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Solubility Determination and Dissolution Mechanism of Nintedanib in Binary Solvent Mixtures: Experimental and Simulation studies
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DOI：10.1016/j.cjche.2026.03.023.png)
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Abstract
En 中文
The solid–liquid equilibrium solubility of Nintedanib in four binary solvent mixtures, namely methanol (MeOH) + H2O, N,N-Dimethylformamide (DMF) + H2O, N,N-Dimethylacetamide (DMA) + H2O, and dichloromethane (DCM) + ethyl acetate (EtOAC), was determined at various temperatures under atmospheric pressure (P = 0.1 MPa) using the laser monitoring technique. The results demonstrated that the mole fraction solubility of Nintedanib in each binary system increased with rising temperature, whereas at a fixed temperature, lower content of the cosolvents (MeOH, DMF, DMA, and DCM) led to decreased solubility. Multiple thermodynamic models, including the Apleblat, λh, Ma, CNIBS/R-K, and Van’t Hoff models, were utilized to correlate the experimental solubility data, revealing that the CNIBS/R-K and Apleblat models produced the smallest relative average deviation values among all models for the studied solvent systems. Analyses of the Hansen solubility parameters for Nintedanib indicated that these parameters could effectively rationalize its solubility behavior in the different binary solvents, with the overall dissolution process being influenced by intermolecular dispersion, hydrogen bonding, and polarity interactions. Furthermore, evaluation of the thermodynamic parameters (ΔsolG°, ΔsolH°, ΔsolS°, ζH, ζTS) using the Van’t Hoff equation confirmed that the dissolution process of Nintedanib in all four binary systems is enthalpy-driven, endothermic, and non-spontaneous, with the positive ΔsolH° predominantly accounting for the observed free energy change (ΔsolG°). Molecular dynamics simulations and radial distribution function analyses of Nintedanib in MeOH–H2O binary solutions showed both solute–solvent and solvent–solvent interactions were dominated by hydrogen bonding. The intensity of solute–solvent interactions matched Nintedanib’s solubility order in different MeOH–H2O systems, while solvent–solvent interactions showed the reverse.
Keywords:
Nintedanib
solubility
binary solvent mixtures
thermodynamic models
molecular dynamics simulation
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