Chaganti Sowmya, Dhiman Vivek, Madhyanapu Golla Vijaya, K R Roshitha, Khemchandani Rahul, Samanthula Gananadhamu
Department of Pharmaceutical Analysis, National Institute of Pharmaceutical Education and Research, Hyderabad, Telangana, India.
Rapid Commun Mass Spectrom. 2023 Sep 30;37(18):e9605. doi: 10.1002/rcm.9605.
Baricitinib (BARI), an inhibitor of Janus kinases 1 and 2 (JAK 1/2), is used for the treatment of rheumatoid arthritis and COVID-19. The present study focuses on establishing the forced degradation behavior of BARI under different degradation conditions (hydrolysis, oxidation, and photolysis) following International Council for Harmonization (ICH) guidelines of Q1A (R2)-Stability testing of new drug substances and products and Q1B-Photostability testing of new drug substances and products. This study helps in monitoring the quality and safety of BARI and its product development.
Prior to conducting the study, the in silico degradation profile of BARI was predicted by Zeneth. Reversed-phase high-performance liquid chromatography employing a gradient program was used for the identification and separation of degradation impurities with an InertSustain C8 column (4.6 × 250 mm, 5 μm). The mobile phases used were 10 mM ammonium formate (pH 2.89) and acetonitrile. High-resolution mass spectrometry (HRMS) was used for the structural elucidation of the degradation impurities.
BARI was labile to hydrolytic (acidic, basic, and neutral) and photolytic degradation conditions which yielded 10 new degradation impurities and it was stable under oxidative (H O ) conditions. The separated degradation impurities were characterized by HRMS and the respective degradation pathways were proposed. The generated information helped to propose a mechanism for the formation of the degradation impurities. Additionally, one-dimensional and two-dimensional nuclear magnetic resonance spectroscopy were used for the characterization of two major degradation impurities.
The forced degradation study of BARI was carried out in accordance with ICH Q1A and Q1B guidelines, which resulted in the formation of 10 new degradation impurities. In our analysis, three degradation impurities were matching with the Zeneth predictions. In silico tools, DEREK Nexus® and SARAH Nexus®, were used for predicting the toxicity and mutagenicity of BARI and its degradation impurities. Overall, this study sheds light on BARI's safety monitoring and storage circumstances.
巴瑞替尼（BARI）是一种 Janus 激酶 1 和 2（JAK 1/2）抑制剂，用于治疗类风湿性关节炎和 COVID-19。本研究的重点是按照国际协调理事会（ICH）关于新药物质和产品稳定性测试的 Q1A（R2）指南以及新药物质和产品光稳定性测试的 Q1B 指南，确定 BARI 在不同降解条件（水解、氧化和光解）下的强制降解行为。这项研究有助于监测 BARI 的质量和安全性及其产品开发。
在进行研究之前，通过 Zeneth 预测了 BARI 的计算机模拟降解概况。采用梯度洗脱程序的反相高效液相色谱法，使用 InertSustain C8 柱（4.6×250 mm，5μm）对降解杂质进行鉴定和分离。所用流动相为 10 mM 甲酸铵（pH 2.89）和乙腈。高分辨率质谱（HRMS）用于降解杂质的结构解析。
BARI 对水解（酸性、碱性和中性）和光解降解条件不稳定，产生了 10 种新的降解杂质，并且在氧化（H₂O₂）条件下稳定。通过 HRMS 对分离出的降解杂质进行了表征，并提出了各自的降解途径。所获得的信息有助于提出降解杂质形成的机制。此外，一维和二维核磁共振光谱用于表征两种主要降解杂质。
按照 ICH Q1A 和 Q1B 指南对 BARI 进行了强制降解研究，结果形成了 10 种新的降解杂质。在我们的分析中，三种降解杂质与 Zeneth 的预测相符。使用计算机模拟工具 DEREK Nexus® 和 SARAH Nexus® 预测了 BARI 及其降解杂质的毒性和致突变性。总体而言，本研究为 BARI 的安全监测和储存条件提供了依据。
