Tuning Physicochemical Properties of Antipsychotic Drug Aripiprazole with Multicomponent Crystal Strategy Based on Structure and Property Relationship

Poor solubility and dissolution property of pharmaceuticals largely limits their bioavailability and efficacy, and development of a multicomponent crystal is one of the effective approaches to potentially address the issue. Herein we investigated the structure and property relationship of multicomponent crystal aiming to improve the pharmaceutical property, using the Biopharmaceutics Drug Disposition Classification System class II antipsychotic drug Aripiprazole (APZ) as model compound. We reported six new discovered multicomponent crystals of APZ salts with all pharmaceutically acceptable coformers. The comprehensive characterizations were done using X-ray diffraction, differential scanning calorimetry, thermogravimetric analysis, and X-ray photoelectron spectroscopy (XPS) techniques. Four multicomponent crystals were structurally solved for the first time by single-crystal X-ray diffraction, demonstrating the proton transfer from the carboxyl group of acids to APZ piperazine. Molecular interactions, crystal packing, and structure similarity analyses performed by Hirshfeld surface and CrystalCMP confirmed the charge-assisted H-bonding sites and structural similarity among the solved crystal structures. The XPS characterization of the other two multicomponent crystals corroborates the salt form as evidenced by the significant chemical shift toward higher binding energy; the pharmaceutical properties including stability, hygroscopicity, and dissolution behavior of all multicomponent crystals were examined by dynamic vapor sorption and high-performance liquid chromatography. It was found all six multicomponent crystals display high stability and low hygroscopicity but divergent dissolution behavior. The variations of these physicochemical properties were further rationalized from their crystal structures and intermolecular interactions.