顶空气相色谱-质谱法测定依度沙班原料药中遗传毒性物质
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摘要
目的建立内标法测定依度沙班原料药中遗传毒性杂质甲磺酸甲酯、甲磺酸乙酯、甲磺酸异丙酯的含量。方法采用顶空气相色谱-质谱法,以DB-WAX毛细管柱(30 m×0.25 mm,0.25μm)为色谱柱,程序升温,高纯氦气为载气,流速为0.6 m L·min~(-1),进样口温度为110℃,进样方式为分流进样,分流比为20∶1;顶空进样,平衡温度为60℃,平衡时间为30 min,进样体积1 m L;检测器为质谱检测器,离子源为EI源,离子源温度为200℃,接口温度为150℃,扫描方式为选择离子检测,电子能量为70 e V。结果甲磺酸甲酯、甲磺酸乙酯和甲磺酸异丙酯在0.05～3.0μg·m L~(-1)(r≥0.998 5)浓度范围内线性关系良好,加样回收率分别为96.4%,96.1%和96.5%,RSD分别为2.0%,1.9%,1.9%(n=6)。结论该方法简便、快速、灵敏度高、专属性好,可为依度沙班原料药的质量控制提供参考依据。
Objective To establish a method for the determination of the genotoxic impurities( methyl methanesulfonate,ethyl methanesulfonate and isopropyl methanesulfonate) in edoxaban with internal standard method.Methods A head-space GC-MS method was used. The column was DB-WAX capillary column( 30 m×0.25 mm,0.25 μm) by programmed temperature,carrier gas was high purity helium,column flow was 0. 6 m L · min~(-1),the inlet temperature was110 ℃,sample mode split injection with a split ratio of 20∶1; Head-space samp-ling was conducted,equilibrium temperature was 60 ℃,equilibrium time was 30 min,injection volume was 1 m L; Detector was a mass spectrometer detector,the ion source was EI source and source temperature was 200 ℃,the interface temperature was 150 ℃,scanning method was selective ion monitoring,electron energy was 70 e V. Results The linear range of methyl methanesulfonate,ethyl methanesulfonate and isopropyl methanesulfonate were 0.05-3.0 μg·m L~(-1)( r≥0.998 5); Recoveries were 96.4%,96.1% and 96.5%,respectively,and RSD were 2.0%,1.9% and 1.9%( n = 6). Conclusion This method is simple,rapid,sensitive,with good specificity,and it can provide a reference for the quality control of edoxaban raw material with internal standard.
Objective To establish a method for the determination of the genotoxic impurities( methyl methanesulfonate,ethyl methanesulfonate and isopropyl methanesulfonate) in edoxaban with internal standard method.Methods A head-space GC-MS method was used. The column was DB-WAX capillary column( 30 m×0.25 mm,0.25 μm) by programmed temperature,carrier gas was high purity helium,column flow was 0. 6 m L · min~(-1),the inlet temperature was110 ℃,sample mode split injection with a split ratio of 20∶1; Head-space samp-ling was conducted,equilibrium temperature was 60 ℃,equilibrium time was 30 min,injection volume was 1 m L; Detector was a mass spectrometer detector,the ion source was EI source and source temperature was 200 ℃,the interface temperature was 150 ℃,scanning method was selective ion monitoring,electron energy was 70 e V. Results The linear range of methyl methanesulfonate,ethyl methanesulfonate and isopropyl methanesulfonate were 0.05-3.0 μg·m L~(-1)( r≥0.998 5); Recoveries were 96.4%,96.1% and 96.5%,respectively,and RSD were 2.0%,1.9% and 1.9%( n = 6). Conclusion This method is simple,rapid,sensitive,with good specificity,and it can provide a reference for the quality control of edoxaban raw material with internal standard.
引文
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[11] European Directorate for Quality and Medicines&HealthCare(EDQM).Methyl,ethyl and isopropyl methanesulfonate inactive substances[S]//European Pharmacopoeia 8. 0.Strasbourg:Council of Europe,2012.
[2]张华.新型口服抗凝药物依度沙班[J].中国新药杂志,2015,24(24):2761-2763.
[3]张清,罗素新,唐炯.新型Xa因子抑制剂——依度沙班在心房颤动患者抗凝治疗中的研究进展[J].心血管病学进展,2016,37(2):151-155.
[4]潘林玉,梁斌,张福利.依度沙班合成路线图解[J].中国医药工业杂志,2013,44(11):1170-1173.
[5]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.
[6] European Medicines Agency.Guideline on the Limits of Genotoxic Impurities[S].2006:4-7.
[7] LI W.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.
[8] WOLLEIN U,SCHRAMEK N.Simultaneous determination of alkyl mesilates and alkyl besilates in finished drug products by direct injection GC/MS[J].Eur J Pharm Sci,2012,45(1/2):201-204.
[9] RAMAKRISHNA K,RAMAN NV,RAO KM,et al.Development and validation of GC-MS method for the determination of methyl methanesulfonate and ethyl methanesulfonate in imatinib mesylate[J].J Pharm Biomed Anal,2008,46(4):780-783.
[10] RAMAN N V,PRASAD A V,REDDY K R,et al.Determination of genotoxic alkyl methane sulfonates and alkyl paratoluene sulfonates in lamivudine using hyphenated techniques[J].J Pharm Anal,2012,2(4):314-318.
[11] European Directorate for Quality and Medicines&HealthCare(EDQM).Methyl,ethyl and isopropyl methanesulfonate inactive substances[S]//European Pharmacopoeia 8. 0.Strasbourg:Council of Europe,2012.