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首页> 外文期刊>Journal of Pharmaceutical and Biomedical Analysis: An International Journal on All Drug-Related Topics in Pharmaceutical, Biomedical and Clinical Analysis >LC-ESI-QTOF-MS analysis utilizing gas-phase fragmentation reactions subjected to ESI-IS-CID and ESI-CID-MS/MS conditions to study the degradation behaviour of sorafenib tosylate: NMR and in vitro cytotoxicity and apoptosis detection studies of hydrolytic degradation products
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LC-ESI-QTOF-MS analysis utilizing gas-phase fragmentation reactions subjected to ESI-IS-CID and ESI-CID-MS/MS conditions to study the degradation behaviour of sorafenib tosylate: NMR and in vitro cytotoxicity and apoptosis detection studies of hydrolytic degradation products

机译：LC-ESI-QTOF-MS分析利用对ESI-IS-CID和ESI-CID-MS / MS / MS条件进行的气相碎片反应研究索拉非苯甲酸辛酸酯的降解行为：NMR和水解的体外细胞毒性和凋亡检测研究 降解产品

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The present study was to investigate the degradation profile of sorafenib tosylate (SORA), a potent oral multi-kinase inhibitor under various stress conditions as per ICH (Q1A (R2)) guidelines. Separation of SORA and its degradation products (DP-1-DP-5) was achieved on Acquity UPLC BEH C18 (100 mm x 2.1 mm x 1.7 mu m) column using a gradient elution of 0.1% formic acid and acetonitrile at a flow rate of 0.3 mL/min within 12 min. High resolution quadruple time-of-flight mass spectrometer (Q-TOF/MS) was utilized for characterization of all DPs. In ESI/CID-MS/MS experiments, the protonated DP-1 and DP-2 exhibited few interesting product ions which provide a compelling evidence for the compounds to undergo gas phase rearrangement reaction justified by its mechanistic explanation in support with density functional theory (DFT). In-source collision-induced dissociation (IS-CID) fragmentation using ESI/APCI-MS analysis exhibited the formation of N-deoxygenated product ion peak corresponds to pyridine N-oxide moiety as in DP-5. Further, major hydrolytic DPs (DP-2 and DP-3) were isolated on preparative HPLC and structural elucidation was done using ID NMR (H-1, C-13 and DEPT-135) experiments. In vitro cytotoxicity study for SORA and its isolated DPs were assessed by observing morphological changes in HepG2 cell lines under phase-contrast microscopy and MTT assay. Taken together, it was known that DP-2 and DP-3 were less potent with a cell viability of more than 90% and IC50 >50 mu M in comparison with SORA (IC50 = 2.99 +/- 0.35 mu M). The developed method was validated in terms of specificity, limit of detection, limit of quantification, linearity, accuracy, precision and robustness. (C) 2019 Elsevier B.V. All rights reserved.
机译：本研究是研究索拉非苯甲酸辛酸酯（SORA），效率的口服多激酶抑制剂在各种应激条件下的降解型材（Q1A（R2））指南。使用0.1％甲酸和乙腈以流速的梯度洗脱在Acquity UPLC BEB（100mM×2.1mm×1.7μm）柱上达到Sora及其降解产物（DP-1-DP-5） 12分钟内0.3毫升/分钟。高分辨率四重飞行时间质谱仪（Q-TOF / MS）用于所有DPS的表征。在ESI / CID-MS / MS实验中，质子化DP-1和DP-2表现出很少有趣的产品离子，其为化合物提供了令人焦虑的证据，该化合物通过其机械解释支持密度函数理论（ DFT）。使用ESI / APCI-MS分析的源自碰撞诱导的解离（IS-CID）碎片表现出N-脱氧产物离子峰的形成对应于吡啶N-氧化物部分，如DP-5中。此外，将主要水解DPS（DP-2和DP-3）分离在制备型HPLC上，并且使用ID NMR（H-1，C-13和DEPT-135）实验进行结构阐明。通过观察相对造影显微镜和MTT测定，通过观察HepG2细胞系的形态变化来评估SORA的体外细胞毒性研究及其分离的DPS。众所周知，与Sora（IC50 = 2.99 +/-0.35μm）相比，DP-2和DP-3具有超过90％和IC50>50μm的细胞活力。在特异性，检测极限，定量限制，线性，精度，精度和鲁棒性方面验证了开发的方法。 （c）2019 Elsevier B.v.保留所有权利。

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