HPLC-UV法测定卡培他滨中的对甲苯磺酸酯
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摘要
建立了高效液相色谱法测定卡培他滨原料药中的基因毒性杂质对甲苯磺酸甲酯(MepTS)、对甲苯磺酸乙酯(Etp TS)和对甲苯磺酸异丙酯(iPrpTS)。采用C_(18)色谱柱(250 mm×4.6 mm,5μm),紫外检测器在225 nm下直接进样测定。三种对甲苯磺酸酯在0.015～0.15μg/m L浓度范围内线性关系良好,定量限均为0.015μg/m L,检测限均为0.005μg/m L,平均回收率在89.2%～100.3%。该方法简单、准确、专属性强且重现性好,适用于卡培他滨中对甲苯磺酸酯基因毒性杂质的测定。
A high performance liquid chromatography method was established for the determination of genotoxic impurities methyl p-toluenesulfonate( MepTS),ethyl p-toluenesulfonate( EtpTS) and isopropyl p-toluenesulfonate( i Prp TS) in capecitabine. A C18 column( 250 mm×4. 6 mm,5 !m) was used to separate,and ultraviolet detector was used for direct detection at 225 nm. Calibration curves showed good linearity over the concentration range of 0. 015 ～0. 15 μg/m L for three p-toluenesulfonates. The limits of quantification were all 0. 015 μg/m L and the limits of detection were all 0. 005 μg/m L. The average recoveries were between 89. 2% and 100. 3%. The established method showed satisfactory convenience,accuracy,specificity and repeatability. This method could be used for the determination of ptoluenesulfonates in capecitabine.
A high performance liquid chromatography method was established for the determination of genotoxic impurities methyl p-toluenesulfonate( MepTS),ethyl p-toluenesulfonate( EtpTS) and isopropyl p-toluenesulfonate( i Prp TS) in capecitabine. A C18 column( 250 mm×4. 6 mm,5 !m) was used to separate,and ultraviolet detector was used for direct detection at 225 nm. Calibration curves showed good linearity over the concentration range of 0. 015 ～0. 15 μg/m L for three p-toluenesulfonates. The limits of quantification were all 0. 015 μg/m L and the limits of detection were all 0. 005 μg/m L. The average recoveries were between 89. 2% and 100. 3%. The established method showed satisfactory convenience,accuracy,specificity and repeatability. This method could be used for the determination of ptoluenesulfonates in capecitabine.
引文
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[12]霍立,刘艳妮.气质联用技术检测对甲苯磺酸酯类杂质[J].中国新技术新产,2016(2):55.
[13]J G An,M J Sun,L Bai,et al. A practical derivatization LC/MS approach for determination of trace level alkyl sulfonates and dialkyl sulfates genotoxic impurities in drug substances[J]. J. Pharm Biomed Anal,2008,48(3):1006-1010.
[14]A M van Wijk,H A G Niederlnder,A H G Siebum,et al. A new derivatization reagent for LC-MS/MS screening of potential genotoxic alkylation compounds[J]. J Pharm Biomed Anal,2013,74(4):133-140.
[15]P R Kakadiya,T G Chandrashekhar,S Ganguly,et al. Low level determinations of methyl methanesulfonate and ethyl methanesulfonate impurities in Emtricitabine active pharmaceutical ingredient by LC/MS/MS using electrospray ionization[J]. Analytical Chemistry Insights,2011,6(1):21-28.
[2]H G Ramjit,M M Singh,A B Coddington. Gas chromatographic/mass spectrometric analysis of methyl methanesulphonate and ethyl methanesulphonate in the bismesylate salt of DPI 201-106,a positive inotropic agent for the treatment of heart failure[J]. J Mass Spectrom,2015,31(8):867-872.
[3]Committee for Medicinal Products for Human Use(CHMP). Guidelines on the limits of genotoxic impurities(CPMP/SWP/5199/02)[S].London:European Medicines Agency Evaluation of Medicines for Human Use(EMEA),2006.
[4]U. S. Food and Drug Administration,Department of Health and Human Services,Center for Drug Evaluation and Research(CDER). Guidance for industry:genotoxic and carcinogenic impurities in drug substances and products:recommended approaches(draft)[S]. Silver Spring:U. S. Food and Drug Administration,2008.
[5]K Jacq,E Delaney,A Teasdale,et al. Development and validation of an automated static headspace gas chromatography-mass spectrometry(SHS-GC-MS)method for monitoring the formation of ethyl methane sulfonate from ethanol and methane sulfonic acid[J]. J Pharm Biomed Anal,2008,48(5):1339-1344.
[6]N A Devenport,L C Sealey,F H Alruways,et al. Direct detection of a sulfonate ester genotoxic impurity by atmospheric-pressure thermal desorption-extractive electrospray-mass spectrometry[J]. Anal Chem.,2013,85(13):6224-6227.
[7]安富荣,戈升荣,祝德秋.卡培他滨的药理特性及临床应用进展[J].中国新药与临床杂质,2002,21(8):503-507.
[8]陈莉莉,岑均达.卡培他滨的新合成路线[J].中国药物化学杂志,2010,20(4):275-277.
[9]European Pharmacopoeia 8. 0,2. 5. 37. Methyl,ethyl and isopropyl methanesulfonate in methanesulfonic acid,8th ed.[M]. Strasbourg,2013.
[10]C R Lee,F Guivarch,C N Van Dau,et al. Determination of polar alkylating agents as thiocyanate/isothiocyanate derivatives by reaction headspace gas chromatography[J]. Analyst,2003,128(7):857-863.
[11]R Alzaga,R W Ryan,K Taylor-Worth,et al. A generic approach for the determination of residues of alkylating agents in active pharmaceutical ingredients by in situ derivatization-headspace-gas chromatography-mass spectrometry[J]. J Pharm Biomed Anal,2007,45(3):472-479.
[12]霍立,刘艳妮.气质联用技术检测对甲苯磺酸酯类杂质[J].中国新技术新产,2016(2):55.
[13]J G An,M J Sun,L Bai,et al. A practical derivatization LC/MS approach for determination of trace level alkyl sulfonates and dialkyl sulfates genotoxic impurities in drug substances[J]. J. Pharm Biomed Anal,2008,48(3):1006-1010.
[14]A M van Wijk,H A G Niederlnder,A H G Siebum,et al. A new derivatization reagent for LC-MS/MS screening of potential genotoxic alkylation compounds[J]. J Pharm Biomed Anal,2013,74(4):133-140.
[15]P R Kakadiya,T G Chandrashekhar,S Ganguly,et al. Low level determinations of methyl methanesulfonate and ethyl methanesulfonate impurities in Emtricitabine active pharmaceutical ingredient by LC/MS/MS using electrospray ionization[J]. Analytical Chemistry Insights,2011,6(1):21-28.