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.
Zhang
Fa
F
Johnson & Johnson CPWW, Drug Development R&D Support, Skillman, NJ 08558-9418, USA. fzhang1@cpcus.jnj.com
Nunes
Mathews
M
D000935:Antifungal Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics*; D000975:Antioxidants / Q000737:chemistry*; D002084:Butylated Hydroxytoluene / Q000737:chemistry*; D002851:Chromatography, High Pressure Liquid; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D008825:Miconazole / Q000138:chemical synthesis* / Q000493:pharmacokinetics*; D009824:Ointments; D010084:Oxidation-Reduction; D021241:Spectrometry, Mass, Electrospray Ionization; D013056:Spectrophotometry, Ultraviolet
D000935:Antifungal Agents; D000975:Antioxidants; D007202:Indicators and Reagents; D009824:Ointments; D002084:Butylated Hydroxytoluene; D008825:Miconazole