Engineering a Remedy to Modulate and Optimize Biopharmaceutical Properties of Rebamipide by Synthesizing New Cocrystal: In Silico and Experimental Studies

Purpose Rebamipide (REB) a potent anti-ulcer agent, has not been exploited to its full potential, owing to it extremely poor solubility, leading to highly diminutive bioavailability (<10%). The purpose is to carry out its solid-state modification. Method Cocrystallisation was done with three GRAS coformers namely citric acid (CA), 3,4-dihydroxybenzoic acid (DHBA) and oxalic acid (OXA) employing the liquid-assisted grinding method. Cocrystal formation was based upon amide-carboxyl and amide-hydroxyl supramolecular synthons. Characterization of novel cocrystals i.e. RCA, RDHBA and ROXA was carried out by DSC, PXRD and additionally by FT-IR spectroscopy. Chemical structures have been determined utilizing the PXRD pattern by Material Studio (R). Furthermore, cocrystals were subjected to solubility and intrinsic dissolution rate (IDR) evaluation. Also, pharmacodynamic and pharmacokinetic studies were performed and compared with pure rebamipide. Result The appearances of a single sharp melting endotherm in DSC, along with novel characteristic peaks in PXRD infer the existence of a new crystalline form. Shifting in characteristic vibrations in FT-IR spectroscopy supports the establishment of distinct hydrogen-bonded networks. Structural determination revealed that RCA crystallizes in 'Bb2b' space groups whereas RDHBA in 'P1' and ROXA crystallize out in the 'P-1' space group. All the cocrystals exhibited superior apparent solubility and almost 7-13 folds increase in IDR. Furthermore, 1.6-2.5 folds enhancement in relative bioavailability and remarkable amplification in anti-ulcer, anti-inflammatory and the antioxidant potential of these cocrystals were observed. Conclusion The study ascertains the advantages of cocrystallization, with RCA showing greatest potential and suggests a viable alternative approach for improved formulation of rebamipide.

Automated summary

This study successfully enhanced the solubility, intrinsic dissolution rate, and bioavailability of rebamipide through cocrystallization modification, leading to significant improvements in its anti-ulcer, anti-inflammatory, and antioxidant potentials.