Non covalent derivatives of selective antiulcer agents using crystal engineering in silico and experimental approach

Abstract

The present work demonstrates the utility of non-covalent derivatization in fine- tuning the biopharmaceutical parameters of three antiulcer agents Rebamipide (REB), famotidine (FMT) and mesalamine (MES). These have not been exploited to their full potential, owing to their extremely poor solubility, leading to highly diminutive bioavailability. The purpose was to carry out their solid-state modification by generating cocrystals with optimized physicochemical properties. Coformers with complementary functional groups, after evaluation of synthon propensity, generated three novel cocrystals of Rebamipide, two cocrystals of Famotidine and three cocrystals of Mesalamine. These cocrystals were characterised, using DSC and HSM. The distinct melting endotherms in DSC, visually observed by HSM, indicated the possible formation of new cocrystalline-phase. Substantiation of cocrystals formation was however provided by signature peaks in PXRD pattern. Moreover, shifting of characteristic frequencies in FTIR infer the presence of intermolecular hydrogen bonding. Structural determination carried out, revealed the participation of amidic and carbonyl functionalities in the formation of supramolecular motifs. Further, the study covered the evaluation of the successful translation of the cocrystal formation to improved physicochemical parameters. This was followed by optimized pharmacokinetic parameters with enhanced antioxidant, antiulcer and anti- inflammatory activity of cocrystals as compared to their respective pure drugs. All the cocrystals had a 6-12-fold increase in apparent solubility, which was mirrored by increase in the IDRs (5-13 folds). This can be accredited to the presence of hydrophilic coformers and formation of new crystalline lattice. This summarise that the development of the cocrystals bestows an alternative approach for solid-dosage- form modifications. newline