Chemistry - Doctoral Theses

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    Electrochemical sensors for integration on silicon
    (University College Cork, 2022-03-31) Barry, Fiona; Rohan, James; Nagle, Lorraine; Science Foundation Ireland; Analog Devices; Department of Agriculture, Food and the Marine, Ireland
    Water quality monitoring is crucial to ensure the safe consumption of drinking water by humans. It is of such importance that the UN has included a specific goal for the improvement of water and sanitation in their Sustainable Development Goals (SDG). According to the UN, a staggering 3 in 10 people are without access to safely managed drinking water. At present the standard method for water quality monitoring is by laboratory testing. These typically require transportation of the sample from source to the laboratory, additional reagents, and specialised personnel and equipment to carry out the analysis. In this thesis, electrochemical methods at micro-electrodes are explored and developed for reagent-free, point-of-care analysis that does not require the need for specialised training. The main goal of the thesis is to develop low-power micro-sensors for point-of-care analysis. To achieve this, interdigitated micro-electrodes were investigated wherein each comb of electrodes could be biased separately allowing for unique analysis opportunities. Discussed herein simulations of electrode geometries are used to establish the optimum design for the interdigitated electrode arrays. The fabricated interdigitated arrays are subsequently modified with nanoporous gold resulting in an increase in current for the detection of lead by 1.5-fold. These modified interdigitated electrodes successfully detected lead in 0.1 M acetate buffer pH 4.6 with a limit of detection of 0.43 ppb. However, issues arise when applying these electrodes to reagent-free tap water, where there is no discernible peak for lead seen below 50 ppb. To overcome this obstacle the interdigitated arrangement of the electrodes can be used to electrochemically control the pH of tap water without the need for additional reagents. This leads to the successful detection of lead in tap water to as low as 10 ppb.
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    Synthesis of novel quorum sensing inhibitors of DSF
    (University College Cork, 2022) Horgan, Conor; O'Sullivan, Tim; Irish Research Council; Higher Education Authority
    Antimicrobial resistance (AMR) has become a growing concern among the medical community with many previously effective antibiotics losing their efficacy. Much of this AMR is thought to stem from biofilm formation controlled by cell-to-cell signalling. Chapter 1 introduces quorum sensing with a particular focus on the Diffusible Signal Factor (DSF) family of autoinducers. Given that these molecules contain a carboxylic acid, this chapter also contains a review of the literature relating to carboxylic acid bioisosteres which have emerged since 2013. Quorum sensing interference is an increasingly attractive target for combatting bacterial infections. Accordingly, the work in this thesis focusses on the synthesis of sulfonamide-based bioisosteric derivatives of Burkholderia DSF (BDSF). In Chapter 2, 15 novel N-acyl sulfonamide analogues of BDSF are prepared and tested for biological activity. Some of these compounds display significant activity against many strains of bacteria both in vitro and in vivo. The cis-α,β-unsaturated double bond, a key factor in the biological activity of BDSF, is susceptible to isomerisation. The preparation and subsequent biological evaluation of 16 potentially more stable aromatic N-acyl sulfonamide analogues of BDSF is detailed in Chapter 3. Many of these compounds significantly inhibited biofilm formation and enhanced the efficacy of last-resort antibiotics against S. maltophilia and B. cenocepacia. In Chapter 4, X. fastidiosa, a bacterium responsible for diseases such as olive quick decline syndrome, is introduced. Some of the aromatic N-acyl sulfonamide analogues inhibited the formation of biofilm biomass and cell growth in the bacterium. The synthesis and subsequent testing of the parent signalling molecules and aromatic analogues containing a longer alkyl chain is also described. A practical synthetic route to a new class of aryl sulfonamide analogues of BDSF is presented in Chapter 5. Using SwissADME and MarvinSketch, important ADME properties of a virtual library containing 16 potential aryl sulfonamides, and the pre-existing olefinic and aromatic N-acyl sulfonamides are analysed to determine their suitability as drug candidates.
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    SMARTProbe, a needle integrated with a portable handheld impedance analyser for real-time breast disease detection
    (University College Cork, 2022-05) Ugwahy, Anulika Justina; Moore, Eric; O'Donnell, Brian; O'Sullivan, Martin; Irish Research Council for Science, Engineering and Technology; Cork Academy of Regional Anaesthesia
    Breast cancer is common, affecting 2 out of 10 women with a suspicious lesion. There is no real-time preoperative diagnosis for breast disease. The triple assessment for detection includes a self/clinical breast examination, a mammogram, and an ultrasound-guided biopsy with histological evaluations. Different technologies are being researched to enhance the diagnostic pathway. The addition of novel technology to existing diagnostic tools and processes might provide greater diagnostic accuracy and expedite the time to arrive at a definitive diagnosis. Bioimpedance is a fast, non-destructive technique that can be investigated for real- time detection of breast disease. Alterations in the electrochemical properties of the breast, which occur with metaplastic and neoplastic cellular proliferation, can be identified and monitored using bioimpedance. Impedance measurements can give quantitative information and a signature of the electrical properties of tissue. The current clinical pathway review identified that the biopsy procedure could be improved. The design and fabrication of sensors on a Core Needle Biopsy were explored to evaluate the electrical properties of breast tissue. Nanoscale imaging and composition analysis of sensor surfaces were used to investigate the fabricated sensors. Electroanalytical characterisations of the needle sensors were performed in solutions of known concentrations. Tissue-mimicking breast phantoms were developed and interrogated with the device developed. A prototype integrating the needle sensors and a 3D printed biopsy firing mechanism was achieved. The clinical investigation of the excised breast tissue using the developed sensors was conducted at the Cork University Hospital (CUH). The bioimpedance sensor evaluated the differences in the electrical properties of excised healthy and diseased breast tissue. The results were analysed, and a preliminary prediction model examined the discriminatory ability of the device. The bioimpedance results for excised tissue type were correlated with histological reports. Hence, this research contributes to the proof of concept in ex-vivo breast tissue that will guide the in-vivo clinical investigation. The future work required to demonstrate the technology in a real-space environment is also detailed. This biomedical prototype designed, fabricated, and characterised in this thesis is called the SMARTProbe. The SMARTProbe's novelty lies in being a hand-held biopsy system with a tissue discrimination function. Commercially available pre-and intra- operative technologies in breast disease management are not miniaturised like the SMARTProbe. The device can be easily adapted to the current clinical diagnostic pathway to provide more information on tissue type at the needle location during a biopsy procedure. It is envisaged that the device will enhance representative sampling, reducing the number of cores taken. The technology will improve the biopsy procedure for both the patient and the radiologist. The different processes used in the fabrication process are easily translated to large scale manufacturing as they are already used in the biomedical device industry.
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    Applications of Broadband Acoustic Resonance Dissolution Spectroscopy (BARDS) in pharmaceutical analysis
    (University College Cork, 2022-02-08) O'Mahoney, Niamh; Fitzpatrick, Dara; National University of Ireland
    Dissolution testing is one of the most time-consuming, costly, and laborious tasks in the pharmaceutical industry, and yet it is a cornerstone of quality control testing and product release. Dissolution testing is a prerequisite for the quality control and release to market of nearly every prescription and over the counter product. It is one of the few technologies which has not undergone disruption of any kind. Practices have changed little in decades, with liquid samples being taken at regular intervals over several hours and tested using expensive analytical instruments. Most routine testing can take upwards of a day to perform. Speeding up these processes is vital. This thesis highlights a modern complementary approach to existing dissolution testing practices for powder, pellet, tablet and liquid formulations called Broadband Acoustic Resonance Dissolution Spectroscopy (BARDS). BARDS is an innovative technique that can economise production processes for drug formulations. BARDS is based on reproducible changes in a solvent's compressibility as a sample dissolves. It is a rapid and straightforward method that utilises a magnetic stir bar to mix added solute and induce a vessel's acoustic resonance containing a fixed volume of solvent. As a sample is wetted and subsequently dissolved, gas is released from the solvent, altering the resonance frequency. Adding a solute to a solvent reduces the solubility of dissolved gases in solution, leading to gas oversaturation and outgassing of the solvent, changing the solvent system's compressibility, and reducing the velocity of sound in the solvent. In the results section of this thesis, Broadband Acoustic Resonance Dissolution Spectroscopy (BARDS) is used to characterise several pharmaceutical formulations, including enteric-coated microspheres, tablets and multiple-unit pellet systems (MUPS). Effervescent tablets, chewable tablets and liquid formulations were also analysed. A single replicate BARDS measurement can provide data relevant to multiple dissolution processes in a time-efficient manner by tracking the Erosion of the enteric coating, Disintegration, Deaggregation and overall Dissolution of the formulations while assessing the formulation's integrity using an EDDDI Plot. BARDS can determine the thickness of the drug and enteric coatings, characterise various dosage forms and test formulation integrity. Ultra Violet -Visable Spectroscopy (UV-Vis) has been used in the cross-validation of the technique. Tablets, pellets, and multiple-unit pellet system (MUPS) formulations were examined to investigate the effect of polymer coating and formulation core degradation over time. BARDS can enable the rapid development of solid drug formulation dissolution and disintegration testing as an In-Process and In-Line Control test and drug stability analysis. In combination with minimal Ultra Violet - Visible Spectroscopy usage, BARDS can effectively track these changes, therefore assessing a formulation's stability. BARDS data also indicates which aspect of a formulation may be unstable, whether a coating, sub-coating or core. Paediatric and geriatric formulations were studied in detail in this thesis. Chewable, effervescent and liquid dosage forms were characterised for formulation attributes using BARDS. Nutraceutical and pharmaceutical chewable and effervescent formulations were investigated in tablet form to examine how the formulation disintegrates and dissolves. The data show that a solid oral dose formulation has an intrinsic acoustic signature specific to the method of manufacture and excipient composition. Effervescent tablets disintegrate rapidly due to a chemical reaction. The reaction causes carbon dioxide gas production and subsequent release, resulting in the characteristic effervescent fizz, which can be tracked acoustically using BARDS. This thesis will highlight BARDS as a rapid characterisation technique to track the chemical reaction associated with effervescent dosage forms. BARDS can be used as an analytical tool to quantify the dissolution of liquid formulations. This has been demonstrated by a test model using two different liquid formulation types, suspension formulations and syrup formulations. Similarities between different brands were apparent when tested. BARDS can qualitatively discriminate between Active Pharmaceutical Ingredient (API) dosage, API type, and discriminate whether an API has been partially dissolved in the suspension media before addition to the BARDS instrument. In conclusion, various applications with the tremendous novelty of this platform technology have been proven. This project can potentially impact the methodology for dissolution testing with a high capability to influence regulatory policies and practices worldwide. BARDS can enable the rapid development of solid drug formulation dissolution and disintegration testing as an in-process control test and drug stability analysis. The data shows that a dosage formulation has an intrinsic acoustic signature specific to the method of manufacture, excipient composition and elapsed time since the production of a product. In addition, BARDS is a time-efficient, cost-effective and green approach to formulation characterisation.
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    Studies in the synthesis and analysis of novel heterocyclic synthetic cannabinoid receptor agonists
    (University College Cork, 2022-03-08) Alam, Ryan; Keating, J J; Eli Lilly and Company
    Over the past decade, synthetic cannabinoid receptor agonists (SCRA) have come to represent a diverse category of new psychoactive substance (NPS). However, from a chemical perspective, little is known about the clandestine chemical syntheses of SCRAs. To contextualise the latter paucity of information, this thesis introduces the pharmacological significance of the endocannabinoid system and describes the subsequent advances that have been made to develop synthetic cannabinoid-based therapeutics. The repurposing of cannabinoids that were developed as a part of legitimate drug discovery programmes, for recreational use as illicit NPS, is then discussed with a particular focus on the structural diversity, toxicological adverse effects, legislative control, and chemical characterisation of newly emerging SCRA ligands. Following the assembly of the key heterocyclic building block in the synthesis of indazole-type SCRA ligands, 1H-indazole-3-carboxylic acid, this work describes the development and application of a protocol for the regioselective (>99%) N-1 alkylation of the indazole scaffold to generate a wide range of structurally diverse N-1 substituted indazole derivatives in excellent yield (up to 99%). Additionally, the latter optimised N-alkylation protocol is also shown to regioselectively (> 99%) afford N-2 substituted indazoles. Through the variation of “tail” and “head” group motifs inspired by structural trends observed in newly emerging cannabimimetic SCRA NPS, we have generated a prophetic library of novel 1,3-disubstituted indazole-3-carboxamide derivatives. The subsequent discussion of notable spectroscopic features of these heterocyclic SCRA analogues provides further information of forensic interest. Finally, the development and optimisation of a methodology for an expedient approach to analogous, novel, 1,3-disubstituted pyrazolo[3,4-b]pyridine-3- carboxamide SCRA derivatives in high yield (up to 99%), via palladium-catalysed aminocarbonylation is described. This aminocarbonylation protocol is applied to the synthesis of isomeric 4-, 5-, 6-, and 7-azaindazole analogues of the known illicit indazole SCRA ligand, MDMB-PINACA, to facilitate their unambiguous spectroscopic differentiation and structural confirmation. The latter work provides a robust and convenient methodology for the synthesis of pyrazolopyridine-3-carboxamides and presents the first reported spectroscopic discussion of azaindazole-type SCRA NPS.