Date of Award

December 2018

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Chemistry

Advisor(s)

Lisa Manning

Second Advisor

Timothy Korter

Keywords

cocrystal, density functional theory, polymorph, solid state, terahertz

Subject Categories

Physical Sciences and Mathematics

Abstract

The stability of pharmaceutical solids is impacted by the properties of both active and inactive ingredients. Given that the aqueous solubility of solid-state medicinal products can be directly linked to the component properties, it is prudent to carefully study these materials to predict bioavailability and shelf stability. The relative energetic stabilities of the molecular crystals of interest are governed by both the intermolecular forces and the molecular conformations within the structure. In this research, the electronic origins of crystalline stability were investigated using a combination of solid-state density functional theory (ss-DFT) and terahertz time-domain spectroscopy (THz-TDS). Terahertz spectroscopy of the lattice vibrations offers a sensitive probe of solid-state interactions and serves as a rigorous benchmark for testing the quality of the applied theoretical methods. Vibrational simulations of different polymorphic forms are also useful for investigating the relative thermodynamic stabilities of these structures. Through the calculation of Gibbs free energy versus temperature trends, it was possible to not only identify enantiotropic or monotropic relationships between polymorphs, but also the precise transition temperature linking enantiotropic pairs. These combined experimental and computational methods were extended to analyzing the relative stabilities of not only pure solids, but also cocrystals. The successful use of DFT for identifying relative stabilities of known crystal structures led to its use for crystal structure prediction. Overall, this work has demonstrated the extensive applicability of ss-DFT in the analysis of electronic and thermodynamic relationships within polymorphic and pseudopolymorhic systems. Application of this methodology to pharmaceutical solids has provided new insights into the most important contributors to the stabilities of these materials.

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Open Access

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