Structure and generation mechanism of a novel degradation product formed by oxidatively induced coupling of miconazole nitrate with butylated hydroxytoluene in a topical ointment studied by HPLC-ESI-MS and organic synthesis.

In a petrolatum based topical ointment formulation containing miconazole nitrate (1) as the active ingredient and 2,6-di-t-butyl-4-methylphenol (BHT) as a vehicle antioxidant, an oxidatively induced coupling reaction between miconazole nitrate and BHT occurred to form a novel adduct 1-(3,5-di-tert-butyl-4-hydroxy-benzyl)-3-[2-(2,4-dichloro-benzyloxy)-2-(2,4-dichloro-phenyl)-ethyl]-3H-imidazol-1-ium nitrate (2). The structure of 2 was established using high-performance liquid chromatography coupled with electrospray ionization mass spectrometry and was confirmed by comparing with a synthesized reference compound. The reaction proceeded through a quinone methide intermediate from BHT. Two synthetic methods were established for preparing 2. © 2004 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 93:300–309, 2004