酮康唑相关杂质国家标准物质的研制

目的: 研制酮康唑相关杂质标准物质,提升国内酮康唑品种的质控标准. 方法: 对酮康唑杂质B、C、D、E进行合成与结构确证,并采用中国药典2010年版二部酮康唑有关物质检查方法测定各杂质的纯度,再根据各杂质的水分和炽灼残渣结果用质量平衡法确定首批各杂质国家标准物质的含量.最后采用标准曲线法测定了酮康唑诸杂质对酮康唑在220 nm检测波长下的相对校正因子. 结果: 研制的酮康唑杂质B、C、D、E标准物质与欧洲药典(EP 8.0版)中规定的结构一致.中国药典2010年版二部中酮康唑有关物质检查项下规定的色谱系统对酮康唑及其各杂质均能有效分离.以质量平衡法表示,本研究标定的酮康唑各杂质B、C、D、E的含量分别为95.2%、97.9%、98.5%和99.4%.各杂质对酮康唑的相对校正因子分别为1.13、1.08、0.94、1.01. 结论: 建立了首批酮康唑杂质B、C、D、E国家标准物质.

Objective: To develop reference standards of ketoconazole impurities to improve the standard of quality control of ketoconazole and its preparations in China. Method: After ketoconazole impurities B,C,D and E were synthesized,their structures were validated by infrared,mass spectrum and nuclear magnetic resonance method.Then,the purity of these four impurities was determined using the related substances test of ketoconazole in Chinese pharmacopeia(2010 version,Volume 2).The content of the first batch of national standard substances of these impurities was calculated by mass balance method based on their water content and residue on ignition.Finally,the relative correction factor to ketoconazole of each impurity at 220 nm was determined using standard curve method. Results: The structures of ketoconazole impurities B,C,D and E were identical with those in European pharmacopoeia(8.0 edition).Ketoconazole and its impurities(B,C,D and E)can be completely separated by the HPLC system of ketoconazole in Chinese pharmacopeia.The contents of impurities B,C,D and E obtained were 95.2%,97.9%,98.5% and 99.4%,calculated by mass balance method,and their relative correction factors to ketoconazole was 1.13,1.08,0.94,1.01,respectively. Conclusion: The first batch of national standard substances of ketoconazole impurities B,C,D and E were successfully developed.