Evaluating the roles of conformational strain and cohesive binding in crystalline polymorphs of aripiprazole

The relative stabilities of crystalline polymorphs are an important aspect of the manufacturing and effective utilization of pharmaceuticals. These stabilities are driven by both molecular conformational energy within the solid-state components and cohesive binding energy of the crystalline arrangement. The combined approach of experimental vibrational terahertz spectroscopy with solid-state density functional theory provides a powerful tool to study such properties and is applied here in the analysis of conformational polymorphism in crystalline aripiprazole. The low-frequency (<95 cm ^-1) terahertz vibrations of several aripiprazole polymorphs were measured, revealing distinct spectral features that uniquely identify each form. Solid-state density functional theory was employed to interpret the experimental terahertz spectra, correlating the observed spectral features to specific atomic motions within the crystalline lattice. The computational analysis provides insight into the formation and stability of the polymorphs by revealing the balance between the external binding forces and internal molecular forces that is ultimately responsible for the physical characteristics of the numerous crystalline polymorphs of aripiprazole.