Thermodynamic analysis and molecular dynamic simulation of solid–liquid equilibrium behavior of antipsychotic drug aripiprazole (Form III) in three binary solvent mixtures

Aripiprazole (APZ), an effective second-generation antipsychotic drug indicated for the treatment of schizophrenia, was chosen to investigate its solubility in three binary solvent mixtures at the temperature range of 278.15–318.15 K. Due to clinical usage Form III is metastable, and the solubility was studied via the synthetic method. It was found that in the butanone + acetone and butanone + ethyl acetate mixed solvent systems, the solubility values of APZ Form III increased with the increase of the proportion of butanone solvent, and the maximum mole fraction solubility at each selected temperature point ranges from 0.001924 to 0.009015. However, in the mixed solvent system of butanone and n-propanol, the solubility of APZ Form III reaches its maximum when the molar fraction of butanone is 0.6 with the maximum mole fraction solubility at each selected temperature point ranging from 0.003126 to 0.012721. The modified Apelblat model, λh model, Van’t Hoff model, and NRTL model were used to correlate the experimental solubility data of APZ Form III, and the results showed that these models are suitable. In addition, according to the result of mixing thermodynamic functions, the negative values of ΔmixG and ΔmixH in all binary solvent mixtures are negative, indicating that the dissolution process of APZ Form III in the binary solvent mixtures is spontaneous and entropy-driven. Furthermore, the molecular dynamic simulations were used to illustrate and understand the dissolution behavior of APZ Form III in selected solvents from a molecular perspective.