title: Hydrolysis of the quinone methide of butylated hydroxytoluene in aqueous solutions.
abstract: Butylated hydroxytoluene or BHT is an antioxidant commonly used in pharmaceutical formulations. BHT upon oxidation forms a quinone methide (QM). QM is a highly reactive electrophilic species that can undergo nucleophilic addition. Here, the kinetic reactivity of QM with water at various apparent pH values in a 50% (v/v) water-acetonitrile solution at constant ionic strength of I = 0.5 (NaCl)4 , was studied. The hydrolysis of QM in the presence of added acid, base, sodium chloride, and phosphate buffer resulted in the formation of only one product--the corresponding 3,5-di-tert-butyl-4-hydroxybenzyl alcohol (BA). The rate of BA formation was catalyzed by the addition of acid and base, but not chloride and phosphate species. Nucleophilic excipients, used in the pharmaceutical formulation, or nucleophilic groups on active pharmaceutical ingredient molecule may form adducts with QM, the immediate oxidative product of BHT degradation, thus having implications for drug product impurity profiles. Because of these considerations, BHT should be used with caution in formulations containing drugs or excipients capable of acting as nucleophiles.
authors.affiliation: Small Molecule Process and Product Development, Amgen Inc, South San Francisco, California, 94080.
authors.forename: Maren Gulsrud
authors.initials: MG
authors.lastname: Willcockson
authors.forename: Maria M
authors.initials: MM
authors.lastname: Toteva
authors.forename: Valentino J
authors.initials: VJ
authors.lastname: Stella
mesh_terms: D000097:Acetonitriles / Q000737:chemistry; D001592:Benzyl Alcohols / Q000737:chemistry; D002084:Butylated Hydroxytoluene / Q000737:chemistry*; D002626:Chemistry, Pharmaceutical / Q000379:methods; D005079:Excipients / Q000737:chemistry; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D045563:Indolequinones / Q000737:chemistry*; D007700:Kinetics; D012996:Solutions / Q000737:chemistry*; D014867:Water / Q000737:chemistry*
chemical_list: D000097:Acetonitriles; D001592:Benzyl Alcohols; D005079:Excipients; D045563:Indolequinones; D012996:Solutions; D014867:Water; C068040:quinone methide; C018966:4-hydroxybenzyl alcohol; D002084:Butylated Hydroxytoluene; C032159:acetonitrile
keywords: BHT; adduct; antioxidants; butylated hydroxytoluene; chemical stability; degradation products; hydrolysis; kinetics; quinone methide