Bonciarelli Stefano, Desantis Jenny, Cerquiglini Simone, Goracci Laura
Department of Chemistry, Biology and Biotechnology, University of Perugia, Via Elce di Sotto 8, 06123Perugia, Italy.
ACS Omega. 2023 Feb 9;8(7):7005-7016. doi: 10.1021/acsomega.2c07815. eCollection 2023 Feb 21.
Drugs must satisfy several protocols and tests before being approved for the market. Among them, forced degradation studies aim to evaluate drug stability under stressful conditions in order to predict the formation of harmful degradation products (DPs). Recent advances in LC-MS instrumentation have facilitated the structure elucidation of degradants, although a comprehensive data analysis still represents a bottle-neck due to the massive amount of data that can be easily generated. MassChemSite has been recently described as a promising informatics solution for LC-MS/MS and UV data analysis of forced degradation experiments and for the automated structural identification of DPs. Here, we applied MassChemSite to investigate the forced degradation of three poly(ADP-ribose) polymerase inhibitors (olaparib, rucaparib, and niraparib) under basic, acidic, neutral, and oxidative stress conditions. Samples were analyzed by UHPLC with online DAD coupled to high-resolution mass spectrometry. The kinetic evolution of the reactions and the influence of solvent on the degradation process were also assessed. Our investigation confirmed the formation of three DPs of olaparib and the wide degradation of the drug under the basic condition. Intriguingly, base-catalyzed hydrolysis of olaparib was greater when the content of aprotic-dipolar solvent in the mixture decreased. For the other two compounds, whose stability has been much less studied previously, six new degradants of rucaparib were identified under oxidative degradation, while niraparib emerged as stable under all stress conditions tested.
药物在获得市场批准之前必须满足多项协议和测试。其中，强制降解研究旨在评估药物在应激条件下的稳定性，以预测有害降解产物（DPs）的形成。液相色谱 - 质谱联用仪器的最新进展有助于降解产物的结构解析，尽管由于能够轻松生成大量数据，全面的数据分析仍然是一个瓶颈。MassChemSite最近被描述为一种有前景的信息学解决方案，用于强制降解实验的液相色谱 - 串联质谱和紫外数据分析以及降解产物的自动结构鉴定。在此，我们应用MassChemSite研究三种聚（ADP - 核糖）聚合酶抑制剂（奥拉帕利、卢卡帕利和尼拉帕利）在碱性、酸性、中性和氧化应激条件下的强制降解。通过超高效液相色谱与在线二极管阵列检测器联用高分辨率质谱对样品进行分析。还评估了反应的动力学演变以及溶剂对降解过程的影响。我们的研究证实了奥拉帕利三种降解产物的形成以及该药物在碱性条件下的广泛降解。有趣的是，当混合物中非质子偶极溶剂的含量降低时，奥拉帕利的碱催化水解作用更强。对于另外两种之前稳定性研究较少的化合物，在氧化降解条件下鉴定出卢卡帕利的六种新降解产物，而尼拉帕利在所有测试的应激条件下均表现稳定。
