The aqueous solubility of solid-state pharmaceuticals can often be enhanced by cocrystallization with a coformer to create a binary cocrystal with preferred physical properties. Greater understanding of the internal and external forces that dictate molecular structure and intermolecular packing arrangements enables more efficient design of new cocrystals. Low-frequency (sub-200 cm-1) Raman spectroscopy experiments and solid-state density functional theory simulations have been utilized together to investigate the crystal lattice vibrations of mycophenolic acid, an immunosuppressive drug, in its pure form and as a cocrystal with 2,2'-dipyridylamine. The lattice vibrations primarily consist of large-amplitude translations and rotations of the crystal components, thereby providing insights into the critical intermolecular forces governing cohesion of the molecular solids. The simulations reveal that despite mycophenolic acid having a significantly unfavorable conformation in the cocrystal as compared to the pure solid, the cocrystal exhibits greater thermodynamic stability over a wide temperature range. The energetic penalty due to the conformational strain is more than compensated for by the strong intermolecular forces between the drug and 2,2'-dipyridylamine. Quantifying the balance of internal and external energy factors in cocrystal formation indicates a path forward in the development of future mycophenolic acid cocrystals.
Keywords: crystal engineering; periodic boundary conditions; terahertz vibrations; vibrational spectroscopy.