Review Article Analytical Methods For Determination Of .
Int. J. Pharm. Sci. Rev. Res., 43(1), March - April 2017; Article No. 41, Pages: 217-225ISSN 0976 – 044XReview ArticleAnalytical Methods for Determination of Sitagliptin: An Updated Reviewa*aaabbArul Caroline Grace , Thangavel Prabha , Murugesan Jagadeeswaran , Kulandaivel Srinivasan , Thangavel SivakumarDepartment of Pharmaceutical Analysis, bDepartment of Pharmaceutical Chemistry, Nandha college of Pharmacy, Erode, Tamilnadu,India.*Corresponding author’s E-mail: carodani24@gmail.comReceived: 10-02-2017; Revised: 06-03-2017; Accepted: 20-03-2017.ABSTRACTSitagliptin is an oral anti-hyperglycemic agent of the dipeptidyl peptidase-4 (DPP-4) inhibitor class used in the treatment of type-2diabetes. It stimulates insulin release and reduces glucagon level by inhibition of inactivation of the incretin in a glucose-dependantmanner. In 2013 it was the second best-selling drug in the U.S. This review explores the reported analytical methods so far in theliterature for the estimation of sitagliptin in bulk drug, pharmaceutical formulations and in biological matrix. This assessmentencompasses various analytical methods such as spectrometry, high performance liquid chromatography (HPLC), liquidchromatography-electrospray ionization-mass spectrometry (LC-ESI-MS-MS), liquid chromatography-mass spectrometry (LC-MS),capillary electrophoresis (CE), ultra performance liquid chromatography (UPLC), high performance thin layer chromatography(HPTLC) and gas chromatography-mass spectrometry (GC-MS) for the estimation of sitagliptin in single and/or in combination.Keywords: Sitagliptin, Analytical methods, Type-2 diabetes.INTRODUCTIONSitagliptin (SITA) chemically (3R) ,4]triazolo[3,4-c] pyrazin-7-yl]-4-(2,4,5-trifluorophenyl) butan1-one (Figure 1), is an oral anti-diabetic agent that blocksDPP-4 activity, used in the treatment of type 2 diabetes. 1,2DPP-4 enzyme breaks down the incretin hormonesincluding glucagon like peptide-1 (GLP-1) and glucosedependent insolinotropic polypeptide (GIP). GLP-1 andGIP are gastrointestinal hormones released in response toa meal. By preventing GLP-1 and GIP inactivation, they areable to increase the secretion of insulin and suppress therelease of glucagon by the pancreas. This drives blood3,4glucose levels towards normal.The absolutebioavailability of SITA is approximately 87%. The coadministration of high fat meal with SITA has no effect onthe pharmacokinetics. It may be administered with or1without food. Approximately 80% of the SITA excretedunchanged in urine. The fecal route accounts for 13% ofelimination.5 The benefit of this medicine is its lower sideeffects like less hypoglycemic and less weight gain. It isused alone or in combination with metformin orsimvastatin to treat diabetes.Figure 1: Structure of SitagliptinSITA is a white to off white, crystalline, non-hygroscopicpowder and has a molecular formula ofC16H15F6N5O.H3PO4.H2O. The molecular weight is 523.32.It is soluble in water and N, N-Dimethyl formamide;slightly soluble in methanol; very slightly soluble inethanol, acetone and acetonitrile; and insoluble inisopropanol and isopropyl acetate.1 In this review thevarious analytical methods published in the literaturehitherto for the determination of sitagliptin in bulk drug,pharmaceutical formulations and in biological matrix ance liquid chromatography (HPLC), ectrometry (LC-ESI-MS-MS), liquid chromatographymass spectrometry (LC-MS), capillary electrophoresis(CE), ultra performance liquid chromatography (UPLC),high performance thin layer chromatography (HPTLC) andgas chromatography-mass spectrometry (GC-MS) havebeen used for analysis of SITA. Overview of thesemethods for determination of SITA is shown in figure 2.Figure 2:overview of Analytical methods fordetermination of Sitagliptin in Biological andPharmaceutical samples.International Journal of Pharmaceutical Sciences Review and ResearchAvailable online at www.globalresearchonline.net Copyright protected. Unauthorised republication, reproduction, distribution, dissemination and copying of this document in whole or in part is strictly prohibited.217
Int. J. Pharm. Sci. Rev. Res., 43(1), March - April 2017; Article No. 41, Pages: 217-225ISSN 0976 – 044XSample PreparationSolubilityAccording to biopharmaceutical classification system(BCS), the SITA falls in BCS class-I, meaning high solubility6and high permeability. The pH of a saturated watersolution of SITA is 4.4. The partition coefficient is 1.8 andpKa is 7.7.7 The solubility of the drug was tested insolvents routinely used for analytical methodology.Sample preparation strategiesAbout 80% of the total analysis time is spent on samplepreparation in most of the methods. The quality ofsample preparation is a key factor for success of analysis.8Figure 3 shows various diluents used in the analysis ofSITA. In most of the spectrometric methods distilledwater, in some cases methanol is used as diluent. Thesample preparation techniques for the extraction of SITAfrom biological matrices (plasma, urine) include proteinprecipitation with acetonitrile (ACN) and methanol, solidphase extraction(SPE) using id-liquidextraction(LLE) using tert butyl methyl ether(TBME) andethyl acetate.Figure 3:SitagliptinVarious diluents used for the analysis ofHPLCBiological samplesAnil Dubala et al. developed a method in human plasmafor estimation of SITA for application in pharmacokineticstudies. The mobile phase used in this method is amixture of 0.5%v/v triethylamine and ACN (77:23 v/v).They performed the validation studies and the LOD andLOQ was found to be 1ng/mL and 10 ng/mL.33 ArunM.Kashid et al. reported a method in human plasma forestimation of SITA from dosage form duringpharmacokinetic study. ACN: Methanol: Buffer (2:3:5 v/v)is used as mobile phase. The LLOQ was found to be 25µg/mL.34Analytical MethodsSpectrometryIn the literature about 25 methods were reported for theestimation of SITA using spectrometry, of which 11methods are for determination of SITA alone, while theothers are for quantifying SITA in combination with otherdrug substances. The summary of reported spectrometricmethods indicating the basic principle, λmax, solvent andlimit of detection (LOD) is shown in table 1.2, 9-32Pharmaceutical samplesAnalytical methods for the determination of SITA in bulkdrug and pharmaceutical dosage forms using HPLC areshown in table 2.35-50Table 1: Summary of spectrometric methods for the analysis of SITA either alone or in combination with other drugs likeGliclazide (GLZ), Metformin (MET), Simvastatin (SIMV).CompoundsMethodsλmax (nm)Solvent/ProcedureLOD (µg/mL)Ref.SITAFirst order derivative275Water2.382SITAMethod A Method B267 275Methanol & Water0.09636 0.41259SITA 267Methanol6.0310SITAMethod A (Abs. ratio)Method B (AUC)267 261270Water11.85 14.0511SITAExtractive Visible MethodA-BTB Visible Method BBCGMethanol 12SITA 267Water0.226913SITAMethod for dissolutionstudy2670.01M HCl/USP apparatus 1(basket) 14SITAZero order, First order,Second order derivative267, 213, 276Methanol6.03, 4.14, 3.4315SITA 2670.1N HCl0.13916430Water/ Primary aminogroup of SITA with acetylacetone & HCHO givesyellow color.1.94717SITAVisible method412419International Journal of Pharmaceutical Sciences Review and ResearchAvailable online at www.globalresearchonline.net Copyright protected. Unauthorised republication, reproduction, distribution, dissemination and copying of this document in whole or in part is strictly prohibited.218
Int. J. Pharm. Sci. Rev. Res., 43(1), March - April 2017; Article No. 41, Pages: 217-225ISSN 0976 – 044XSITAVisible method338Water/ SITA with OPA,NAC & borate buffer giveschromogen.1.118SITA, GLZMulti-wavelength method267, 226Methanol & Water0.2269,0.3119SITA, METMulti-wavelength method267, 231Water0.954, 1.220SITA, METVierodt’s methodSecond order derivative267, 232249, 278Water0.825,0.0860.106,0.63021SITA, SIMVVierodt’s method267, 238Methanol: Water (90:10)-22SITA. METVierodt’s method266, 232Water0.01693, 0.263823SITA, METAbsorption maxima methodArea under curve method266, 232.244-279,222-240.Water-24SITA, SIMVQ-Absorbance ratio method267, 239Methanol: Water (40:60)0.0012, 0.09125SITA, GLZQ-Absorbance ratio method267, 226Methanol & Water-26SITA, SIMVQ-Absorbance ratio method267, 237Methanol: Water (60:40)14.05,0.7827SITA, SIMV--Buffer: Methanol (25:75)0.964, 3.628SITA, METVierodt’s method273, 237Methanol: Water (40:60)0.3784, 0.019629SITASpectrofluorimetric method267, 297Water0.0787830SITA, METSpectrofluorimetric,Zero,First.263, 475267,275&246Methanol0.05,2.88, 14.92,0.2431SITASpectrofluorimetric method270, 300Deionized water0.0053132Table 2: Reported HPLC methods for determination of SITA either alone or in combination with other drugs inpharmaceutical dosage forms.Study aimColumnMobile phaseDetectionλmax(nm)Flow ratemL/minLODµg/mLRef.Content analysis &Dissolution study-Buffer:ACN (60:40)v/vUV2571-35In bulk and Tabletdosage formZorbaxEclipse XDBC18(150 x 4.6mm x5µ)0.01M KH2PO4:Methanol(50:50)v/vPDA2670.70.636Chiral separationof SITA enantiomerChiralpak AD-H(250 x 4.6mm x 5µ)Heptane: Ethanol:Diethylamine(35:65:0.1) v/vUV2651.00.1537Simultaneousestimation withMETHypersil BDS C18(150 x 4.6mm x 5µ)PDOP: Methanol(50:50) v/vPDA2601-38Simultaneous withMETXterra Symmetry C8(100 x 4.6mm x 5µ)Methanol: ACN:PB(20:35:45) v/vUV2541.00.24,0.4239Simultaneous withMETHypersil BDS C18(250 x 4.0mm x 5µ)PB:ACN (60:40)v/vUV2601.0-40Simultaneous withSIMVInertsil ODS-3 C18(75mm x 4.6mm x5µ)0.05M AAB: ACN(60:40)v/vUV2531.0-41Simultaneous withMET in bulk &dosage formInertsil ODS(250 x 4.6mm x 5µ)Ammoniumdihydrogen PB:ACN (74:26) v/vUV2461.00.06,0.1342Simultaneous withMET &AtorvastatinHypersil GOLD(150 x 4.6mm x 5µ)Buffer: al Journal of Pharmaceutical Sciences Review and ResearchAvailable online at www.globalresearchonline.net Copyright protected. Unauthorised republication, reproduction, distribution, dissemination and copying of this document in whole or in part is strictly prohibited.219
Int. J. Pharm. Sci. Rev. Res., 43(1), March - April 2017; Article No. 41, Pages: 217-225ISSN 0976 – 044XSimultaneous withMET in bulk &tablet dosage formHypersil BDS C18(100 x 4.6mm x 5µ)PDOP: Methanol(50:50)v/vUV2151.00.07,0.0844Simultaneous withSIMV in bulk &tablet dosage formNucleosil C18(150 x 4.6mm x 5µ)PB:ACN (30:70)v/vUV2541.01.305,0.25745Simultaneous withMET in tabletdosage formSymmetry C18(250 x 4.6mm x 5µ)Methanol:PB(60:40) v/vUV2581.03.0, 2.946Simultaneous withMETPhenomenex C18(250 x 4.6mm x multaneous withSIMV in bulk &tablet dosage formHypersil C18(150 x 4.6mm x 5µ)Buffer:ACN(30:70) v/vUV2541.02.95,3.0248Simultaneous withSIMV in bulk &tablet dosage formHi-Q Sil C18(250 x 4.6mm x 5µ)ACN: Methanol: 10mM PB(65:25:10) v/vPDA2501.251.50,6.8049Simultaneous withSIMVAgilent C8(250 x 4.6mm x 5µ)Methanol: Water(25:75) v/vPDA2661.0-50Stability indicating methodIn the literature eight stability indicating methods were reported. Table 3 shows the summary of the methods. 51-58Table 3: Summary of stability indicating HPLC methods for determination of SITA either alone or in combination withother drugs.Study aimStress conditionDetectionType of studyRef.SITA in bulk drug & tabletsAcid, alkali, oxidation,thermal, lightDAD- 260nmSeparation in presence ofdegradation product.51SITA in tabletsAcid, alkali, oxidation,thermal, lightPDA-264nmIsolation, characterization ofdegradation products.52SITA simultaneous withMETAlkaliUV-220nmSeparation of SITA & MET inpresence of SITA alkalinedegradation product.53SITA simultaneous withMET in tablet-UV-245Separation of SITA & MET inpresence of added impurities.54SITA simultaneous withSIMV in tabletAcid, alkali, oxidation,thermal, lightUV-252Separation of SITA & SIMV inpresence of degradation products.55SITA simultaneous withSIMV in tabletAcid, alkali, oxidation,thermal, lightPDA-236Separation of SITA & SIMV inpresence of degradation products.56SITA simultaneous withMET in bulk drug & tabletAcid, alkali, oxidation,thermal, lightPDA-254Separation of SITA & MET inpresence of degradation product.57SITA simultaneous withSIMV in tabletAcid, alkali, oxidation,thermal, lightPDA-253Separation of SITA & SIMV inpresence of degradation products.58LC-MSSitadevi et al. developed a method for comparison ofconventional and supported liquid extraction methods forthe determination of SITA and Simvastatin (SIMV) in ratplasma by LC-ESI-MS/MS. Three extraction methods werecompared for their efficiency to analyze SITA and SIMVincluding LLE, SPE and supported liquid extraction (SLE).Venlafaxine hydrochloride was used as internal standard(IS). Chromatographic separation was performed on anOyster ODS3 (4.6 mm x 50 mm, 3 µm). Comparison ofrecoveries of analytes revealed that SLE was the bestextraction method. The detection was facilitated with iontrap mass spectrometer by multiple reactions monitoring(MRM) in a positive ion mode with ESI. The transitionsmonitored were m/z 441.1 325.2 for SIMV,408.2 235.1 for SITA and 278.1 260.1 for the IS. Theauthors demonstrated that the efficient SLE rendered themethod useful in high-throughput analysis. The methodwas applied to pharmacokinetic study in rats.59Rapid LC-ESI-MS-MS method was discussed bySamanthula Gananadhamu et al. for the simultaneousdetermination of SITA and Pioglitazone (PIO) in rat plasmaInternational Journal of Pharmaceutical Sciences Review and ResearchAvailable online at www.globalresearchonline.net Copyright protected. Unauthorised republication, reproduction, distribution, dissemination and copying of this document in whole or in part is strictly prohibited.220
Int. J. Pharm. Sci. Rev. Res., 43(1), March - April 2017; Article No. 41, Pages: 217-225and its application to pharmacokinetic study. The methodwas based on HPLC separation on the reverse phasephenomenex synergy C18 column (36 mm length, 4.6 mminternal diameter and 4 µm particle size) at atemperature of 40 C using a binary gradient mobile phaseconsisting of methanol and 2M ammonium acetate bufferpH adjusted to 4.5 with acetic acid, at a flow rate of 1mL/min. Tolbutamide was used as an internal standard(IS). Detection of analytes was achieved with LC/MS/MSsystem in MRM mode. The method was validated overconcentration range of 10.98-2091.77 ng/mL for SITA and8.25 – 1571.63 ng/mL for PIO. Within batch and betweenbatch recovery for SITA was found within 96.9 – 100.3and for PIO 100.0 – 104.3. The authors successfullyapplied this method to monitor the pharmacokineticsprofile of both SITA and PIO on simultaneous oraladministration to rats. This method can be applicable for60pharmacokinetic drug-drug interaction studies.A simple and sensitive LC/MS/MS method was developedby Bhonde et al. for simultaneous determination ofMetformin (MET) and SITA in human plasma usingMetformin-d6 HCl and Sitagliptin-d4 HCl as ISrespectively. After ACN- induced protein precipitation ofplasma samples, MET, SITA and IS were chromatographedon reverse phase C18 (50mm x 4.6mm i.d., 5µm)analytical column. Quantitation was performed on a triplequadrupole mass spectrometer employing ESI techniqueand operating in MRM and positive ion mode. The runtime was 2.0 min and calibration curves were linear overthe concentration range of 25-3000 ng/mL for MET and 5800 ng/mL for SITA. The recoveries obtained for MET andits IS was 39% and SITA and its IS was 64%. Inter-batchand intra-batch coefficient of variation across fivevalidation runs (LLOQ, LOC, MQC1, MQC and HQC) wasless than 7.5% for both MET and SITA. The authorsreported that the proposed method is suitable lence study and therapeutic drug monitoring,following combined administration.61For analysis of the anti-diabetic drugs MET and SITA andthe renal clearance marker creatinine in the same humandried blood spot (DBS) extract two liquid chromatographymethods employing HPLC/UV and LC-ESI-MS/MS havebeen developed and validated. An accurate volume of40μL blood was spotted on a sampling paper which wasextracted using 90% ACN with 10% formic acid. Thevalidated ranges were 0.2-5μg/mL for MET, 1.5-15μg/mLfor creatinine and 3-500ng/mL for SITA. Since druganalysis in DBS determines whole blood concentrations asopposed to the typically used plasma levels the partitionratios between human plasma and blood cells, c(P)/c(BC),were elucidated in-vitro to gain insight into thesignificance of blood cells as compartment of distributionfor both compounds. The c(P)/c(BC) was found to be4.65 0.73 for MET and 5.58 0.98 for SITA. The analyticalmethods were successfully applied to authentic capillaryblood samples from two diabetic patients regularly takinga combination of MET and SITA. Both samples revealedISSN 0976 – 044Xanalyte trough concentrations well above the lower limitof quantification of the respective compounds. This studyoffered a methodological basis for the DBS analysis ofMET and SITA in relation to the patient’s creatinineconcentration.62Burugula et al. developed a simple, rapid and sensitive LCMS/MS assay method for simultaneous quantification ofSITA and SIMV in human plasma. Carbamazepine wasused as an IS. The analytes and IS were extracted fromthe human plasma by LLE technique. The reconstitutedsamples were chromatographed on an Alltima HP C18column using an isocratic solvent mixture [acetonitrile5 mM ammonium acetate (pH 4.5), 85:15 (v/v)] at a flowrate of 1.0 mL/min. The calibration curves obtained werelinear (r2 0.99) over the concentration range of 0.10-501and 0.05-105 ng/mL for SITA and SIMV, respectively. Theresults of the intra-day and inter-day precision andaccuracy studies were well within the acceptable limits.Both the analytes were found to be stable in a battery ofstability studies. A run time of 3.0 min for each samplemade it possible to analyze more than 300 plasmasamples per day. The developed assay was successfullyapplied to a pharmacokinetic study in humanvolunteers.63HPTLCRathod Sonali et al. reported a HPTLC method forsimultaneous estimation of SITA and SIMV. A precoatedsilica gel 60 F254 (0.2 mm thickness) on aluminium sheetswas employed to carry out the separation. Chloroform:methanol in the ratio of 8:2 v/v was used as mobilephase. The developing chamber was run up to 8 cm. TheRf values were found to be 0.13 and 0.75 for SITA andSIMV. The plate was scanned and quantified at 217 nm.The linear detector response was observed between 2000ng/spot to 7000 ng/spot and 250 ng/spot to 750 ng/spotfor SITA and SIMV. The LOD and LOQ were found to be660, 2000 ng/spot and 50, 150 ng/spot, respectively forSITA and SIMV. The Average recovery was found to be92.80 % and 98.01 % for SITA and SIMV. The proposedmethod was specific and accurate.64A simple, sensitive and accurate HPTLC method wasdeveloped by Chirag Patel et al. for simultaneousdetermination of MET and SITA in marketed formulation.The mobile phase used was 1% w/v ammonium acetate inmethanol. The detection of spots was carried outdensitometrically using a UV detector at 257 nm inabsorbance mode. The Rf value for MET and SITA wasfound to be 0.43 0.009 and 0.60 0.013. The calibrationcurve was found to be linear between 600 to 2000 and1000 to 7000 ng/spot for MET and SITA respectively. Thelimits of detection and quantitation were found to be76.257 and 231.083 ng/spot, respectively for MET and65.080 and 197.212 ng/spot, respectively for SITA. Theauthors demonstrated that the proposed HPTLC methodwas highly reproducible and reliable.65International Journal of Pharmaceutical Sciences Review and ResearchAvailable online at www.globalresearchonline.net Copyright protected. Unauthorised republication, reproduction, distribution, dissemination and copying of this document in whole or in part is strictly prohibi
Pharmaceutical samples Analytical methods for the determination of SITA in bulk drug and pharmaceutical dosage forms using HPLC are shown in table 2.35-50 Table 1: Summary of spectrometric methods for the analysis of SITA either alone or in combination with other drugs li
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