Phenytoin prodrugs IV: Hydrolysis of various 3-(hydroxymethyl)phenytoin esters.

The aqueous chemical stability of various bioreversible derivatives or prodrugs of phenytoin, a poorly water-soluble and erratically absorbed drug after both oral and intramuscular parenteral dosing, were evaluated. This study, together with assessments of other physiochemical properties including cleavage in the presence of various animal tissues and anticonvulsant activity in mice, helped identify a number of promising candidate prodrugs. Various amino groups containing acyl esters of 3-(hydroxymethyl)phenytoin [3-(hydroxymethyl)-5,5-diphenylhydantoin] were identified as potential orally and perhaps parenterally useful prodrugs, while the disodium phosphate ester of 3-(hydroxymethyl)phenytoin appears to be ideally suited as a parenteral form of phenytoin.