LC-MS/MS法同时测定艾司奥美拉唑钠中3个杂质

目的：建立LC-MS/MS法测定艾司奥美拉唑钠中杂质E、杂质I和杂质Ⅳ。方法：采用Agela Venusil MP C₁₈色谱柱（2.1 mm&#215;100 mm，3 μm），以乙腈-水为流动相，梯度洗脱，流速0.2 mL&#183;min^-1，柱温35℃，进样量1 μL；质谱离子化方式为ESI，负离子模式，多反应监测（MRM），杂质E检测离子质核比为m/z 360.1→194.0/218.0，杂质I检测离子质核比为m/z 375.8→145.6/210.7，杂质Ⅳ检测离子质核比为m/z 330.2→312.1/193.6。结果：杂质E、杂质I和杂质Ⅳ质量浓度分别在1.26~44.8、1.34~45.2、18.9~1 260 ng&#183;mL^-1范围内（进样量1 μL）与峰面积线性关系良好，相关系数（r）分别为0.995、0.993、0.991；检测下限分别为0.000 38 ng（S/N=5）、0.000 38 ng（S/N=4）、0.002 1 ng（S/N=5）；精密度试验，上述3个杂质峰面积的RSD均小于5%；6 h稳定性试验（20℃和4℃），杂质E、杂质I峰面积的RSD均<10%，杂质ⅳ峰面积的rsd>15%；杂质E、杂质I和杂质Ⅳ平均加样回收率（n=9）分别为94.8%、95.3%、98.7%，RSD均小于5%。3批样品中3个杂质的测定结果：杂质E，0.000 83%、0.000 21%、0.000 14%；杂质I，0.000 22%、0.000 09%、0.000 07%；杂质Ⅳ，0.002 68%、0.004 03%、0.002 19%。结论：本法可测定艾司奥美拉唑钠中杂质E、杂质I和杂质Ⅳ。

Objective:To establish an LC-MS/MS method for the determination of impurity E,impurity I and impurity Ⅳ in esomeprazole sodium. Methods:The separation was performed on an Agela Venusil MP C₁₈ column(2.1 mm&#215;100 mm,3 μm)with acetonitrile-water as the mobile phase with elution gradient at the flow rate of 0.2 mL&#183;min^-1 and the column temperature was 35℃.The analytes were analyzed by electro-spray ionization(ESI)in the multiple reaction monitoring mode,negative ion. The precursors of production transitions of m/z impurity E 360.1→194.0/218.0,impurity I 375.8→145.6/210.7,impurity Ⅳ 330.2→312.1/193.6 were used to measure impurity. Results:The linearity ranges of impurity E,impurity Ⅰ and impurity Ⅳ were 1.26-44.8 ng&#183;mL^-1(r=0.995),1.34-45.2 ng&#183;mL^-1(r=0.993)and 1.89-1 260 ng&#183;mL^-1(r=0.991),respectively;and the detection limits were 0.000 38 ng(S/N=5),0.000 38 ng (S/N=4),0.002 1 ng(S/N=5),respectively. The precision test,RSD ≤ 5%;the stability test,RSDs of impurity E and impurity I were less than 10%,and RSD of impurity Ⅳ was more than 15%. The average recoveries of impurity E,impurity I and impurity Ⅳ were 94.8%,95.3%,98.7% with RSD<5%(n=9),respectively. The contents of impurity E in three batches were 0.000 83%,0.000 21%,0.000 14%,that of impurity I were 0.000 22%,0.000 09%, 0.000 07%,and that impurity Ⅳ were 0.002 68%,0.004 03%,0.002 19%. Conclusion:This method is suitable for the determination of impurity E,impurity I and impurity Ⅳ in esomeprazole sodium.

[1] 国家药典委员会.中华人民共和国药典临床用药须知.化学药和生物制品卷[S].2010年版.北京:中国医药科技出版社,2011:372 Chinese Pharmacopoeia Commission.Notes on Clinical Use of Pharmacopoeia of the People's Republic of China.Chemical and Biological Volume[S].2010 Ed.Beijing:China Medical Science Press,2011:372
[2] 中华人民共和国药典2015年版.二部[S].2015:127 ChP 2015.Vol Ⅱ[S].2015:127
[3] [H]GPH3-1化学药物杂质研究技术指导原则[S].2005[H]GPH3-1 Technical Guidelines for the Study of Chemical Drug Impurities[S].2005
[4] ICH Harmonized Tripartite Guideline:Impurities in New Drug Substances,Q3A(R)[S].2002
[5] ICH Harmonized Tripartite Guideline:Impurities in New Drug Products,Q3B(R)[S].2003
[6] 马延,王媛,罗智敏,等.HPLC法测定埃索美拉唑钠的有关物质[J].西北药学杂志,2016,31(2):154 MA Y,WANG Y,LUO ZM,et al.Related substances analysis for esomeprazole sodium by HPLC[J].Northwest Pharm J,2016,31(2):154
[7] 郑景哲,牟玲丽.RP-HPLC法测定埃索美拉唑镁的含量及有关物质[J].湖南师范大学学报(医学版),2014,11(1):90 ZHENG JZ,MOU LL.RP-HPLC determination of esomeprazole magnesium and its related substances[J].J Hunan Normal Univ(Med Sci),2014,11(1):90
[8] 陈芳晓,王磊,曾环想,等.埃索美拉唑镁肠溶胶囊有关物质的HPLC法测定[J].中国医药工业杂志,2014,45(6):560 CHEN FX,WANG L,ZENG HX,et al.Determination of related substances in esomeprazole magnesium enteric-coated capsules by HPLC[J].Chin J Pharm,2014,45(6):560
[9] 陈赛赛,顾文平.艾司奥美拉唑钠有关物质的反相-HPLC法测定[J].科技创新与应用,2016(17):52 CHEN SS,GU WP.RP-HPLC determination of related substances in esomeprazole sodium[J].J Sci Technol Innov Appl,2016(17):52
[10] 夏品思,闫冬,姚宏涛,等.反相高效液相色谱法测定注射用埃索美拉唑钠有关物质[J].中南药学,2014,12(11):1131 XIA PS,YAN D,YAO HT,et al.Determination of related substances in esomeprazole sodium for injection by RP-HPLC[J].Cent South Pharm,2014,12(11):1131
[11] 张闪闪,吴燕,张福成.高效液相色谱法测定埃索美拉唑镁肠溶片的有关物质[J].中国医院药学杂志,2016,36(19):1704 ZHANG SS,WU Y,ZHANG FC.Determination of related substances in esomeprazole magnesium enteric-coated pellets-type tablets by gradient HPLC[J].Chin Hosp Pharm J,2016,36(19):1704
[12] 秦序锋,王开颖,方明春,等.注射用埃索美拉唑钠中杂质的检查及控制[J].山东化工,2014,43(3):21 QIN XF,WANG KY,FANG MC,et al.Determination and control of esomeprazole sodium injection[J].Shandong Chem Ind,2014,43(3):21
[13] 徐晓娟,唐云.注射用埃索美拉唑钠的研制及其稳定性考察[J].科技创新导报,2014(34):206 XU XJ,TANG Y.Preparation and stability of esomeprazole sodium injection[J].Sci Technol Innov Her,2014(34):206
[14] 李婷婷,郑子栋.RP-HPLC法测定埃索美拉唑钠的有关物质[J].药物分析杂志,2013,33(4):656 LI TT,ZHENG ZD.Determination of related substances in esomeprazole sodium by RP-HPLC[J].Chin J Pharm Anal,2013,33(4):656
[15] 宁二娟,王庆鹏,王玉拓,等.HPLC法测定埃索美拉唑镁肠溶胶囊的有关物质[J].分析试验室,2015,34(2):209 NING EJ,WANG QP,WANG YT,et al.Determination of related substances in esomeprazole magnesium enteric-coated capsules by HPLC[J].Chin J Anal Lab,2015,34(2):209