Quantitative surface and Hirshfeld surface analysis of nicorandil molecule and further insight into its solubility in several aqueous protic and aprotic cosolvent solutions

The quantum-chemical quantities of highest negative surface electrostatic potential and lowest surface average local ionization energy as well as Hirshfeld surface were used herein to explain the electrostatic features of both basicity and acidity of nicorandil molecule. The primary electrophilic and nucleophilic sites are the-N@and > NH groups, respectively. According to the nicorandil solubility in solutions of isopropanol (1) + water (2), ethanol (1) + water (2), DMF (1) + water (2), and methanol (1) + water (2), preferential solvation of nicorandil was investigated using the famous inverse Kirkwood-Buff integrals approach. In poor water composition areas, nicorandil was surrounded preferentially by organic solvent, showing the selective solvation of nicorandil by methanol/DMF/ethanol/isopropanol. This performance was due to high basicity of organic solvents compared with water, which favors interactions with nicorandil's acidic groups. The Hansen solubility parameter was used to evaluate the performance of nicorandil solubility in depth. The derived dissolution Gibbs energy change, enthalpy and entropy indicated that the solubilization capacity improved with increasing methanol/DMF/ethanol/isopropanol compositions. As the proportions of methanol/DMF/ethanol/isopropanol rose, analysis of enthalpy- entropy compensation revealed a shift in main dissolving mechanism from enthalpy-driven to entropy-driven (alcohol solutions) or from entropy-driven to enthalpy-driven (DMF solutions). (c) 2022 Elsevier B.V. All rights reserved.

Automated summary

This study used quantum-chemical parameters to explain the electrostatic features of basicity and acidity in the nicorandil molecule. It was found that nicorandil exhibited better solubility in organic solvents compared to water, which can be attributed to the higher basicity of organic solvents, promoting interactions with the acidic groups of nicorandil.