Forced Degradation of an Anticancer Drug Apalutamide: Impurity Profiling and Structure Elucidation Study

IF 1.2 4区化学 Q4 BIOCHEMICAL RESEARCH METHODS

Chromatographia Pub Date : 2023-11-09 DOI:10.1007/s10337-023-04294-9

Rekha Sapkal, Sadaf Quadri, Rupali Mahajan, Hara Prasad Padhy, Amit Asthana, Gananadhamu Samanthula, Amol G. Dikundwar

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Abstract

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

Abstract Image

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抗癌药物阿帕鲁胺的强制降解：杂质分析和结构阐明研究

美国食品和药物管理局于 2018 年批准的抗癌药物阿帕鲁胺是用于治疗前列腺癌的最常用处方化疗药物之一。本研究旨在确定该活性药物成分在不同强制降解条件下形成的所有降解产物的化学结构。在国际协调理事会推荐的水解（酸性、碱性和中性）、氧化、光解和热应力条件下对阿帕鲁胺的降解进行了研究。总共观察到七种降解产物（DP-1 至 DP-7），这些降解产物在高效液相色谱法中成功分离，并通过液相色谱-质谱四极杆飞行时间（LC-MS/MS-QTOF）进一步定性。根据原料药和二价磷的质量碎片模式，提出了所观察到的每种二价磷的降解途径，并确定了潜在的化学转化。使用 Zeneth 软件工具对 DPs 进行了预测，并将预测结果与实验观察结果进行了比较。使用 Derek 套件进行的硅学毒性评估揭示了其中一些 DPs 的毒性。

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来源期刊

Chromatographia 化学-分析化学

CiteScore

3.40

自引率

5.90%

发文量

103

审稿时长

2.2 months

期刊介绍： Separation sciences, in all their various forms such as chromatography, field-flow fractionation, and electrophoresis, provide some of the most powerful techniques in analytical chemistry and are applied within a number of important application areas, including archaeology, biotechnology, clinical, environmental, food, medical, petroleum, pharmaceutical, polymer and biopolymer research. Beyond serving analytical purposes, separation techniques are also used for preparative and process-scale applications. The scope and power of separation sciences is significantly extended by combination with spectroscopic detection methods (e.g., laser-based approaches, nuclear-magnetic resonance, Raman, chemiluminescence) and particularly, mass spectrometry, to create hyphenated techniques. In addition to exciting new developments in chromatography, such as ultra high-pressure systems, multidimensional separations, and high-temperature approaches, there have also been great advances in hybrid methods combining chromatography and electro-based separations, especially on the micro- and nanoscale. Integrated biological procedures (e.g., enzymatic, immunological, receptor-based assays) can also be part of the overall analytical process.