Analytical & Biological Chemistry Research Facility - Doctoral Theses
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Item Synthesis of novel cycloperoxides(University College Cork, 2023) Hennessy, Mary C.; O'Sullivan, Tim; Irish Research CouncilCycloperoxides 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.Item Cocrystallization of organic compounds(University College Cork, 2023) Huang, Shan; Lawrence, Simon; Science Foundation IrelandThis 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.Item 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, DublinIn 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.Item Investigation of a process analytical technology (PAT) for rapid cleaning verification in the pharmaceutical industry to reduce product changeover time(University College Cork, 2023) Sarwar, Apu; Moore, Eric; McSweeney, Conor; Irish Research CouncilWithin the pharmaceutical industry, it is a regulatory requirement that the equipment's cleanliness must be verified prior to use in order to avoid contaminated or adulterated products. Currently, the techniques used for cleaning verification are extremely variable as the sampling technique categorically relies on human performance. The most commonly used technique for cleaning verification is known as swab and rinse. These techniques are based on the assumption that the contamination is completely removed from the surface during sampling while there is no direct measurement system in place to ensure that 100% of the contamination is removed. This assumption could produce extremely misleading results and ultimately could put patient's lives at risk. This has been proved by the FDA’s recent citation where it said, most of the drug manufacturing-related problems leading to product recalls and manufacturing disruption are caused by cross-contamination. Another immense drawback of the current technique is that it may take up to 3 weeks to complete the verification study, and during this time, the manufacturing equipment is not in use. In addition to this downtime, another major drawback of the current method is the poor swab recovery which may lead to an ambiguous result. Therefore, the pharma regulators are encouraging to develop and use of more science-based analytical tools, and the pharma industries are searching hard for a better alternative. This project was initiated to use a scientifically sound hand-held analytical tool to validate/verify equipment cleanliness in real-time without sampling and laboratory testing. A Specular-Reflectance Fourier Transform Infrared Spectroscopy (SRFTIR) was identified to investigate the capability to detect and quantify surface contamination and produce the result instantaneously & eliminate human error. It is anticipated that this project will deliver a significant reduction in cleaning time which will affect the entire pharmaceutical industry within Ireland and worldwide. Currently, the most commonly used analytical method for cleaning verification in the pharmaceutical industry is swab and rinse testing. These methods are also known as indirect methods, which require extracting contaminants from the surface of the manufacturing equipment. These methods are extremely inefficient and require strong technical and analytical skills to perform. In the Pfizer tablet manufacturing plant, an assessment was performed to calculate the time required to verify the equipment cleanliness, and it was found that completing a cleaning verification study for an equipment train with 10 swab samples will require approximately working 52 hours of laboratory testing. Further assessment was performed in Pfizer large molecule site; they found it required 1-3 weeks to perform the cleaning verification study, depending on the nature of the contaminant. For multi-product facilities, the equipment downtime is a huge forfeiture for the business; ultimately, all of this cost is added up to the final price of the drug/s. The average equipment downtime for Pfizer multi-product facilities is 30% of the total manufacturing time. In addition, there is a great variation in the swabbing technique and recovery. The introduction of an innovative approach to reduce error and improve the consistency of the sampling would be a significant development in the field of cleaning validation and verification for the pharmaceutical industry.Item Utilisation of novel marine biocatalysts in enantioselective synthesis(University College Cork, 2022-12-02) Murphy, Edel J.; Maguire, Anita; Collins, Stuart; Irish Research Council; GlaxoSmithKline; Thermo ScientificThis project focuses on the utilisation of hydrolases and transaminases as biocatalysts in asymmetric synthesis. The primary aim of this work is the investigation of the synthetic utility of marine biocatalysts, which were isolated from a saltwater lake in West Cork, in enantioselective synthesis. Chapter 1 provides a literature overview focussing on the substrate scope of transaminases, highlighting the applicability of wild-type and engineered transaminases in enantioselective synthesis of primary amines. Chapter 2 describes the use of a novel marine esterase, esterase 26D, for the kinetic resolution of various ester substrates. In particular, it was found that the substrate scope of esterase 26D is complementary to the substrate scope of a number of commercially available hydrolases. The distinctive substrate scope of the marine esterase resulted in improved activity towards substrates which could not be readily resolved in a synthetically useful manner using commercially available enzymes. Thus, this biocatalyst was employed to provide highly enantioenriched carboxylic acids and alcohols where the stereogenic centre was not at the reacting site, but one or two carbons away. Chapter 3 describes the investigation of the substrate scope and synthetic utility of marine transaminases, building on earlier work carried out in the group. Two marine whole cell transaminases, P-ω-TA and P-ω-TAad2, were utilised in the kinetic resolution of various racemic primary amines, such as 1-aminotetralins and 1-aminoindanes. Once again, the work focused in particular on the resolution of amines which contained an additional stereogenic centre, two or three carbons removed from the amino substituent. The activity, enantioselectivity and remote diastereoselectivity of the marine transaminases were compared to that of known transaminase Cv-ω-TA. Most significantly, across the substrate screen, marine transaminases P-ω-TA and P-ω-TAad2 display remote diastereoselectivity, which is not seen with Cv-ω-TA. In this chapter the genome sequence alignment and molecular modeling information were used to rationalize the observed similarities and differences in the activity and selectivity of the three transaminases, P-ω-TA, P-ω-TAad2 and Cv-ω-TA. Chapter 4 summarises the investigation of the use of purified and immobilised transaminases, Cv-ω-TA and P-ω-TA, in the kinetic resolution process, with the ultimate objective of use of the immobilised transaminases in a continuous flow process. Chapter 5 details the overall conclusions of this thesis and future work. Lastly, chapter 6 contains the full experimental details and spectroscopic characterisation of the compounds synthesised in this work.