The relative stabilities of crystalline
polymorphs are an important aspect of the manufacturing and effective
utilization of pharmaceuticals. These stabilities are driven by both
molecular conformational energy within the solid-state components
and cohesive binding energy of the crystalline arrangement. The combined
approach of experimental vibrational terahertz spectroscopy with solid-state
density functional theory provides a powerful tool to study such properties
and is applied here in the analysis of conformational polymorphism
in crystalline aripiprazole. The low-frequency (<95 cm–1) terahertz vibrations of several aripiprazole polymorphs were measured,
revealing distinct spectral features that uniquely identify each form.
Solid-state density functional theory was employed to interpret the
experimental terahertz spectra, correlating the observed spectral
features to specific atomic motions within the crystalline lattice.
The computational analysis provides insight into the formation and
stability of the polymorphs by revealing the balance between the external
binding forces and internal molecular forces that is ultimately responsible
for the physical characteristics of the numerous crystalline polymorphs
of aripiprazole.
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.
Terahertz spectroscopy is sensitive to the interactions between molecules in the solid-state and recently has emerged as a new analytical tool for investigating polymorphism. Here, this technique is applied for the first time to the phenomenon of tautomeric polymorphism where the crystal structures of anthranilic acid (2-aminobenzoic acid) have been investigated. Three polymorphs of anthranilic acid (denoted Forms I, II and III) were studied using terahertz spectroscopy and the vibrational modes and relative polymorph stabilities analyzed using solid-state density functional theory calculations augmented with London dispersion force corrections. Form I consists of both neutral and zwitterionic molecules and was found to be the most stable polymorph as compared to Forms II and III (both containing only neutral molecules). The simulations suggest that a balance between steric interactions and electrostatic forces is responsible for the favoring of the mixed neutral/zwitterion solid over the all neutral or all zwitterion crystalline arrangements.
The terahertz (THz) spectra of crystalline solids are typically uniquely sensitive to the molecular packing configurations, allowing for the detection of polymorphs and hydrates by THz spectroscopic techniques. It is possible, however, that coincident absorptions may be observed between related crystal forms, in which case careful assessment of the lattice vibrations of each system must be performed. Presented here is a THz spectroscopic investigation of citric acid in its anhydrous and monohydrate phases. Remarkably similar features were observed in the THz spectra of both systems, requiring the accurate calculation of the low-frequency vibrational modes by solid-state density functional theory to determine the origins of these spectral features. The results of the simulations demonstrate the necessity of reliable and rigorous methods for THz vibrational modes to ensure the proper evaluation of the THz spectra of molecular solids.
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