An unexpected degradation pathway of N-hydroxy-5-methylfuran-2-sulfonamide (BMS-986231), a pH sensitive prodrug of HNO, in a prototype formulation solution

•A metastable degradant of Cimlanod was isolated via LC-HRMS/MS guided synthesis.•Structure elucidation of the degradant was conducted via single crystal X-ray crystallography.•Plausible degradation pathways of Cimlanod in the prototype formulation solution under stressed conditions were proposed. N-hydroxy-5-methylfuran-2-sulfonamide (BMS-986231, Cimlanod) was being developed as a pH-sensitive prodrug of HNO (nitroxyl) for the treatment of acute decompensated heart failure. During a stressed study of Cimlanod in a prototype formulation solution (pH 4.5) at 40°C, a predominant unknown degradant along with three previously identified degradants were observed. The unknown degradant was isolated from the stressed solution via preparative HPLC but totally decomposed during freeze-drying. LC-HRMS analysis of the isolated unknown degradant, prior to freeze-drying, revealed an empirical formula equivalent to the adduct of Cimlanod with SO2 even though SO2 was not added in the prototype formulation solution. The unknown degradant was synthesized from Cimlanod and DABSO ((1,4-diazabiscyclo[2,2,2]octane bis(sulfur dioxide) adduct) and isolated as a crystalline DABCO (1,4-diazabiscyclo[2,2,2]octane) salt for single crystal X-ray structure elucidation. The degradation of Cimlanod increased when the solution was exposed to air, as compared to N2 atmosphere. A plausible mechanism was postulated for the unexpected degradation pathway of Cimlanod. This study provided in-depth stability knowledge of Cimlanod, which will be beneficial to the subsequent stability indicating method development and validation as well as the registrational applications on the content and qualification of impurities in new drug products.