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 phenytoin in aqueous, organic solvents and simulated intestinal fluid were evaluated. Based on the hypothesis that these low melting prodrugs may have improved physical properties such as solubility and dissolution rate in gastrointestinal fluid, an enhanced bioavailability of these prodrugs may be observed relative to phenytoin. Melting points, aqueous solubilities, and octanol–water (Poct) and cylcohexane–water (Pcyc) partition coefficients of phenytoin and its prodrugs were determined. A simulated intestinal bile salts–lecithin mixture (SIBLM) was also 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 coefficients (Kapp) were calculated by using the aqueous and SIBLM equilibrium solubility data. These properties were qualitatively or quantitatively correlated to the alkyl chain length of the prodrugs. The melting points and aqueous solubilities of all the prodrugs were lower than that of 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 relationship was complex. There was a disproportionate increase in the interaction between the micelle and the prodrug with the prodrugs with alkyl groups larger than four carbons. In SIBLM, the solubilities and dissolution 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 solubilties, especially after a meal inducing bile flow.