School of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, 110016, China.
School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, 110016, China.
J Pharm Biomed Anal. 2020 Nov 30;191:113591. doi: 10.1016/j.jpba.2020.113591. Epub 2020 Aug 29.
Profiling impurities for the active pharmaceutical ingredients (APIs) is an indispensable step in drug development process. Nowadays, high resolution mass spectrometry is the first choice for determining the chemical formula of organic impurities. However, merely base on the accurate mass to screen the formula is obviously not a flawless method. In this paper, a reliable strategy based on Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR MS) was presented to profile the related impurities. Firstly, Cefteram pivoxil was subjected to forced degration under hydrolytic (acidic and basic), oxidative, photolytic and thermal conditions according to ICH guidelines. Then, a highly specific and efficient HPLC-FT-ICR MS compatible method was developed and it was used to separate and characterize the process related substances and the major degradation products in Cefteram pivoxil. Next, isotopic fine structures (IFSs) of all impurities were acquired to decisively determine their elemental composition. Finally, the possible chemical structures of impurities were predicted by combining the information of accurate mass, retention time, IFSs and characteristic fragmentation ions. As a result, a total of 20 related substances including 6 process related substances and 14 degradation products were identified and characterized. To the best of our knowledge, 13 of these related substances were not reported in the previous literature. It indicates that the developed strategy is accurate and standard independent to determine the chemical formulae of organic impurities in APIs. In conclusion, the impurity profiles obtained in this study are critical to the quality control and stability study of Cefteram pivoxil. Moreover, the developed method can be used as a versatile workflow to profile the impurities in APIs in the future, especially for the unknown impurities.
对原料药（API）中的杂质进行分析是药物开发过程中不可或缺的一步。如今，高分辨率质谱是确定有机杂质化学式的首选方法。然而，仅仅基于精确质量来筛选公式显然不是一种完美的方法。本文提出了一种基于傅里叶变换离子回旋共振质谱（FT-ICR MS）的可靠策略，用于分析相关杂质。首先，根据 ICH 指南，将头孢他美酯进行酸、碱、氧化、光解和热破坏性降解。然后，开发了一种高度特异和高效的 HPLC-FT-ICR MS 兼容方法，用于分离和鉴定头孢他美酯中的工艺相关物质和主要降解产物。接下来，获取所有杂质的同位素精细结构（IFS），以确定其元素组成。最后，结合精确质量、保留时间、IFS 和特征碎片离子的信息，预测杂质的可能化学结构。结果，共鉴定并表征了 20 种相关物质，包括 6 种工艺相关物质和 14 种降解产物。据我们所知，其中 13 种相关物质在以前的文献中没有报道过。这表明，所开发的策略准确且独立于标准，可用于确定 API 中有机杂质的化学式。总之，本研究中获得的杂质谱对于头孢他美酯的质量控制和稳定性研究至关重要。此外，该方法可用于未来 API 中杂质的分析，特别是未知杂质。
