The dissolution mechanism, molecular dynamics simulation and thermodynamic analysis of nirmatrelvir (treatment of COVID-19) in aqueous ethanol mixtures

Abstract

This research investigates the cosolvent effect of nirmatrelvir (treatment of COVID-19) in ethanol + water mixtures. The result shows that the maximum solubility in mole fraction is 8.313 × 10−2 at the ethanol mass fraction of 80%, which is greater than that in pure water. The solvent effect analysis indicates that the hydrogen bond acidity (HBA) of solvent has the greatest impact on the solubility of nirmatrelvir solubility. The negative preferential solvation values in water-rich regions indicate that nirmatrelvir molecules are preferentially solvated by water molecules. With the rising mass fraction of cosolvent, ethanol disrupts the ordered structure of water molecules in solution through hydrogen bonding, allowing nirmatrelvir molecules to be preferentially solvated by ethanol. Nonetheless, nirmatrelvir molecules are preferentially solvated by water again in ethanol-rich regions. Through molecular dynamics calculations (MD), it could be found that the dissolution behavior is consistent with its calculated by solvation free energy calculation. Furthermore, the tall and sharp peak of the RDF plots of O···H-O (ethanol/water) and N-H···O (ethanol/water) were attained at 1.50–2.50 Å, indicating that ethanol and water molecules form a regular and definite coordination sphere around the nirmatrelvir moiety at the distance of 1.50–2.50 Å through hydrogen bonding form. Additionally, the correlation fitting was performed for the solubility data through the Jouyban-Acree model and its derivative models. Moreover, “Apparent thermodynamic analysis” of nirmatrelvir dissolution process in aqueous ethanol mixtures including entropy, enthalpy and Gibbs free energy were completed.