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.