Baclofen ester and carbamate prodrug candidates: a simultaneous chromatographic assay, resolution optimized with DryLab

Abstract

Baclofen exhibits insufficient CNS-availability when dosed systemically. Hence, prodrug candidates (methyl, ethyl, 1-propyl, 2-propyl and butyl 4-(tert-butoxycarbonyl amino)-3-(4-chlorophenyl) butanoate) were synthesized aiming at CNS-levels appropriate for the treatment of spastic disorders. The characterization of some biopharmaceutically highly relevant physicochemical properties (LogP and aqueous solubility) and the evaluation of biophase levels represent one important component of the project. The overall research aim was to generate an HPLC optimized method using DryLab, a simulation software for the optimization of a RP-HPLC method, which was optimized using a simulation software (DryLab), for the simultaneous determination of baclofen and ten synthesized prodrug candidates. The chromatographic resolution predicted and obtained via the simulation is Rs >1.5 for all baclofen derivatives, as well as, with parent baclofen. The method was used to assay the prodrugs and determine their purities, solubility and lipophilicity parameters. The designed analytical method also permits the tracking of the new prodrug candidates' hydrolysis in vitro and in vivo. The determined physicochemical properties indicate for some of the compounds that they might be suitable for CNS-targeting which was exemplified by the detection of significant baclofen levels in rat brain tissues following an i.p. dose of ethyl carbamate (vs. ethyl ester, for which only traces of baclofen were detected).