994

[208] A Zarghi A Shafaati S M Foroutan and A KhoddamldquoDevelopment of a rapid HPLC method for determinationof famotidine in human plasma using a monolithic columnrdquoJournal of Pharmaceutical and Biomedical Analysis vol 39 no3-4 pp 677ndash680 2005

[209] B V Kamath K Shivram B L Newalkar and A C Shah ldquoLiq-uid chromatographic analysis anddegradation kinetics of famo-tidinerdquo Journal of Liquid Chromatography amp Related Technolo-gies vol 16 no 5 pp 1007ndash1014 1993

[210] N Helali and L Monser ldquoStability indicating method for famo-tidine in pharmaceuticals using porous graphitic carbon col-umnrdquo Journal of Separation Science vol 31 no 2 pp 276ndash2822008

[211] N Sultana M S Arayne S Shamim and A Naz ldquoValidatedmethod for the simultaneous determination of gemifloxacinand H

2-receptor antagonists in bulk pharmaceutical formula-

tions and human serum by RP-HPLC in-vitro applicationsrdquoJournal of the Chinese Chemical Society vol 58 no 5 pp 629ndash636 2011

[212] S Naveed N Sultana M S Arayne et al ldquoSimultaneous deter-mination of lisinopril and H

2antagonists in API formulations

and human serum by using two different HPLC systemsrdquoMedicinal Chemistry Research vol 21 no 12 pp 4037ndash40422012

[213] N Sultan S Naveed and M S Arayne ldquoRP-HPLC method forthe simultaneous determination of captopril and H

2-receptor

antagonist application to interaction studiesrdquoMedicinal Chem-istry vol 3 no 1 pp 183ndash187 2013

[214] M S Arayne N Sultana M H Zuberi and F A SiddiquildquoSimultaneous determination of metformin cimetidine famo-tidine and ranitidine in human serum and dosage formulationsusing HPLC with UV detectionrdquo Journal of ChromatographicScience vol 48 no 9 pp 721ndash725 2010

[215] S Najma M S Arayne S Naz et al ldquoSimultaneous determi-nation of prazosin andH

2receptor antagonists from bulkmate-

rials pharmaceutical formulations and human serum by RP-HPLCrdquo Inventi Impact vol 2010 article Inventipaqa37102010

[216] N SultanaM Saeed Arayne S Gul M Akhtar and S ShamimldquoSimultaneous determination of sparfloxacin and commonlyused H

2receptor antagonists by RP-HPLC application to

in vitro drug interactionsrdquo Medicinal Chemistry Research vol21 no 7 pp 974ndash982 2012

[217] C HO H-M Huang S-Y Hsu C-Y Shaw and B-L ChangldquoSimultaneous high-performance liquid chromatographic anal-ysis for famotidine ranitidine HCl cimetidine and nizatidinein commercial productsrdquo Drug Development and IndustrialPharmacy vol 25 no 3 pp 379ndash385 1999

[218] D Zendelovska and T Stafilov ldquoDevelopment of an HPLCmethod for the determination of ranitidine and cimetidine inhuman plasma following SPErdquo Journal of Pharmaceutical andBiomedical Analysis vol 33 no 2 pp 165ndash173 2003

Submit your manuscripts athttpwwwhindawicom

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N

S

O O

CH3

O

NH3C CH3

OCH3

Figure 1 Diltiazem

15 Famotidine Famotidine 3-[[[2-[(aminoiminomethyl)amino]-4-thiazolyl]methyl]thio]-N (aminosulfonyl) (Figure4) is highly selective histamine H

2receptor antagonist indi-

cated for the treatment of duodenal ulcer gastric ulcer gas-troesophageal reflux disease and Zollinger-Ellison syndrome[8] in the treatment of Parkinsonrsquos and inhibits basal andnoc-turnal gastric secretion as well as secretion stimulated by foodand pentagastrin [9]

The present review article deals with the analytical meth-ods that are useful for pure form pharmaceutical formula-tions and biological specimens of diltiazem and H

2receptor

antagonists (cimetidine ranitidine and famotidine) werefocused and summarized

2 Analytical Methods

Assay method development is very significant for pharma-ceutical industries and pathological laboratories and thisis always desirable to select and develop simple accurateprecise and economical method for the determination ofdrugs in pharmaceutical dosage forms and pathologicalsamples Analytical data are used to screen potential drugs inbiological samples aid in the development of drug synthesessupport formulation studies monitor the stability of bulkpharmaceuticals and formulated products and test finalproducts for release [10]

3 Official and Compendial Methodsof Analysis

Monographs in the ldquoAnalytical Profile of Drug Substancesrdquoseries were also published for diltiazem [11] cimetidine [12]and ranitidine [13] Eur Ph 2002 [14] recommends an HPLCassay for diltiazem in its dosage forms Stability-indicatingmethod for the determination of diltiazem hydrochloride informulated oral preparations by the HPLC technique hasbeen recommended in USP 29 [15] High-performance liquidchromatographic methods are prescribed according to BP2011 and USP 34 for quantitative analysis of pharmaceuticalscontaining cimetidine ranitidine hydrochloride and famoti-dine [16ndash20] Chromatographic conditions of official meth-ods are presented in Table 1 However British Pharmacopeia[21] recommended potentiometric titration method with01M NaOH for ranitidine hydrochloride

NH

N

H3C

H3C

S N

CN

NH

NH

Figure 2 Cimetidine

4 Reported Methods of Analysis

41 Diltiazem Literature survey revealed that a number ofassaymethods have been used for analysis of diltiazem in bulkdrug pharmaceutical preparations and serumusing differenttechniques including LC-MSMS [22ndash24] gas chromatogra-phy [25ndash28] and electron capture gas chromatography [29]

411 Spectrophotometric Methods Many research papershave described the spectrophotometric methods for thedetection of diltiazem in rawmaterials and different pharma-ceutical formulations Recently Ayad et al [30] established amethod by kinetic spectrophotometric and spectrofluorimet-ric technique using NBD-Cl (4-Chloro-7-nitrobenzene-2-oxa-13-diazole) The reported method has many advantagesin contrast with other methods in terms of sensitivity andselectivity by way of high-quality precision and accuracyHosny [31] reported an ion-pair complex formation methodfor the assaying of diltiazem in its formulation by usingchromotrope 2R and rose bengal reagents Another spectro-photometric determination of diltiazem by ternary complexformation reaction with cobalt thiocyanate at acidic pH (3ndash5) After extraction complex was deliberated at 627 nm [32]Pietras et al [33] compare the classical and derivative spec-trophotometric method for the quantitations of diltiazemin bulk and formulation Assay was performed by the first-and second-order method with the application of ldquopeak-zerordquo and ldquopeak-peakrdquo techniques with excellent correlationcoefficient (1199032 lt 09999) Sabino et al [34] presented a verysensitive determination of diltiazem by the reduction ofCu(II) in buffer (pH 7) and micellar medium be full of 44-dicarboxy-22 biquinoline acid Cu(I) produced as a result ofreduction of Cu(II) reacts with 44-dicarboxy-22 biquinolineacid-formed complexes which was quantitatively detectedat 558 nm Similarly chloro drug derivative of diltiazemwas formed by means of reaction involving tertiary aminogroup of diltiazem and sodium hypochlorite Newly formedderivative then reacted with starch and potassium iodidein sodium bicarbonate solution given blue color complexquantitatively read out at 540 nm [35] Leitaoa and Esteves daSilva reported a spectrophotometricmethod based on kineticstudy by factorial analysis Drug was reacted in two stageswith hydroxylamine and a ferric salt as a result hydrox-amic acid and ferric hydroxamate were formed respectively[36] Diltiazem was quantitatively investigated in capsuleand tablet dosage form by means of reaction with sodiummetavanadate in acidic medium (sulfuric acid) and spectro-photometrically measured at 750 nm [37] Ayad et al [38]describe an analytical method bymeans of oxidation reactionof diltiazem with iron(III) in acidic environment while






[16]


[17]


[18]




[20]

ON

H3CS

HNH

N

CH3 NO2

CH3

Figure 3 Ranitidine

S

N NH2N NH2

SN

NH2

S

NH2

OO

Figure 4 Famotidine




70)
























2


4OAC-




42 Cimetidine






8









228 nm [146]


320 nm [160]


229 nm [162]



228 nm [167]


230 nm [172]


315 nm [173]


254 nm [176]



267 nm [191]


265 nm [206]



265 nm [210]

43 Ranitidine







44 Famotidine























229 [214]




230 nm [217]

5 Conclusion




References

















































































































































































































2-receptor

































2-receptor




















Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of






[16]


[17]


[18]




[20]

ON

H3CS

HNH

N

CH3 NO2

CH3

Figure 3 Ranitidine

S

N NH2N NH2

SN

NH2

S

NH2

OO

Figure 4 Famotidine




70)
























2


4OAC-




42 Cimetidine






8









228 nm [146]


320 nm [160]


229 nm [162]



228 nm [167]


230 nm [172]


315 nm [173]


254 nm [176]



267 nm [191]


265 nm [206]



265 nm [210]

43 Ranitidine







44 Famotidine























229 [214]




230 nm [217]

5 Conclusion




References

















































































































































































































2-receptor

































2-receptor




















Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of






















2


4OAC-




42 Cimetidine






8









228 nm [146]


320 nm [160]


229 nm [162]



228 nm [167]


230 nm [172]


315 nm [173]


254 nm [176]



267 nm [191]


265 nm [206]



265 nm [210]

43 Ranitidine







44 Famotidine























229 [214]




230 nm [217]

5 Conclusion




References

















































































































































































































2-receptor

































2-receptor




















Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of







2


4OAC-




42 Cimetidine






8









228 nm [146]


320 nm [160]


229 nm [162]



228 nm [167]


230 nm [172]


315 nm [173]


254 nm [176]



267 nm [191]


265 nm [206]



265 nm [210]

43 Ranitidine







44 Famotidine























229 [214]




230 nm [217]

5 Conclusion




References

















































































































































































































2-receptor

































2-receptor




















Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of



42 Cimetidine






8









228 nm [146]


320 nm [160]


229 nm [162]



228 nm [167]


230 nm [172]


315 nm [173]


254 nm [176]



267 nm [191]


265 nm [206]



265 nm [210]

43 Ranitidine







44 Famotidine























229 [214]




230 nm [217]

5 Conclusion




References

















































































































































































































2-receptor

































2-receptor




















Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of







228 nm [146]


320 nm [160]


229 nm [162]



228 nm [167]


230 nm [172]


315 nm [173]


254 nm [176]



267 nm [191]


265 nm [206]



265 nm [210]

43 Ranitidine







44 Famotidine























229 [214]




230 nm [217]

5 Conclusion




References

















































































































































































































2-receptor

































2-receptor




















Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of



44 Famotidine























229 [214]




230 nm [217]

5 Conclusion




References

















































































































































































































2-receptor

































2-receptor




















Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of










229 [214]




230 nm [217]

5 Conclusion




References

















































































































































































































2-receptor

































2-receptor




















Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of




























































































































































































2-receptor

































2-receptor




















Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of



























































































































































2-receptor

































2-receptor




















Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of






























































































































2-receptor

































2-receptor




















Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of





























































































2-receptor

































2-receptor




















Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of

























































2-receptor

































2-receptor




















Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of






















2-receptor

































2-receptor




















Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of





















2-receptor




















Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of










Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of

Documents

Review Article An Overview of Analytical Determination of