Title

Characterizing Pharmaceutical Polymorphs Using Terahertz Spectroscopy

Date of Award

May 2014

Degree Type

Dissertation

Embargo Date

2-7-2015

Degree Name

Doctor of Philosophy (PhD)

Department

Chemistry

Advisor(s)

Timothy M. Korter

Keywords

low-frequency vibrations, molecular binding forces, polymorphs, solid-state DFT, Terahertz spectroscopy

Subject Categories

Physical Sciences and Mathematics

Abstract

During drug manufacturing, pharmaceutical companies need to fully investigate

the solid-state assemblies of the molecules being produced. Even slight variations in the

solid-state packing arrangement of the active pharmaceutical ingredient (API) can greatly

influence the effectiveness of the product. This work investigates various aspects of the

pharmaceutical screening process, including: the characterization of polymorphs

(external changes in the solid-state packing arrangement of a solid or internal

conformational), investigation of disorder (conformational or positional), and the

formation of cocrystals. The chosen tool for these investigations is terahertz

spectroscopy. Terahertz spectroscopy probes the solid-state lattice specific, lowfrequency

vibrations (sub-100 cm-1) of molecular solids, providing a useful tool for the

differentiation of polymorphs. In this work, terahertz spectroscopy is used to detect and

identify different polymorphic materials, with up to eight polymorphs that exhibit

disorder (both internal and external), undergo solid-state phase transitions, are affected by

humidity, or exist as cocrystals. The relative stabilities of the crystalline polymorphs are

an important aspect of the manufacturing and effective utilization of pharmaceuticals and

can be investigated using solid-state density functional theory in combination with

terahertz spectroscopy. The approach of combining these experimental and theoretical

methods yields insight into the formation and stability of the polymorphs by revealing the

balance between the intermolecular and intramolecular forces that is ultimately

responsible for the physical characteristics.

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