Evaluating Hydrogen Bonding in Organic Cocrystals Using Low-Frequency Raman Vibrational Spectroscopy and Quantum Mechanical Simulations

Cocrystallization can provide a potential route to usability for active pharmaceutical ingredients that are eliminated in the drug discovery process due to their low bioavailability. In this work, cocrystals of urea and thiourea with glutaric acid and tartaric acid were used as model systems to experimentally and computationally investigate the intermolecular energy factors within heterogeneous molecular crystals. The tools employed in this study were low-frequency Raman vibrational spectroscopy and solid-state density functional theory (ss-DFT). The sub-200 cm^-1Raman spectra give insights into vibrations that are characteristic of the crystal packing and the intermolecular forces within the samples. ss-DFT allows for the analysis of these vibrations and of the specific energies involved in the collective cocrystal. Moreover, ss-DFT permits the computational investigation of hypothetical cocrystals, utilized here to predict the properties of the unrealized thiourea:dl-tartaric acid cocrystal. These analyses demonstrated that it is both experimentally and computationally favorable for the urea and thiourea glutaric acid cocrystals to form, as well as the urea:dl-tartaric acid cocrystal, when compared to the crystallization of the pure component materials. However, changes in the hydrogen bonding network yield a thiourea:dl-tartaric acid cocrystal that corresponds to an energetic minimum on the potential energy surface but has a Gibbs free energy that prevents it from experimental formation under ambient conditions.