Determination of the position of the ester bond in a micellar prodrug of phenytoin

Abstract

It was previously determined that the nearly 200-fold increase in the observed precipitation times of aqueous prodrug solutions of 3-( N, N-dimethylglycyloxymethyl)-5,5-diphenyl hydantoin methane sulphonate (DDMS) was a result of a decrease in the rate of hydrolysis of the prodrug as well as an increase in the solubility of phenytoin in the presence of DDMS. The formation of a series of associative species by the prodrug are probably responsible for the changes observed in solubility and the rate of hydrolysis. Final proof of the presence of micellar prodrug species was obtained with NMR studies. The major upfield shift shown by the protons of the phenyl groups substantiated the hypothesis that the hydrophobic groups of the prodrug molecules formed the hydrophobic core of the micelles, which enabled the inclusion of the phenytoin, which is hydrophobic, and thereby causes the phenytoin to be solubilized. The NMR results also showed that the labile ester binding of the prodrug was submerged into the micelle which could explain the decrease in the rate of hydrolysis of the prodrug that was previously reported.