Aripiprazole and Dehydro-Aripiprazole Solid Solutions: Crystalline Combinations of Drug and Active Metabolite in Tailored Compositions

Solid solutions of aripiprazole (APZ) and its active metabolite, dehydro-aripiprazole (dAPZ), have been prepared as free form (neat or nonsolvated), hydrated, or alcohol-solvated modifications with methanol (MeOH), ethanol, propan-1-ol, isopropyl alcohol, and propylene glycol, and full physiochemical characterization of these materials was performed. The various compositions of the free solid solutions were isomorphous with the thermodynamically stable form of dAPZ, form V, and the hydrated solid solution was isomorphous throughout its compositional range. Dissolution studies of the hydrated system demonstrated the ability to deliver varying drug content from a single phase of two molecules, potentially paving the way for the treatment of CYP2D6-deficient patients without the need for dose adjustments. The set of all alcohol solvate solids are nearly isomorphous on the basis of PXRD patterns, and upon desolvation, the MeOH-solvated solid solution in the range of 25-60% APZ showed a new powder diffraction pattern distinct from that of any known APZ or dAPZ crystal form. The emergence of the new diffraction pattern suggests that solid solutions can be used to generate previously unknown phases. Crystal structure and powder diffraction pattern analysis of the solid solutions revealed that subtle shifting in distances of the crystal planes was a function of APZ and dAPZ content, controlled by the cumulative effects of hydrogen bonding and steric bulk in these molecules. Melting temperatures and other transitions of the solid material can be finely tuned while a single phase is maintained through tailoring the APZ and dAPZ composition. This study illustrates that, despite the extreme conformational flexibility and dissimilar crystal form diversity of APZ and dAPZ, isomorphous compositions combining both APZ and dAPZ in a single phase can be prepared as a way of fine-tuning physicochemical properties.