Venetoclax is a selective orally active Bcl-2 protein inhibitor very recently approved by USFDA to treat chronic lymphocytic leukemia and other hematological malignancies. Postmarketing surveillance of any drug depends on its acceptability based on risk to benefit ratio. When risk outweighs the benefits, withdrawal of an already marketed drug is warranted. Presence of impurity is the primary cause of increased risk in a drug substance or drug product. With the discovery of newer molecules, it is of great importance to establish advanced analytical techniques for quantification of the drugs as well as their related impurities to address the prospective regulatory queries even if it is already in the market. In this study, a quantitative analytical assay method has been developed and validated for quantification of venetoclax in presence of its degradation impurities. A stress study was performed to examine the stability of the drug in hydrolytic, oxidative, thermolytic and photolytic environments. Venetoclax was found to be prone to degradation in acidic hydrolytic and oxidative stress conditions. Three new degradation impurities have been identified and characterized with the help of LC-Q-TOF-MS with accurate mass measurement and their putative structures have been proposed. Furthermore, for the first time, a possible degradation pathway has been established with mechanistic explanation. Moreover, the analytical method developed in this study will be of immense help for routine analysis of quality control and stability study samples of venetoclax in industry and research laboratories.

中文翻译：

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LC-Q-TOF-MS 驱动的维奈托克潜在降解杂质的鉴定、降解途径的机理解释和定量分析方法的建立

Venetoclax 是一种选择性口服活性 Bcl-2 蛋白抑制剂，最近被美国食品药品监督管理局批准用于治疗慢性淋巴细胞白血病和其他血液系统恶性肿瘤。任何药物的上市后监测取决于其基于风险收益比的可接受性。当风险大于收益时，有必要撤回已经上市的药物。杂质的存在是原料药或制剂风险增加的主要原因。随着新分子的发现，建立先进的分析技术来量化药物及其相关杂质以解决潜在的监管问题非常重要，即使它已经在市场上。在这项研究中，已经开发并验证了一种定量分析方法，用于在存在降解杂质的情况下对 venetoclax 进行定量。进行压力研究以检查药物在水解、氧化、热解和光解环境中的稳定性。发现 Venetoclax 在酸性水解和氧化应激条件下易于降解。借助具有精确质量测量的 LC-Q-TOF-MS 鉴定和表征了三种新的降解杂质，并提出了它们的推定结构。此外，首次通过机理解释建立了可能的降解途径。而且，