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Low-melting phenytoin prodrugs as alternative oral delivery modes for phenytoin: a model for other high-melting sparingly water-soluble drugs.

Phenytoin is a high-melting, weakly acidic, and sparingly water-soluble drug. Because of these physicochemical properties, phenytoin is subject to erratic bioavailability in a variety of dosage forms both in its acidic as well as sodium salt forms. A homologous series of 3-acyloxymethyl derivatives of phenytoin (acetyl through decanoyl) were synthesized and various physicochemical properties measured. The prodrugs were more readily soluble in various metabolizable glycerol esters such as tributyrin, trioctanoin, and triolein than phenytoin. The solubility of the prodrugs in the various organic vehicles studies was closely correlated to the melting point of the prodrug: the lower the melting point the greater the solubility. The cleavage rates of the prodrugs in plasma and tissue homogenates followed a parabolic relationship with chain length. The prodrug, 3-pentanoyloxymethyl-5,5-diphenylhydantoin when administered in tributyrin gave superior oral phenytoin bioavailability in rats when compared with sodium phenytoin administered as an aqueous solution.