Oxidative Degradation of a Sulfonamide-Containing 5,6-Dihydro-4-Hydroxy-2-Pyrone in Aqueous/Organic Cosolvent Mixtures

Purpose. To predict the oxidative stability of a sulfonamide-containing 5,6-dihydro-4-hydroxy-2-pyrone in lipid-based delivery systems, N-(3-{1[(3,6R)-4-hydroxy-2-oxo-6-phenyl-6-propyltetrahydro-2H-pyran-3-yl]propyl}phenyl)-5-(trifluoromethyl)-2-pyridinylsulfonamide (DHP) was oxidized by peroxides and peroxyl radicals in binary mixtures of water and organic cosolvents.Methods. DHP was oxidized by hydrogen peroxide, t-butylhydroperoxide, or peroxyl radicals derived from the thermal decomposition of 2,2-azobis(2-amidinopropane) dihydrochloride (AAPH) in 40% (v/v) organic cosolvent and 5 mM buffer at or near 40°C. Interactions between DHP and ]propane sulfonic acid and imidazole) and DH^– were assessed by ¹H-NMR spectroscopy. The formation of CO likely involves a free radical mechanism.Results. The reaction of DHP with peroxides in 40% (v/v) acetonitrile yields epimeric monohydroxylation products, R-OH and S-OH, at C-3 of the pyrone ring, and a keto-derivative (CO). Hydroxylation rates depend on the protonation state of DHP, and the nature of buffer and the organic cosolvent. Organonitriles accelerate the oxidation through formation of peroxycarboximidic acid. Peroxyl radicals do not yield significant amounts of R/S-OH or CO.Conclusions. The hydrogen peroxide-induced degradation of DHP in the presence of acetonitrile involves two reactions, hydroxylation and carbonyl formatin. Hydroxylation proceeds via nucleophilic attack by the monodeprotonated form of DHP (DH^–) on peroxycarboximidic acid. The oxidation rate is slowed by ion pairing between nitrogen-containing buffers ([3-N-morpholino]propane sulfonic acid and imidazole) and DH^–. The formation of CO likely involves a free radical mechanism.