Structure Elucidation and Mechanistic Study of a New Dimeric Degradant in Ropinirole Hydrochloride Extended-Release Tablets

Purpose The goal of the study was to elucidate the structure of a new degradant (1,3′-Dimer), generated in the stability testing of ropinirole extended-release tablets, and the formation mechanism of 1,3′-Dimer and its isomer (3,3′-Dimer). Methods The strategy of combining LC-PDA/UV-MS n ( n = 1, 2) and NMR in conjunction with mechanism-based forced degradation study was employed to identify the structure of the unknown degradant and the formation mechanism of this dimeric degradant as well as its isomer, 3,3′-Dimer. The forced degradation was conducted by treating ropinirole API with formaldehyde under alkaline catalysis. A compatibility study between ropinirole and lactose was also performed. Results The degradant was isolated from the forced degradation sample and characterized by LC-PDA/UV-MS n as well as NMR measurement. The impurity was identified as a new dimeric degradant of ropinirole connected by a methylene bridge via the 1- and 3′-position of each ropinirole unit (i.e., 1,3′-Dimer of ropinirole), which is an isomer of a known dimeric degradant of ropinirole, namely 3,3′-Dimer. Conclusions The newly occurred unknown degradant in ropinirole extended-release tablets was elucidated as the methylene-bridged 1,3′-Dimer of ropinirole. Based on the mechanistic study, 1,3′-Dimer and its isomer (3,3′-Dimer) were both formed by the reaction of ropinirole with residual formaldehyde present or formed in lactose, a main excipient of the formulation.