Cocrystallization-Driven Double-Optimized Stratagem toward Directional Self-Assembly for the First Ternary Salt Cocrystal of Cardiotonic Drug Milrinone with Different Phenolic Acids Exhibits Optimal / Biopharmaceutical Peculiarities.

The current research leverages the structural features and property superiorities along with benefits in protecting cardiovascular system of gallic acid (GLC) and gentisic acid (HGA) to optimize / peculiarities of cardiotonic drug milrinone (MIL) through developing a stratagem of cocrystallization-driven double-optimized ternary salt cocrystal. This strategy assembles MIL ternary salt cocrystal by shaping a cocrystallization moiety relying on noncovalent interplays with GLC to obtain permeability advancement and molding a salt segment via the salification of proton transfer between HGA and MIL molecules to facilitate solubility enhancement. While the ameliorative properties further modulate the pharmacokinetic behaviors, thus fulfilling a dual optimization of MIL's biopharmaceutical characteristics on both and aspects. Along this line, the first MIL ternary salt cocrystal, viz., [HMIL-GA]-MIL-GLC-HO (denoted as MTSC hereinafter), has been satisfactorily constructed and precisely structurally identified by diversified techniques. The single-crystal X-ray diffraction experiment validates that a molecular salt [HMIL-GA] species cocrystallizes with one neutral MIL, two GLC, and five solvent water molecules, among which the organic constituents compose laminated hydrogen bond networks, and then are self-assembled by water molecules to a 3D supramolecular structure. The unique structural feature and stacking pattern of MTSC make both the permeability and solubility be respectively enhanced by 9.69 times and 5.17- to 6.03-fold compared with the parent drug . The experimental outcomes are powerfully supported by associated calculations based on density functional theory. Intriguingly, these optimal physicochemical natures of MTSC have been potently converted into strengths of pharmacokinetics, showcasing the elevated drug plasma concentration, elongated half-life, alongside advanced bioavailability. Consequently, this presentation not just contributes a brand-new crystalline form with utility values, but ushers in a new dimension of ternary salt cocrystals for improving / limitations of poor drug bioavailability.