The first zwitterionic cocrystal of indomethacin with amino acid showing optimized physicochemical properties as well as accelerated absorption and slowed elimination in vivo

Abstract

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 diffraction and TGA–DSC and IR analyses. Single crystal X-ray diffraction revealed that there is a two-dimensional hydrogen bonding network with the surfaces being 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 the INC–PL-H₂O cocrystal were both improved in comparison with pure INC, and the enhanced solubility was comparatively more obvious than its penetrability. These strengthened properties in vitro may mainly be attributed to the advantageous nature of the zwitterionic PL and the cocrystal structure in which INC self-dimers have been broken, and these INC molecules are grafted upon the column type supermolecular motifs constructed from PL molecules. Interestingly, the increased in vitro properties of the cocrystal have converted to satisfactory in vivo pharmacokinetics, showing a shorter peak time and a longer retention time compared with INC per se. These results not only provided an important scientific basis for PL in regulating properties in vitro and in vivo of drugs, but also tapped into its potential as an auxiliary agent to combine with NSAIDs in the treatment of joint diseases.