Du Yi, Wu Yinnan, Liu Yang, Meng Changhong, Tan Li, Cai Tiantian, Wang Yuxin, Lu Yihong
The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Traditional Chinese Medicine), Hangzhou, China.
Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, China.
Drug Chem Toxicol. 2022 Sep;45(5):2116-2122. doi: 10.1080/01480545.2021.1908712. Epub 2021 Apr 8.
Rabeprazole sodium is a widely used drug for gastrointestinal disorders. Several analytical methods for identifying rabeprazole sodium and its impurities have been reported. However, the genotoxicity of rabeprazole sodium and its impurities is still unclear. Thus, it is necessary to develop analytical methods that can identify the structures of its impurities and evaluate their genotoxicity. Here, we used high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry for identifying the impurities in rabeprazole sodium enteric-coated tablets. Impurities in the samples were matched with synthesized impurities based on the exact mass and secondary mass spectrometry characteristics and then subjected to analysis using the Derek and Sarah software, as well as genotoxicity evaluations. Our method successfully identified the impurities as 2-[[4-(3-methoxy propane)-3-methyl-N-oxido-2-pyridyl] methyl sulfonyl]-1H-benzimidazole (impurity I), 2-[[4-(3-methoxy propane)-3-methyl-2-pyridyl]methyl sulfonyl]-benzimidazole (impurity II), 2-[[4-(3-methoxy propane)-3-methyl-2-pyridyl] methionyl]-1H-benzimidazole (impurity III), and 2-mercapto benzimidazole (impurity IV). analysis predicted that impurity III demonstrated a structural alert; thus, this impurity was evaluated for genotoxicity using the Ames test and chromosomal aberration assay. Impurity III at concentrations of 7.5-30 μg/mL had an aberration rate of over 5% with or without S-9 mix. Furthermore, impurity III at concentrations of 40-1000 μg/plate significantly increased the number of mutagenic colonies with or without S-9 mix. These results indicated that impurity III should be regulated to the limit of 0.01%.
雷贝拉唑钠是一种广泛用于治疗胃肠道疾病的药物。已经报道了几种用于鉴定雷贝拉唑钠及其杂质的分析方法。然而，雷贝拉唑钠及其杂质的遗传毒性仍不清楚。因此，有必要开发能够鉴定其杂质结构并评估其遗传毒性的分析方法。在此，我们使用高效液相色谱-四极杆飞行时间质谱法来鉴定雷贝拉唑钠肠溶片的杂质。根据精确质量和二级质谱特征，将样品中的杂质与合成杂质进行匹配，然后使用Derek和Sarah软件进行分析以及遗传毒性评估。我们的方法成功鉴定出杂质为2-[[4-(3-甲氧基丙烷)-3-甲基-N-氧化-2-吡啶基]甲基磺酰基]-1H-苯并咪唑（杂质I）、2-[[4-(3-甲氧基丙烷)-3-甲基-2-吡啶基]甲基磺酰基]-苯并咪唑（杂质II）、2-[[4-(3-甲氧基丙烷)-3-甲基-2-吡啶基]甲硫基]-1H-苯并咪唑（杂质III）和2-巯基苯并咪唑（杂质IV）。分析预测杂质III显示出结构警示；因此，使用Ames试验和染色体畸变试验对该杂质进行遗传毒性评估。杂质III在浓度为7.5 - 30μg/mL时，无论有无S-9混合液，畸变率均超过5%。此外，杂质III在浓度为40 - 1000μg/平板时，无论有无S-9混合液，均显著增加了诱变菌落的数量。这些结果表明，杂质III应将限度规定为0.01%。
