WATER-SOLUBLE AMINOALKYLBENZOATE ESTERS OF PHENOLS AS PRODRUGS - SYNTHESIS, ENZYMATIC-HYDROLYSIS AND CHEMICAL-STABILITY OF PARACETAMOL ESTERS

Various aminoalkylbenzoate esters of paracetamol and phenol were synthesized and evaluated as water-soluble prodrugs with the aim of developing solution-stable formulations of phenolic drugs suitable for e.g. parenteral or ocular administration. The esters studied comprised 2-, 3- and 4-N-substituted amino-methylbenzoate esters as well as an unsubstituted 4-aminomethylbenzoate and a 4-aminoethylbenzoate ester. Except for the 2-aminomethylbenzoate ester, all esters were hydrolyzed enzymatically by human plasma although with rates depending on the structure of the amino group and its position relative to the ester moiety. The pH-rate profiles for the hydrolysis of the esters were obtained at 60-degrees-C. Maximal stability occurred around pH 4. The N-substituted 2-aminomethylbenzoate ester was shown to be much more unstable than analogous 3- and 4-aminomethylbenzoate esters at pH 5-8, which was ascribed to the occurrence of intramolecular catalysis of ester hydrolysis by the neighbouring aminomethyl group. From temperature-accelerated studies, shelf-lives of aqueous solutions (pH 4.0) of the 3- or 4-aminomethylbenzoate esters of paracetamol were predicted to be 2-4 months at 5-degrees-C, which are markedly higher than that predicted (43 h) for the N,N-diethylglycine ester of paracetamol, a recently introduced paracetamol prodrug.