Synthesis and Solid State Pharmaceutical Centre (SSPC) - Doctoral Theses

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    Cocrystallising acids and amides: towards pharmaceutical cocrystals
    (University College Cork, 2021-07-20) Stokes, Stephen P.; Lawrence, Simon E.; Maguire, Anita; Science Foundation Ireland
    The work presented in this dissertation focuses on the molecular features of small molecules and their interactions with pharmaceutically relevant molecules. Emphasis is placed on cocrystallisation; a method that facilitates the formation of multicomponent forms of molecules with non-ionisable or weakly ionisable functional groups. This research has been divided into nine chapters. Chapter 1 describes the concept of crystallisation and introduces supramolecular chemistry. Through the explanation of hydrogen and halogen bonding, which is prominent throughout this work, the concept of supramolecular synthons is unveiled for multicomponent compounds. Finally, applications of cocrystals involving pharmaceutically industrially relevant compounds amongst others are discussed. Chapter 2 gives an overview of the general procedures carried out in this work. Furthermore, a list of the analytical equipment employed is described. Chapter 3 initially describes the crystal landscape of the secondary amide γ-lactam, 2-pyrrolidone, 1, with extension to other lactam systems. This compound is of relevance as it is used routinely as a high boiling solvent in the pharmaceutical industry. A cocrystal screen of 1 was carried out with a range of amide and carboxylic acid based coformers, and fenamic acid active pharmaceutical ingredients (APIs). The common structural motifs of the successfully resolved single crystals were grouped and discussed, and the robustness of the cocrystal forming abilities of 1 demonstrated. Chapter 4 discusses the benzene fused γ-lactam, 2-oxindole, 2, which is the benzene fused analogue of 1. An initial polymorphic screen was employed with a subsequent cocrystal screen of 2 with a range of coformers similar to 1. From this, an investigation into the solid-state similarities between cocrystals of 1 and 2 was conducted, revealing both similarities and variations in the observed motifs. Chapter 5 focuses on a molecule of pharmaceutical relevance, namely modafinil, 3, an anti-narcoleptic drug. In an attempt to utilise the halogen bonding potential of both 3 and 1,4-diiodotetraflourobenzene, the discovery of a dihydrate of 3 is described with characterisation of the resultant solid-state structure. Chapter 6 focuses on 6-propyl-2-thiouracil, 4, an API used in the treatment of Graves’ disease. A cocrystal screening involving acids, amides, fenamic acids and other API molecules was conducted. The motifs of successful single crystal structures are discussed and the structural properties rationalised. Chapter 7 describes the synthetic strategies to synthesise four fenamic acid based molecules, two of which are novel molecules containing methylene linkers. Chapter 8 Conclusion summarising the main findings of the entire work. Chapter 9 Appendix
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    Telescoping of transition metal catalysed and biocatalysed reactions
    (University College Cork, 2020-11-10) Kelly, Áine; Moynihan, Humphrey A.; Science Foundation Ireland
    This thesis describes the telescoping reactions which exploit the diverse catalytic approaches of transition metal catalysis and biocatalysed processes. These processes would normally have conditions that are incompatible. Telescoping these processes into a single process will provide powerful enantioselectivity which exploits the efficiency of transition metal catalysis and the stereoselectivity of biocatalysis. Chapter one provides an overview of asymmetric synthesis, both –diazocarbonyl compound synthesis and reactions, and biotransformations. It also gives an overview of telescoping systems from the literature. The results of this research are discussed in both chapter two and three. Chapter two describes the initial work undertaken during this project including attempting intramolecular X–H insertion reactions and intramolecular C–H insertion and then the Baker’s yeast reduction of those products. The batchwise step–by–step transformations were undertaken initially and then telescoped together overcoming problems associated with the process. Chapter three describes the C–H intramolecular reactions with both rhodium (II) acetate and copper (II) triflate to produce a range of 2–benzenesulfonyl substituted cyclopentanone compounds. These compounds were then kinetically resolved via a Baker’s yeast mediated reduction. These individual steps were optimised before they were telescoped together. The range of 2–benzenesulfonyl substituted cyclopentanone compounds also underwent ring cleavage to give simple carboxylic acids which could then be desulfonylated to simple alcohol compounds with a stereocentre in the middle of the chain. Chapter four contains the full experimental details and spectral characterisation of all the compounds synthesised in this project, while the details of the chiral stationary phase HPLC analysis is included in the appendix.
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    Telescoping the synthesis and heterogeneous transition metal catalysed asymmetric transformations of α-diazoketones and α-diazoacetamides in continuous flow
    (University College Cork, 2020-09-17) Crowley, Daniel C.; Maguire, Anita; Irish Research Council
    This project aims to expand the extensive work carried out by the Maguire group on the synthesis and reactivity of α-diazocarbonyl compounds over the last 25 years, with primary focus on the intramolecular aromatic addition of α-diazoketones. This transformation is studied in depth with particular focus on exploiting contemporary techniques and methodologies, such as immobilised catalysis and continuous flow processing, to enhance the practical synthetic potential of this powerful transformation. Chapter 1 provides a literature review as background to this research project focussing, in particular, on methodologies for the synthesis of α-diazocarbonyl compounds and selectivity patterns in intramolecular aromatic addition processes. Chapter 2 focuses on the synthesis of α-diazocarbonyl compounds including α-diazoketones, α-diazo-β-ketonitriles, α-cyano-α-diazoamides and α-diazo-β-diketones. Traditional methods, such as acylation of diazoalkanes, are compared to newer, safer methods proceeding via diazo transfer on continuous flow, developed during this work. Specifically, continuous flow processing is utilised to harness the powerful synthetic utility of hazardous triflyl azide for α-diazocarbonyl compound synthesis, while offsetting the potential hazards inherent in its use. Chapter 3 describes the transition metal catalysed transformations of the α-diazocarbonyl compounds synthesised in Chapter 2. Results achieved with homogeneous copper–bis(oxazoline) catalyst systems are compared with those achieved with novel immobilised copper catalysts in both batch and continuous flow; the synthesis of the immobilised copper catalysts is also discussed. This is the first report of enantioselective, copper mediated aromatic addition using an immobilised catalyst in either batch or continuous flow with enantiopurities of up to 85% ee achieved. Furthermore, novel rhodium(II) mandelate catalysts, designed by the Maguire group, are applied across the array of α-diazocarbonyl compounds studied in the project, investigating their chemo- and stereoselectivity for intramolecular aromatic addition. Excellent control of both the chemo- and enantioselection (up to 89% ee) was achieved with the novel rhodium(II) mandelate catalysts. Finally, Chapter 4 combines the sulfonyl azide synthesis and α-diazocarbonyl compound synthesis explored in Chapter 2 with the transition metal catalysed transformation studied in Chapter 3. This furnishes a three-step telescoped sequence, whereby hazardous sulfonyl azides and α-diazocarbonyl compounds are synthesised in situ from readily handled starting iv materials, and, without being isolated or stored, are subjected directly to transition metal catalysis downstream, furnishing enantioenriched products. This chapter describes the steps taken in the process to ensure removal of by-products from upstream transformations, which would be detrimental to the transition metal catalysts, as well discussing the studies undertaken to ensure the safety of the transformation. This telescoped process realises the synthetic potential of these hazardous reagents in a manner safer than traditional batch processes, and the scale-up of the three-step telescoped process is successfully explored. Chapter 5 contains the full experimental details and spectroscopic characterisation of the compounds synthesised in this work.
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    Development and application of synthetic methodologies based on organosulfur and organophosphorus chemistry
    (University College Cork, 2020-05-22) Flynn, Aaran J.; Maguire, Anita; Science Foundation Ireland
    This thesis describes the development and application of synthetic methodologies based on various aspects of organosulfur and organophosphorus chemistry with a focus on understanding the underlying features and synthetic application. The first chapter systematically compiles and reviews, for the first time, the synthetic and mechanistic aspects of sulfonyl migrations over the last twenty years. Notably, the fact that these reactions are frequently described as ‘unusual’, ‘unprecedented’, ‘unexpected’, ‘serendipitous’ and ‘novel’ by authors, highlights that these potentially synthetically powerful transformations remain only partially understood. This introductory chapter explores the synthetic utility of sulfonyl migrations, while significant attention is afforded to the efforts made to elucidate their underlying mechanisms. This literature review was inspired by the observation of an ‘unprecedented’ carbon–carbon 1,2-sulfonyl migration in our work, which is discussed in detail in Chapter 2. The second chapter describes the use of α-thio-β-chloroacrylamides, a series of highly functionalised sulfur containing compounds pioneered in our group, as versatile dipolarophiles in [3+2] dipolar cycloaddition reactions. The [3+2] dipolar cycloaddition of highly reactive α-diazoalkanes with a range of dipolarophiles is well explored in the synthesis of pyrazolines and pyrazoles, however, analogous cycloadditions of electron deficient terminal diazo compounds such as α-diazoacetates, α-diazosulfones and α-diazoacetamides remains significantly less studied despite the synthetic and biological importance of ester, sulfone and amide moieties. The reactivity of these α-thio-β-chloroacrylamides at each of the sulfide, sulfoxide and sulfone oxidation levels with electron deficient α-diazoacetates, and related derivatives, is explored in the formation of densely functionalised pyrazole derivatives that would otherwise be difficult to obtain via traditional methods. Observation of an unprecedented 1,2-carbon to carbon sulfonyl migration is of particular interest. Significant attention is afforded to the elucidation of the tautomeric composition of the 3,4,5-substituted pyrazole products, while the synthetic versatility of these products is demonstrated via a series of derivatisations. Chapter three details the design and preparation of a series of acyclic α-carboxy nucleoside phosphonate derivatives envisaged to possess anti-viral and/or anti-cancer properties. This chapter details the use of Mitsunobu coupling and transition metal catalysed O–H insertion methodology as key synthetic steps in the formation of these biological targets. This work was conducted in collaboration with Prof. Dr. Christa Müller and Prof. Jan Balzarini. The fourth chapter explores in detail synthetic challenges in the copper-catalysed asymmetric sulfur oxidation of aryl benzyl sulfides. Significant attention is afforded to the concept of self-disproportionation of enantiomers (SDE), an underappreciated phenomenon despite being known in the literature, but also to the observation of localised partitioning of enantiomers in the solid state even in the absence of SDE, which can lead to erroneous determination of enantiopurity. Each of chapters 2–4 is concluded with the associated experimental details, including spectroscopic and analytical data, for compounds synthesised during this work.
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    Application of pharmaceutical quality approaches and the development of process analytical technologies to improve pharmaceutical product and process understanding
    (University College Cork, 2020-09-29) Queiroz, Ana Luiza P.; Crean, Abina; Vucen, Sonja; Science Foundation Ireland; European Regional Development Fund
    The pharmaceutical industry is undergoing a paradigm change with the advancement towards the Fourth Industrial Revolution. The manufacturing framework is moving from batch to continuous, which has been accompanied by the necessity of the implementation of process analytical technologies (PAT) for continuous process monitoring and control. There has also been a need to develop advanced quality approaches such as Quality by Design (QbD) and Quality by Control (QbC). Within these quality approaches, modelling has been used to expand knowledge related to raw material attributes and transformations that happen during the process, and to monitor and control process parameters. Besides the development of models for process and product transformations understanding and monitoring, predictive models have been an important advancement to reduce experimental cost during formulation development and process design. There are challenges that need to be addressed in order to complete the implementation of continuous process and advanced quality approaches in that pharmaceutical sector. It is necessary to extend the full mechanistic knowledge of processes, to develop data analysis and computer simulation, to expand the number of equipment and models to scale up solutions, and to upskill personnel to work with the technologies required. The general aim of this thesis was to increase understanding of pharmaceutical materials and processes by the development of PAT and models for quantitative characterization and prediction of drug substance and drug product critical properties. To achieve this aim, several specific objectives were established focused on different aspects of oral dosage form manufacture. Initially, a PAT was developed to rapidly characterize microcrystalline cellulose (MCC) percentage crystallinity index. MCC crystallinity was determined from Raman spectral data. Then, MCC moisture sorption and moisture monolayer were determined from isotherms obtained using dynamic vapor sorption (DVS). A correlation between both attributes was investigated. However, it was not possible to confirm the relationship between the monolayer moisture sorption and the percentage crystallinity. A total of 30 commercial batches of MCC were used to design and validate the MCC crystallinity model. Furthermore, a web application, McCrystal, was designed to disseminate the model. Available at Secondly, a PAT was developed to determine the endpoint and monitor form changes during slurry co-crystallization. This PAT tool involved the application of in situ Raman spectroscopy combined with principal component analysis (PCA). An additional PAT tool was developed using Mid Infrared spectroscopy (MIRS) combined with multivariate curve resolution (MCR) in order to quantitatively evaluate phase purity of co-crystals produced by slow evaporation and slurry co-crystallization. The models developed were applied to different combinations of active pharmaceutical ingredients (APIs) and coformers, and were able to determine the co-crystallization endpoint for all systems where the solvents exhibited a weak Raman signal. Moreover, the phase purity for all co-crystals systems investigated was determined. The third challenge addressed by this study relates to particle-particle interactions in powder blends to predict the general behaviour of the blend when it is directly compressed into pharmaceutical tablets. Percolation threshold model was used to determine a critical drug load, above which the powder blend behaves similarly to the drug substance. As a result, the formulation may show undesirable properties above the threshold, which can lead to non-compliance or process difficulties. The application of PCA to determine the critical drug loading was investigated. The predicted values of critical drug loading were confirmed by changes in powder flowability, tablet weight variation, and Raman spectroscopic analysis of drug distribution. PCA was not able to precisely predict the threshold, however, it aided in clarifying differences between the blends containing different ibuprofen loadings and different MCC grades. Expanding on the impact of critical drug loading on tablet critical quality attributes, the final objective was to investigate the impact of critical drug loads, determined from compaction data, on disintegration and dissolution performance. The application of novel process analytical technologies, in-process video microscopy (PVM) and focused-beam reflectance measurement (FBRM), to study tablet disintegration was also proposed and investigated in-depth. FBRM and PVM provided important information of tablet disintegration behaviour that cannot be captured by the traditional disintegration testing. The critical drug load predicted from compaction data was also relevant for disintegration and dissolution behaviour. Above the threshold drug loading, disintegration and drug release rates were decreased. A PCA model developed from Raman spectra acquired from tablet surfaces further supported the finding that blends manufactured with different grades of MCC differed more significantly above the critical drug load. The work presented in this thesis is a contribution to solid dosage formulation design, co-crystallization understanding, tableting process scale up and scale down, and data handling. The models and PAT developed can be used to predict formulation performance, determine process parameters based on raw material critical attributes, determine process endpoint, and thoroughly assess final product critical quality attributes.