Mechanistic Study on the Effect of Solvents on Polymorphic Transformation of Aripiprazole by Solvent Property Parameters and Molecular Dynamics Simulation

The choice of solvent is crucial in the drug crystallization process, and the mechanism of solvent effect on the crystallization results can be conducive to the selection of solvents. In this work, the effect of solvents on the suspension crystallization process of Aripiprazole (APZ) was explored by generalized solvent property parameters and molecular dynamics simulation. Eight different crystal products of APZ (Form III, Form IV, Form V, and five solvates) were obtained after suspension crystallization in 15 different solvents, in which APZ semiethylene glycol solvate (S_EG) is one newly discovered product, and its crystal structure was elucidated. Besides, the crystal transformation processes were studied using molecular dynamics simulations. Conformational search was also adopted to investigate the formation mechanisms of different forms. The results indicated that van der Waals interactions between the solute and solvents dominate the conformations of the APZ molecules in the solvents and further influence the crystal form of the products. However, the polymorphism of APZ in solvents with similar van der Waals interactions may also be different, suggesting that other solvent properties also influence the polymorphism results. Thus, the solvent property parameters were analyzed in detail, and the results indicated that in addition to the van der Waals interaction energy between the solvent molecules and the APZ molecules, the hydrogen bond donor propensity, the volume, the sphericity, and the cohesive energy density of the solvent molecules are also decisive for the suspension crystallization results of APZ. Finally, the mechanism of the effects of solvents species on the suspension crystallization results was proposed and discussed.