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

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 center dot center dot center dot H and N center dot center dot center dot 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.(c) 2022 Elsevier B.V. All rights reserved.

Automated summary

This study employed molecular electrostatic potential surface and Hirshfeld surface analysis to investigate the charge distribution and inter/intra-molecular interactions of milrinone. The results showed that milrinone has a good solubility in ethanol/isopropanol/DMF + water solution, and exhibits preferential solvation by ethanol/isopropanol/DMF. The transfer and thermodynamic dissolution properties of milrinone were derived from the changes in entropy, enthalpy, and Gibbs free energy.