Low-Temperature Phase Transition in Crystalline Aripiprazole Leads to an Eighth Polymorph

A new
crystalline polymorph (Form VIII) of the antidepressant drug
aripiprazole has been discovered, resulting from a previously unknown
enantiotropic phase transition from Form II at 225 K. This finding
makes aripiprazole one of the most polymorphic flexible organic solids
currently known, equaling flufenamic acid in number of solved forms
(eight polymorphs). Enantiotropic solid–solid phase transitions
are relatively uncommon for pharmaceuticals; however, for the aripiprazole
system, such phase transitions play a central role in several of its
polymorphic transformations. A combination of solid-state density
functional theory and single-crystal X-ray diffraction has been used
to investigate the energies involved in the formation of Form VIII.
This work reveals that Form VIII is stable despite containing molecules
with unfavorable conformations. The stability of this polymorph originates
from improved intermolecular binding energy due to enhanced London
dispersion forces at low temperatures.