The cocrystallization of active pharmaceutical ingredients with inactive coformers is commonly utilized to alter the solubility of solid-state drug formulations. The search for appropriate coformers that produce desired physical properties generally involves the selection of candidates with the intention to establish a particular pattern of crystalline intermolecular interactions. Hydrogen bonding networks are often the focus and these can be modified through the introduction of participating atoms other than the typical hydrogen bond partners. In this work, we evaluate the impact of substituting sulfur atoms for oxygen by considering the structures, energies, and vibrational dynamics of various organic molecules cocrystallized with urea (CH4N2O) and thiourea (CH4N2S). Carboxylic acid model systems such as tartaric, glutaric, and succinic acids are the foundation of this investigation, but cocrystals with carbamazepine and 5-fluorouracil will be discussed as well. Experimental and computational techniques are combined and applied to the cocrystals in this study, with measurements made using single-crystal and powder X-ray diffraction, low-frequency Raman spectroscopy, and terahertz time-domain spectroscopy. Solid-state density functional theory is used extensively to support and extend the experimental results, with the low-frequency vibrational data of the crystal lattices being of great value in validating the intermolecular force modeling. In addition to calculating conformation and cohesion energies within the cocrystalline solids, crystal orbital overlap/Hamiltonian population (COOP/COHP) analyses of the electronic states in the cocrystals permits specific atom-atom interaction strengths to be quantified and orbital contributions detailed. The synergy of this multifaceted approach serves to improve our understanding of known crystal structures, but also aids in the prediction of undiscovered cocrystals with new physical properties.

Evaluating hydrogen bonding in molecular cocrystals using low-frequency vibrational spectroscopy and solid-state density functional theory

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.