A STUDY OF THE RELATIONSHIP BETWEEN THE STRUCTURE AND PHYSICOCHEMICALPARAMETERS OF A HOMOLOGOUS SERIES OF OXPRENOLOL ESTERS AT VARIOUS PH VALUES AND TEMPERATURES

A number of beta-adrenergic blockers, including timolol and propranolo l, are administered in eyedrops for the treatment of glaucoma, but the ir therapeutic value is limited by a relatively high incidence of card iovascular and respiratory side effects. Because of poor ocular bioava ilability, many ocular drugs are applied in high concentrations, which give rise to both ocular and systemic side effects. Methods to increa se ocular bioavailability include (a) the development of drug delivery devices designed to release drugs at controlled rates, (b) the use of various vehicles that retard precorneal drug loss, and (c) the conver sion of drugs to biologically reversible derivatives (prodrugs) with i ncreased corneal penetration properties, from which the active drugs a re released by enzymatic hydrolysis. A homologous series of aliphatic esters of oxprenolol were synthesized and investigated as potential pr odrugs for ocular use. The stability of each O-acyl derivative was inv estigated in aqueous solutions over the pH range 2.2-9.0 at 37 degrees C. The observed rate constants (k(obs)), shelf-lives (t(90)), lipophi licities, and Arrhenius parameters were determined for each ester. A s tudy of the relationship between the structure and physicochemical par ameters of the homologous series of oxprenolol esters at various pH va lues and temperatures was made.