HPLC-MS测定奥美沙坦酯中有关基因毒性杂质
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摘要
建立一种直接测定奥美沙坦酯中基因毒性杂质5-(4′-溴甲基联苯-2-基)四氮唑和5-(4′-二溴甲基联苯-2-基)四氮唑的液相色谱-质谱联用方法。采用色谱柱Agilent Zorbax Eclipse Plus C_(18)(250 mm×4.6 mm,5μm),以0.1%甲酸水溶液-乙腈为流动相;在电喷雾正离子模式下,对m/z 315和m/z 395离子进行选择性监测。5-(4′-溴甲基联苯-2-基)四氮唑和5-(4′-二溴甲基联苯-2-基)四氮唑的质量浓度分别在0.009 4～0.561 0μg/mL和0.018 2～0.547 5μg/mL范围内与峰面积呈良好线性关系;定量限分别为9.35和18.25 ng/mL;检测限分别为3.12和6.08 ng/mL;平均回收率分别为96.5%(n=9,RSD=4.8%)和98.0%(n=9,RSD=5.1%)。本法操作简便、专属性好、准确度高,可用于奥美沙坦酯中基因毒性杂质5-(4′-溴甲基联苯-2-基)四氮唑和5-(4′-二溴甲基联苯-2-基)四氮唑的检测。
The aim of this study was to establish a high performance liquid chromatography-mass spectrometry method for the determination of 5-(4′-(bromomethyl)-[1,1′-biphenyl]-2-yl)-1H-tetrazole(BBT1) and 5-(4′-(dibromomethyl)-[1,1′-biphenyl]-2-yl)-1H-tetrazole(BBT2),which are two genotoxic impurities in olmesartan medoxomil.Chromatographic separation was based on an Agilent Zorbax Eclipse Plus C_(18)(250 mm × 4.6 mm,5 μm) column using water(containing 0.1% formic acid)-acetonitrile as mobile phase in gradient elution mode.Mass spectrometry was operated in positive ion mode.Selective ion monitors were set at m/z 315 for BBT1 and at m/z 395 for BBT2.Good linear correlations were observed in the range of 0.009 4-0.561 0 μg/mL(r=0.998) with the quantification limit at 9.35 ng/mL and the detection limit at 3.12 ng/mL for BBT1,and in the range of 0.018 2-0.547 5 μg/mL(r=0.999) with the quantification limit at 18.25 ng/mL and the detection limit at 6.08 ng/mL for BBT2.Furthermore,the average recoveries of the three spiked concentration level were 96.5%(n=9,RSD=4.8%) and 98.0%(n=9,RSD=5.1%) for BBT1 and BBT2,respectively.The proposed method is simple,specific and accurate,and quite suitable for the determination of BBT1 and BBT2 in olmesartan medoxomil.
The aim of this study was to establish a high performance liquid chromatography-mass spectrometry method for the determination of 5-(4′-(bromomethyl)-[1,1′-biphenyl]-2-yl)-1H-tetrazole(BBT1) and 5-(4′-(dibromomethyl)-[1,1′-biphenyl]-2-yl)-1H-tetrazole(BBT2),which are two genotoxic impurities in olmesartan medoxomil.Chromatographic separation was based on an Agilent Zorbax Eclipse Plus C_(18)(250 mm × 4.6 mm,5 μm) column using water(containing 0.1% formic acid)-acetonitrile as mobile phase in gradient elution mode.Mass spectrometry was operated in positive ion mode.Selective ion monitors were set at m/z 315 for BBT1 and at m/z 395 for BBT2.Good linear correlations were observed in the range of 0.009 4-0.561 0 μg/mL(r=0.998) with the quantification limit at 9.35 ng/mL and the detection limit at 3.12 ng/mL for BBT1,and in the range of 0.018 2-0.547 5 μg/mL(r=0.999) with the quantification limit at 18.25 ng/mL and the detection limit at 6.08 ng/mL for BBT2.Furthermore,the average recoveries of the three spiked concentration level were 96.5%(n=9,RSD=4.8%) and 98.0%(n=9,RSD=5.1%) for BBT1 and BBT2,respectively.The proposed method is simple,specific and accurate,and quite suitable for the determination of BBT1 and BBT2 in olmesartan medoxomil.
引文
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[8] Antonio G,Werner K,Hans UG.Overall impact of the regulatory requirements for genotoxic impurities on the drug development process[J].J Pharm Sci,2011,43(1/2):1-15.
[9] Fan ZP.Pharmacological and Toxicological Research Progress on Olmesartan Medoxomil[J].Food Drug(食品与药品),2014,16(5):376-378.
[10] Feng YF,Lei J,Lv JL,et al.A new angiotensin n receptor blocker,olmesartan medoxomil[J].Chin New Drugs J(中国新药杂志),2003,12(7):520-523.
[11] Koike H,Sada T,Mizuno M.In vitro and in vivo pharmacology of olmesartan medoxomil,an angiotensin II type AT1 receptor antagonist[J].J Hypertens Suppl,2001,19(1):s3-14.
[12] Zhu JB,Qiu XM,Guo SW,et al.To establish an HPLC Method for determination of olmesartan medoxomil and its related substances[J].J Hunan Normal Univ (湖南师范大学学报),2013,10(2):81-84.
[13] Yuan QY.Analytical Separation of genotoxic impurities and new quality standard for olmesartan medoxomil prodution[D].Zhejiang:Zhejiang University of Technology,2017.
[14] Pan HJ,Wu TZ,Zhang FL,et al.HPLC determination of olmesartan medoxomil and its related substances[J].Chin J Pharm Anal(药物分析杂志),2008,28(11):1883-1886.
[15] Yuan QY,Chen C,Li JC,et al.Determination of genotoxic impurity in olmesartan medoxomil by HPLC[J].Chin J Mod Appl Pharm(中国现代应用药学),2017,34(3):407-409.
[2] CHMP Safety Working Party.Question & answers on the CHMP Guideline on Limits of Genotoxic Impurities[S/OL].(2009-12)[2019-01].http://www.EMA.europa.eu/docs/en_ GB/document_ library/ Scientific_ guideline/2009/09/WC500002907.pdf.
[3] Food and Drug Administration.Guidance for Industry:Genotoxic and Carcinogenic Impurities in Drug Substances and Products:Recommended Approaches(Draft Guideline)[S].USA:U.S.Department of Health and Human Services,Food and Drug Administration,Center for Drug Evaluation and Research (CDER),2008.
[4] The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use.ICH Harmonised Trepartite Guideline:Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk M7 (R1)[S/OL].(2017-05)[2019-01].https://www.ich.org/fileadmin/ Public_Web_Site/ICH_Products/Guidelines/Multidisciplinary/M7/M7_R1_Addendum_Step_4_2017_0331.pdf.
[5] Argentine MD,Owens PK,Olsen BA.Strategies for the investigation and control of process-related impurities in drug substances[J].Adv Drug Deliv Rev,2007,59(1):12-28.
[6] Song DM,Xu QY,Ren MT,et al.HPLC-QTOF MS determination of ethyl p-toluenesulfonate in enalapril maleate and its intermediate[J].Chin J Pharm Anal(药物分析杂志),2012,32(5):834-837.
[7] Raman NV,Prasad AV,Ratnakar RK.Strategies for the identification,control and determination of genotoxic impurities in drug substances:a pharmaceutical industry perspective[J].J Pharm Biomed Anal,2011,55(4):662-667.
[8] Antonio G,Werner K,Hans UG.Overall impact of the regulatory requirements for genotoxic impurities on the drug development process[J].J Pharm Sci,2011,43(1/2):1-15.
[9] Fan ZP.Pharmacological and Toxicological Research Progress on Olmesartan Medoxomil[J].Food Drug(食品与药品),2014,16(5):376-378.
[10] Feng YF,Lei J,Lv JL,et al.A new angiotensin n receptor blocker,olmesartan medoxomil[J].Chin New Drugs J(中国新药杂志),2003,12(7):520-523.
[11] Koike H,Sada T,Mizuno M.In vitro and in vivo pharmacology of olmesartan medoxomil,an angiotensin II type AT1 receptor antagonist[J].J Hypertens Suppl,2001,19(1):s3-14.
[12] Zhu JB,Qiu XM,Guo SW,et al.To establish an HPLC Method for determination of olmesartan medoxomil and its related substances[J].J Hunan Normal Univ (湖南师范大学学报),2013,10(2):81-84.
[13] Yuan QY.Analytical Separation of genotoxic impurities and new quality standard for olmesartan medoxomil prodution[D].Zhejiang:Zhejiang University of Technology,2017.
[14] Pan HJ,Wu TZ,Zhang FL,et al.HPLC determination of olmesartan medoxomil and its related substances[J].Chin J Pharm Anal(药物分析杂志),2008,28(11):1883-1886.
[15] Yuan QY,Chen C,Li JC,et al.Determination of genotoxic impurity in olmesartan medoxomil by HPLC[J].Chin J Mod Appl Pharm(中国现代应用药学),2017,34(3):407-409.