Abstract：
The recent discovery of N-nitrosodimethylamine (NDMA), a mutagenic N-nitrosamine, in pharmaceuticals has adversely impacted the global supply of relevant pharmaceutical products. Contamination by N-nitrosamines diverts resources and time from research and development or pharmaceutical production, representing a bottleneck in drug development. Therefore, predicting the risk of N-nitrosamine contamination is an important step in preventing pharmaceutical contamination by DNA-reactive impurities for the production of high-quality pharmaceuticals. In this study, we first predicted the degradation pathways and impurities of model pharmaceuticals, namely gliclazide and indapamide, in silico using an expert-knowledge software. Second, we verified the prediction results with a demonstration test, which confirmed that N-nitrosamines formed from the degradation of gliclazide and indapamide in the presence of hydrogen peroxide, especially under alkaline conditions. Furthermore, the pathways by which degradation products formed were determined using ranitidine, a compound previously demonstrated to generate NDMA. The prediction indicated that a ranitidine-related compound served as a potential source of nitroso groups for NDMA formation. In silico software is expected to be useful for developing methods to assess the risk of N-nitrosamine formation from pharmaceuticals.
摘要：
最近发现的N-亚硝基二甲胺（NDMA），一种诱变的N-亚硝胺,对相关药品的全球供应产生了不利影响。N-亚硝胺污染转移了研发或药物生产的资源和时间，代表了药物开发的瓶颈。因此,预测N-亚硝胺污染的风险是防止DNA反应性杂质污染用于生产高质量药物的重要步骤。在这项研究中,我们首先预测了模型药物的降解途径和杂质，即格列齐特和茚达帕胺，在计算机上使用专家知识软件。第二,我们通过示范试验验证了预测结果，这证实了N-亚硝胺在过氧化氢存在下由格列齐特和茚达帕胺的降解形成，特别是在碱性条件下。此外，使用雷尼替丁确定降解产物形成的途径，一种先前证明能产生NDMA的化合物。预测表明，雷尼替丁相关化合物是NDMA形成亚硝基的潜在来源。预计计算机软件可用于开发评估药物中N-亚硝胺形成风险的方法。
