Calculating the Fugacity of Pure, Low Volatile Liquids via Molecular Simulation with Application to Acetanilide, Acetaminophen, and Phenacetin

Conventional molecular simulation free energy calculations and standard thermodynamic relations are applied to compute the pure liquid fugacity of low volatile liquids and compared to reference Monte Carlo simulations. The method involves the calculation of the residual chemical potential and the molar volume of the liquid at the conditions of interest. For substances that are solid at the conditions of interest, simulations may be performed at elevated temperatures and extrapolated to subcooled conditions. It is shown that direct calculations at subcooled conditions provide erroneous values of the fugacity. Knowledge of the pure liquid fugacity is essential to compute activity coefficients defined with respect to a Lewis–Randall standard state for thermodynamic property modeling. The validity of the method is verified by comparing to reference simulation results for n-octane, 3,4-dimethylhexane, cyclohexane, methanol, 1-propanol, and 2-propanol. The method is then applied to acetanilide, acetaminophen, and phenacetin, all of which are solid at ambient conditions. The results for the six reference compounds are in good agreement with standard Monte Carlo simulations, suggesting that free energy based calculations of the fugacity may be used to accurately normalize activity coefficients of low volatile liquids computed via molecular simulation.