Analytical & Biological Chemistry Research Facility - Doctoral Theses

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Now showing 1 - 5 of 48
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    Studies in the synthesis and impurity profiling of pharmacologically active benzodifurans
    (University College Cork, 2022) O'Connor, Richard Eric; Keating, J J; Higher Education Authority
    Substituted 2,3-dihydrobenzofuran derivatives as well as their benzofuran and benzodifuranyl analogues are versatile heterocycles that are increasing in prominence as key building blocks in organic chemistry. In particular, benzodifuran-containing structures are gaining significant interest in medicinal chemistry as pharmacophores and in industrial chemistry as scaffolds for organic electroluminescent devices, organic field-effect transistors, solar cell sensitizers and semiconducting polymers. The synthesis of pharmacologically active benzodifurans are complex multi-step processes and each individual step has the potential for considerable side-product/impurity formation. This project focused on synthetic strategies to benzofuran and benzodifuran derivatives in addition to their hydrogenated and substituted analogues. The chosen synthetic routes to target molecules further focused on the propensity of synthetic steps to produce impurities, modifiable variables to modulate impurity formation and the impurity profile of each synthetic route explored. Organic process impurities identified were isolated and fully characterised where possible, in addition to intended products.
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    Development of rapid analytical separation methods for the detection of NSAIDs in wastewater
    (University College Cork, 2023) Alatawi, Hanan; Moore, Eric; Saudi Arabian Cultural Bureau
    Recently, non-steroidal anti-inflammatory drugs (NSAIDs) have been increasingly used in humans and animals. Despite being effective against a wide variety of diseases, they pose a threat to aquatic environments. Since NSAIDs are poorly degraded and highly water-soluble, they are able to pass through all-natural filtration processes. It has been well known that conventional wastewater treatment plants (WWTPs) were not made to completely remove these compounds because they were not intended to do so. As a result, several pharmaceuticals are released back into the environment. It is essential to develop fast, simple, and reliable analytical methods for detecting NSAIDs in environmental water. Capillary electrophoresis (CE) has been used for many years to determine various classes of pharmaceuticals in various sample matrices due to its advantages of high separation efficiency and rapid analysis time. The interest in CE has led to the miniaturization of microchip electrophoresis (ME). ME has advantages over traditional analysis techniques, such as fast separation, high separation efficiency, low reagent volume, decreased waste generation, and low-power requirement (the maximum voltage that can be used is 3 kV), and its potential of portability and disposability. The goal of this project was to develop novel methods for rapid separation and detection of NSAIDs in wastewater using capillary and microchip electrophoresis with UV and C4D detections. The methods were validated using solid phase extraction(SPE), and two different cartridges (C18 and Oasis HLB) were optimized to enhance the recoveries. The results of the research project showed that NSAIDs compounds could be well separated in less than 1 min and had excellent analytical performances with LODs ranging between 0.125 and 0.5 mg/L. The microchip system has proved to be an excellent analytical technique for fast and reliable environmental applications.
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    Synthesis of novel cycloperoxides
    (University College Cork, 2023) Hennessy, Mary C.; O'Sullivan, Tim; Irish Research Council
    Cycloperoxides represent an important class of compounds for synthetic chemists. Their asymmetric synthesis will be the focus of this thesis, specifically using organocatalysis. Chapter 1 contains a review of organocatalysed peroxidations from the literature and within the research group to date. The key aims and objectives of this project are also outlined. Chapter 2 describes the generation of a diverse library of trans-γ,δ-unsaturated β-keto esters. The preparation of these compounds involves both Wittig chemistry and Lewis acid-catalysed C-H insertion strategies. The synthesis of a cis-γ,δ-unsaturated β-keto ester and a non-enolisable α,α-disubstituted β-keto ester are also outlined. The optimisation of the organocatalysed peroxidation of γ,δ-unsaturated β-keto esters in terms of enantioselectivity and yields is described in Chapter 3. To determine the enantioselectivity of the peroxidation reaction, a robust chiral HPLC methodology is required. The development of a suitable separation methodology is outlined in this chapter. Chapter 4 describes a novel synthetic route to 3,5-substituted 1,2-dioxolane ethyl esters through the chemoselective reduction of a δ-peroxy-β-keto ester to the corresponding δ-peroxy-β-hydroxy ester, and subsequent phosphorus pentoxide-mediated cyclisation. Chapter 5 outlines our preparation of several novel 1,2-dioxolane carboxylic acids and various attempts at subsequently introducing an N-acyl sulfonamide to the 1,2-dioxolane core. Chapter 6 details the main conclusions of this work and proposes several avenues of research to investigate in future. Chapter 7 contains all relevant experimental procedures, including spectroscopic and analytical data.
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    Cocrystallization of organic compounds
    (University College Cork, 2023) Huang, Shan; Lawrence, Simon; Science Foundation Ireland
    This thesis discusses the synthesis, characterization, and properties of multi-component crystalline materials of active pharmaceutical ingredients. A special emphasis is placed on cocrystallization, which is the supramolecular phenomenon of aggregation of two or more different chemical entities in a crystalline lattice through non-covalent interactions. This research has been divided into seven chapters. Chapter 1 gives an overview of the concept of multi-component crystalline materials and cocrystallization, where the design, methodology, characterization and application of cocrystals are also included. Chapter 2 discusses the synthesis of multi-component crystal forms of a sulfonamide compound, sulfasalazine, through cocrystallization and explores the crystal structure landscape of sulfasalazine. Furthermore, the differences are illustrated between cocrystals and salts of sulfasalazine via structural analysis, Hirshfeld surface analysis and frontier molecular orbitals analysis. Chapter 3 investigates the hydrogen bonding interactions in cocrystals of a frequently used sulfonamide compound, sulfaguanidine, by both experimental methods and theoretical calculations including the analysis of Hirshfeld surface, molecular electrostatic potential surfaces and quantum theory of atoms in molecules. Chapter 4 focuses on pharmaceutical salts of piroxicam and meloxicam with three basic organic counterions, respectively. The solubility of six salts and two parent drugs in sodium phosphate solution were conducted. Furthermore, piroxicam and its salts exhibited different luminescent properties, thus, the different luminescent mechanisms were discussed. Chapter 5 explores cocrystallization of 19 natural L-amino acids and both enantiomers of four pharmaceutically relevant chiral compounds. The formation of diastereomeric or enantiospecific systems were explored using an examination of their hydrogen bonding motifs. Chapter 6 investigates the formation of diastereomeric cocrystal pairs of S mandelamide with both enantiomers of mandelic acid and proline, respectively. In addition, the crystal structures of (±)-mandelamide, S-mandelamide and enantio-enriched mandelamide (94 S:6 R) were determined. Detailed crystal structural analyses together with Hirshfeld surface analysis were carried out. Chapter 7 summarizes the main findings of the entire work and examines future work, such as the use of ternary phase diagrams to assist in developing chiral separation processes.
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    Development of stationary phase materials and methods for analysis of pharmaceuticals via high-performance liquid chromatography and electrochemical detection
    (University College Cork, 2022) Alghamdi, Huda; Glennon, Jeremy; Ministry of Education, Saudi Arabia; Cultural Bureau, Dublin
    In recent years there has been a significant research focus on developing more efficient chromatographic materials and methods for pharmaceutical analysis. Determination of pharmaceutically active compounds in pharmaceutical formulations requires the development of efficient, rapid and sensitive analytical methods. In addition to providing an overview of different analytical methods used for pharmaceutical analysis via liquid chromatography (LC) and electrochemical analysis at a boron-doped diamond (BDD) electrode this research explores and characterises a novel polymer immobilised porous silica particle phase for fast LC analysis of selected pharmaceutical actives. In this thesis, a Nafion polymer-coated silica stationary phase material for the fast and efficient separation of pharmaceutical solutes is reported. Initially, quaternary amine functionalised fully porous and non-porous silica particles (3 µm) were prepared for subsequent coating with Nafion perfluorinated resin (2 % w/v in ethanol). Elemental analysis (CHN), thermogravimetric analysis (TGA), attenuated total reflection Fourier-transform infrared spectroscopy (ATR-FTIR), zeta potential measurement and scanning electron microscopy (SEM) with energy dispersive X-ray detector (EDX) confirmed the stepwise silica surface functionalisation. The Nafion-coated phases were evaluated for ion-exchange retention behaviour after they were slurry-packed into stainless steel columns (2.1 x 30 mm). These columns were applied to the separation of pharmaceutically-active tetracaine hydrochloride (TCH), oxymetazoline hydrochloride (OZH) and benzalkonium chloride (BAK) through the use of high-performance liquid chromatography (HPLC). Attention was then placed on the rapid separation and sensitive detection of the local anaesthetic TCH and the nasal decongestant OZH combining the high separation efficiencies and the short analysis time of core-shell silica particles with the sensitivity of a BDD electrode. The chromatographic separation was carried out using a poroshell 120 EC-C18 (2.1 × 50 mm, 2.7 μm) column, and isocratic elution is followed by ultraviolet (UV) and amperometric detection at the boron-doped diamond electrode. Rapid reversed-phase (RP) separation of TCH and OZH in nasal spray and ophthalmic formulations was achieved within 45 sec, by adjusting the ratio of organic solvent, mobile phase pH and detection potential. Limits of detections (LODs) of TCH and OZH with BDD electrode are 12 ng/mL and 20 ng/mL respectively, lower than that obtained with UV detection (60 and 89 ng/mL respectively). In addition, a sensitive detection method was developed for the detection of BAK (which is of importance as a preservative and antimicrobial agent in the pharmaceutical industry), using direct electroanalysis at a pristine BDD electrode. The detection limit of BAK homologs with the BDD electrode was 0.4 µg/mL lower than that obtained with a glassy carbon (GC) electrode (0.68 µg/mL) in a non-aqueous medium using square wave voltammetry (SWV). The method was extended to the detection of the C12 homolog in three ophthalmic formulations, and the results were validated by HPLC. The chromatographic separation of BAK homologs (C12, C14, C16, and C18) was carried out using reversed-phase HPLC with a poroshell 120 EC-C8 (2.1 × 50 mm, 1.9 μm) column. The HPLC results confirmed the presence of one single homolog (C12) in the three ophthalmic formulations. The research outcomes represent an advancement in the separation and detection of pharmaceuticals of importance in the pharmaceutical industry at a time when the number of samples and sample matrices in the pharmaceutical industry is on the rise.