磺酸酯类基因毒性杂质研究进展
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摘要
基因毒性杂质在低暴露水平下就可能引起DNA损伤,增加患癌的风险,这为用药安全带来了极大的挑战。目前,基因毒性杂质含量监测已经成为国内外的研究热点。本文概述了基因毒性杂质和磺酸酯类杂质的相关法规和指南以及磺酸酯类杂质在药物生产过程中的形成机理,重点介绍了磺酸酯类基因毒性杂质的气相色谱分析方法和液相色谱分析方法。期望为药物中基因毒性杂质合理控制提供指导。
Genotoxic impurities at low exposure levels may cause DNA damage and increase the risk of cancer, which poses a great challenge to drug safety. At present, monitoring the content of genotoxic impurities has become a research hotspot at home and abroad. The relevant regulations and guidelines for genotoxic impurities and sulfonate impurities as well as the formation mechanism of sulfonate impurities in drug production were summarized. The analytical methods of sulfonate impurities by gas chromatography and liquid chromatography were introduced in detail. It was expected to provide guidance for rational control of genotoxic impurities in drugs.
Genotoxic impurities at low exposure levels may cause DNA damage and increase the risk of cancer, which poses a great challenge to drug safety. At present, monitoring the content of genotoxic impurities has become a research hotspot at home and abroad. The relevant regulations and guidelines for genotoxic impurities and sulfonate impurities as well as the formation mechanism of sulfonate impurities in drug production were summarized. The analytical methods of sulfonate impurities by gas chromatography and liquid chromatography were introduced in detail. It was expected to provide guidance for rational control of genotoxic impurities in drugs.
引文
[1] 刘雪薇,厉程,韩海云,等.药物中磺酸酯类基因毒性杂质研究进展[J].色谱,2018,36(10):952-961.
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[5] Colon I,Richoll S M.Determination of methyl and ethyl esters of methanesulfonic,benzenesulfonic and p-toluenesulfonic acids in active pharmaceutical ingredients by solid-phase microextraction (SPME) coupled to GC/SIM-MS[J].J Pharm Biomed Anal,2005,39(3-4):477-485.
[6] European Directorate for Quality and Medicines & HealthCare (EDQM).European Pharmacopoeia 9.0[M].Strasbourg:Council of Europe,2017:176-181.
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[8] 张倩颖,冯芳.GC-ECD法检测甲磺酸伊马替尼中甲磺酸烷基酯[J].广州化工,2018,46(9):66-68.
[9] 连小刚,李孝壁,程红艳.衍生气相色谱法测定甲磺酸伊马替尼中甲磺酸烷基酯类[J].药品鉴定,2013,3(17):128-130.
[10] Zhou J,Xu J,Zheng X Y,et al.Determination of methyl methanesulfonate and ethyl methanesulfonate in methanesulfonic acid by derivatization followed by high-performance liquid chromatography with ultraviolet detection[J].J Sep Sci,2017,40(17):3414-3421.
[11] 庞红霞,李春花.布洛芬中对甲苯磺酸乙酯检测方法的研究[J].山西医药杂志,2015,44(12):1435-1437.
[12] 杨宝玲,何晶晶,倪翔,等.甲苯磺酸拉帕替尼中对甲苯磺酸酯的柱前SPE-HPLC法测定[J].中国医药工业杂志,2017,48(12):1786-1790.
[13] García A,Rupérez F J,Florencia Ceppa F,et al.Development of chromatographic methods for the determination of genotoxic impurities in cloperastine fendizoate[J].J Pharm Biomed Anal,2012,61:230-236.
[14] Guo T,Shi Y,Zheng L,et al.Rapid and simultaneous determination of sulfonate ester genotoxic impurities in drug substance by liquid chromatography coupled to tandem mass spectrometry:Comparison of different ionization modes[J].Journal of Chromatography A,2014,1355:73-79.
[15] An J G,Sun M J,Bai L,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.
[2] 沈芳,苏颀,周伟澄.成盐药物的研究与开发[J].药学进展,2012,36(4):151-157.
[3] Zhang C,Huang L,Wu Z,et al.Determination of sulfonate ester genotoxic impurities in imatinib mesylate by gas chromatography with mass spectrometry[J].Journal of Separation Science,2016,39(18):3558-3563.
[4] Li Weiyong.Trace analysis of residual methyl methanesulfonate,ethyl methanesulfonate and isopropyl methanesulfonate in pharmaceuticals by capillary gas chromatography with flame ionization detection[J].J Chromatogr A,2004,1046(1-2):297-301.
[5] Colon I,Richoll S M.Determination of methyl and ethyl esters of methanesulfonic,benzenesulfonic and p-toluenesulfonic acids in active pharmaceutical ingredients by solid-phase microextraction (SPME) coupled to GC/SIM-MS[J].J Pharm Biomed Anal,2005,39(3-4):477-485.
[6] European Directorate for Quality and Medicines & HealthCare (EDQM).European Pharmacopoeia 9.0[M].Strasbourg:Council of Europe,2017:176-181.
[7] Alzaga R,Ryan R W,Taylor-Worth K,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.
[8] 张倩颖,冯芳.GC-ECD法检测甲磺酸伊马替尼中甲磺酸烷基酯[J].广州化工,2018,46(9):66-68.
[9] 连小刚,李孝壁,程红艳.衍生气相色谱法测定甲磺酸伊马替尼中甲磺酸烷基酯类[J].药品鉴定,2013,3(17):128-130.
[10] Zhou J,Xu J,Zheng X Y,et al.Determination of methyl methanesulfonate and ethyl methanesulfonate in methanesulfonic acid by derivatization followed by high-performance liquid chromatography with ultraviolet detection[J].J Sep Sci,2017,40(17):3414-3421.
[11] 庞红霞,李春花.布洛芬中对甲苯磺酸乙酯检测方法的研究[J].山西医药杂志,2015,44(12):1435-1437.
[12] 杨宝玲,何晶晶,倪翔,等.甲苯磺酸拉帕替尼中对甲苯磺酸酯的柱前SPE-HPLC法测定[J].中国医药工业杂志,2017,48(12):1786-1790.
[13] García A,Rupérez F J,Florencia Ceppa F,et al.Development of chromatographic methods for the determination of genotoxic impurities in cloperastine fendizoate[J].J Pharm Biomed Anal,2012,61:230-236.
[14] Guo T,Shi Y,Zheng L,et al.Rapid and simultaneous determination of sulfonate ester genotoxic impurities in drug substance by liquid chromatography coupled to tandem mass spectrometry:Comparison of different ionization modes[J].Journal of Chromatography A,2014,1355:73-79.
[15] An J G,Sun M J,Bai L,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.