HPLC法测定甲磺酸达比加群酯的有关物质

目的： 建立HPLC法测定甲磺酸达比加群酯有关物质。方法： 采用十八烷基键合硅胶填充色谱柱，以醋酸铵缓冲溶液-乙腈为流动相，梯度洗脱，流速1.0 mL·min^-1，二极管阵列检测器选取242 nm（检测杂质B、D、G）、310 nm（检测杂质A、E、F、I）、340 nm（检测杂质C、H）3个波长进行检测，计算杂质含量。结果： 主成分与各已知杂质分离度良好，各杂质能够准确定量。在3个不同批次的原料药中只检测到了杂质B、C和I，测得3个批次中的最大单杂含量分别为0.15%、0.14%和0.16%，杂质总量分别为0.30%、0.29%和0.27%。在室温下，供试品溶液不稳定，应临用新配或4~8℃保存。结论： 本方法可用于甲磺酸达比加群酯的有关物质检查。

Objective: To establish an HPLC method for the determination of related substances in dabigatran etexilate mesylate.Methods: The separation was performed on a C₁₈ column.The mobile phase consisted of ammonium acetate buffer solution and acetonitrile with linear gradient elution and at a flow rate of 1.0 mL·min^-1. A photodiode array(PDA)detector was chosen to detect and estimate the content of the impurities under the wavelength of 242 nm(estimate impurities A,E,F and I),310 nm(estimate impurities B,D and G)and 340 nm(estimate impurities C and H).Results: Known impurities were completely separated from the main constituent,and the impurities can be accurately quantified.Impurities B,C and I were detected in the three different batches of drug substance.The maximum impurity content in the three batches was 0.15%,0.14% and 0.16%,and the total impurities were 0.30%,0.29% and 0.27%.At room temperature,the sample solution is unstable and should be stored at 4-8℃ or freshly prepared.Conclusion: The method can be used for the determination of the related substances in dabigatran etexilate mesylate.

[1] 任小婵,罗选娟,杨欢,等.新型口服抗凝药的临床应用研究进展[J].中华全科医学,2018,16(4):615 REN XC,LUO XJ,YANG H,et al.New oral anticoagulants clinical application progress[J].Chin J Gen Pract,2018,16(4):615
[2] 张广求,张美祥,王树平,等.新型口服抗凝药的药理学特点及其应用[J].临床合理用药杂志,2019,12(3):110 ZHANG GQ,ZHANG MX,WANG SP,et al.Pharmacological characteristics and application of new oral anticoagulants[J].Chin J Clin Rat Drug Use,2019,12(3):110
[3] 孟璐,丁琮洋,安静,等.口服抗凝药的临床治疗研究进展[J].药学服务与研究,2019,19(3):166 MENG L,DING CY,AN J,et al.Research progress in clinical treatment of oral anticoagulants[J].Pharm Care Res,2019,19(3):166
[4] 黄晓飞.达比加群酯抗凝效果监测及其对凝血功能影响机制探讨[D].苏州:苏州大学,2016 HUANG XF.The Influence of Dabigatran on Coagulation Assays:How and Why[D].Suzhou:Soochow University,2016
[5] 汤宝鹏,芦颜美.新型口服抗凝药的临床应用拓展[J].实用医院临床杂志,2017,14(1):12 TANG BP,LU YM.Clinical application development of novel oral anticoagulants[J].Pract J Clin Med,2017,14(1):12
[6] WEITZ JI,HARENBERG J.New developments in anticoagulants:past,present and future[J].Thromb Haemost,2017,117(7):1283
[7] 尤国皎,都丽萍,陈跃鑫,等.我国已上市新型抗凝药物的特点及临床应用进展[J].临床药物治疗杂志,2017,15(1):7 YOU GJ,DU LP CHEN YX,et al.Characteristics of novel anticoagulants marketed in China and the development of their clinical application[J].Clin Med J,2017,15(1):7
[8] 康银花.国外新型抗凝药物的临床研发动态[J].中国新药杂志,2013,22(1):53 KANG YH.Advance in clinical study of new anticoagulants in foreign countries[J].Chin J New Drugs,2013,22(1):53
[9] 韩舒,谷元,张爱杰,等.高效液相色谱-串联质谱法测定大鼠血浆中的达比加群[J].中国临床药理学与治疗学,2015,20(12):1354 HAN S,GU Y,ZHANG AJ,et al.Development and validation of a sensitive high performance liquid chromatography-tandem mass spectrometry method for the determination of dabigatran in rat plasma[J].Chin J Clin Pharmacol Ther,2015,20(12):1354
[10] 向志雄,马文狄,夏广新.Beagle犬血浆中达比加群的UPLC-MS/MS法测定[J].中国医药工业杂志,2015,46(10):1096 XIANG ZX,MA WD,XIA GX.Determination of dabigatran in Beagle dog plasma by UPLC-MS/MS[J].Chin J Pharm,2015,46(10):1096
[11] 贾玲晓,唐磊,张淑婷,等.HPLC测定甲磺酸达比加群酯的含量[J].食品与药品,2015,17(3):195 JIA LX,TANG L,ZHANG ST,et al.Determination of dabigatran etexilate mesylate by HPLC[J].Food Drug,2015,17(3):195
[12] 屠莹,陈丽娟,王平.HPLC测定达比加群酯中的有关物质[J].中国现代应用药学,2016,33(9):1165 TU Y,CHEN LJ,WANG P.Determination of the related substances of dabigatran etexilate by HPLC[J].Chin J Mod Appl Pharm,2016,33(9):1165
[13] 常晓辉,王胡博,谢华,等.甲磺酸达比加群酯原料药中有关物质的UPLC法测定[J].中国医药工业杂志,2017,48(3):422 CHANG XH,WANG HB,XIE H,et al.Determination of related substances in dabigatran etexilate methanesulfonate bulk drug by UPLC[J].Chin J Pharm,2017,48(3):422
[14] 薛晓楠,张正进,邹强,等.高效液相色谱法检测甲磺酸达比加群酯及有关物质[J].中国药科大学学报,2017,48(6):711 XUE XN,ZHANG ZJ,ZOU Q,et al.Determination of dabigatran etexilate mesylate and related substances by HPLC[J].J China Pharm Univ,2017,48(6):711
[15] 郭萍,高爽,孙丽娇,等.HPLC-DAD可变波长法测定甲磺酸达比加群酯原料药中10种已知杂质的含量[J].沈阳药科大学学报,2018,35(5):384 GUO P,GAO S,SUN LJ,et al.Determination of related substances in dabigatranet exilate mesylate by HPLC-DAD[J].J Shenyang Pharm U,2018,35(5):384
[16] JX20110125国家食品药品监督管理局进口药品注册标准[S].2011 JX20110125 National Food and Drug Administration Import Drug Registration Standards[S].2011