《中国药典》2015年版中关于双氢青蒿素原料药有关物质检测方法的评价与优化
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摘要
考察双氢青蒿素(DHA)差向异构体转化现象对有关物质测定结果的影响,评价并优化2015年版药典中双氢青蒿素有关物质测定方法,采用HPLC-UV法,用十八烷基硅烷键合硅胶(4.6 mm×250 mm,5μm)为填充剂,采用梯度洗脱,检测波长为216 nm;流速为1.0 mL/min,采用甲醇为样品溶剂,且前处理温度不超过25℃。双氢青蒿素进样量在0.193 0~48.25μg(r=1)范围内线性关系良好。α-双氢青蒿素的检出限、定量限分别为0.533 ng、1.78 ng;β-双氢青蒿素的检出限、定量限分别为2.22 ng、7.39 ng。对5批原料药进行有关物质检查,结果均符合药典规定。优化了《中国药典》2015年版中关于双氢青蒿素原料药有关物质检测方法;并弥补了该方法的不足。为双氢青蒿素建立稳定、可靠、全面的质量标准提供科学依据。
In order to investigate the effect of Dihydroartemisinin( DHA) epimer transformation on the determination of related substances,and development and validation for the determination of Dihydroartemisinin's related substances in Ch P 2015,the highperformance liquid chromatography was carried out on a column packed with octadecylsilane bonded silica gel( 4. 6 mm × 250 mm,5 μm),using gradient elution as the mobile phase. The detection wavelength was set at 216 nm and the flow rate was 1. 0 m L/min. Methanol was chosen as the solvent for the DHA bulk drug,and the pretreatment temperature not exceeding 25 ℃. Thelinear range of DHA calibration curve was0. 193 0 ~ 48. 25 μg( r = 1). Thedetectionlimitand quantitation limit of α-DHA were 0. 533 ng,1. 78 ng,and β-DHA were 2. 22 ng、7. 39 ng. The five batches of drug substance were examined and the tested results of related substances were all in accordance with the requirements of the pharmacopoeia. Compared with the method includedin Ch P,the precision of the established related substances determination method is improved significantly. It is accurate,reliable,and comprehensively for evaluation the related substances determination of DHA.
In order to investigate the effect of Dihydroartemisinin( DHA) epimer transformation on the determination of related substances,and development and validation for the determination of Dihydroartemisinin's related substances in Ch P 2015,the highperformance liquid chromatography was carried out on a column packed with octadecylsilane bonded silica gel( 4. 6 mm × 250 mm,5 μm),using gradient elution as the mobile phase. The detection wavelength was set at 216 nm and the flow rate was 1. 0 m L/min. Methanol was chosen as the solvent for the DHA bulk drug,and the pretreatment temperature not exceeding 25 ℃. Thelinear range of DHA calibration curve was0. 193 0 ~ 48. 25 μg( r = 1). Thedetectionlimitand quantitation limit of α-DHA were 0. 533 ng,1. 78 ng,and β-DHA were 2. 22 ng、7. 39 ng. The five batches of drug substance were examined and the tested results of related substances were all in accordance with the requirements of the pharmacopoeia. Compared with the method includedin Ch P,the precision of the established related substances determination method is improved significantly. It is accurate,reliable,and comprehensively for evaluation the related substances determination of DHA.
引文
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3徐溢,范琪,盛静,等.青蒿素的提取分离和检测方法研究进展.药物分析杂志,2013;33(9):1465-1470Xu Yi,Fan Qi,Sheng Jing,et al.Research and development of separation and detection methods for Artemisinin.Chin J Pharm Anal,2013;33(9):1465-1470
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7郑小红,邵强,夏瀛,等.抗血吸虫药吡喹酮合成中间体BTIQ的拆分研究.科学技术与工程,2016;16(4):161-162Zheng Xiaohong,Shao Qiang,Xia Ying,et al.Resolution on synthetic intermediate of praziquantel.Science Technology and Engineering,2016;16(4):161-162
8刘宁,杨腊虎,张正行,等.双氢青蒿素差向异构体转化的研究.药物分析杂志,2002;22(4):303-306Liu Ning,Yang Lahu,Zhang Zhengxing,et al.Studies on the conversion of epimers of Dihydroartemisinin.Chin J Pharm Anal,2002;2(4):303-306
9王辉,杨培慧,黄连喜,等.基于DHA-L-cys复合物电化学探针对错配碱基DNA的识别与检测.分析化学,2010;38(11):1647-1651Wang Hui,Yang Peihui,Huang Lianxi,et al.Detection of sulfhydryl compounds based on Dihydroartemisininsulfhydryl compounds complex electrochemical probe.Chin J Anal Chem,2010;38(11):1647-1651
10张荣林,张素秋,孙博航,等.β-双氢青蒿素在不同溶剂中的核磁共振研究.沈阳药科大学学报,2008;25(4):275-278Zhang Ronglin,Zhang Suqiu,Sun Bohang,et al.NMR Study ofβ-Dihydroartmisinin in different solvents.J Shenyang Pharm Univ,2008;25(4):275-278
11梁静,周琳,罗立骏,等.双氢青蒿素差向异构体的转化与含量测定方法的研究.中国药学杂志,2016;5(5):396-399Liang Jing,Zhou Lin,Luo Lijun,et al.The research of epimers conversion and the an HPLC eethod for content determination of Dihydroartemisinin.Chin Pharm J,2016;5(5):396-399
12国家药典委员会.中国药典:2010年版Ⅱ部.北京:中国医药科技出版社,2010Chinese Parmacopoeta Commission.Chinese pharmacopoeia.2010Vol II.Beijing:China Medical Sciensce Press,2010
13国家药典委员会.中国药典.2015年版二部.北京:中国医药科技出版社,2015Chinese Parmacopoeta Commission.Chinese pharmacopoeia.2015Vol II.Beijing:China Medical Sciensce Press,2015
14 World Health Organization.Introduction of International Phamacopoeia.Geneva:WHO,2011:215-218
15 Walter C,Alessia C,Ilaria D A,et al.On-column epimerization of Dihydroartemisinin:An effective analyticalapproach to overcome the shortcomings of the International Pharmacopoeia monograph.Journal of Chromatography B,2008;875:180-191
2宋晓凯.天然药物化学.3版.北京:化学工业出版社,2004:152Song Xiaokai.Medicinal chemistry of natural products.3nd ed.Beijing:Chemical Industry Press,2004:152
3徐溢,范琪,盛静,等.青蒿素的提取分离和检测方法研究进展.药物分析杂志,2013;33(9):1465-1470Xu Yi,Fan Qi,Sheng Jing,et al.Research and development of separation and detection methods for Artemisinin.Chin J Pharm Anal,2013;33(9):1465-1470
4骆伟,刘杨,丛琳,等.青蒿素及其衍生物的研究进展.中国药物化学杂志,2012;22(2):155-166Luo Wei,Liu Yang,Cong Lin,et al.The research progress in Artemisinin and its derivatives.Chin J Med Chem,2012;22(2):155-166
5王仲山,曹秀玲.二氢青蒿素的变旋作用于差向异构体转化研究.药学学报,1988;23(8):610-615Wang Zhongshan,Cao Xiuling.Studies on mutarotation and anomeric conversion of Dihydroqinhaosu.Acta Pharm Sin,1988;23(8):610-615
6邹磊,杨建云,肖炳坤,等.高效液相色谱法测定苯并三嗪-1,4-二氧化物衍生物SR-H22及其有关物质.科学技术与工程,2016;16(4):155-160Zou Lei,Yang Jianyun,Xiao Bingkun,et al.Determination of the content and the related substances of 3-amine-1,2,4-benzotriazine-1,4-dioxide derivative.Science Technology and Engineering,2016;16(4):155-160
7郑小红,邵强,夏瀛,等.抗血吸虫药吡喹酮合成中间体BTIQ的拆分研究.科学技术与工程,2016;16(4):161-162Zheng Xiaohong,Shao Qiang,Xia Ying,et al.Resolution on synthetic intermediate of praziquantel.Science Technology and Engineering,2016;16(4):161-162
8刘宁,杨腊虎,张正行,等.双氢青蒿素差向异构体转化的研究.药物分析杂志,2002;22(4):303-306Liu Ning,Yang Lahu,Zhang Zhengxing,et al.Studies on the conversion of epimers of Dihydroartemisinin.Chin J Pharm Anal,2002;2(4):303-306
9王辉,杨培慧,黄连喜,等.基于DHA-L-cys复合物电化学探针对错配碱基DNA的识别与检测.分析化学,2010;38(11):1647-1651Wang Hui,Yang Peihui,Huang Lianxi,et al.Detection of sulfhydryl compounds based on Dihydroartemisininsulfhydryl compounds complex electrochemical probe.Chin J Anal Chem,2010;38(11):1647-1651
10张荣林,张素秋,孙博航,等.β-双氢青蒿素在不同溶剂中的核磁共振研究.沈阳药科大学学报,2008;25(4):275-278Zhang Ronglin,Zhang Suqiu,Sun Bohang,et al.NMR Study ofβ-Dihydroartmisinin in different solvents.J Shenyang Pharm Univ,2008;25(4):275-278
11梁静,周琳,罗立骏,等.双氢青蒿素差向异构体的转化与含量测定方法的研究.中国药学杂志,2016;5(5):396-399Liang Jing,Zhou Lin,Luo Lijun,et al.The research of epimers conversion and the an HPLC eethod for content determination of Dihydroartemisinin.Chin Pharm J,2016;5(5):396-399
12国家药典委员会.中国药典:2010年版Ⅱ部.北京:中国医药科技出版社,2010Chinese Parmacopoeta Commission.Chinese pharmacopoeia.2010Vol II.Beijing:China Medical Sciensce Press,2010
13国家药典委员会.中国药典.2015年版二部.北京:中国医药科技出版社,2015Chinese Parmacopoeta Commission.Chinese pharmacopoeia.2015Vol II.Beijing:China Medical Sciensce Press,2015
14 World Health Organization.Introduction of International Phamacopoeia.Geneva:WHO,2011:215-218
15 Walter C,Alessia C,Ilaria D A,et al.On-column epimerization of Dihydroartemisinin:An effective analyticalapproach to overcome the shortcomings of the International Pharmacopoeia monograph.Journal of Chromatography B,2008;875:180-191