氟康唑杂质H国家标准物质的研制

冯艳春, 王晨, 田冶, 常祎卓, 马步芳, 姚尚辰, 胡昌勤

中国药学杂志 ›› 2018, Vol. 53 ›› Issue (17) : 1516-1522.

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中国药学杂志 ›› 2018, Vol. 53 ›› Issue (17) : 1516-1522. DOI: 10.11669/cpj.2018.17.017
论著

氟康唑杂质H国家标准物质的研制

  • 冯艳春, 王晨, 田冶, 常祎卓, 马步芳, 姚尚辰, 胡昌勤*
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Establishment of National Reference Standard of Fluconazole Impurity H

  • FENG Yan-chun, WANG Chen, TIAN Ye, CHANG Yi-zhuo, MA Bu-fang, YAO Shang-chen, HU Chang-qin*
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摘要

目的 以氟康唑杂质H为例,介绍氟康唑系列杂质标准物质研制过程,同时揭示杂质标准物质研制过程中的一些特殊问题。方法 第一采用质谱、红外和核磁方法对该杂质进行结构确证,第二采用《欧洲药典》8.0版和《中国药典》2010年版二部氟康唑有关物质检查方法测定原料的纯度,采用LC-MS等方法对2个液相色谱系统产生的主要杂质进行分析,并测定了氟康唑杂质H的水分和炽灼残渣,第三采用核磁定量方法确定了氟康唑杂质的含量。结果 氟康唑杂质H与《欧洲药典》8.0版中规定的结构一致。水分含量0.05%,无机杂质含量0.04%,HPLC有关物质测定过程中发现氟康唑杂质H在水溶液中会部分降解为杂质G,有关物质不能准确测定。核磁方法测定氟康唑杂质H含量为99.5%。结论 由于氟康唑杂质H本身结构的特点,使得常规的质量平衡法不适合为该杂质赋值,定量核磁共振法成为为标准物质定值的有力补充方法。

Abstract

OBJECTIVE To introduce the procedure of developing reference standards of fluconazole impurities using fluconazole impurity H as an example and reveal a special problem for establishment of national reference standards. METHODS Firstly, the structure of fluconazole impurity H was validated by infrared, mass spectrum and nuclear magnetic resonance method. Secondly, its purity was determined using the related substances test of fluconazole in European Pharmacopoeia 8.0 (EP8.0) and Chinese Pharmacopeia (2010 version, Volume 2, ChP2010). Then the major impurities determined by the above two HPLC systems were analyzed by LC-MS method. Finally, the content of fluconazole impurity H, its water content and inorganic impurities were determined by quantitative nuclear magnetic resonance (qNMR) method, Karl Fischer titrimetry method and residue on ignition method respectively. RESULTS The structure of fluconazole impurity H was identical with that in EP 8.0. The contents of water and inorganic impurities were 0.05% and 0.04%, respectively. It was found that fluconazole impurity H would be partially degraded into fluconazole impurity G in water solution, which resulted in the inaccuracy of the related substances test. The content of impurity H was 99.5% by qNMR method. CONCLUSION Due to the structural characteristics of fluconazole impurity H, the mass balance method, which is the routine method for determination of the content of reference standards, is not suitable for fluconazole impurity H. In the circumstances, qNMR method can be used as a complementary method for the content determination of reference standards.

关键词

国家标准物质 / 氟康唑杂质 / 氟康唑杂质H / 有关物质

Key words

national reference standard / fluconazole impurity / fluconazole impurity H / related substance

引用本文

导出引用
冯艳春, 王晨, 田冶, 常祎卓, 马步芳, 姚尚辰, 胡昌勤. 氟康唑杂质H国家标准物质的研制[J]. 中国药学杂志, 2018, 53(17): 1516-1522 https://doi.org/10.11669/cpj.2018.17.017
FENG Yan-chun, WANG Chen, TIAN Ye, CHANG Yi-zhuo, MA Bu-fang, YAO Shang-chen, HU Chang-qin. Establishment of National Reference Standard of Fluconazole Impurity H[J]. Chinese Pharmaceutical Journal, 2018, 53(17): 1516-1522 https://doi.org/10.11669/cpj.2018.17.017
中图分类号: R917   

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