Studies on the oxidative degradation of fluphenazine decanoate in oily solution
Oxidation of fluphenazine decanoate, a member of the neuroleptic phenothiazine drugs, is believed to occur in oily solution via the hydroperoxides formed as a result of autoxidation of the oil. Synthesis and characterisation of the expected oxidation products of the drug was undertaken so that the formation of these degradation products in oily solution, could be accurately determined. By this means the rate of oxidation of fluphenazine decanoate by various hydroperoxides was determined. Only in the case of the C-IB unsaturated fatty esters did the overall oxidation process obey simple kinetics (2nd order) enabling values for the respective rate-constants to be calculated. The presence of acid was clearly demonstrated to catalyse oxidation of the tertiary amine centres in the molecule, a finding contrary to reports in the literature. In addition, the catalytic effect was shown to be related to the pKa value of the acid. Benzyl alcohol is commonly added as a preservative to oily formulations and thus the effect of this material on the rate of fluphenazine decanoate oxidation was investigated. Evidence for the enhanced oxidation of the drug in the presence of benzyl alcohol in a naturally ageing formulation was obtained and a plausible mechanism for this phenomenon was sought. Autoxidation of the benzyl alcohol was deemed a likely explanation and since little information on this aspect of benzyl alcohol chemistry could be found in the literature an extensive study of benzyl alcohol autoxidation was conducted. It was finally concluded that autoxidation of benzyl alcohol leads directly to hydrogen peroxide offering one viable explanation of the enhanced degradation of the drug observed in the presence of the preservative.