An anticancer drug apalutamide approved by United States Food and Drug Administration in 2018 is one of the most commonly prescribed chemotherapeutic agents used for the treatment of prostate cancer. The present study aims at establishing the chemical structures of all the degradation products of the active pharmaceutical ingredient (API) formed under different forced degradation conditions. Apalutamide degradation was studied under International Council for Harmonisation recommended conditions of hydrolysis (acidic, alkaline, and neutral), oxidation, photolysis, and thermal stress. In total, seven degradation products (DP-1 to DP-7) were observed which were successfully separated on high-performance liquid chromatography and further characterized using liquid chromatography–mass spectrometry quadrupole time-of-flight (LC–MS/MS-QTOF). Degradation pathways for each of the observed DPs have been proposed based on the mass fragmentation pattern of API as well as DPs, identifying the underlying chemical transformations. Prediction of DPs was performed with Zeneth software tool, and the results were compared with the experimental observations. In silico toxicity assessment carried out using Derek suite reveals toxic nature of some of these DPs.

Graphical Abstract

中文翻译：

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抗癌药物 Apalutamide 的强制降解：杂质分析和结构解析研究

美国食品和药物管理局于 2018 年批准的抗癌药物阿帕他胺是用于治疗前列腺癌的最常用处方化疗药物之一。本研究旨在建立活性药物成分（API）在不同强制降解条件下形成的所有降解产物的化学结构。在国际协调委员会推荐的水解（酸性、碱性和中性）、氧化、光解和热应力条件下研究了阿帕他胺的降解。总共观察到七种降解产物（DP-1 至 DP-7），这些产物在高效液相色谱上成功分离，并使用液相色谱-质谱四极杆飞行时间 (LC-MS/MS-QTOF) 进一步表征）。根据 API 和 DP 的质量碎片模式，提出了每个观察到的 DP 的降解途径，从而确定了潜在的化学转化。利用Zeneth软件工具对DP进行预测，并将结果与​​实验观察结果进行比较。使用 Derek 套件进行的计算机毒性评估揭示了其中一些 DP 的毒性。

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