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HPLC-MS测定奥美沙坦酯中有关基因毒性杂质

栾保磊, 徐新军, 梁桂挺, 游孟梦, 刘国柱

栾保磊, 徐新军, 梁桂挺, 游孟梦, 刘国柱. HPLC-MS测定奥美沙坦酯中有关基因毒性杂质[J]. 中国药科大学学报, 2019, 50(3): 325-329. DOI: 10.11665/j.issn.1000-5048.20190308
引用本文: 栾保磊, 徐新军, 梁桂挺, 游孟梦, 刘国柱. HPLC-MS测定奥美沙坦酯中有关基因毒性杂质[J]. 中国药科大学学报, 2019, 50(3): 325-329. DOI: 10.11665/j.issn.1000-5048.20190308
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LUAN Baolei, XU Xinjun, LIANG Guiting, YOU Mengmeng, LIU Guozhu. Determination of related genotoxic impurities in olmesartan medoxomil by HPLC-MS[J]. Journal of China Pharmaceutical University, 2019, 50(3): 325-329. DOI: 10.11665/j.issn.1000-5048.20190308
Citation: LUAN Baolei, XU Xinjun, LIANG Guiting, YOU Mengmeng, LIU Guozhu. Determination of related genotoxic impurities in olmesartan medoxomil by HPLC-MS[J]. Journal of China Pharmaceutical University, 2019, 50(3): 325-329. DOI: 10.11665/j.issn.1000-5048.20190308
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HPLC-MS测定奥美沙坦酯中有关基因毒性杂质

  • 1.

    中山大学药学院

  • 2.

    东阳光药物研究院

基金项目: 广东省科技厅2017年“扬帆计划”引进创新团队(No.2017YT05S029)

Determination of related genotoxic impurities in olmesartan medoxomil by HPLC-MS

摘要

    摘要
  • 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 C18(250 mm×4.6 mm，5 μm)，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 0 μg/mL和0.018 2~0.547 5 μg/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。
    Abstract: 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 C18(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.
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    • 参考文献(15)
  • [1] EMA(European Medicines Agency).Guidelines on the Limits of Genotoxic Impurities[S/OL].(2006-06-28)[2019-01] .http://www.EMA.europa.eu/docs/en_GB/document_ library / Scientific_ guideline/2009/09/WC500002903.pdf.
    [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.
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    [13] Yuan QY.Analytical Separation of genotoxic impurities and new quality standard for olmesartan medoxomil prodution[D].Zhejiang:Zhejiang University of Technology,2017.
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  • 刊出日期:  2019-06-24

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