MORPHOLINOALKYL ESTER PRODRUGS OF DICLOFENAC - SYNTHESIS, IN-VITRO AND IN-VIVO EVALUATION

Morpholinoalkyl esters (HCI salts) of diclofenac (1) were synthesized and evaluated in vitro and in vivo for their potential use as prodrugs for oral delivery. Prodrugs were freely soluble in simulated gastric fluid (SGF) and pH 7.4 phosphate buffer and showed a minimum of a 2000 -foId increase in solubility over the parent drug. All prodrugs were m ore lipophilic than 1 as indicated by n-octanol/pH 7.4 buffer partitio n coefficients, but less lipophilic than 1 in terms of n-octanol/ SGF partition coefficients. Potentiometrically determined ionization const ants (pK(a)s) were in the range of 7.52 to 8.40 at 25 degrees C. The c hemical and enzymatic hydrolyses of prodrugs were evaluated in SGF/pH 7.4 phosphate buffer and rat plasma, respectively, at 37 degrees C. Al l prodrugs were quantitatively hydrolyzed to 1 by either chemical and/ or enzymatic means. An increase in carbon chain length rendered the pr odrugs more stable at pH 7.4, but less stable in SGF. In general, the esters were hydrolyzed rapidly in rat plasma at 37 degrees C, the half -lives of hydrolysis being in the range of 4.85 to 23.49 min. Based on in vitro results, prodrug 2 was chosen to evaluate solid-state stabil ity, bioavailability, and in vivo ulcerogenicity. At elevated temperat ures, the solid-state decomposition of 2 followed biphasic kinetics, w ith rapid decomposition occurring initially. The extent, but not the r ate, of absorption was significantly greater in rats for prodrug 2 tha n 1 following single dose oral administration. Prodrug 2 was significa ntly less irritating to gastric mucosa than 1 following single and chr onic oral administration in rats.