SOME RELATIONSHIPS BETWEEN THE PHYSICAL-PROPERTIES OF VARIOUS 3-ACYLOXYMETHYL PRODRUGS OF PHENYTOIN TO STRUCTURE - POTENTIAL IN-VIVO PERFORMANCE IMPLICATIONS

Physicochemical properties of neutral N-acyloxyalkyl derivatives of ph enytoin in aqueous, organic solvents and simulated intestinal fluid we re evaluated. Based on the hypothesis that these low melting prodrugs may have improved physical properties such as solubility and dissoluti on rate in gastrointestinal fluid, an enhanced bioavailability of thes e prodrugs may be observed relative to phenytoin. Melting points, aque ous solubilities, and octanol-water (P-oct) and cylcohexane-water (P-c yc) partition coefficients of phenytoin and its prodrugs were determin ed. A simulated intestinal bile salts-lecithin mixture (SIBLM) was als o prepared to possibly mimic the intestinal fluid content. Solubility and dissolution rates of phenytoin and its prodrugs were conducted in aqueous buffer and SIBLM. Apparent micelle-water partition coefficient s (K-app) were calculated by using the aqueous and SIBLM equilibrium s olubility data, These properties were qualitatively or quantitatively correlated to the alkyl chain length of the prodrugs. The melting poin ts and aqueous solubilities of all the prodrugs were lower than that o f the parent compound, phenytoin. The apparent micelle-water partition coefficient increased with an increase in chain length but unlike the octanol-water and cyclohexane-water partition coefficients the relati onship was complex. There was a disproportionate increase in the inter action between the micelle and the prodrug with the prodrugs with alky l groups larger than four carbons. In SIBLM, the solubilities and diss olution rates were increased to a greater extent for the prodrugs than that for phenytoin. The implications are that the bioavailability of phenytoin from these prodrugs may be comparable to or higher than that of phenytoin despite having lower aqueous solubilities, especially af ter a meal inducing bile flow.