Equilibrium Solubility and Solution Structure of Paracetamol: A Molecular Dynamics Study Spanning Four Orders of...

Molecular dynamics simulations are used to investigate the equilibrium solubility and solution structure of paracetamol (or acetaminophen) in water, ethanol, acetone, diethylamine, dimethylformamide, dimethyl sulfoxide, toluene, and cyclohexane. A rigorous thermodynamic framework relates the solution-phase concentration-dependent number density and solvation free energy to the pure crystalline excess Gibbs free energy, predicting solubility across four orders of magnitude. Results for ethanol agree with experimental data and reference simulations. The infinite dilution approximation is established as a rapid diagnostic tool and strategic method for staging simulations, especially for sparingly soluble systems where standard simulations are inherently supersaturated. In diethylamine, the model under-predicted solubility by two orders of magnitude. Structural analysis reveals that underestimating solvent-solute hydrogen bonding leads to unphysical aggregation, illustrating the critical distinction between experimental and model equilibrium. This work highlights phase equilibria expressions as essential diagnostics for the future parameterization of force fields for complex, multifunctional molecules.