Reactivity of the Quinone Methide of Butylated hydroxytoluene in Solution

Abstract

BHT is a common antioxidant in pharmaceutical formulations and when oxidized it forms a quinone methide (QM). QM is a highly reactive electrophilic species which can undergo nucleophilic addition. This research investigated the kinetic reactivity of QM with water at various pH values and in the presence of sodium chloride and phosphate, acetate, and TAPS buffers. The presence of HCl, HClO4, NaOH, NaCl, and phosphate buffers resulted in simple first order kinetics for disappearance of QM and the formation of a single product (OH-adduct); the reaction was subject to strong acid/base catalysis. The presence of acetate and TAPS buffers resulted in complicated kinetics suggesting the formation of an additional product in equilibrium with QM. These results indicate adduct formation with other nucleophilic excipients is likely which has implications for both the drug product impurity profile and specifications. Due to these considerations BHT should be used with caution.