Reversible immobilization of drugs on a hydrogel matrix, 3. Hydrolysis of chloramphenicol precursors

Abstract

AbstractKinetics of hydrolytic release of chloramphenicol (1) chemically immobilized on HEMA‐based ophthalmic hydrogels were examined. The rate constants of hydrolysis of the phenolic ester and acetal bonds of the spacer immobilizing the drug were determined at 37°C, and essentially at neutral pH, for the monomeric drug, the soluble copolymers and the cross‐linked hydrogels, respectively. A drastic decrease in reactivity of the ester bond was observed from the small monomeric molecule to the soluble chains and then to the swollen network (relative reactivities ≈ 1300/25/1), whereas the acetal bond is less reactive, with a rate constant apparently independent of the size of the carrier. It is suggested that in all cases the ester bond is cleaved at first, liberating a drug bearing acetal intermediate which is then slowly hydrolysed to free chloramphenicol. All reactions were observed to be first order with respect to the hydrolysable precursor. When the rate constants are low enough, which is the case when considering the hydrogels, a pseudo‐zero order is obtained and the release rate of chloramphenicol is constant over a long period of time and depends only on the initial concentration of immobilized, drug. Nevertheless, the too slow acetal hydrolysis in neutral physiological conditions limits the daily delivery to a few micrograms for a standard corneal lens with a 5 mol‐% drug loading.