Stability of Solvates and Packing Systematics of Nine Crystal Forms of the Antipsychotic Drug Aripiprazole

A comprehensive characterization (thermal, spectroscopic, crystallographic, temperature- and moisture-dependent stability, and transition characteristics) of solvates of aripiprazole (APZ) with methanol (1:1), ethanol (2:1), dichloroethane (2:1), and a monohydrate is presented. To gain insight into packing similarities and differences, the four hydrate/solvate crystal structures and five APZ modifications were compared using the program XPac. It was found that all forms apart from the hydrate are based on either a common dimeric or catemeric motif of H-bonded APZ molecules, and this analysis confirmed also the isostructurality of the three solvates and pointed to possible mechanisms for the desolvation of the solvates and the transformation between forms X° and I. The fact that the intermolecular interactions in the monohydrate are completely different from those found in the isostructural solvates was further confirmed by analyzing the Hirshfeld fingerprint plots. The desolvation of all solvated forms results in form III. The order of their measured stabilities correlates well with variations in the intermolecular APZ/solvent interactions. Additionally, solubility and solvent-mediated transition rates were determined in a 1-PrOH/water mixture (3:7) for transformations to the monohydrate from the metastable form III and from the thermodynamically stable form at room temperature (form X°).