酒石酸唑吡坦关键中间体的有关物质检测与主要杂质合成  

Detection of Related Substances of Key Intermediates of Zolpidem Tartrate and Synthesis of Main Impurities

作　　者：李翼 刘秀 王玲兰 钟超泽 朱跃芳 LI Yi;LIU Xiu;WANG Linglan;ZHONG Chaoze;ZHU Yuefang(Zhuzhou Qianjin Pharmaceutical Co.,Ltd.,Zhuzhou,Hunan,China 412000;Zhuzhou Institute for Food and Drug Control of Hunan Province,Zhuzhou,Hunan,China 412000)

机构地区：[1]株洲千金药业股份有限公司,湖南株洲412000 [2]湖南省株洲市食品药品检验所,湖南株洲412000

出　　处：《中国药业》2024年第21期23-27,共5页China Pharmaceuticals

基　　金：湖南省自然科学基金[2022JJ80048]。

摘　　要：目的控制酒石酸唑吡坦关键中间体化合物3的质量。方法采用高效液相色谱法检测化合物3中有关物质,色谱柱为Agilent Pursuit 5 C_(18)柱(150 mm×3.9 mm,5μm),流动相为pH 6.0磷酸盐缓冲液-甲醇-乙腈(梯度洗脱),流速为1.2 mL/min,柱温为30℃,检测波长为254nm,进样量为20μL。合成化合物3中的主要杂质,并通过质谱法、核磁共振波谱法对其进行结构确认。结果化合物3的质量浓度在0.0928~556.7689μg/mL范围内与峰面积线性关系良好(r=0.9997,n=5);检测限为1.0 ng,定量限为2.0 ng;精密度、稳定性、重复性试验的结果均符合要求。6批化合物3的纯度均大于90%,均检出有关物质杂质1、杂质2、未知杂质、化合物2,其相对保留时间分别为0.32,1.12,2.23,1.67。以化合物3为原料,合成得到杂质1和杂质2,纯度分别为99.04%和98.72%。结论该方法专属性强、准确度高、稳定性好,可为酒石酸唑吡坦的质量控制提供参考。合成的杂质纯度高,可作为杂质对照品使用。Objective To control the quality of key intermediate compound 3 of zolpidem tartrate.Methods High-performance liquid chromatography(HPLC)method was used to detect the related substances in compound 3,the chromatographic column was Agilent Pursuit 5 C_(18) column(150 mm×3.9 mm,5μm),the mobile phase was pH 6.0 phosphate buffer-methanol-acetonitrile(gradient elution),the flow rate was 1.2 mL/min,the column temperature was 30℃,the detection wavelength was 254 nm,and the injection volume was 20μL.The main impurities in compound 3 were synthesized and their structures were confirmed by the mass spectrometry and nuclear magnetic resonance spectroscopy.Results The linear range of compound 3 was 0.0928-556.7689μg/mL(r=0.9997,n=5).The limit of detection(LOD)was 1.0 ng,and the limit of quantification(LOQ)was 2.0 ng.The precision,stability,and repeatability test results all meet the requirements.The purity of six batches of compound 3 was higher than 90%,with the detected relevant substances being impurity 1,impurity 2,unknown impurity,and compound 2,and their relative retention time was 0.32,1.12,2.23,and 1.67,respectively.With compound 3 as the raw material,impurity 1 and impurity 2 were synthesized with purities of 99.04%and 98.72%,respectively.Conclusion The method has strong specificity,high accuracy,and good stability,which can provide a reference for the quality control of zolpidem tartrate.The synthesized impurities have high purity and can be used as impurity reference standards.

关 键 词：酒石酸唑吡坦 中间体化合物 有关物质 杂质合成 高效液相色谱法 质谱法 核磁共振波谱法 

分 类 号：R943[医药卫生—药剂学]