利用液相色谱-质谱联用仪和核磁共振波谱分析马伐康坦的稳定性:对降解产物的毒性和诱变性进行硅学预测。

IF 1.9 3区 化学 Q3 BIOCHEMICAL RESEARCH METHODS
Vijaya Madhyanapu Golla, Mallika Kalyan, Upasana Gholap, Hara Prasad Padhy, Roshitha K. Ramachandran, Gananadhamu Samanthula
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引用次数: 0

摘要

本研究旨在分离、鉴定和描述马伐康坦暴露于应激降解时形成的降解产物以及该药物在各种环境中的稳定性,同时了解其降解化学性质。根据观察到的降解产物,对其毒性和致突变性进行了硅学预测。对马伐康坦进行了应力降解、稳定性研究和降解动力学研究,并通过高效液相色谱法分离降解产物。通过串联质谱研究,利用产物离子碎片确定了降解产物的结构特征。此外,还进行了核磁共振实验,以阐明在确定降解产物结构时存在的不明确之处。利用现有知识的风险演绎估算和使用假设软件的结构活性关系分析,确定了马伐康坦及其降解产物的硅学毒性和致突变性特征。对在酸性水解胁迫条件下发现的两种马伐卡滕降解产物进行了分离、鉴定和特征描述,并提出这两种降解产物为 1-异丙基嘧啶-2,4,6(1H,3H,5H)-三酮和 1-苯乙胺。研究发现,Mavacamten 在不同的 pH 值和胃肠道条件下都很稳定。在 1 N 酸性条件下,马伐卡滕的降解动力学遵循零阶动力学,并在 6 小时内完全降解。硅学毒性和致突变性研究表明,1-苯乙胺可能是一种皮肤致敏物质。研究人员开发了一种高效液相色谱法,用于分离马伐康坦的降解产物,并利用液相色谱-串联质谱法和核磁共振法对降解产物进行了表征。在药物产品的生产和储存过程中,由于药物在酸性条件下容易水解,因此在处理酸性溶液时需要采取预防措施。由于 1-苯基乙胺是一种皮肤过敏物质,因此需要监测在这些条件下 1-苯基乙胺的形成情况。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Discerning the stability behaviour of mavacamten availing liquid chromatography-mass spectrometry and nuclear magnetic resonance spectroscopy: In silico toxicity and mutagenicity prediction of degradation products

The present study aimed to separate, identify, and characterise the degradation products formed when mavacamten is exposed to stress degradation as well as the stability of the drug in various environments and also to understand its degradation chemistry. Prediction of in silico toxicity and mutagenicity was aimed at the observed degradation products. Stress degradation along with stability studies and degradation kinetics were performed on mavacamten, and separation of degradation products was carried out by high-performance liquid chromatography. Tandem mass spectrometry studies were executed to characterise the structures of degradation products using product ion fragments. Orthogonally, nuclear magnetic resonance experiments were conducted to elucidate the structures having ambiguity in characterising them. Deductive Estimation of Risk from Existing Knowledge and Structure Activity Relationship Analysis using Hypotheses software were used to establish in silico toxicity and mutagenic profiles of mavacamten and its degradation products. Two degradation products of mavacamten found in acidic hydrolytic stress conditions were separated, identified, characterised, and proposed as 1-isopropylpyrimidine-2,4,6(1H,3H,5H)-trione and 1-phenylethanamine. Mavacamten was found to be stable under different pH and gastrointestinal conditions. The degradation kinetics of mavacamten under 1 N acidic condition followed zero-order kinetics, and it was degraded completely within 6 h. In silico toxicity and mutagenicity studies revealed that 1-phenylethanamine can be a skin sensitiser. A high-performance liquid chromatography method was developed for the separation of degradation products of mavacamten and characterised by liquid chromatography–tandem mass spectrometry and nuclear magnetic resonance. During the manufacturing and storage of drug product, precautions need to be taken when dealing with acidic solutions as the drug is prone to hydrolysis in acidic conditions. The formation of 1-phenylethanamine under these conditions is to be monitored as it is a skin sensitiser.

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来源期刊
Journal of Mass Spectrometry
Journal of Mass Spectrometry 化学-光谱学
CiteScore
5.10
自引率
0.00%
发文量
84
审稿时长
1.5 months
期刊介绍: The Journal of Mass Spectrometry publishes papers on a broad range of topics of interest to scientists working in both fundamental and applied areas involving the study of gaseous ions. The aim of JMS is to serve the scientific community with information provided and arranged to help senior investigators to better stay abreast of new discoveries and studies in their own field, to make them aware of events and developments in associated fields, and to provide students and newcomers the basic tools with which to learn fundamental and applied aspects of mass spectrometry.
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