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Applications in supramolecular chemistry and solid-state reactivity: template-mediated solid-state reactions, dynamic covalent chemistry, mechanochemistry, and pharmaceutical co-crystalsOburn, Shalisa M 01 August 2019 (has links)
Supramolecular chemistry and crystal engineering seek to control molecular packing in the solid state to influence the physical and chemical properties of crystalline solid materials. A goal of supramolecular chemistry that seeks to control molecular packing in the solid state focuses on exploiting non-covalent interactions to assemble molecules into desirable arrangements. Strategies implemented to control molecular packing rely on strong, directional interactions such as hydrogen bonding, halogen bonding, and metal coordination to direct localized arrangement of molecules in solids. In this context, small molecules can be used as linear templates in co-crystals to assemble reactive alkenes into specific geometries allowing reactivity in the solid state. A linear template method has been used to achieve [2+2] photocycloadditions of discrete assemblies containing alkenes to afford cyclobutanes in high stereospecificity and in quantitative yield.
Herein, we describe the use of a nonlinear template, in the form of 1,4-butynediol (1,4-bd), to pre-organize alkenes in the solid state. The nonlinear template of 1,4-bd hydrogen-bonds to the alkene 1,2-bis(N-pyridyl)ethene (where N = 3 or 4) to form 1D hydrogen-bonded polymers. The hydrogen-bonded polymer chains form infinite stacks which are sustained by C-H···O interactions occurring between polymer chains. The stacked alkenes undergo a UV-induced [2+2] photocycloaddition to produce rctt-tetrakis(N-pyridyl)cyclobutane photoproducts (where N = 3 and 4) in non-quantitative yields. The yield of the photoreaction is increased to nearly quantitative by applying a supramolecular catalysis approach with the 1,4-bd template.
Functional groups on reactant molecules can compete via non-covalent interactions with templates employed for the self-assembly process. One method to inhibit competition between functional groups involves chemically modifying a functional group employing a supramolecular protecting group. Here, we describe an acetyl supramolecular protecting group approach employed to mask alkenes containing phenolic and pyridyl functional groups. The acetyl protecting group prevents the phenolic substituents of the targeted alkene from participating in non-covalent interactions employed for the template-mediated self-assembly process. Thus, a cyclobutane molecule was obtained using the novel acetyl supramolecular protecting group strategy applied to a solid-state [2+2] photodimerization that affords a head-to-head cyclobutane. After deprotection, the resulting cyclobutane possessed tetrahedrally-disposed cis-hydrogen-bond-donor and cis-hydrogen-bond-acceptor groups. Thus, a purely organic three-dimensional hydrogen-bonded network based on a rare Michael O'Keeffe (mok) topology was constructed using an organic molecule synthesized in the organic solid state. The phenolic substituents of the cyclobutane adopt different orientations (syn-, anti-, and gauche-) to conform to the structural requirements of the mok net.
A challenge surrounding template-directed solid-state reactivity requires alkenes to be lined with functional groups that coordinate (or bind through other non-covalent interactions) to the template. Herein, we describe a dual approach of supramolecular assistance to covalent bond formation that utilizes a combination of imine and metal-organic chemistry to generate cyclobutanes lined with aldehyde groups. Specifically, dynamic imine chemistry was implemented to install a temporary recognition site on an aldehyde-containing alkene of cinnamaldehyde for a template-directed [2+2] photocycloaddition in the solid state. The resulting modified alkene aligns using Ag(I) ions into desirable arrangements for the covalent-bond-forming [2+2] photocycloaddition. The result is a 1D coordination polymer undergoes a UV-induced, regio-controlled [2+2] photocycloaddition in the solid state. The photoreaction proceeds stereospecifically with quantitative yield of the corresponding aldehyde-functionalized photodimer, α-truxilaldehyde. Additionally, we investigate the influence of the Ag(I) counterions on the assembly of imine containing alkenes to generate reactive assemblies for the purpose of producing aldehyde-containing cyclobutanes.
This dissertation also encompasses research pertaining to pharmaceutical solids and mechanical properties of organic molecular crystals. Specifically, we describe the discovery of two polymorphic co-crystals containing acetylsalicylic acid (aspirin) combined with 4,4’-bipyridine. The initial discovery of the form I polymorph was aided by mechanical dry-grinding, while an additional form II polymorph was revealed by rapid cooling in ethanol. The polymorphs differ by relative twists of carboxylic acid groups of the aspirin molecules and of the pyridyl rings of 4,4’-bipyridine. Additionally, the form I polymorph contains aspirin molecules that are linked via discrete catemeric methyl C-H···O interactions, while the form II polymorph is linked via both infinite methyl C-H···O catemers and centrosymmetric dimers. These results demonstrate the importance of dry mechanical grinding for the discovery of pharmaceutical co-crystals and polymorphs.
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Hydrogen-bond driven supramolecular chemistry for modulating physical properties of pharmaceutical compoundsForbes, Safiyyah January 1900 (has links)
Doctor of Philosophy / Department of Chemistry / Christer B. Aakeroy / The ability to predict and control molecular arrangements without compromising the individual molecules themselves still remains an important goal in supramolecular chemistry. This can be accomplished by establishing a hierarchy of intermolecular interactions such as hydrogen and halogen bond, which may facilitate supramolecular assembly processes.
Several acetaminopyridine/acetaminomethylpyridine supramolecular reactants (SR’s) were prepared with aliphatic carboxylic acids in order to determine patterns of molecular recognition preferences of the N-H moiety. The results obtained revealed the formation of molecular cocrystals through heteromeric O-H…N/N-H…O hydrogen bonds with the acetaminopyridine/acetaminomethylpyridine binding site. Furthermore, the SR’s also reacted with metal ions resulting in robust 1D and 2D metal-containing architectures.
A series of pyridyl/pyrazine mono-N-oxide compounds were synthesized and reacted with a variety of halogenated benzoic acids, in order to assess the ability of these molecules to establish binding selectivity when both a hydrogen and halogen bond donor is present. The results obtained revealed that the pyridyl/carboxylic acid synthon formed 7/7 times and halogen bonds (N-O…I or N-O…Br) extended the SR/acid dimers into 1D and 2D networks. These results were rationalized via charge calculations as well as through the hierarchical view of intermolecular interactions consisting of hydrogen and halogen bonds.
Furthermore, a series of thienyl compounds were synthesized and allowed to react with halogen bond donors to determine whether the halogen bond is purely electrostatic or based on the hard and soft acids and bases principles. The results obtained showed that of the 34 reactions between a halogen bond donor and thienyl compounds, the halogen bond is predominantly electrostatic in nature.
Finally, as a result of our improved understanding on molecular recognition, we were able to carry out systematic structure-property studies on a series of cocrystals of anti-cancer drug molecules with aliphatic carboxylic acids. This study revealed that systematic changes to the molecular nature of the co-crystallizing agent combined with control over the way individual building blocks are organized within the crystalline lattice makes it possible to establish predictable links between molecular structure and macroscopic physical properties, such as melting behavior, solubility, dissolution rate, etc.
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Crystal Engineering of Multiple Component Crystal Forms of Active Pharmaceutical IngredientsWeyna, David Rudy 01 January 2011 (has links)
Enhancing the physicochemical properties of solid-state materials through crystal engineering enables optimization of these materials without covalent modification. Cocrystals have become a reliable means to generate novel crystalline forms with multiple components and they exhibit different physicochemical properties compared to the individual components. This dissertation exemplifies methodologies to generate cocrystals of active pharmaceutical ingredients (API's) based upon knowledge of supramolecular interactions (supramolecular synthons), while focusing on enhanced delivery through in vitro and in vivo processes with both salts and cocrystals respectively.
The utility of mechanochemistry involving small amounts of an appropriate solvent, or solvent drop grinding (SDG), has been shown to reliably reproduce cocrystals with the anti-convulsant carbamazepine that were originally obtained by solution crystallization. This technique has been confirmed as a reliable screening method using solvents in which both components exhibit some solubility. The benefits of this technique lie in the time and cost efficiency associated with it as well as its inherently small environmental impact making it a "Green" method. SDG was also used as an efficient way to discover cocrystals of the anti-inflammatory meloxicam with carboxylic acids after analysis of existing reports and the analysis of structural data from the Cambridge Structural Database (CSD) to guide the choice of coformer. It has been shown that SDG can be used to screen for cocrystalline forms that are also obtainable by solution crystallization which is important in later stage development and manufacturing including but not limited to large scale up processes. Single crystals suitable for single crystal X-ray diffraction were obtained with meloxicam and two of the coformers, fumaric and succinic acid. Some of the meloxicam cocrystals exhibited enhanced pharmacokinetic (PK) profiles in rats exemplifying significantly higher serum concentrations after only fifteen minutes and consistently higher exposure over the time studied while others maintained lower exposure. This reveals that cocrystals can fine tune the PK profile of meloxicam in order to reduce or enhance exposure.
Two different sulfonate salts, 4-hydroxybenzenesulfonate (p-phenolsulfonate) and 4-chlorobenzenesulfonate, of the anti-spastic agent (R,S) baclofen were developed by strategically interrupting the intramolecularly stabilized zwitterionic structure of baclofen. This zwitterionic structure results in low solubility associated with physiological pH required for intrathecal administration. Structural data for both salts in the form of single crystal X-ray diffraction data was successfully obtained. Solubility based on baclofen was assessed and shown to increase in pure water and at pH's 1 and 7. Only the 4-chlorobenzenesulonate salt maintained an increased solubility over two days at pH 7 making it a viable candidate for further study in terms of intrathecal administration. During crystallization experiments with (R,S) baclofen two polymorphic forms of the baclofen lactam were generated, Forms II and III. Both forms are conformational polymorphs confirmed by single crystal X-ray diffraction and Form II has a Z' of 4 with an unusual arrangement of enantiomers.
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The Role of Cocrystals in Solid-State Synthesis of Imides and the Development of Novel Crystalline Forms of Active Pharmaceutical IngredientsCheney, Miranda L. 09 November 2009 (has links)
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.
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Crystal Engineering of Multi-Component Crystal Forms: The Opportunities and Challenges in DesignClarke, Heather Dawn Marie 01 January 2012 (has links)
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.
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Stability of Pharmaceutical Cocrystal During Milling: A Case Study of 1:1 Caffeine-Glutaric AcidChow, P.S., Lau, G., Ng, W.K., Vangala, Venu R. 2017 June 1927 (has links)
Yes / Despite the rising interest in pharmaceutical cocrystals in the past decade, there is a lack of research in the solid processing of cocrystals downstream to crystallization. Mechanical stress induced by unit operations such as milling could affect the integrity of the material. The purpose of this study is to investigate the effect of milling on pharmaceutical cocrystal and compare the performance of ball mill and jet mill, using caffeine-glutaric acid (1:1) cocrystal as the model compound. Our results show that ball milling induced polymorphic transformation from the stable Form II to the metastable Form I; whereas Form II remained intact after jet milling. Jet milling was found to be effective in reducing particle size but ball milling was unable to reduce the particle beyond certain limit even with increasing milling intensity. Heating effect during ball milling was proposed as a possible explanation for the difference in the performance of the two types of mill. The local increase in temperature beyond the polymorphic transformation temperature may lead to the conversion from stable to metastable form. At longer ball milling duration, the local temperature could exceed the melting point of Form I, leading to surface melting and subsequent recrystallization of Form I from the melt and agglomeration of the crystals. The findings in this study have broader implications on the selection of mill and interpretation of milling results for not only pharmaceutical cocrystals but pharmaceutical compounds in general.
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