关键词: 药物杂质, 降解杂质, 液相色谱-二极管阵列检测器-固相萃取-核磁共振/质谱联用技术, 结构解析, 分析方法

Abstract:

Hyphenated LC-DAD-SPE-NMR/MS technique was successfully used to characterize one novel degradation impurity with 0.3%~0.4% level in cabazitaxel injection. In the LC analysis, the impurity was co-eluted with tween-80, one important excipient contained in cabazitaxel injection, so high purity of degradation impurity is not available with preparation scale isolation for structure elucidation. In this work, hyphenated LC-DAD-SPE-NMR/MS was used to trap the impurity with automatically SPE technique, then CD₃CN solvent was used to rinse the analyte in the SPE cartridge dried with N₂ gas, finally 1D and 2D NMR measurement were performed to characterize the structure of the impurity. In the ¹H NMR spectrum, partial peaks of the impurity was overlaid with co-eluted tween-80, so ¹H-¹H, ¹H-¹³C correlations, ¹H and ¹³C chemical shifts were extracted from the interfering peaks of tween-80 based on the extensive analysis of ¹H-¹H COSY, ¹H-¹H NOESY, ¹H-¹³C HSQC and ¹H-¹³C HMBC 2D spectra, the structure of impurity was elucidated to one cabazitaxel isomer with rearranged taxane skeleton. In this work, the trace degradation impurity was elucidated out from the complex mixture in less than 48 hours, which was a successful application of  LC-DAD-SPE-NMR/MS hyphenation in the structure elucidation of trace impurity in pharmaceutical drug, demonstrated it’s powerful capability in structure elucidation, which also suggested it’s broad application prospect in pharmaceutical industry.

Key words: Cabazitaxel, Degradation impurity, LC-DAD-SPE-NMR/MS, Cabazitaxel, Structure identification, Analytical method