Micellar Effects upon the Alkaline Hydrolysis of Acetaminophen Prodrugs: Carboxylic and Carbonic Acid Esters

Abstract

The rates of alkaline hydrolysis for four carboxylate esters (4-acetaminophenyl acetate, 4-acetaminophenyl butyrate, 4-acetaminophenyl heptanoate and 4-acetaminophenyl benzoate) and three carbonate ester (4-acetaminophenyl methylcarbonate, 4-acetaminophenyl ethylcarbonates and 4-acetaminophenyl propylcarbonates) prodrugs of acetaminophen derivatives were determined in aqueous and micellar media. The cationic micelles of cetyltrimethylammonium bromide (CTABr) and cetyltrimethylammonium sulfate [(CTA)2SO4] catalyzed the rate of the reaction. The anionic sodium dodecyl sulphate (SDS) and non-ionic Brij-35 surfactants inhibited the rate of the reaction. Added salt did not influence the rate of the reaction in the aqueous medium but decreased the values of observed rate constant in the micellar media. The rate enhancement in cationic micelles was treated by applying the pseudophase ion exchange model while the inhibition effect on the rate of hydrolysis was described using the Poisson–Boltzman pseudophase model. The binding constant (K s ) for the acetaminophen derivatives increased with increasing hydrocarbon chain length while the values of micellar rate constant (k m ) decreased with the increase in chain length. The increase in values of K s and decrease in k m are ascribed to the hydrophobic interaction between the acetaminophen derivative and surfactant molecule and molecular orientation of the substrate in the micelles.