Forced degradation study of etrasimod: Structural elucidation and transformation pathways of its major degradation products

Etrasimod is a sphingosine-1-phosphate receptor 1 (S1P1) receptor modulator and has been used for the treatment of moderate to severe ulcerative colitis. Understanding its chemical degradation behaviors is important for evaluation of intrinsic stability and degradation impurities. Herein, the degradation chemistry of solid etrasimod was systematically investigated under ICH-recommended stress conditions. Eight degradation products were detected by using reversed-phase HPLC, and three major products (DP-6, DP-4, and DP-2) was isolated and structurally elucidated by LC-MS combined with multidimensional NMR spectroscopy. DP-6 was assigned as an oxygenated lactone-containing degradation product, DP-4 as a ring-expanded dicarbonyl product, and DP-2 as an open-chain succinic acid derivative. Time-dependent transformation experiments demonstrated the conversion of DP-6 to DP-4 under oxidative conditions and DP-4 to DP-2 under alkaline conditions. These experimentally established transformation relationships, together with the structural information obtained for the major degradation products, support an interconnected degradation pathways involving oxidative transformation and subsequent alkaline hydrolysis. Overall, this study provides experimentally supported insights into the degradation chemistry and transformation relationships of etrasimod, which may facilitate the identification and monitoring of degradation impurities, the assessment of drug-substance stability, and the development of appropriate impurity control strategies during pharmaceutical development.