Polymorphism of Dehydro-Aripiprazole, the Active Metabolite of the Antipsychotic Drug Aripiprazole (Abilify)

Crystal form exploration of dehydro-aripiprazole (dAPZ), the active metabolite of the antipsychotic drug aripiprazole (APZ), elucidated five polymorphs (I, II, III, IV, and V), two methanol solvates, and a monohydrate. The forms were characterized by thermal microscopy, differential scanning calorimetry (DSC), thermal gravimetric analysis (TGA), single and powder X-ray diffraction (SCXRD and PXRD), and infrared spectroscopy. DSC analysis showed monotropic relationships among polymorphs I, II, III, and IV and enantiotropic relationships for the two form pairs I ↔ V and II ↔ V. Solvent-mediated conversion experiments indicated that Form V is the thermodynamically stable form in the temperature range 5–60 °C and Form I is the stable form at ≥70 °C, where a transition temperature lies between 60 and 70 °C. Two polymorphs of the methanol solvate (SMeOH1 and SMeOH2) were crystallized from methanol solutions in 1:1 dAPZ/methanol molar ratio. SMeOH2 is the thermodynamically stable form of the two methanol solvates at ambient temperature. The monohydrate (SH2O) was obtained by solvent-mediated conversion experiments of any of the methanol solvates in water. Single-crystal structure analysis of polymorphs I, II, V and the two methanol solvates showed the formation of dimeric structures with N–H···OC (amide–amide) hydrogen-bonded homodimer synthons. In the case of SH2O, two water molecules are present between the units of the dimer, and each water molecule exhibits hydrogen-bonding with one of the piperazine nitrogen atoms of a third dAPZ molecule. Analysis of the crystal structures and PXRD patterns for both the APZ and dAPZ nonsolvated polymorphs reveals that all the forms are distinct from one another. When solvates and hydrates were added to the comparison (a total of 18 crystalline forms of APZ and dAPZ), only SMeOH2 of dAPZ was found to have an identical packing arrangement to the APZ methanol solvate. This study illustrates that despite the chemical structure similarity between dAPZ and APZthe differences being one CC double-bond vs a C–C single-bond and a molecular weight change of 2 Da out of 448the observed crystal packing arrangement in the polymorphs of the active metabolite differs significantly from those observed for the parent drug.