Ji Shunli, Gao Hongbin, Xia Xingya, Zheng Feng
Key Laboratory of Drug Quality Control and Pharmacovigilance, Ministry of Education, China Pharmaceutical University 24 Tongjiaxiang Nanjing 210009 China
Department of Pharmaceutical Analysis, China Pharmaceutical University 24 Tongjiaxiang Nanjing 210009 China.
RSC Adv. 2019 Aug 16;9(44):25797-25804. doi: 10.1039/c9ra03835c. eCollection 2019 Aug 13.
Benzyl halides, widely used as alkylation reagents in drug synthesis, are potential genotoxic impurities (PGTIs) required to be controlled at trace levels. However, the existing analytical methods for benzyl halides often suffer from matrix interferences or low derivatization efficiency of benzyl chlorides. In this paper, a simple derivatization HPLC-UV method was developed for the analysis of these residual trace benzyl halides in drug substances. 1-(4-Nitrophenyl) piperazine (4-NPP) was selected as a new derivatization reagent because it shifted well the benzyl halides derivatives away to the near visible range (392 nm), which could minimize the matrix interferences from the drug substances and related impurities. Meanwhile, potassium iodide (KI) was used to convert the mixed benzyl halides into benzyl iodides before derivatization. The derivatization parameters were also optimized using the design of experiments (DoE) for achieving the best reaction efficiency. The results showed that the new approach had high specificity and sensitivity, and the LOQs were 7-9 μg g relative to 5 mg mL antipyrine and 17.5-22.5 μg g relative to 2 mg mL oroxylin A. The method is a valuable alternative for the determination of residual benzyl halides in the drug substances.
卤代苄在药物合成中广泛用作烷基化试剂，是需要控制在痕量水平的潜在基因毒性杂质（PGTIs）。然而，现有的卤代苄分析方法常常受到基质干扰或苄基氯衍生化效率低的困扰。本文开发了一种简单的衍生化高效液相色谱 - 紫外法，用于分析药物中这些残留的痕量卤代苄。选择1 - （4 - 硝基苯基）哌嗪（4 - NPP）作为一种新的衍生化试剂，因为它能将卤代苄衍生物的峰很好地转移到近可见光范围（392 nm），这可以最大限度地减少药物和相关杂质的基质干扰。同时，碘化钾（KI）用于在衍生化之前将混合的卤代苄转化为苄基碘。还使用实验设计（DoE）优化衍生化参数以实现最佳反应效率。结果表明，新方法具有高特异性和灵敏度，相对于5 mg/mL安替比林，定量限为7 - 9 μg/g，相对于2 mg/mL木犀草素，定量限为17.5 - 22.5 μg/g。该方法是测定药物中残留卤代苄的一种有价值的替代方法。
