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| Determination on the contents of ethyl methanesulfonate in Levofloxacin Mesylate Tablets by gas chromatography-mass spectrometry |
| HOU Jinfeng LI Min QI Lin LI Wendong CHE Baoquan WANG Junqiu |
| Beijing Key Laboratory of Component Analysis and Biological Assessment on Chinese Medicine, Beijing Institute for Drug Control, Beijing 102206, China |
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Abstract Objective To establish a derivative gas chromatography-mass spectrometry (GC-MS) method for analyzing the contents of ethyl methanesulfonate (EMS) in Levofloxacin Mesylate Tablets. Methods Pre-column NaI-H2O derivating method was used, and the derivatives ethyl iodide and iodine butane were obtained from EMS and n-butyl methanesulfonate (BMS) derivatization. The derivatives were separated on a DB-WAX (0.32 mm×60 m, 0.25 μm) fused-silica capillary column firstly, and then detected by mass spectrometry under single ion monitoring (SIM) mode. The content of EMS was calculated by the area ratio of ethyl iodide to iodine butane. Results The method showed good linearity (r ＞ 0.9999) over the range of 2.5-150 ng/mL. The limit of detection was 0.5 ng/mL, the recovery was 100.5% (RSD = 1.2%) and the repeatability RSD was 0.6% (n = 6). The method also showed good robustness. No ethyl methanesulfonate was detected in one batch of API and three batches of tablets. Conclusion The method is sensitive, simple, accurate and rapid, and it can be used for the determination of genotoxic impurity EMS, which may be generated in the synthesis and preparation of Levofloxacin Mesylate.
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[1] 李晓冰，何晓静，徐辉，等.左氧氟沙星在肺炎克雷伯菌肺部感染小鼠体内的药动学[J].中国医院药学杂志，2017， 37（7）：575-578.
[2] 国家药典委员会.临床用药须知[M].北京：人民卫生出版社，2005：563-565.
[3] 郭成，何伟.甲磺酸左氧氟沙星的合成及结构确证[J].安徽医药，2010，14（4）：401-403.
[4] Snodin DJ. Residues of genetic alkyl mesylates in mesylate salt drug substance：real or imaginary problems? [J]. Regul Toxicol Pharm，2006，45（1）：79-90.
[5] Szekely G，Amores de Sousa MC，Gil M，et al. Genotoxic impurities in pharmaceutical manufacturing：source，regulation，and mitigation [J]. Chem Rev，2015，115（16）：8182-8229.
[6] Dobo KL，Greene N，Cyr MO，et al. The application of structure- based assessment to support safety and chemistry diligence to manage genotoxic impurities in active pharmaceutical ingredients during drug development [J]. Reg Toxicol Pharm，2006，44（3）：282-293.
[7] Benigni R，Bossa C. Mechanisms of chemical carcinogenicity and mutagenicity：a review with implications for predictive toxicology [J]. Chem Rev，2011，111（4）：2507-2536.
[8] Guidelines on the Limits of Genotoxic Impurities [EB/OL]. EMEA，2006. [2006-6-28]. http：//www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500002903.pdf.
[9] Nancy Bower. A review of the new draft FDA guidance on genotoxic and carcinogenic impurities [J]. Regulatory Rapporteur，2009，6（4）：13-15.
[10] Kroes R，Kleiner，Renwick A. The threshold of toxicological concern concept in risk Assessment [J]. Toxicol Sci，2005，86（2）：226-230.
[11] 邱妍川，李跃芬，钟玲，等.毛细管气相色谱法测定阿仑膦酸钠原料药中甲烷磺酸乙酯的残留量[J].中国药房，2014，25（24）：2295-2297.
[12] 范达，涂家生.顶空气相色谱法测定注射用甲磺酸吉米沙星中基因毒性杂质[J].药学进展，2014，38（3）：220-223.
[13] 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].中国医药科学，2013，3（17）：128-130.
[14] 刘俊华，钟雅妮，熊渊，等.LC-MS测定甲磺酸伊马替尼中基因毒性杂质的含量[J].药物分析杂志，2013，33（7）：1168-1170.
[15] Kakadiya PR，Chandrashekhar TG，Ganguly S，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]. Anal Chem Insights，2011，6：21-28.
[16] 陈成，尹璐，王媛，等.LC-MS/MS法测定2-脱氧-D-核糖中的甲磺酸甲酯和甲磺酸乙酯的含量[J].沈阳药科大学学报，2015，32（9）：695-698.
[17] 刘立云，张倩如，孙连福，等.GC-MS法同时测定盐酸决奈达隆中的3种甲磺酸酯[J].中国药师，2014，17（8）：1274-1276.
[18] 毛颐晴，李纬，朱丽君.GC-MS法测定甲磺酸萘莫司他原料药中的遗传毒性杂质[J].中国药房，2016，27（18）：2555-2557.
[19] 易大为，邹宇，赵晓东，等.GC-MS法测定甲磺酸培氟沙星中甲磺酸酯杂质的研究[J].中国抗生素杂志，2017， 42（6）：521-525.
[20] Council of Europe. European Pharmacopoeia 8.0 [S]. Strasbourg：Directorate for the Quality of Medicines & HealthCare of the Council of Europe（EDQM），2013：170-171.
[21] European Medicines Agency. Evaluation of medicines for human use，guideline on the limits of genotoxic impurities [EB/OL]. [2014-01-27]. http：//www.rsihata.com/updateguidance/emea /old/519902en.pdf. |
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