Dissertation
Crystal engineering of supramolecular assemblies: active pharmaceutical ingredients, unsymmetric coformers and nutraceuticals in the solid state
University of Iowa
Doctor of Philosophy (PhD), University of Iowa
Spring 2024
DOI: 10.25820/etd.007421
Abstract
The continuous search for novel synthetic methods has led supramolecular chemists and crystal engineers to mirror nature’s ways to overcome its own challenges by guiding the assembly of small building blocks through noncovalent interactions. This strategy is known as self-assembly and allows for a self-correcting process modulated by supramolecular interactions until the system is optimized for its required function. In this context, supramolecular chemists and crystal engineers aim to control the manner in which molecules pack together in the solid state, consequently influencing the properties of crystalline materials. Considerable effort has been devoted to orchestrating molecular packing in solids by means of noncovalent interactions such as hydrogen bonds, halogen bonds, metal coordination and aromatic interactions.
Across four sections, the current dissertation addresses challenges in areas of pharmaceutical solids and solid-state synthesis by using concepts of supramolecular design and crystal engineering strategies to control the way molecules organize in the solid state.
The first section of this work describes development of a method to obtain single crystals of the opioid antagonist naloxone in the free base form that is facilitated using mechanochemistry. The application of mechanochemistry reduces the number of steps and makes single crystals readily available compared to using an approach based exclusively on solution or the reported method based on sublimation. X-ray data confirms the structure determined using powder diffraction and provides details of hydrogen bonding.
The second part of this project involves the formation of O-H···N and/or N-H···N hydrogen-bonded supramolecular assemblies to study the ability of the organic unsymmetric hydrogen-bond donors 3-X-catechols (where X = F, Cl and Br) to direct the organization of the alkenes 1,2-di(N-pyridyl)ethylene (where N = 2, 3 or 4) into the formation of discrete, unidirectional assemblies. The assemblies were then irradiated with UV light to study the possibility of the systems to react in the solid state.
With cocrystallization being widely employed to design and synthesize complex molecular solids to form functional materials, the formation of a cocrystal relies on the constituent molecules assembling via noncovalent interactions to form a lattice composed of two or more different molecules. Thus, chapter 4 describes the study of mixed crystals, a term that includes cocrystals and solid solutions, of the active pharmaceutical ingredients 5-fluorouracil and 5-iodouracil with trans-bis(N-pyridyl)ethylene (where N = 2, 3 or 4). The nutraceuticals resveratrol and phloroglucinol were also studied with the mentioned alkenes. We also have discovered a polymorph of a binary cocrystal involving 5-fluorouracil with trans-bis(4-pyridyl)ethylene that originates from rare supramolecular isomerism.
Lastly, with the emergence of higher order cocrystals (i.e., cocrystals with more than two different molecules in the crystal lattice), the strategies and principle to their design are still being understood. Chapter 5 describes supramolecular synthesis of the first ternary cocrystals involving 1) resveratrol and 5-fluorouracil with trans-bis(4-pyridyl)ethylene; and 2) resveratrol, phenazine and trans-bis(4-pyridyl)ethylene.
Details
- Title: Subtitle
- Crystal engineering of supramolecular assemblies: active pharmaceutical ingredients, unsymmetric coformers and nutraceuticals in the solid state
- Creators
- Celymar del R Ortiz-de Leon
- Contributors
- Leonard R MacGillivray (Advisor)James B Gloer (Committee Member)Johna Leddy (Committee Member)Alexei V Tivanski (Committee Member)Florence J Williams (Committee Member)
- Resource Type
- Dissertation
- Degree Awarded
- Doctor of Philosophy (PhD), University of Iowa
- Degree in
- Chemistry
- Date degree season
- Spring 2024
- DOI
- 10.25820/etd.007421
- Publisher
- University of Iowa
- Number of pages
- xii, 124 pages
- Copyright
- Copyright 2024 Celymar del R Ortiz-de Leon
- Language
- English
- Date submitted
- 01/03/2024
- Description illustrations
- illustrations, tables
- Description bibliographic
- Includes bibliographical references (pages 111-122).
- Public Abstract (ETD)
- Supramolecular chemistry is the chemistry of the structures and functions of entities that form through the noncovalent association of two or more chemical species. The continuous search of novel synthetic methods has led supramolecular chemists and crystal engineers to mirror nature’s ways to overcome its own challenges by guiding the assembly of small building blocks through noncovalent interactions. The resulting materials are designed to have particularly desired physical and chemical properties for their intended applications. Research herein aims to highlight studies in solids to understand the ways in which molecules organize in the solid state by means of a) small modifications to the backbone of a family of molecules; b) substituting one molecule with another of similar shape and size; and b) apply environmentally friendly and waste-minimizing techniques to free-base pharmaceuticals. To this end, we describe the use of crystal engineering to control the way molecules organize in the solid state. A high level of organization can be achieved through noncovalent interactions to modulate the physical and chemical properties of crystalline solid materials. The results of the presented work include the synthesis of new materials of a very common anti-cancer drug, and the use of naturally-occurring molecules to guide reactions in the solid state.
- Academic Unit
- Chemistry
- Record Identifier
- 9984647557702771
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