A new polymorph of aripiprazole has been discovered, making it the most polymorphic drug to date with twelve reported anhydrous forms, and a record-breaking ninth solved crystal structure. The new form was induced by seeding with crystals of the active metabolite dehydro-aripiprazole.
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 MeOHsolvated 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.
Brexpiprazole (BPZ) is an atypical antipsychotic drug indicated for the treatment of schizophrenia and depression. Crystal form screening of BPZ resulted in the formation of three polymorphs (I, II, and III), two methanol solvates, a toluene hemisolvate, and a dihydrate. Thermal analysis and solvent-mediated conversion experiments of the three unsolvated polymorphs established that Form I is the thermodynamically stable form at ambient temperature. All three polymorphs are monotropically related, whereby Forms I and II are the most and least stable forms, respectively. Structural diversity of BPZ was compared with two chemically related analogues, aripiprazole (APZ) and its active metabolite dehydroaripiprazole (dAPZ). Like APZ and dAPZ, BPZ was shown to form a thermodynamically stable, hydrated crystal form when exposed to an aqueous environment; however, while APZ and dAPZ were characterized as monohydrates, BPZ is a dihydrate. The crystal structure of BPZ dihydrate (S 2H 2 O ) showed two water molecules connecting two BPZ molecules, with hydrogen bonding occurring between both the piperazine nitrogen and the oxygen of the carbonyl moiety with different water molecules. Despite the chemical similarity of BPZ, APZ, and dAPZ, comparison of all accumulated crystal structures reveals wide structural diversity, with a significant impact on physicochemical properties. In particular, the solubility of BPZ is significantly lower in water across the physiologically relevant pH range. Implications to drug delivery of these findings are discussed.
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