Characterization of stress degradation products of bedaquiline fumarate and bedaquiline by LC-PDA and LC-MS

Abstract

Bedaquiline fumarate was a first-in-class diarylquinoline drug used for the treatment of M. tuberculosis and its main biologically active form was bedaquiline. This paper studied and compared the degradation products of bedaquiline fumarate and bedaquiline using LC-PDA, LC-MS, and NMR techniques under thermal, alkaline, acidic, oxidative, and photolytic conditions respectively. A LC method was established and optimized to separate all analytes of bedaquiline fumarate and bedaquiline. All degradation products were identified by LC-HRMS/MS and LC-MSⁿ. Bedaquiline fumarate formed three degradation products (DP1, DP2, and DP3) related to fumarate under photolytic condition and formed demethylation product DP4 under acid condition. Bedaquiline formed four degradation products (IM1, IM2, IM3, and IM4) related to the side chains of tertiary alcohol and tertiary amine groups under photolytic condition and formed DP4 under acid condition. The two compounds were stable under thermal, alkaline, and oxidative conditions. DP1 and DP2 indicate that the fumarate could take cis-trans isomerization under light condition. DP3, IM3 and IM4 were first reported degradation products of bedaquiline fumarate and bedaquiline. Compared the degradation behavior of bedaquiline fumarate with bedaquiline, the fumarate form can make the side chain of bedaquiline more stable. It is better to avoid acid and light contact during their storage and manufacturing process.

Keywords: Bedaquiline; Bedaquiline fumarate; Degradation products; LC-MS.