Theses and Dissertations from UMD
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Item INTEGRATED PROCESS MODELING AND EXPERIMENTAL ANALYSIS FOR OPTIMIZING CONTINUOUS MANUFACTURE OF DRUG SUBSTANCE CARBAMAZEPINE(2024) Kraus, Harrison; Choi, Kyu Yong; Chemical Engineering; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)This dissertation presents a comprehensive study on the continuous manufacture (CM) of the drug substance (DS) carbamazepine (CBZ), a widely used anti-epileptic medication, aimed at enhancing process efficiency and product quality. The research progresses through a series of investigations, beginning with the development of kinetic models for CBZ synthesis from iminostilbene via two different synthetic routes using urea and potassium cyanate across various reactor setups, including batch and continuous flow systems. Discrepancies between batch and continuous models, particularly in yield prediction and impurity formation, are thoroughly examined and addressed through adjustments in reactant addition methods and system designs. This demonstrates the value of mechanistic modeling, a tool that has been undervalued in recent research particularly for its ability to compare between batch and continuous systems. Subsequently, the research delves into the crystallization processes, employing a population balance model (PBM) to study CBZ polymorph form III crystal formation, highlighting the influence of seed crystal size distribution on product crystal quality. It also provides novel strategies for modeling the evolution of crystal size distribution (CSD) due to nucleation and growth and evaluates the robustness of these strategies as seed CSD varies. Lastly, the scope is expanded to a holistic view of the integrated synthesis and crystallization process presenting one of the first studies of a complete DS CM system and emphasizing the development of a robust Quality-by-Control (QbC) framework. This includes the implementation of in-line Raman spectroscopy for real-time concentration monitoring, an active feedback level control system, dynamic modeling of impurity partitioning for enhancing disturbance mitigation across the CM process, and a retrograde design strategy that optimizes the upstream synthesis based on downstream purification capabilities/limitations. Through all these contributions, the dissertation aims to advance the modernization of continuous manufacturing practices in the pharmaceutical industry and promotes a shift towards more adaptive and controlled production environments.Item Nanostructured Reactive Metals, Alloys, and Composites: Aerosol- and Laser-Assisted Synthesis, Assembly, and Characterization for Tunable Energy Release(2022) Ghildiyal, Pankaj; Zachariah, Michael R.; Chemistry; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Nanostructured heterogeneous energetic materials are a class of high-energy materials that utilize intimately mixed fuel and oxidizer particles to rapidly release a large amount of stored chemical energy in the form of heat, light, and intense pressures. Developing robust and scalable strategies to modify the structural features of these materials to tailor their energy release behavior is paramount to their success in large-scale propellant applications, which demand a consistent and predictable delivery of the stored material energy. This dissertation explores a multi-scale structure modification (nano-micro-macro) approach to achieve tunability in the functional energetic properties of reactive metal-based nanoscale fuels. Specifically, I have developed scalable aerosol- and laser-assisted techniques for the synthesis and assembly of nanostructured reactive metals, alloys, and their composites. This dissertation also identifies key fabrication, design, and assembly parameters that enable the tuning of material structural features such as particle size, composition, aggregate morphology, microstructure, and porosity. Additionally, the role of these structural modifications on their functional properties such as energy density, oxidation behavior, reaction pathways, ignition, and energy release characteristics has been extensively studied. Therefore, through these investigations, the dissertation establishes the critical process design-structure-property-function relationships in metal-based fuel systems. To achieve structural and reaction control on the nanoparticle scale, three strategies are explored. First, a vapor-phase route to surface-pure, core−shell nanoscale magnesium particles (Mg NPs) is employed, whereby controlled evaporation and growth are used to tune nanoparticle sizes and their size-dependent oxidation and energy release behavior are evaluated. Through direct observations from extensive in situ characterizations, I demonstrate that the remarkably high reactivity of Mg NPs (up to 10-fold higher than Al NPs) is a direct consequence of enhanced vaporization and Mg release from their high-energy surfaces that result in the accelerated energy release kinetics from their composites. Secondly, the synergistic role of Mg NP additives in inducing heterogeneous etching reactions on the surface of boron nanoparticles is studied. Specifically, I show that Mg NPs rapidly release vapor-phase Mg (~100 µs), which reacts exothermically (∆H_r= -420 kJ mol-1) with the molten B2O3 layer and assists in its removal during the reaction, causing ~6-fold reactivity enhancement and ~60% reduction in the burn times of boron. A third approach utilizes an in-flight surface modification of Mg NPs with a reactive element (Si) to form core-shell Mg-Si nanoparticles. Through mechanistic investigations of these systems, I find that the Si-coated Mg NPs themselves undergo an intraparticle condensed-phase alloying reaction between the Mg core and Si shell at relatively low-temperatures (400-500°C), resulting in highly accelerated reaction rates (~3-9-fold shorter reaction timescales) and lower ignition temperatures (~210°C lowering) than unfunctionalized Mg particles. Next, two aerosol-phase assembly techniques are explored to control the micron-scale structural and aggregation features of metal nanoparticle assemblies. First, an electrospray approach is used to incorporate plasma-synthesized ultrasmall Si particles to fill in the void structure of Al-based microparticles to augment their volumetric energy density and reactivity. This approach results in ~21% enhancement in energy density due to partial filling of structural voids and ~2-3-fold enhancement of reaction rates due to enhanced transport in ultrafine silicon particles. Another vapor-phase assembly approach employing external magnetic fields during synthesis is explored in directing the in-flight assembly of ferromagnetic metal nanoparticles into distinct aggregate morphologies with altered fractal dimensions. For control over the macroscale features of nanostructured composites, three robust and scalable techniques are employed. The first method utilizes spray drying as a highly scalable approach (production rates up to ~275 g h-1) to assemble metal and oxidizer nanoparticles into microparticle composites with ~2-7-fold higher reactivities than their physically mixed counterparts as a result of rapid gas generation and reduced nanoparticle sintering. I further demonstrate that these nanostructured microparticles can be further processed and additively manufactured into macroscale, hierarchical films (macro-micro-nano) without compromising their structural integrity. The third technique I have developed for macroscale structure modulation is by employing spatially and temporally resolved CO2 laser pulses to fabricate and write a high concentration of unaggregated, sub-10 nm metal nanoparticles directly in polymer films. Using this approach, I demonstrate that laser parameters – pulse duration, laser energy flux, and pulsed thermal loads – can be used for direct, in-situ modulation of particle size distributions of metal nanoclusters in polymer matrices. Rapid heating timescales employed in this approach allow for the scalable manufacturing and structural control of metal nanoclusters with production rates up to 1 g min-1. In conjunction with each other, all three techniques enable high-yield manufacturing of metal-based composites with a broad, nano- to macro-scale structural control. Finally, the structure and reaction modulation strategies are suggested for other fuel systems such as nanoscale reactive alloys (Al-Mg) to achieve controllable energy release behavior through further modifications of fuel composition and morphological features. The techniques developed in this dissertation will allow the strategic design of metal-based nanostructured energetic composites with tailored energy release rates and controllable structural features over a wide range of length scales.Item SYNTHESIS OF PNAG ANALOGS TO PROFILE BIOFILM GLYCOSIDASES(2021) Wang, Shaochi; Poulin, Myles; Chemistry; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Bacteria biofilms consisting of surface-attached bacterial communities embedded in an extracellular matrix serve as a defense mechanism for many medically important bacterial species. Exopolysaccharides of partially de-N-acetylated poly-β-D-(1->6)-N-acetyl-glucosamine (dPNAG) are key structural components in the biofilm of many human pathogens. Dispersin B (DspB), a family 20 glycoside hydrolase produced by the Aggregatibacter actinomycetemcomitans, catalyzes the hydrolysis of dPNAG to disrupt biofilm formation leading to its use as an aniti-biofilm agent. Yet little is known of substrate recognition by DspB.Here, we describe the synthesis of two series of PNAG trisaccharide analogs with defined N-acetylation pattern (2.1 – 2.5) or containing glucose moiety (2.32 and 2.33) prepared through an iterative one-pot glycosylation approach and used to profile the activity and substrate preference of DspB (Chapter 2). These studies suggest that DspB hydrolyzes dPNAG polysaccharides via both exo- or endoglycosidase mechanisms and has a substrate preference for cationic substrates at the +2 position of the binding site. Understanding the activity and specificity of DspB provides a valuable guide to develop biocatalyst with improved biofilm dispersal activity. Next, colorimetric (Chapter 3) and fluorogenic (Chapters 4 & 5) PNAG analogs were developed as substrates for high-throughput PNAG glycosidase assay development. PNAG disaccharide probes (3.1 and 5.1) demonstrate exclusive specificity for enzymes capable of hydrolyzing PNAG and monosaccharide analog AMC-GlcNAc (4.1) acts as a general hexosaminidases enzyme substrate. We showed that all the analogs can detect DspB activity in crude E. coli cell lysates, and thus could be applied for functional metagenomic screening to discover novel PNAG glycosidase enzyms. Finally, a series of PNAG triazinyl glycosides (6.1, 6.2 and 6.3) were designed, synthesized and evaluated as affinity labeling reagents for PNAG binding proteins, using a catalytically inactive DspB E184Q mutant as a model PNAG binding protein (Chapter 6). However, only non-specific background signal was observed. In the future, recombinant enzymes or lectins that have higher binding affinity to the PNAG might be used to revisit these labeling results.Item Biomimetic polymer based composites with 1-D titania fillers for dental applications(2018) Mallu, Rashmi Reddy; Lloyd, Isabel K; Material Science and Engineering; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)The aim of this study was to develop acrylic matrix composites reinforced with one-dimensional (1-D) titanium dioxide (TiO2) micro and nano fillers that mimic the structure of enamel. To accomplish this, 1-D TiO2 was synthesized without surfactants or templates using a sol-gel assisted hydrothermal process. Two different approaches were investigated. One used titanium metal powder and yielded TiO2 rutile microrods. The other used titanium tetraisopropoxide (TTIP) and created TiO2 anatase nanorods. TiO2 morphology (size, aspect ratio and state of agglomeration) was affected by glycolic acid concentration and phosphate ion concentration for the titanium metal-based powders, and NaOH concentration for TTIP based powders. Composites were made with silanized TiO2 micro- and nano-rods in a 50:50 BisGMA:TEGDMA matrix. Organized composites made by injection molding or centrifuging and settling had more uniform mechanical properties (hardness, strength, Young’s modulus and toughness) than unorganized composites. Curing the composites under pressure reduced porosity enhancing mechanical behavior.Item Building Block Synthesis and Recognition Properties of Cucurbit[n]uril (n = 7, 8) Derivatives(2015) Vinciguerra, Brittany Marie; Isaacs, Lyle; Chemistry; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Molecular containers have been a topic of interest for chemists since the discovery of crown ethers and their molecular recognition properties in the late 1960’s. Since then, the field of molecular containers has expanded rapidly to include many high affinity and highly selective host molecules. Chapter 1 introduces common molecular containers and goes on to discuss the CB[n] family of molecular containers. The CB[n] family are an exemplary group of hosts because they exhibit extremely high affinities (Ka values up to 1017 M-1) and high selectivity towards their guests which make them excellent candidates for many supramolecular applications. In order to maximize the use of CB[n], it became important to access specialized and functionalized derivatives to cater to various applications and chemistry. Early functionalization routes were limited by a lack of mechanistic understanding, but the mechanistic work of the Isaacs, Kim, and Day groups led to more successful syntheses. Chapter 2 discusses a building block synthesis towards water-soluble CB[7] derivatives Me2CB[7] and CyCB[7]. The recognition properties of Me2CB[7] are investigated as well as its use in drug solubilization. It is found that Me2CB[7], though 10 times more water soluble than CB[7], is able to solubilize drugs only as well as CB[7]. Additionally, a route towards a monofunctionalized CB[7] derivative, Cl-CB[7], bearing a primary chloride which is able to undergo further functionalization to a clickable azide by SN2 chemistry is presented. A click reaction with a small alkyne is performed resulting in a self-associating host whose self-assembly process is further investigated. Chapter 3 discusses a building block synthesis towards the first water-soluble CB[8] hosts Me4CB[8] and Cy2CB[8]. Mechanistic details of the CB[8] formation are elucidated from contrasting experiments and the recognition properties of the CB[8] derivatives are investigated by 1H NMR spectroscopy and X-ray crystallography. The CB[8] derivatives are investigated as potential drug solubilizing agents and it is found that they are able to solubilize several larger pharmaceutical molecules whereas CB[8] is water insoluble.Item Synthesis and Characterization of Products Produced from Aluminum Monohalide Precursors(2015) DeCarlo, Samantha; Eichhorn, Bryan W; Chemistry; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)In this thesis, the synthesis, characterization and applications of aluminum compounds and cluster from aluminum monohalide solutions, AlX (where X = Cl or Br) are described. Chemistry of AlX solutions is not well understood, but AlX has proven adept at producing aluminum metalloid clusters (AlnLm where n>m). A brief overview of the renaissance of low-valent aluminum chemistry and select low-valent Al products is presented as background. The neutral mononuclear aluminum tris-bpy complexes [Al(Mebpy)3] and [Al(tBubpy)3] have been synthesized, isolated, and structurally characterized via X-ray single crystal diffraction. These complexes are the first structurally characterized homoleptic tris-bpy complexes and were studied via ESI-MS, d.c. magnetic susceptibility, electrochemical analyses. Electrochemistry demonstrates that six oxidation states are accessible from both neutral complexes: [Al(Rbpy)]n (n = -3 to 3, R = Me or tBu). The [Al(Mebpy)3] complex demonstrates unexpected magnetic ordering at 19 K which is not observed in [Al(tBubpy)3] nor in transition metal centered tris-bpy congeners. Synthesis, isolation, and characterization of the low-valent aluminum cluster [LiOEt2]2[HAl3(PPh2)6] via NMR and ESI-MS studies are also described. These experiments proved the presence of an H atom, and developed a complete and comprehensive picture of the structure, magnetism, and spectroscopy of this compound. Solution studies of reactions of AlBr with tBu-thiolate via ESI-MS show the formation and identification of [Al17Br(StBu)10S3]1-, [Al10(StBu)4S5]1-, [Al13(StBu)4BrS]1-, and [Al5(StBu)7Br]1-¬ in solution. The preparation and characterization of the aluminum (III) thiolate complex, Na[Al(SPh)4], is also described. These studies demonstrate the importance of reaction conditions in the formation of aluminum clusters in solution, and the viability of thiolate ligands to isolate low-valent aluminum products. Al nanoparticles (NP) can be produced from AlX solutions and have been successfully supported on both graphene and graphene oxide. The reduction of AlX solutions are quick, facile, and performed at low temperatures (-78°C). In the presence of graphene, faceted and well-dispersed graphene supported Al-NPs can be obtained. The [AlBrNEt3]4 cluster is isolated from AlBr⋅NEt3 solution and is soluble in toluene and diethyl ether. The burning rate of the hydrocarbon fuel doped with the tetramer is studied. There is an increase in burning rate attributed to the presence of [AlBrNEt3]4.Item Acyclic Congeners of Cucurbit[n]uril and a Related Mechanistic Study on the Cucurbit[n]uril Forming Reaction.(2010) Ma, Da; Isaacs, Lyle D; Chemistry; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Supramolecular chemistry has been a very important research area in the past several decades. In this research field, molecular containers, such as cyclodextrin, attracts special attention due to their wide applications both in academia and industry. Cucurbit[n]uril (CB[n]), as a new generation molecular container, has selective and tight binding towards lots of cations and neutral molecules. A homologous family of CB[n] has been discovered including CB[5]-CB[8], CB[10], iCB[n], ns-CB[10] and ns-CB[6]. CB[n] analogues and derivatives have also been developed. CB[n] still has several issues, such as low solubility in water, difficulty to be functionalized, and slow association and dissociation kinetics. This thesis describes efforts to address these issues by developing new CB[n] type molecular containers and carrying out mechanistic investigations. Three chapters are included in this thesis. Chapter 1 is a literature review of molecular encapsulation and molecular container chemistry. We first introduced general concepts of molecular encapsulation and present examples of molecular container, such as cyclodextrin. This is followed by an introduction to CB[n] molecular containers and their supramolecular chemistry. Chapter 2 introduces new acyclic CB[n] congeners II-5a and II-5b. II-5a and II-5b are obtained from step-wise synthesis with reasonable yields. This step-wise synthetic route avoids difficult separation process. We measured the binding constants of II-5a towards a number of guests and found the binding affinity is usually comparable to CB[7]. The recognition property of II-5a is investigated in depth. We found that the length and functional groups of the guests greatly influence the binding affinity. Nevertheless, the charge and size of the guests do not have as a big influence on the binding constants as CB[7]. We discovered that the ionic strength of the buffer is critical for the binding constant. By comparing the recognition property of II-5a and II-6, it is discovered that the substituted o-xylyene walls are important for the tight binding compounds. II-5a and II-5b are new examples of CB[n] type molecular containers. They retain most of the good recognition property of CB[n] and have advantages compared to CB[n], including 1) aromatic walls that makes further functionalization possible; 2) acyclic structure that enables fast association and dissociation kinetics. Chapter 3 describes the mechanistic study of CB[n] forming reactions. Another possible way to synthesize CB[n] molecular container is to use aldehydes instead of paraformaldehyde. But neither previous researchers nor our work has succeeded to make the aldehydes participating CB[n] forming reactions happen. Mechanistic investigation was carried out to explain why this reaction simply does not occur. We used III-7 instead of glycoluril to avoid cyclization reactions. Several reasons are discovered: 1) side products are formed, such as III-SP1 and III-SP2; 2) S-shape intermediates are yielded, such as III-15S, III-16S, III-17S and III-18S, which are not able to continue the reaction to form macrocycles; 3) a small equilibrium constant for the chain grouth reaction. This study explains why aldehydes usually do not participate in CB[n] forming reactions. This work could also lead to the discovery of certain aldehydes that can form CB[n] type macrocycles.