衍生化-顶空气相色谱法测定甲硫酸新斯的明原料药中基因毒性杂质硫酸二甲酯  

Determination of Genotoxic Impurity Dimethyl Sulfate in Neostigmine Methylsulfate Bulk Drug by Derivatization HS-GC-FID

作　　者：吴频平 夏小菊 王小青 赵昕钰 刘淇 郑金琪 WU Pinping;XIA Xiaoju;WANG Xiaoqing;ZHAO Xinyu;LIU Qi;ZHENG Jinqi(NMPA Key Laboratory for Core Technology of Generic Drug Evaluation,Key Laboratory of Drug Contacting Material Quality Control of Zhejiang Province,Zhejiang Institute for Food and Drug Control,Hangzhou 310052,China;Zhejiang Haisheng Pharmaceutical Co.,Ltd.,Quzhou 321004,China;Zhejiang University of Technology,Hangzhou 310014,China;Hangzhou Medical College,Hangzhou 310053,China)

机构地区：[1]浙江省食品药品检验研究院,浙江省药品接触材料质量控制研究重点实验室,国家药品监督管理局仿制药评价关键技术重点实验室,杭州310052 [2]浙江海昇药业股份有限公司,浙江衢州324004 [3]浙江工业大学,杭州310014 [4]杭州医学院,杭州310053

出　　处：《中国药学杂志》2024年第19期1868-1873,共6页Chinese Pharmaceutical Journal

摘　　要：目的建立一种新的衍生化顶空-气相色谱-FID法测定甲硫酸新斯的明原料药中硫酸二甲酯的残留量。方法筛选多种衍生化方法并进行优化,采用正丁醇作为衍生剂,50℃条件下与硫酸二甲酯进行甲基化反应,生成1-甲基正丁醚;选用DB-624(0.32 mm×30 m,1.8μm)为色谱柱,程序升温,起始温度为40℃,维持8 min,以30℃·min^(-1)的升温速率升温至220℃,保持2 min;以氮气为载气;流速为2.0 mL·min^(-1);采用FID检测器,进样口温度为200℃;检测器温度为230℃。结果甲硫酸新斯的明对硫酸二甲酯的检测无假阳性干扰,硫酸二甲酯在6.066~151.7μg·mL^(-1)内线性关系良好(r^(2)=0.9999),硫酸二甲酯的平均回收率为99.9%,相对标准偏差(RSD)为2.6%(n=9)。经检测,3批原料药中均未检出硫酸二甲酯。结论本方法专属性好、操作简便、准确度高,适用于甲硫酸新斯的明原料药中硫酸二甲酯基因毒性杂质的检测。OBJECTIVE To establish a new derivatization headspace gas chromatography-flame ionization detection(HS-GC-FID)method to detect the residual amount of dimethyl sulfate in neostigmine methylsulfate bulk drug.METHODS Various derivatization methods were screened and then optimized.n-Butanol was used as the derivatization agent and methylated with dimethyl sulfate at the temperature of 50℃,producing the derivatization product methyl n-butyl ether.The analytical column was DB-624(0.32 mm×30 m,1.8μm).The column temperature was maintained at 40℃,holding for 8 min,then was raised to 220℃at the rate of 30℃·min^(-1),holding for 2 min.The flow rate of carrier gas nitrogen was 2.0 mL·min^(-1).The detection was achieved in FID with the injection port temperature of 200℃and the detector temperature of 230℃.RESULTS Neostigmine methylsulfate showed no false positive interference with the detection of dimethyl sulfate.The calibration curve of dimethyl sulfate had good linearity over the range of 6.066 to 151.7μg·mL^(-1)(r^(2)=0.9999).The average recovery of dimethyl sulfate was 99.9%,and the RSD was 2.6%(n=9).CONCLUSION This method exhibits good specificity,simplicity,and high accuracy,and it can be used for the determination of genotoxic impurity dimethyl sulfate in neostigmine methylsulfate bulk drug.

关 键 词：甲硫酸新斯的明 硫酸二甲酯 甲基化 气相色谱 

分 类 号：R917[医药卫生—药物分析学]