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 reaction solution, we speculate that the crystallization of 3 and 4 is controlled by the products solubility. Dissolution studies indicate that both the maximum solubility and dissolution rate of 1-4 in simulated succus gastricus are improved. Furthermore, pharmacokinetic behavior of compounds 1-4 was investigated in rats and the results indicate that the bioavailability of 1, 3, and 4 upon oral administration is enhanced compared to that of API.