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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 >Solution degradant of mirabegron extended release tablets resulting from a Strecker-like reaction between mirabegron, minute amounts of hydrogen cyanide in acetonitrile, and formaldehyde in PEG during sample preparation
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Solution degradant of mirabegron extended release tablets resulting from a Strecker-like reaction between mirabegron, minute amounts of hydrogen cyanide in acetonitrile, and formaldehyde in PEG during sample preparation

机译：溶液降解M拉释延长释放片剂，由M拉释，乙腈中的微米氰化物之间的含量样反应，以及在样品制备期间PEG中的甲醛相反

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摘要

During the related substances testing of mirabegron extended release tablets, an unknown peal< was observed in HPLC chromatograms in a level exceeding the identification threshold. By using a strategy that combines LC-PDA/UV-MSn with mechanism-based stress studies, the unknown peak was rapidly identified as cyanomethyl mirabegron, a solution degradant that is caused by a Strecker-like reaction between the API, formaldehyde (an impurity in PEG), and HCN (an impurity in HPLC grade acetonitrile). The mechanism of the solution degradation chemistry was verified by stressing mirabegron with formaldehyde and trimethylsilyl cyanide (TMSCN, a synthetic reagent that generates HCN upon contact with water), in which the secondary amine group of mirabegron first reacts with formaldehyde to form the iminium ion intermediate; the latter then undergoes a nucleophilic attack by cyanide to yield the cyanomethyl mirabegron. The structure of the impurity was further confirmed through the synthesis of the impurity and subsequent structure characterization by 1D and 2D NMR. Due to the ubiquitous presence of formaldehyde in pharmaceutical excipients (e.g., PEG and polysorbate) and trace amount of HCN in HPLC grade acetonitrile, this type of solution degradation would likely occur in sample preparations of pharmaceutical finished products containing APIs with primary and secondary amine moieties. In a GMP environment, such an event may trigger undesirable out-of-specification (OOS) investigations; the results of this paper should help resolve such OOS investigations or even prevent these events from happening in the first place. (C) 2019 Elsevier B.V. All rights reserved.
机译：在相关物质测试期间，在M拉释延长释放片剂中，在超出识别阈值的水平中在HPLC色谱图中观察到未知的Peal <。通过使用将LC-PDA / UV-MSN与基于机理的应力研究结合的策略，未知峰迅速鉴定为氰基甲基M拉释，一种由API，甲醛（杂质）之间的斑点状反应引起的溶液降解剂。在PEG）和HCN（HPLC级乙腈中的杂质）。通过用甲醛和三甲基甲硅烷基氰化物（TMSCN，在与水接触时产生HCN的合成试剂）来验证溶液降解化学的机制，其中丙萨克朗的仲胺基首先与甲醛反应以形成亚胺离子中间体;后者然后经过氰化物进行亲核攻击，得到氰基甲基·米拉巴克群。通过合成杂质和随后的结构表征1D和2D NMR，进一步证实杂质的结构。由于在HPLC级乙腈中的药物赋形剂（例如，PEG和聚山梨醇酯）中的甲醛存在普遍存在（例如，PEG和聚山梨醇酯）和痕量的HCN，这种类型的溶液降解可能发生在含有初级和仲胺部分的药物成品的样品制剂中。在GMP环境中，这样的事件可能会引发不可取的规范（OOS）调查;本文的结果应有助于解决此类OOS调查甚至阻止这些事件首先发生。 （c）2019 Elsevier B.v.保留所有权利。

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