Milrinone solubility in aqueous cosolvent solutions revisited: Inter/intra-molecular interactions, enthalpy-entropy compensation, and preferential solvation

Abstract

• Intermolecular interactions and charge distribution of milrinone were studied by MEPS and HS analysis. • Solvent effect was studied via linear solvation energy relationships. • Preferential solvation were investigated via inverse Kirkwood–Buff integrals method. • Transfer and dissolution properties together with enthalpy-entropy compensation was studied. Analysis of molecular electrostatic potential surface and Hirshfeld surface were severally employed here to probe into the overall charge distribution and inter/intra-molecular interactions of milrinone. H···H and N···H contacts predominate among all contact interactions and milrinone has powerful ability of hydrogen-bonding donor and acceptor. The solubility profile of milrinone was additionally illustrated by means of three-dimensional Hansen solubility parameters. The mole fraction solubility at 298.15 K in ethanol/ethylene glycol(EG)/isopropanol/ N , N -dimethylformamide(DMF) + water was inspected in the light of molecular interactions via the well-known linear solvation energy relationships. The solubility parameter, dipolarity-polarizability and hydrogen-bonding acidity of systems presented dominant contributions to the solubility variation. The inverse Kirkwood–Buff integrals was applied to probe the local compositions of milrinone in the aqueous solutions of co-solvent. Regarding the aqueous ethanol/isopropanol/DMF solutions within middle and ethanol/isopropanol/DMF-rich mole fractions, preferential solvation of milrinone by ethanol/isopropanol/DMF was observed. Milrinone was not solvated favorably by EG molecule in above regions. The transfer and thermodynamic dissolution properties including entropy, enthalpy and Gibbs free energy change were derived. Moreover, the analysis of enthalpy-entropy compensation was carried out, stating that the milrinone solubility variation in solutions was controlled by two mechanisms, enthalpy-driven and entropy-driven.