Solid-liquid phase equilibrium of busulfan in fifteen pure solvents: Solubility determination, solvent effect, model correlation and thermodynamic analysis

Abstract

The equilibrium solubility and thermodynamic properties of busulfan in fifteen organic single solvents were reported. Solubility determinations were performed through the laser monitoring method at T = (278.15–323.15) K (except DMSO at 298.15–323.15 K) and p = 101.3 kPa. It can be found that the mole fraction solubility of busulfan increases apparently with the augmented experimental temperature. The solubility of busulfan in single solvents exhibits the following order from maximum to minimal at 303.15 K: NMP (4.870e−2) > DMSO (4.591e−2) > DMF (3.966e−2) > methyl acetate (4.502e−3) > 2-methoxyethanol (3.105e−3) > ethyl acetate (2.090e−3) > n-propyl acetate (1.367e−3) > 2-ethoxyethanol (1.280e−3) > n-butyl acetate (9.618e−4) > 2-propoxyethanol (6.930e−4) > 2-butoxyethanol (5.219 e−4) > methanol (3.787e−4) > ethanol (1.423e−4) > n-propanol (6.680e−5) > n-butanol (6.350e−5). The maximum value in busulfan solubility profile is related to DMSO at 323.15 K (x1 = 1.035 e−1) and the minimum one is obtained for n-butanol (6.800e−6, T = 278.15 K). The results of using KAT-LSER model to study the solvent effect of busulfan solubility in fifteen single solvents show that solute-solvent interactions are principally attributed to the dipolarity/polarizability interaction and the hydrogen bonding basicity. And then, the determined solubility values of busulfan have been fitted to five widely used thermodynamic models, namely, λh, modified Apleblat, NRTL, NRTL-SAC and UNIQUAC models. The calculated results via the five models were all consistent with the solubility values, indicating that all models could provide high fitting accuracy. Moreover, according to the results of apparent thermodynamic properties calculated by Van’t Hoff equation, it can be stated that the dissolution process of busulfan in all selected solvents is recorded as an endothermic, non-spontaneous process driven by entropy.