注射用更昔洛韦及其原料的杂质谱分析  

Impurity spectrum analysis of ganciclovir for injection and its raw materials

作　　者：尧爱珉 王丽 申兰慧 Ai-Min YAO;Li WANG;Lan-Hui SHEN(Wuxi Institute for Drug Control,Wuxi 214028,Jiangsu Province,China)

机构地区：[1]无锡市药品安全检验检测中心,江苏无锡214028

出　　处：《药物流行病学杂志》2023年第8期915-924,共10页Chinese Journal of Pharmacoepidemiology

基　　金：国家药品监督管理局化学药品杂质谱研究重点实验室开放课题项目(NMPA-KLIPCD-2020-02)。

摘　　要：目的探讨注射用更昔洛韦及更昔洛韦原料的杂质谱,并比较各企业样品间的杂质情况。方法采用HPLC法,色谱柱为CAPCELL PAK SCX UG80柱(250 mm×4.6 mm,5μm),流动相为0.05%三氟乙酸水溶液-乙腈(50∶50),流速为1.5 mL·min^(-1),检测波长为254 nm,柱温为40℃,进样体积为20μL。进一步结合强制降解试验、影响因素试验和加速试验探讨杂质来源,对含量超过0.1%的杂质进行质谱解析,采用毒性预测软件进行杂质毒性评估。结果更昔洛韦原料及制剂杂质谱显示共检出19个杂质峰,5个为已知杂质,14个为未知杂质,对样品中检出含量超过0.1%的5个杂质和强制降解试验的主要杂质产物进行质谱解析;强制降解试验表明氧化、酸性条件下样品更易降解产生杂质;不同企业间原料、制剂的杂质谱均有差异,同一企业不同批次原料杂质谱也有差异,制剂的杂质主要来源于原料的合成过程,制剂企业的生产工艺相对稳定;与参比制剂(赛美维)相比,国内产品杂质谱更复杂。结论更昔洛韦原料企业应加强对生产工艺稳定性、产品杂质的含量及个数的控制,以优化产品质量。Objective To investigate the impurities of ganciclovir for injection and its raw materials,and compare the impurities among different batches of raw materials and preparations.Methods The HPLC method was performed on an CAPCELL PAK SCX UG80 column(250 mmx4.6 mm,5μm),the mobile phase was 0.05%trifluoroacetic acid solution-acetonitrile(50:50)at a flow rate of 1.5 mL·min^(-1),the detection wavelength was 254 nm,the column temperature was 40℃,and the injection volume was 20μL.The source of impurities was discussed by means of degradation test,stress test,and accelerated test.The structure of impurities exceeding 0.1%was analyzed by mass spectrometry,and their toxicity was evaluated by toxicity prediction software.Results The impurity spectrum of ganciclovir showed that a total of 19 impurity peaks were detected,5 were known impurities and 14 were unknown impurities.The structures of 5 impurities with content greater than 0.1%were analyzed.Degradation test showed that ganciclovir was easier to degrade under oxidative or acidic conditions.The impurity spectrums of raw materials and preparations are different between different enterprises,and the impurity spectrums of different batches of raw materials in the same enterprise are also different.The related substances in preparations were mainly derived from raw materials and the production process of preparation enterprises is relatively stable.Compared with the reference preparation Cymevene,the impurity profiles of the domestic products were more complex.Conclusion Ganciclovir raw material enterprises should strengthen the control of the stability of the production process,strengthen the control of the content and number of impurities in the product,and optimize product quality.

关 键 词：更昔洛韦 注射用更昔洛韦 抗病毒药 杂质谱 有关物质 杂质来源 质谱解析 高效液相色谱法 

分 类 号：R927.11[医药卫生—药学]