Morpholinoalkyl Ester Prodrugs of Diclofenac: Synthesis, In Vitro and In Vivo Evaluation

Morpholinoalkyl esters (HCI salts) of diclofenac (1) were synthesized and evaluatedin vitroandin vivofor 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‐fold increase in solubility over the parent drug. All prodrugs were more lipophilic than1as indicated byn‐octanol/pH 7.4 buffer partition coefficients, but less lipophilic than1in terms ofn‐octanol/SGF partition coefficients. Potentiometrically determined ionization constants (pKas) were in the range of 7.52 to 8.40 at 25 °C. The chemical and enzymatic hydrolyses of prodrugs were evaluated in SGF/pH 7.4 phosphate buffer and rat plasma, respectively, at 37 °C. All prodrugs were quantitatively hydrolyzed to1by either chemical and/or enzymatic means. An increase in carbon chain length rendered the prodrugs more stable at pH 7.4, but less stable in SGF. In general, the esters were hydrolyzed rapidly in rat plasma at 37 °C, the half‐lives of hydrolysis being in the range of 4.85 to 23.49 min. Based onin vitroresults, prodrug2was chosen to evaluate solid‐state stability, bioavailability, andin vivoulcerogenicity. At elevated temperatures, the solid‐state decomposition of2followed biphasic kinetics, with rapid decomposition occurring initially. The extent, but not the rate, of absorption was significantly greater in rats for prodrug2than1following single dose oral administration. Prodrug2was significantly less irritating to gastric mucosa than1following single and chronic oral administration in rats.