The first zwitterionic cocrystal of indomethacin with amino acid showing optimized physicochemical properties as well as accelerated absorption and slowed elimination in vivo
The first zwitterionic cocrystal of indomethacin (INC) with amino acid, INC-PL-H2O, where PL represents L-proline, was prepared and thoroughly characterized by single crystal and powder X-ray diffractions, TGA-DSC and IR analyses. The single crystal X-ray diffraction revealed that there is a two-dimensional hydrogen bonding network with the surfaces covered by hydrophobic groups in the cocrystal. The relevant pharmaceutical properties including solubility, permeability, and intrinsic dissolution rate in vitro, along with the in vivo pharmacokinetics were systematically studied. It has been found that the dissolubility and penetrability of INC from INC-PL-H2O cocrystal were both improved in comparison with pure INC, and the enhanced solubility was comparatively more obvious than that of its penetrability. These strengthened properties in vitro may mainly attributed to the advantageous natures of the zwitterionic PL and the cocrystal structure in which INC self-dimers has been broken, and these INC molecules are grafted upon the column type supermolecular motifs constructed by PL molecules. Interestingly, the increased in vitro properties of the cocrystal have converted to satisfactory in vivo pharmacokinetics, performing shorter peak time and longer retention time compared with INC per se. These results not only provided important scientific basis for PL in regulating properties in vitro and in vivo of drugs, but also taped into its potentials as an auxiliary agent to combine with NSAIDs in treatments of joint diseases.