GC-MS法测定甲磺酸萘莫司他原料药中的遗传毒性杂质
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摘要
目的:建立同时测定甲磺酸萘莫司他原料药中遗传毒性杂质甲磺酸甲酯、甲磺酸乙酯、甲磺酸异丙酯的方法。方法:采用气相色谱-质谱联用法,使用二氯甲烷进行提取。色谱柱为DB-5毛细管柱,柱温采用程序升温,进样口温度为240℃,柱流量为3.0 ml/min,吹扫流量为6.0 ml/min,进样方式为不分流进样,载气为高纯氦气,检测器为质谱检测器,离子源温度为230℃,接口温度为230℃,溶剂延迟时间为2.5 min,离子化模式为电子轰击离子化模式,检测器电压为相对于调谐结果,扫描(检测)方式为选择性离子检测,电子能量为70 e V,进样量为1.0μl。结果:3种杂质成分之间的分离度均>2.0;3种杂质成分检测质量浓度线性范围均为0.10~20μg/ml(r≥0.999 5);精密度、稳定性、重复性试验的RSD<2%;加样回收率分别为97.7%~104.8%、102.5%~110.7%、103.0%~107.6%,RSD分别为2.8%、2.6%、1.6%(n=9)。结论:该方法简便、准确、灵敏、迅速,可用于甲磺酸萘莫司他原料药中3种遗传毒性杂质的测定。
OBJECTIVE:To establish a method for determination the genotoxicity impurities(methyl methanesulfonate,ethyl methanesulfonate and isopropyl methanesulfonate) in mesylate nafamostat raw materia. METHODS:GC-MS was conducted,and the genotoxicity impurities were extracted by dichloromethane. The column was DB-5 capillary column by programmed temperature,the inlet temperature was 240 ℃,column flow was 3.0 ml/min,purge flow was 6.0 ml/min,sample mode splitless injection,carrier gas was high purity helium,detector is a mass spectrometer detector,ion source temperature was 230 ℃,the interface temperature was 230 ℃,the delay time of solvent was 2.5 min,ionization mode was electron impact,detector voltage was respect to the tuning results,scanning(detection)method was selective ion monitoring,electron energy was 70 e V,and the injection volume was 1.0 μl. RESULTS:The separation degree of 3 impurities were greater than 2.0;the linear range of 3 impurities were 0.10-20 μg/ml(r≥0.999 5);RSDs of precision,stability and reproducibility tests were lower than 2%;recoveries were 97.7%-104.8%(RSD=2.8%,n=9),102.5%-110.7%(RSD=2.6%,n=9)and 103.0%-107.6%(RSD=1.6%,n=9). CONCLUSIONS:The method is simple,accurate,sensitive and rapid,and can be used for the genotoxicity impurities in mesylate nafamostat raw materia.
OBJECTIVE:To establish a method for determination the genotoxicity impurities(methyl methanesulfonate,ethyl methanesulfonate and isopropyl methanesulfonate) in mesylate nafamostat raw materia. METHODS:GC-MS was conducted,and the genotoxicity impurities were extracted by dichloromethane. The column was DB-5 capillary column by programmed temperature,the inlet temperature was 240 ℃,column flow was 3.0 ml/min,purge flow was 6.0 ml/min,sample mode splitless injection,carrier gas was high purity helium,detector is a mass spectrometer detector,ion source temperature was 230 ℃,the interface temperature was 230 ℃,the delay time of solvent was 2.5 min,ionization mode was electron impact,detector voltage was respect to the tuning results,scanning(detection)method was selective ion monitoring,electron energy was 70 e V,and the injection volume was 1.0 μl. RESULTS:The separation degree of 3 impurities were greater than 2.0;the linear range of 3 impurities were 0.10-20 μg/ml(r≥0.999 5);RSDs of precision,stability and reproducibility tests were lower than 2%;recoveries were 97.7%-104.8%(RSD=2.8%,n=9),102.5%-110.7%(RSD=2.6%,n=9)and 103.0%-107.6%(RSD=1.6%,n=9). CONCLUSIONS:The method is simple,accurate,sensitive and rapid,and can be used for the genotoxicity impurities in mesylate nafamostat raw materia.
引文
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[7]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.
[8]张萌萌,潘红娟,陈佳,等.盐酸达泊西汀中甲磺酸甲酯、甲磺酸乙酯及甲磺酸异丙酯的顶空毛细管GC-ECD法测定[J].中国医药工业杂志,2015,46(1):55.
[9]丁逸梅,吴娟,陆春晓,等.盐酸决奈达隆中甲磺酸甲酯和甲磺酸乙酯的GC-MS法测定[J].中国药师,2014,17(8):1 274.
[10]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].中国医药工业杂志,2014,45(11):1 069.
[11]王莉芳,郭文敏,杨汉煜,等.GC-MS法同时测定SIPI5357甲磺酸盐中3种甲磺酸酯[J].中国新药杂志,2014,23(11):1 326.
[12]冯慧敏,杭太俊,高新桃,等.LC-MS法同时检测甲磺酸伊马替尼中3个磺酸酯基因毒杂质[J].药物分析杂志,2014,34(12):2 202.
[13]European Medicines Agency.European Pharmacopoeia8.0[S].2012:170-171.
[2]陈宝泉,赵煜松,欧阳杰,等.甲磺酸萘莫司他的合成[J].中国医药工业杂志,2007,38(8):545.
[3]张园园,李银峰,王杰晶,等.药物中痕量磺酸酯类物质的检测技术研究进展[J].药物评价研究,2012,35(4):304.
[4]European Medicines Agency.Guideline on the Limits of Henotoxic Impurities[S].2006.
[5]史继峰.EMEA《遗传毒性杂质限度指导原则》介绍[EB/OL].(2007-08-20)[2013-08-01].http://www.cde.org.cn/dzkw.do?method=large Page&id=2054.
[6]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(3):220.
[7]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.
[8]张萌萌,潘红娟,陈佳,等.盐酸达泊西汀中甲磺酸甲酯、甲磺酸乙酯及甲磺酸异丙酯的顶空毛细管GC-ECD法测定[J].中国医药工业杂志,2015,46(1):55.
[9]丁逸梅,吴娟,陆春晓,等.盐酸决奈达隆中甲磺酸甲酯和甲磺酸乙酯的GC-MS法测定[J].中国药师,2014,17(8):1 274.
[10]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].中国医药工业杂志,2014,45(11):1 069.
[11]王莉芳,郭文敏,杨汉煜,等.GC-MS法同时测定SIPI5357甲磺酸盐中3种甲磺酸酯[J].中国新药杂志,2014,23(11):1 326.
[12]冯慧敏,杭太俊,高新桃,等.LC-MS法同时检测甲磺酸伊马替尼中3个磺酸酯基因毒杂质[J].药物分析杂志,2014,34(12):2 202.
[13]European Medicines Agency.European Pharmacopoeia8.0[S].2012:170-171.