Solubility of 5-Fluorocytosine in Different Pure and Binary Mixed Solvents: Measurement, Model Correlation, Solvent Effect, and Preferential Solvation

In this work, the phase equilibrium solubility of 5-fluorocytosine (5-FC) in dimethyl sulfoxide (DMSO), N,N-dimethylformamide (DMF), 1-butanol, acetonitrile, 1-propanol, 1,4-dioxane, acetone, ethyl acetate, 2-propanol, 2-butanone, and mixture systems (DMSO + 2-propanol and DMF + 2-propanol) at a series of temperatures (283.15-323.15 K) is determined, and model correlation, solvent effect, and preferential solvation analysis are researched. The solubility of 5-FC is related to temperature, which decreases with decreasing temperature. For monosolvent systems, the mole solubility order is DMSO > DMF > 1-butanol > 1-propanol > 2-propanol > acetone > 2-butanone > 1,4-dioxane > acetonitrile > ethyl acetate. The solvent effect has been studied in monosolvents, hydrogen-bonding acceptor (HBA) interactions and nonspecific dipolarity/polarizability interactions favor dissolution, and solvent self-cohesiveness is not beneficial to dissolution. For two mixture systems, the mole solubility of 5-FC in DMSO + 2-propanol solvent systems is higher than that in DMF + 2-propanol solvent systems. A dimensionless parameter (delta) is defined to observe the deviation from ideality of mixed solvents whose values are all greater than zero. The equilibrium constant of the solvent exchange process (K-ps) can be used to evaluate the preferential solvation of 5-FC. DMSO or DMF dissolves 5-FC in the local region around 5-FC preferentially. The equilibrium solubility data is correlated by four correlation models (modified Apelblat, lambda h, CNIBS/R-K, and Jouyban-Acree models). The greatest relative average deviation (RAD) and root-mean-square deviation (RMSD) values are 2.01% and 11.87 x 10(-5) in pure solvent systems and 2.20% and 5.99 x 10(-5) in mixture systems, respectively. These four models show excellent correlation with the experimental solubility data.