An integrated experimental and theoretical research on ternary salt-cocrystal of anti-heart failure medicine milrinone with different substituted benzoic acids

For the sake of fully laying stress on the advantages of multi-component cocrystals in ameliorating limitations of poor pharmaceutical peculiarities, and further offering fresh insights for the application of salt-type cocrystals in the optimization of anti-heart failure medication milrinone (MIL), the present project exploits the structural characteristic and property preponderance of gallic acid (GLC) and 3,5-dinitrobenzoic acid (HBA) to design and assemble MIL ternary salt cocrystal via a combination tactic of cocrystallization and salification. This strategy organizes the ternary salt-cocrystal by fashioning a salt portion to foster solubility enhancement and shaping a cocrystal moiety to achieve permeability advancement. Following this thread, the MIL ternary salt-cocrystal, namely [HMIL+-BA−]-GLC-H2O (indicated as TSC there-in-after), is accurately authenticated by comprehensive characterization means. Single-crystal X-ray diffraction affirms that the asymmetric unit of TSC comprises a [HMIL+-BA−] salt, one neutral GLC molecule along with three water molecules, all of which build a three-dimensional hydrogen-bonding network containing electrostatic forces and π-π stacking interactions. Such unique structural feature and aggregation motif make MIL in TSC achieve a coinstantaneous elevation of 10.59 times in permeability and 4.76−5.15 folds in solubility versus the parent medicine itself at different physiological pH, which supports well agreement with the DFT-based theoretical investigations including reduced density gradient, molecular electrostatic potential surface, topology, Hirshfeld surface analysis, together with Gibbs free energy of solvation. All of these not only contribute a completely new cocrystalline model for MIL with synchronously optimizing dissolubility and permeability, but demonstrate the feasibility and effectiveness of ternary salt cocrystals in modifying the properties of anti-heart failure medicines.