Abstract
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–1 Raman 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.
Highlights
Crystal engineering is a concept applied in various fields to improve a material by tuning its physical and chemical properties through manipulation of the solid-state structure.[1,2] This is achieved through rational selection of crystal components and control of growth conditions to yield crystal packing arrangements with desired properties
A cocrystal generally consists of an active pharmaceutical ingredient (API) cocrystallized with a second organic molecular species that is typically an inactive excipient or occasionally a complementary API, though more complex cocrystalline pharmaceuticals have been reported.[4−6] Cocrystals are the focus of considerable research since they increase the practicality of the many APIs that are discarded in the drug development process due to lack of bioavailability.[7]
The Gibbs free energies show that the changes in the hydrogen bonding network induced by sulfur make T:TA formation energetically less favorable than that of the readily grown U:TA cocrystalline solid. It is common for the crystal engineering of new cocrystalline materials to leverage modified hydrogen bonding motifs in order to achieve desired functionality
Summary
Crystal engineering is a concept applied in various fields to improve a material by tuning its physical and chemical properties through manipulation of the solid-state structure.[1,2] This is achieved through rational selection of crystal components and control of growth conditions to yield crystal packing arrangements with desired properties. The pharmaceutical industry heavily utilizes crystal engineering ideas and methods in the quest to optimize drug effectiveness, improving important factors such as stability, permeability, and solubility.[3] Cocrystallization is an appealing approach that combines the positive attributes of two (or more) components to produce a single solid that serves as a superior drug formulation In this context, a cocrystal generally consists of an active pharmaceutical ingredient (API) cocrystallized with a second organic molecular species (differentiated from solvates and most salts) that is typically an inactive excipient or occasionally a complementary API, though more complex cocrystalline pharmaceuticals have been reported.[4−6] Cocrystals are the focus of considerable research since they increase the practicality of the many APIs that are discarded in the drug development process due to lack of bioavailability.[7] To help make cocrystal design more effective, research is necessary on the structures and thermodynamics of both successful and unsuccessful cocrystal formations to better understand what determines ideal candidates for cocrystallization
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