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建立了一种同时测定药物中甲磺酸甲酯、甲磺酸乙酯、甲磺酸异丙酯、甲磺酸正丙酯、甲磺酸仲丁酯、甲磺酸异丁酯、甲磺酸正丁酯等7种甲磺酸酯类基因毒性物质的原位衍生-顶空-气相色谱-质谱法,改变衍生反应溶剂和用量,优化了反应时间、温度等反应条件以及孵化温度、平衡时间等顶空萃取条件.经方法学验证,7种甲磺酸酯类化合物在各自的线性范围内线性关系良好(R2>0. 999 0),方法检出限(S/N=3)为0. 21～2. 64μg/L,定量限(S/N=10)为0. 70～8. 81μg/L,日内、日间RSD分别小于10. 3%和5. 07%,加标回收率为88. 2%～115. 1%.对替比培南酯中间体中甲磺酸酯类杂质进行测定,均检出甲磺酸甲酯、甲磺酸乙酯和甲磺酸正丙酯残留.该方法可用于活性物质中甲磺酸酯类杂质的同时测定.
Abstract：A procedure for the simultaneous determination of seven methanesulfonate genotoxic impurities,such as MMS,EMS,i-PMS,n-PMS,s-BMS,i-BMS,n-BMS,employed in drug synthesis was developed and validated by derivatization-headspace-GC-MS. The effects of type and amount of organic phase,reaction temperature and time related to the derivatization were studied and the optimum conditions were determined. The conditions including heating temperature and equilibration time to the headspace method were discussed and optimized,too. The methodological validation showed the good linearity for all the analytes with the correlation coefficients greater than 0. 999 0,the detection limits( S/N = 3)varying from 0. 21 to 2. 64 μg/L,and the limits of quantitation( S/N = 10) from 0. 70 to 8. 81 μg/L. The standard deviations of intra-day and inter-day were less than 10. 3% and 5. 07% respectively,and the recoveries of standard addition ranged from 88. 2% to 115. 1%. The method was successfully used to test tebipenem intermediates and it was found that all the samples tested contained MMS,EMS and n-PMS.The method was suitable for the simultaneous analysis of the methanesulfonate impurities in active substances.
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基本信息:
DOI：10.13705/j.issn.1671-6841.2018240
中图分类号:O657.63;TQ460.72
引用信息:
[1]王少敏,牛颖,代敏等.顶空-气相色谱-质谱法同时测定7种甲磺酸酯类杂质[J],2019,51(03):104-108.DOI:10.13705/j.issn.1671-6841.2018240.
基金信息:
国家自然科学基金项目(21772180)