Coamorphous systems of rebamipide: Selection of amino acid coformers based on protein-ligand docking, in vitro assessment and study of interactions by computational and multivariate analysis.

Three coamorphous systems of Rebamipide (REB) with the amino acids namely, Tryptophan (TRP), Phenylalanine (PHE) and Arginine (ARG) are reported. A unique approach for the virtual screening of amino acid coformers is presented by employing molecular docking studies based on interactions of the drug molecule with various amino acid fragments in the drug-receptor cocrystal structure. Successful formation of stable coamorphous systems with ARG, TRP and PHE served as the proof-of-concept along with negative benchmarking standards Histidine and Aspartic acid, wherein coamorphous systems could not be obtained despite multiple trials which resulted in crystalline physical mixtures. The coamorphous systems were characterized by a halo pattern in Powder XRD and a single glass transition temperature (Tg) in modulated DSC. Physical stability assessments of the coamorphous systems showed direct correlation of Tg with the observed stability of the amorphous phase which was found in the order ARGREB > TRPREB ≥ PHEREB. To determine the specific functional groups engaged in the interactions, multivariate analysis was performed on the FTIR spectra. These interactions were further validated by DFT and QTAIM analysis, which revealed key noncovalent interactions in the three coamorphous systems. All three coamorphous systems showed excellent release profiles of the API as demonstrated by the f2 and DE parameters in the order ARGREB ≥ TRPREB > PHEREB ≥ amorphous drug, far exceeding that of the crystalline drug. The interplay of multivariate analysis and QTAIM can be useful in estimating the interactions within the coamorphous systems which can further contribute to stability and physicochemical properties of the systems.