Theses and Dissertations from UMD
Permanent URI for this communityhttp://hdl.handle.net/1903/2
New submissions to the thesis/dissertation collections are added automatically as they are received from the Graduate School. Currently, the Graduate School deposits all theses and dissertations from a given semester after the official graduation date. This means that there may be up to a 4 month delay in the appearance of a give thesis/dissertation in DRUM
More information is available at Theses and Dissertations at University of Maryland Libraries.
Browse
8 results
Search Results
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 Strategies for small RNA loading into extracellular vesicles(2022) Pottash, Alex; Jay, Steven M; Bioengineering; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Small RNAs are an exciting class of therapeutics with significant untapped therapeutic potential, due to their ability to affect cell behavior at the RNA level. However, delivery of RNA is a challenge due to its size and labile nature. Extracellular vesicles (EVs) are promising as delivery vehicles due to their natural role as physiological intercellular microRNA transporters, and research has shown that EVs have significant advantages compared to competing technologies such as lipid nanoparticles. Specifically, EVs more readily transport through biological barriers, deliver RNA more efficiently, and are less immunogenic. However, intrinsic microRNA content in EVs is low and thus active small RNA loading strategies are needed to enable therapeutic use. Consequently, a variety of small RNA loading methods for EVs have been developed. These include endogenous and exogenous approaches. Exogenous approaches, in which EVs are loaded directly, have been shown to enable loading of hundreds to thousands of small RNAs per EV, but they are not readily amenable to scalable production processes. Endogenous approaches, in which EVs are loaded by upstream manipulation of the producer cell, are compatible with large scale EV production, but loading by these approaches is inconsistent and has scarcely been quantitatively analyzed. The work in this dissertation is focused on enabling small RNA therapeutics via EV delivery. The lack of an ideal small RNA loading approach for EVs is addressed by tackling important issues of both endogenous and exogenous loading. First, the loading capacity of several common endogenous loading methods was optimized and quantitatively analyzed. Additionally, new approaches to endogenous small RNA loading involving genetic manipulation of the RNA structure and the microRNA cellular processing pathway were developed and evaluated. Finally, exogenous loading via sonication was applied to enable delivery of a novel microRNA combination that was identified via a rational selection process. This combination of miR-146a, miR-155, and miR-223 was found to have potentially synergistic anti-inflammatory activity, and EV-mediated delivery of the combination opens the possibility for therapeutic application in inflammatory diseases and conditions such as sepsis. Overall, this work both improves understanding of current techniques for small RNA loading into EVs and opens new opportunities for advanced strategies, bringing EV-based small RNA therapeutics closer to clinical application.Item PROBING BIOPHYSICAL PROPERTIES OF THERAPEUTIC PROTEIN AGGREGATES WITH INTERFEROMETRIC SCATTERING MICROSCOPY(2021) Wong, Nathan A; Woehl, Taylor J; Chemical Engineering; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)A growing biopharmaceutical market increases the importance of therapeutic proteins, of which monoclonal antibodies (mAb) are the largest category. Protein aggregation in biopharmaceutical production has important consequences in mAb immunogenicity. Submicron (100-1000 nm) protein aggregates in particular are a key challenge due to their higher immunogenicity and the relative lack of analytical methods capable of characterizing them. We propose the use of interferometric scattering (IFS) microscopy as a simple and potentially high-throughput orthogonal characterization method of submicron aggregates. We demonstrate its utility by testing two variants of IFS microscopy: (1) Correlative IFS and fluorescence microscopy (2) hyperspectral interferometric scattering (h-IFS) microscopy. Using correlative IFS and fluorescence microscopy, we characterize the size and surface structure of a stirred protein aggregate sample. We find that smaller protein aggregates (~100 nm) have higher surface concentrations of Fc domains and hydrophobic regions. Then, we demonstrate the usage of h-IFS microscopy to differentiate and quantify protein aggregates and contaminants in biologic drugs.Item The manufacture, solubility and stability of hypodermic tablets containing morphine salts(1950) Scigliano, John Anthony; Digital Repository at the University of Maryland; University of Maryland (College Park, Md)Item The role of particle size and shape in the preparation of tablets(1951) Kregiel, Ludmila; Digital Repository at the University of Maryland; University of Maryland (College Park, Md)Item Experiments with the pressure cooker in drug extraction(1948) Greco, Salvatore Joseph; Digital Repository at the University of Maryland; University of Maryland (College Park, Md)Item A comparison of the physical properties and absorption rates of compressed tablets made from microcrystalline and regular sulfadiazine(1950) McKinley, James David; Digital Repository at the University of Maryland; University of Maryland (College Park, Md)Item Investigation of Intercellular Adhesion Molecule-1 Targeted Drug Transport Across the Gastrointestinal Epithelium(2015) Ghaffarian, Rasa; Muro, Silvia; Bioengineering; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Contrary to systemic injection of therapeutics, oral formulations represent clear advantages to patients, healthcare systems, and pharmaceutical companies including safety, low cost and patient compliance. However, oral delivery remains a major obstacle due to (1) drug instability in the harsh environment of the gastrointestinal (GI) tract owing to low gastric pH and enzymatic hydrolysis; (2) low permeability through the mucus layer and subsequent adhesion to the GI epithelium; and (3) suboptimal transport into or across the GI epithelium- the cell barrier responsible for selective absorption of substances into the circulation, for local or systemic delivery. While encapsulation methods have been developed to overcome barriers to stability and adhesion to the GI epithelium, safe and effective transport into and across this lining has not yet been achieved for several drugs, especially biotherapeutics. Hence, our goal is to overcome these challenges for delivery of therapeutics (including biotherapeutics) via the oral route. For this purpose, we targeted drugs to intercellular adhesion molecule-1 (ICAM-1), a protein expressed on the GI epithelium and other cell types. We previously demonstrated, that polymer nanocarriers (NCs) coated with antibodies to bind multiple copies of ICAM-1 (multimeric targeting) triggered uptake and transport across cultured GI epithelial cells, enabling intracellular and transcellular drug delivery. To implement this strategy in vivo, we successfully encapsulated antibody-coated NCs in chitosan-alginate microspheres for gastric protection of labile targeting antibodies, site-specific release in the intestinal environment (the site of drug absorption) and retention of targeting ability following release in vitro, in cell culture, and in vivo. Furthermore, to expand the utility of the ICAM-1 targeting approach, we explored a novel drug delivery system that binds only one to two molecules of ICAM-1 (monomeric targeting), which provides distinct advantages for oral drug delivery compared with multimeric strategies. In order to elucidate the advantages offered by this monomeric targeting approach, we compared the uptake and intracellular trafficking of ICAM-1 targeted monomeric antibodies vs. multimeric antibody-coated NCs in cultured endothelial cells, a commonly used cellular model to study ICAM-1 transport. We then revealed that the distinct itinerary of transport offered by monomeric ICAM-1 targeted antibodies led to enhanced uptake and transport across cultured GI epithelial cells, showing promise for oral delivery. Finally, in order to exploit this transport pathway for oral drug delivery, we conjugated a model drug cargo to monomeric ICAM-1 targeted antibodies, which was shown to endow drug targeting and delivery into and across cultured GI epithelial cells, while preserving the functional activity of the drug cargo. These findings demonstrate that monomeric vehicles serve as a viable alternative to multimeric strategies, expanding the range of oral delivery applications afforded by ICAM-1 targeting. Taken together, the work performed in this dissertation advocates the potential of ICAM-1 targeting strategies for improving oral absorption of therapeutics, and provides a foundation for studying these strategies in vivo.