Title from title page of PDF (University of Missouri--St. Louis, viewed Mar. 3, 2010). Includes bibliographical references.

With a greater understanding of the fundamentals of crystal engineering lays the potential for the development of a vast array of novel materials for a plethora of applications. Addressed herein is the latent potential of the current knowledge base with an emphasis upon cocrystallization and the desire for scientific exploration that will lead to the development of a future generation of novel cocrystals. The focus of this dissertation is to expand the cocrystallization knowledge base in two directions with the utilization of cocrystals in the novel synthetic technique of cocrystal controlled solid-state synthesis and in the development of active pharmaceutical ingredients. Cocrystal controlled solid-state synthesis uses a cocrystal to align the reactive moieties in such a way that the reaction occurs more quickly and in higher yield than the typical solution methodology. The focus herein is upon cocrystal controlled solid-state synthesis of imides where an anhydride and primary amine were the reactive moieties. Forty-nine reactions were attempted and thirty-two resulted in successful imide formation. In addition, the cocrystal was isolated as part of the reaction pathway in three cases and is described in detail. The impact of cocrystals upon active pharmaceutical ingredients is also addressed with a focus upon generating novel crystal forms of lamotrigine and meloxicam. Cocrystallization attempts of lamotrigine resulted in ten novel crystal forms including three cocrystals, one cocrystal solvate, three salts, one solvated salt, a methanol solvate, and an ethanol hydrate. Additionally, cocrystallization attempts of meloxicam afforded seven novel cocrystals. Solubility and pharmacokinetic studies were conducted for a selected set of lamotrigine and meloxicam crystal forms to determine the crystal form with the most desirable properties. Properties between crystal form and cocrystal former were also examined.

There is heightened interest to diversify the range of crystal forms exhibited by active pharmaceutical ingredients (APIs) in the pharmaceutical industry. The crystal form can be regarded as the Achilles' heel in the development of an API as it directly impacts the physicochemical properties, performance and safety of the API. This is of critical importance since the crystal form is the preferred method of oral drug delivery by industry and regulatory bodies. The ability to rationally design materials is a lucrative avenue towards the synthesis of functional molecular solids with customized physicochemical properties such as solubility, bioavailability and stability. Pharmaceutical cocrystals have emerged as a new paradigm in pharmaceutical solid form development because they afford the discovery of novel, diverse crystal forms of APIs, generate new intellectual property and modify physicochemical properties of the API. In addition, pharmaceutical cocrystals are amenable to design from first principles of crystal engineering. This dissertation focuses on the crystal engineering of multi-component crystal forms, in particular pharmaceutical cocrystals and crystalline hydrates. It addresses: (i) the factors involved in the selection of cocrystal formers (ii) design strategies for APIs that exhibit complexity, (iii) the role of water molecules in the design of multi-component crystal forms and (iv) the relationship between the crystal structure and thermal stability of crystalline hydrates. In general, cocrystal former libraries have been limited to pharmaceutically acceptable substances. It was investigated to expand this library to include substances with an acceptable toxicity profile such as nutraceuticals. In other words, can nutraceuticals serve as general purpose cocrystals formers? The model compounds, gallic acid and ferulic acid, were selected since they possess the functional moieties carboxylic acids and phenols, that are known to form persistent supramolecular synthons with complementary functional groups such as basic nitrogen and amides. The result yielded pairs of cocrystals and revealed the hierarchical nature of hydrogen bonding between complementary functional groups. In general, pharmaceutical cocrystals have been designed by determining the empirical guidelines regarding the hierarchy of supramolecular synthons. However, this approach may be inadequate when considering molecules that are complex in nature, such as those having a multiplicity of functional groups and/or numerous degrees of conformational flexibility. A crystal engineering study was done to design multi-component crystal forms of the atypical anti-psychotic drug olanzapine. The approach involved a comprehensive analysis and data mining of existing crystal structures of olanzapine, grouped into categories according to the crystal packing exhibited. The approach yielded isostructural, quaternary multi-component crystal forms of olanzapine. The crystal forms consist of olanzapine, the cocrystal former, a water molecule and a solvate. The role of water molecules in crystal engineering was addressed by investigating the crystal structures of several cocrystals hydrates and their related thermal stability. The cocrystal hydrates were grouped into four categories based upon the thermal stability they exhibit and it was concluded that no structure/stability correlations exist in any of the other categories of hydrate. A Cambridge Structural Database (CSD) analysis was conducted to examine the supramolecular heterosynthons that water molecules exhibit with two of the most relevant functional groups in the context of active pharmaceutical ingredients, carboxylic acids, and alcohols. The analysis suggested that there is a great diversity in the supramolecular heterosynthons exhibited by water molecules when they form hydrogen bonds with carboxylic acids or alcohols. This finding was emphasized by the discovery of two polymorphs of gallic acid monohydrate to it the first tetramorphic hydrate for which fractional coordinates have been determined. Analysis of the crystal structures of gallic acid monohydrate polymorphs revealed that forms I and III exhibit the same supramolecular synthons but different crystal packing and forms II and IV exhibit different supramolecular synthons. Therefore, the promiscuity of water molecules in terms of their supramolecular synthons and their unpredictable thermal stability makes them a special challenge in the context of crystal engineering.

The design and synthesis of novel functional materials with fine-tunable physical and chemical properties has been an aspiration of materials scientists since at least Feynman's famous speech "There's Plenty of Room at the Bottom" which has fittingly been credited with ushering in the nanotechnology era. Crystal engineering, as the solid-state manifestation of supramolecular chemistry, is well positioned to make substantial contributions to this worthwhile endeavor. Within the realm of crystal engineering resides the subdiscipline of metal-organic materials (MOMs) which pertains most simplistically to the coordination bond and includes such objects as coordination polymers, metal-organic frameworks (MOFs), and discrete architectures, each of which share the common aspect that they are designed to be modular in nature. While metal-organic materials have been studied for quite some time, only recently have they enjoyed an explosion in significance and popularity, with much of this increased attention being attributed to two realizations; that this inherent modularity ultimately results in an almost overwhealming degree of diversity and subsequently, that this diversity can give rise to effective control of the properties of functional materials. At long last the goal of attaining fine-tunablity may be within our grasp. In addition to high levels of diversity, MOMs are also characterized by a broad range of complexity, both in their overall structures and in the nature of their constituents. From the simplest molecular polygons to extended 3-periodic frameworks of unprecedented topologies, MOMs have the capacity to adopt an array of structural complexities. Moreover, there has been a recent trend of increasing complexity of the very building blocks that construct the framework. It is the aim of the research presented in this dissertation to survey these two principle aspects of MOMs, diversity and complexity, by focusing upon the use of polycarboxylates and first row transition metals to synthesize several series of closely related materials imbued with varied levels of complexity. Through the use of single crystal X-ray diffraction and the charcterization of the materials' properties, the structure-function relationship has been probed. Finally, novel design strategies incorporating supermolecular building blocks for the creation of a new generation of MOMs has been addressed.

The cocrystallization of two or more pure compounds by crystal engineering to create a new functional material is of a great academic and industrial interest. Pharmaceutical cocrystallization has allured a lot of attention by means of altering the physicochemical properties of Active Pharmaceutical Ingredient (API) such as solubility, stability and bioavailability. Crystal engineering of nutraceuticals can produce novel compounds such as pharmaceutical cocrystals. To establish the importance of nutraceutical cocrystallization and its use; polyphenols, a major class of nutraceuticals and potential disease preventing agents, are the appropriate targets. The work herein focuses on two polyphenols, protocatechuic acid and quercetin, which are strong antioxidants. The cocrystals of quercetin have been synthesized, aiming to modify its poor water solubility and bioavailability which limits its usage. On the other hand, cocrystals of water soluble protocatechuic acid are also prepared to establish its use as a cocrystal former. Seven novel cocrystals of protocatechuic acid and two novel cocrystals of quercetin are obtained and are characterized by FTIR, DSC (Differential Scanning Calorimetry), PXRD (Powder X-Ray Diffraction), single crystal x-ray diffraction and TGA (Thermo Gravimetric Analysis). The new crystal forms have also been studied via dissolution. Dissolution studies show alteration in solubility of a target molecule by its cocrystal irrespective of solubility of the cocrystal former. Overall, the study helps in understanding the role of crystal engineering and its utility.

Flavonoids are a long and well known class of natural products. Their potential health benefits can be attributed to their antioxidant activity, and modulation of cell signaling pathways. Green tea one of the most widely consumed beverages, consist of flavonoids such as catechins and tannins. Epigallocatechin gallate (EGCG) the major catechin of green tea exhibits multiple health benefits due to its antioxidant nature. The radical scavenging activity of EGCG is attributed to its structure. Therefore, a study on molecular features of EGCG would provide valuable information on structural modifications, which may change the physiochemical properties such as bioavailability and solubility. Although flavonoids are abundant and commercially available they are difficult to purify and crystallize. In this respect, crystallizing EGCG was challenging. By exploring different techniques EGCG was crystallized. Here in this study one new form of EGCG and two solvates, acetonitrile and nitrobenzene, have been synthesized and structurally characterized by differential scanning calorimetry (DSC), infrared (IR) and powder X-ray diffraction (PXRD). The crystal structures were solved by single-crystal X-ray diffraction and a detailed description of synthesis and about the supramolecular synthons that exist in these crystal forms are given.

The research presented herein focus upon crystal engineering of co-crystals with an emphasis upon the exploration of co-crystals in the context of delineation of the reliability of hydrogen bonded supramolecular synthons and their hierarchies. The approach involves a combination of systematic Cambridge Structural Database analysis and a series of model co-crystal experiments. In addition, the viability of solid state methodologies toward supramolecular synthesis of co-crystals and the effect on polymorphism is also addressed. The application of the acquired knowledge is towards the crystal engineering of pharmaceutical co-crystals. The rational design and synthesis of pharmaceutical co-crystals accomplished by the selection of appropriate co-crystal formers facilitated by analysis of existing crystals structures in the CSD will be demonstrated. The processing of pharmaceutical co-crystals will also be addressed in terms of slurry conversion, solvent drop grinding and solution crystallization.

Neutral or charge-assisted hydrogen bonds occurring between organic molecules represent strong and directional forces that mediate the molecular self-assembly into well defined supramolecular architectures. A proper understanding of hydrogen bonding interactions, their types, geometries, and occurrence in supramolecular motifs, is a prerequisite to crystal engineering, i.e. to the rational design of functional solid materials.Multiple-component organic crystals represent ideal systems to study the intermolecular interactions between the constituent molecules that can be pre-selected for their hydrogen bonding sites and geometrical capabilities. In particular, the systematic structural analysis of supramolecular systems that are comprised of simple molecules facilitates the development of strategies for the rational design of new multiple-component compounds involving more complex components such as drug molecules.The work presented herein shows a combination of systematic database and experimental studies in the context of reliability and hierarchy of several hydrogen bonded supramolecular synthons that exist in a series of model co-crystals and organic salts. The acquired paradigms are ultimately utilized in crystal engineering of pharmaceuticals. In addition, the viability of a mechanichemical approach toward supramolecular synthesis in the context of its efficacy and the effect on polymorphism in multiple-component compounds is also addressed.

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This thesis describes the host-guest chemistry between cucurbit[7]uril (CB[7]) and various series of guests, including neutral polar organic solvents, bis(pyridinium)alkane dications, local anaesthetics, acetylcholine analogues, as well as succinylcholine and decamethonium analogues, in aqueous solution. A focus of this thesis is the effects of varying the chemical structures within different series of guests upon the nature of the host-guest chemistry, such as the relative position and orientation of the guest relative to the CB[7] cavity, and the strengths of the binding affinities. The binding affinities of polar organic solvents with CB[7] depend upon the hydrophobic effect and dipole-quadrupole interactions. The polar guests align themselves so that their dipole moment is perpendicular to the quadrupole moment of CB[7]. The binding strengths of acetone and acetophenone to CB[7] decrease in the presence of alkali metals. Discrete 1:1 and 2:1 host-guest complexes are formed between CB[7] and a series of bis(pyridinium)alkane guests. In most cases the CB[7] initially occupies the aliphatic linker when the 1:1 complex is formed and migrates to the terminal regions as the second CB[7] is added. When bulky, hydrophobic tert-butyl substituents are present, however, the CB[7] occupies the terminal pyridinium region and not the central linker. Supramolecular complexes between CB[7] and a series of local anaesthetics have binding affinities 2-3 orders of magnitude greater than reported values with beta-cyclodextrin. The first pKa values of the guests increase by 0.5-1.9 units upon complexation. The binding positions of the guests within CB[7] differ in neutral and acidic media, with the systems thus behaving as pH-activated switches. With supramolecular complexes between CB[7] and various cationic cholines and their phosphonium analogues, the CB[7] cavity is occupied by the charge-diffuse cationic region. The binding affinities and positions vary depending on the nature of the onium group as well as the substituents within the guest molecule. Host-guest complexes between CB[7] and dicationic acetylcholinesterase inhibitors have very strong 1:1 binding affinities, with 2:1 binding being significantly weaker. These binding affinities are related to the nature of the cationic onium groups, and the length and hydrophobicity of the connecting linkers. / Thesis (Ph.D, Chemistry) -- Queen's University, 2010-01-28 12:27:37.833