Kovačić Jelena, Amidžić Klarić Daniela, Turk Nikša, Krznarić Željko, Riordan Emma, Mornar Ana
Department of Pharmaceutical Analysis, Faculty of Pharmacy and Biochemistry, University of Zagreb, 10000 Zagreb, Croatia.
Department of Gastroenterology, University Hospital Centre, 10000 Zagreb, Croatia.
Pharmaceuticals (Basel). 2025 Jan 17;18(1):124. doi: 10.3390/ph18010124.
BACKGROUND/OBJECTIVES: Janus kinase inhibitors open new horizons for small-molecule drugs in treating inflammatory bowel disease, with ritlecitinib demonstrating significant efficacy in clinical trials for ulcerative colitis and Crohn's disease. Ritlecitinib, a second-generation JAK3 inhibitor, is a novel therapeutic agent for alopecia areata and other autoimmune conditions.
A new stability-indicating UHPLC-DAD-MS/MS method was developed, validated, and applied for a forced degradation study of ritlecitinib under ICH guidelines.
The method demonstrated high specificity, sensitivity (LOD: 0.04 µg/mL; LOQ: 0.14 µg/mL), precision (RSD ≤ 0.15%), and accuracy (99.9-100.3%). Forced degradation studies under acidic, basic, oxidative, thermal, and photolytic conditions revealed four novel degradation products. Basic degradation followed second-order kinetics, while oxidative degradation followed zero-order kinetics.
The validated method reliably characterized ritlecitinib's stability and degradation products, providing essential data for optimizing formulation, determining proper storage conditions, anticipating drug-excipient interactions, and ensuring quality control. The eco-friendliness and applicability of the developed forced degradation procedure were evaluated using various green and blue metric tools. Incorporating green analytical principles underscores its potential for sustainable pharmaceutical analysis.
背景/目的：Janus激酶抑制剂为小分子药物治疗炎症性肠病开辟了新视野，ritlecitinib在溃疡性结肠炎和克罗恩病的临床试验中显示出显著疗效。Ritlecitinib是一种第二代JAK3抑制剂，是斑秃和其他自身免疫性疾病的新型治疗药物。
开发、验证了一种新的稳定性指示超高效液相色谱-二极管阵列-质谱/质谱法，并将其应用于按照国际人用药品注册技术协调会指南对ritlecitinib进行的强制降解研究。
该方法具有高特异性、灵敏度（检测限：0.04μg/mL；定量限：0.14μg/mL）、精密度（相对标准偏差≤0.15%）和准确度（99.9 - 100.3%）。在酸性、碱性、氧化、热和光解条件下的强制降解研究揭示了四种新的降解产物。碱性降解遵循二级动力学，而氧化降解遵循零级动力学。
经过验证的方法可靠地表征了ritlecitinib的稳定性和降解产物，为优化制剂、确定合适的储存条件、预测药物-辅料相互作用以及确保质量控制提供了重要数据。使用各种绿色和蓝色指标工具评估了所开发的强制降解程序的生态友好性和适用性。纳入绿色分析原则突出了其在可持续药物分析方面的潜力。
