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.

The characterization of crystalline polymorphs of drug molecules is an area of great interest since these variations in solid-state structure directly influence the physical properties of such substances. Terahertz spectroscopy provides a powerful analytical tool for these investigations and has been used here to study tautomeric polymorphism and conformational disorder in crystallized irbesartan, an antihypertensive medication. The low-frequency (<90 cm −1 ) terahertz spectra of both irbesartan Form A and Form B were measured and interpreted using solid-state density functional theory. The spectra reveal distinct identifying features for each polymorph and are indicative of the variations in the packing arrangements of the solids. The computational analyses of the solid-state forms also provide new insights into the origins and temperature dependence of the conformational disorder found in Form B. The results indicate that the disorder present in this crystal structure arises from a competition between internal conformational strain and external cohesive binding.

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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 probes the low-frequency vibrations that are sensitive to both the intermolecular and intramolecular interactions of molecules in the solid state. Thus, terahertz spectroscopy can be a useful tool in the investigation of crystalline pharmaceutical compounds, where slight changes in the packing arrangement can modify the overall effectiveness of a drug formulation. This is especially true for cases of polymorphic systems, hydrates/solvates, and cocrystals. In this work, the cocrystal of flufenamic acid with nicotinamide was investigated using terahertz spectroscopy and solid-state density functional theory. The solid-state simulations enable understanding of the low-frequency vibrations seen in the terahertz spectra, while also providing insight into the energetics involved in the formation of the cocrystal. The comparison of the cocrystal to the pure forms of the molecular components reveals that the cocrystal has better overall binding energy, driven by increased intermolecular hydrogen bond strength and greater London dispersion forces and that the trifluoromethyl torsional potential is significantly different between the studied solids.