Acetaminophen Prodrugs III: Hydrolysis of Carbonate and Carboxylic Acid Esters in Aqueous Buffers

The hydrolysis rates of four carbonate and five carboxylic acid ester prodrugs of acetaminophen were determined in aqueous buffers at various pH's.The hydrolysis reactions of all the compounds except the hemisuccinate were first order in ester and in hydroxyl ion over the relatively alkaline pH ranges studied.The apparent enthalpies of activation were between 18 and 23 kcal./ mole.The results suggest that it should be possible to formulate pharmaceutically stable suspensions of this type of acetaminophen prodrugs.