Sodium Salts and Solvate of Rebamipide: Synthesis, Structure, and Pharmacokinetic Study

Two sodium salts (Na(CH3CH2OH) (HReb) (1) and Na2(H2O)4(Reb) (2)), one methanol solvate (H2Reb·CH3OH (3)), and one methyl ester (4) of the minimally soluble drug, rebamipide (H2Reb), used for the treatment of gastric ulcers and gastritis have been synthesized. For the first time the structure of rebamipide has been determined by single crystal X-ray diffraction. Although salts 1 and 2 were prepared under the similar conditions, their structures are different. In 1, rebamipide loses the proton of the carboxyl group to interact with the sodium ion, but in 2 the drug molecule converts to its prototropic tautomer and then simultaneously loses the protons of the carboxyl and hydroxyl groups to form salt. Control experiments show that reaction temperature is the key factor influencing the formation of salts. Although all methanol was used in the synthesis of 3 and 4, in 3 methanol acts as solvent involved in the lattice, while in 4 it reacts with rebamipide to form ester. By analyzing the mass spectra of the re...