Inter-/intra-molecular interactions, preferential solvation, and dissolution and transfer property for tirofiban in aqueous co-solvent mixtures

Using Hirshfeld surface, interaction region indicator and quantitative molecular surface analysis, the microscopic electrostatic features of basicity and acidity of the tirofiban molecule were clearly demonstrated. Both the O atoms in >SO2 and H atom in -COOH serve as primary electrophilic site and nucleophilic site, respectively. Utilizing solubility data for tirofiban in four different water-based co-solvent mixtures {isopropanol/ethylene glycol (EG)/methanol/ethanol (1) + water (2)}, the inverse Kirkwood-Buff integral method was utilized to determine the preferred solvent for the tirofiban solvation according to the results of preferential solvation analysis. In water-rich composition ranges, the drug is surrounded by water, whereas in isopropanol/methanol/ethanol-intermediate and -rich composition ranges, the drug is surrounded by ethanol/methanol/isopropanol. Isopropanol solutions had the largest magnitude of preferential solvation. Alcohols may have a greater basicity that enhances interactions with the Lewis acidic function groups of tirofiban, giving rise to selective solvation of this drug. The linear solvation energy relationships were used to determine the relative impact of solvent-solvent and solvent-solute interactions in determining the variation of solubility magnitudes. The properties of dissolution and transfer, such as entropy, enthalpy and Gibbs energy change were computed. Entropy-driven and enthalpy-driven mechanisms were shown to be responsible for the change in tirofiban solubility in the four aqueous solutions, according to the enthalpy-entropy compensation analysis. (C) 2022 Elsevier B.V. All rights reserved.