Chemical delivery systems: evaluation of physicochemical properties and enzymatic stability of phenylephrone derivatives

The physicochemical properties and enzymatic stability of esters of phenylephrone, synthesized on the basis of the chemical delivery system (CDS) concept, were studied as a new class of mydriatic agents. Potentiometrically determined ionization constants (pKa) of the novel compounds were in the range 7.19-7.21. The three esters of phenylephrone (isovaleryl, phenylacetyl, and pivalyl) were more lipophilic than phenylephrone as indicated by n-octanol/pH 7.4 buffer partition coefficients (log Papp) and the chromatographic capacity factors (log k'). The chemical stability of the esters of phenylephrone was evaluated in hydrochloric acid, citrate, and phosphate buffers (with pH ranging between 2.0 and 8.0), and the enzymatic hydrolysis in rat and human plasma. The samples were analyzed using HPLC assay procedures. The phenylephrone esters were found to undergo comparatively slow hydrolytic degradation in buffer with pH 3.0 and 4.0, with half-lives ranging from 1136 to 1980 hr at 37 degrees C. The novel esters were readily hydrolyzed in human plasma with half-lives ranging between 16.2 and 47.8 min. The hydrolytic degradation rates were higher in rat plasma than in human plasma, in which the half-lives were in the range of 9.8-38.3 min. In the present investigations, only phenylephrone, not the active species phenylephrine, was detected. Among the esters studied, isovaleryl ester was the most labile. Pivalyl ester, having a tertiary carbon, showed relatively high resistance to chemical and enzymatic hydrolysis because of the steric hindrance, followed by phenyl and isovaleryl esters. The results suggest that the duration of action of the phenylephrone CDS can be controlled with proper chemical manipulations.