Evaluation of the Energetic Factors in Crystalline Pharmaceuticals Using Solid-state Density Functional Theory and Low-frequency Vibrational Spectroscopy
Date of Award
Doctor of Philosophy (PhD)
Korter, Timothy M.
Cocrystals, Density Functional Theory, Low-Frequency Vibrational Spectroscopy, PHARMACEUTICALS, Raman Spectroscopy, ss-DFT
Chemistry | Computational Chemistry | Engineering | Materials Science and Engineering | Physical Chemistry | Physical Sciences and Mathematics
Due to the importance of maintaining stable and effective pharmaceutical solid doses, it is critical to study the variety of solid forms that active pharmaceutical ingredients can adopt including polymorphs, hydrates, and cocrystals. In this work, low-frequency vibrational spectroscopies and rigorous quantum mechanical simulations are combined to provide a new technique for characterizing and investigating pharmaceutically relevant polymorphs, hydrates, and cocrystals as well as a series of model cocrystals. Low-frequency spectra in the sub-200 cm-1 range provide not only unique and characteristic spectra for all of the systems explored here but, along with X-ray structural parameters, they offer a way to benchmark computational models and ensure that the models are fully capturing essential components such as the packing arrangement and the intermolecular forces present. Accurate quantum mechanical simulations allow us to determine the exact motions associated with specific low-frequency vibrational modes and this work demonstrates that large pharmaceuticals, including ones with multiple species like cocrystals, can be successfully modeled with solid-state density functional theory. Solid-state density functional theory also delivers a way to investigate how the conformations of molecules differ between polymorphs and how manipulation of the hydrogen bonding network of a solid may affect the overall stability. By studying the intermolecular forces present in the different forms, insights into stability can be made to aid future pharmaceutical crystal engineering endeavors.
Davis, Margaret P., "Evaluation of the Energetic Factors in Crystalline Pharmaceuticals Using Solid-state Density Functional Theory and Low-frequency Vibrational Spectroscopy" (2022). Dissertations - ALL. 1549.
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