Department of Pharmaceutical Analysis, China Pharmaceutical University, Nanjing, China.
Public Laboratory Platform, China Pharmaceutical University, Nanjing, China.
Rapid Commun Mass Spectrom. 2024 Jan 30;38(2):e9651. doi: 10.1002/rcm.9651.
Pyrrolidone-based drugs find widespread use in treating conditions such as epilepsy and Alzheimer's disease, and in various other medical applications. Brivaracetam, the latest generation of pyrrolidone drugs, has exhibited significant promise owing to chemical structure modifications. Its affinity to the SV2A receptor is double that of the previous-generation drug, levetiracetam. Consequently, brivaracetam holds substantial potential for diverse applications. As a novel drug not yet included in the pharmacopeias of developed nations, comprehensive analysis and research are necessary to guarantee its safe utilization in clinical settings.
A liquid chromatography quadrupole time-of-flight tandem mass spectrometry (LC/QTOFMS) method has been developed to effectively separate, identify and characterize both the degradation products and process-related substances of brivaracetam. Stress testing of the sample was carried out following the guidelines outlined in ICH Q1A(R2). The structures of these impurities were identified through positive electrospray ionization QTOF high-resolution MS and NMR spectroscopy. Additionally, the formation mechanism of each degradation product is thoroughly discussed.
Under the analytical conditions outlined in this paper, brivaracetam and its degradation products were effectively separated. Thirteen degradation products were detected and characterized, shedding light on their origins and degradation pathways. Among these, three degradation products align with previously reported impurities, and two unreported degradation products were synthesized and confirmed through NMR spectroscopy. The stress testing results revealed the instability of brivaracetam under acidic, alkaline, oxidative and thermal stress conditions, while it exhibited relative stability under photolytic stress conditions.
The study developed an analytical method for brivaracetam that enabled the effective detection and separation of brivaracetam and its 13 degradation products. This method addresses a gap in both current domestic and foreign drug standards. The structures of all the major degradation products were characterized by high-resolution LC/QTOFMS, which is essential for quality control during the drug production process, stability evaluation and the establishment of proper storage conditions.
基于吡咯烷酮的药物在治疗癫痫和老年痴呆症等疾病以及各种其他医学应用中得到了广泛应用。作为吡咯烷酮类药物的最新一代，布瓦西坦由于其化学结构的修饰而显示出显著的前景。它与 SV2A 受体的亲和力是前一代药物左乙拉西坦的两倍。因此，布瓦西坦具有广泛的应用潜力。作为一种尚未列入发达国家药典的新型药物，有必要进行全面的分析和研究，以确保其在临床应用中的安全使用。
建立了一种液相色谱-四极杆飞行时间串联质谱（LC/QTOFMS）方法，可有效分离、鉴定和表征布瓦西坦的降解产物和工艺相关物质。按照 ICH Q1A（R2）指南对样品进行了强制降解试验。通过正电喷雾电离 QTOF 高分辨率 MS 和 NMR 光谱鉴定这些杂质的结构。此外，还深入讨论了每个降解产物的形成机制。
在本文所述的分析条件下，布瓦西坦及其降解产物得到了有效分离。共检出并鉴定了 13 个降解产物，阐明了其来源和降解途径。其中，有 3 个降解产物与已报道的杂质一致，还有 2 个未报道的降解产物通过 NMR 光谱合成并确认。稳定性试验结果表明，布瓦西坦在酸性、碱性、氧化和热应力条件下不稳定，而在光解应力条件下相对稳定。
本研究建立了一种分析布瓦西坦的方法，能够有效检测和分离布瓦西坦及其 13 个降解产物。该方法填补了国内外现行药品标准的空白。所有主要降解产物的结构均通过高分辨率 LC/QTOFMS 进行了表征，这对于药品生产过程中的质量控制、稳定性评价和建立适当的储存条件至关重要。
