Degradation mechanism of nefopam in solution under stressed storage conditions

Nefopam, in pH 2.0 and pH 9.0 solutions, was forcibly degraded at 90 +/- 0.2 degrees C for 60 days. At least eight degradation products from the above solutions were collected from a reverse-phase high performance liquid chromatographic (HPLC) system with a C18 semipreparative column. Some minor peaks were considered insignificant, and no attempt was made to collect and identify their structures. The collected eluents under each major peak were further purified by extraction with methylene chloride from alkaline solutions. Proton nuclear magnetic resonance and fast atom bombardment mass spectroscopy were used to characterize the chemical properties of these degradates. The chemical structures of the major degradation products were proposed as (B) or (C) 2,3-dihydro-2(2'-hydroxyethyl)-N-methyl-1-phenyl-isoindole; (D) or (E) 1-hydroxy-3,4,5,6-tetrahydro-5-methyl-1-phenyl-1H-2,5-benzoxazocine++ +; (F) 2-(N-(2-hydroxyethyl)-N-methylaminomethyl) benzhydrol; (G) 2-(N-(2-hydroxyethyl)-N-methylaminoethyl) benzophenone; (H) 1-hydroxy-3,4,5,6-tetrahydro-5-methyl-1-phenyl-1H-2,5-benzoxazocine++ +, where B and C, D and E, are diasteromers. The possible pathways by which the nefopam degradation proceeded in acidic and basic solutions is postulated as Schemes I and II, respectively. The initial ring-opening process at the site of ether linkage appears to be the rate-determining step of degradation in both acidic and basic solutions.