Jin Bo, Wang Yanan, Zhang Tingting, Yin Wanting, Zhang Dongfeng, Huang Haihong, Ma Chen
Institute of Material Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
J Anal Methods Chem. 2019 Jan 14;2019:8789470. doi: 10.1155/2019/8789470. eCollection 2019.
SY0916 has been proven to be a potent treatment agent against rheumatoid arthritis in preclinical studies and has been shown to be safe in phase I clinical trials. However, SY0916 is unstable in water, which is frequently used in pharmaceutical development processes. The degradation behaviour and stability of SY0916 in aqueous solutions were investigated at different pH levels, periods of time, and temperatures. Two degradation products (DPs) were successfully separated and characterized by liquid chromatography coupled to high-resolution tandem mass spectrometry (LC-HRMS/MS), liquid chromatography coupled to nuclear magnetic resonance with solid phase extraction (LC-SPE-NMR), and nuclear magnetic resonance (NMR). SY0916 decomposed to its ,-unsaturated ketone in protonic solvents, and the ,-unsaturated ketone further transformed into its alcohol form through a conjugate addition reaction in aqueous media. The results of this study indicate that the pH of the buffer solutions should be maintained between 3.0 and 3.6 for maximum SY0916 stability. Factors that affect degradation should be carefully controlled to mitigate or avoid drug decay.
SY0916在临床前研究中已被证明是一种有效的抗类风湿性关节炎治疗药物，并且在I期临床试验中已显示出安全性。然而，SY0916在制药开发过程中常用的水中不稳定。在不同的pH值、时间和温度下研究了SY0916在水溶液中的降解行为和稳定性。通过液相色谱-高分辨率串联质谱（LC-HRMS/MS）、固相萃取-液相色谱-核磁共振（LC-SPE-NMR）和核磁共振（NMR）成功分离并表征了两种降解产物（DPs）。SY0916在质子溶剂中分解为其α,β-不饱和酮，并且α,β-不饱和酮在水性介质中通过共轭加成反应进一步转化为其醇形式。本研究结果表明，为使SY0916具有最大稳定性，缓冲溶液的pH值应保持在3.0至3.6之间。应仔细控制影响降解的因素，以减轻或避免药物降解。
