Crystallisation and crystal forms of carbohydrate derivatives

This thesis is focused on the synthesis and solid state analysis of carbohydrate derivatives, including many novel compounds. Although the synthetic chemistry surrounding carbohydrates is well established in the literature, the crystal chemistry of carbohydrates is less well studied. Therefore this research aims to improve understanding of the solid state properties of carbohydrate derivatives through gaining more information on their supramolecular bonding. Chapter One focuses on an introduction to the solid state of organic compounds, with a background to crystallisation, including issues that can arise during crystal growth. Chapter Two is based on glucopyranuronate derivatives which are understudied in terms of their solid state forms. This chapter reports on the formation of novel glucuronamides and utilising the functionality of the amide bond for crystallisation. TEMPO oxidation was completed to form glucopyranuronates by oxidation of the primary alcohol groups of glucosides to the carboxylic acid derivatives, to increase functionality for enhanced crystal growth. Chapter Three reports on the synthesis of glucopyranoside derivatives by O-glycosylation reactions and displays crystal structures, including a number of previously unsolved acetate protected and deprotected crystal structures. More complex glycoside derivatives were also researched in an aim to study the resultant supramolecular motifs. Chapter Four contains the synthesis of aryl cellobioside derivatives including the novel crystal structures that were solved for the acetate protected and deprotected compounds. Research was carried out to determine if 1-deoxycellodextrins could act as putative isostructures for cellulose. Our research displays the presence of isostructural references with 1-deoxycellotriose shown to be similar to cellulose III11, 1-deoxycellotetraose correlates with cellulose IV11 and 1-deoxycellopentose shows isostructurality similar to that of cellulose II. Chapter Five contains the full experimental details and spectral characterisation of all novel compounds synthesised in this project and relevant crystallographic information.

Development of large-scale colloidal crystallisation methods for the production of photonic crystals

Colloidal photonic crystals have potential light manipulation applications including; fabrication of efficient lasers and LEDs, improved optical sensors and interconnects, and improving photovoltaic efficiencies. One road-block of colloidal selfassembly is their inherent defects; however, they can be manufactured cost effectively into large area films compared to micro-fabrication methods. This thesis investigates production of ‘large-area’ colloidal photonic crystals by sonication, under oil co-crystallization and controlled evaporation, with a view to reducing cracking and other defects. A simple monotonic Stöber particle synthesis method was developed producing silica particles in the range of 80 to 600nm in a single step. An analytical method assesses the quality of surface particle ordering in a semiquantitative manner was developed. Using fast Fourier transform (FFT) spot intensities, a grey scale symmetry area method, has been used to quantify the FFT profiles. Adding ultrasonic vibrations during film formation demonstrated large areas could be assembled rapidly, however film ordering suffered as a result. Under oil cocrystallisation results in the particles being bound together during film formation. While having potential to form large areas, it requires further refinement to be established as a production technique. Achieving high quality photonic crystals bonded with low concentrations (<5%) of polymeric adhesives while maintaining refractive index contrast, proved difficult and degraded the film’s uniformity. A controlled evaporation method, using a mixed solvent suspension, represents the most promising method to produce high quality films over large areas, 75mm x 25mm. During this mixed solvent approach, the film is kept in the wet state longer, thus reducing cracks developing during the drying stage. These films are crack-free up to a critical thickness, and show very large domains, which are visible in low magnification SEM images as Moiré fringe patterns. Higher magnification reveals separation between alternate fringe patterns are domain boundaries between individual crystalline growth fronts.

Impurity exclusion and retention during crystallisation and recrystallisation - the phenacetin by ethylation of paracetamol process

Science Foundation Ireland (05/PICA/B802/EC07, 07/SRC/B1158 and 12/RC/227505); Irish Research Council (Enterprise Partnership Scheme (IRSCET-Clarochem-2010-02)); University College Cork (UCC 2013 Strategic Research Fund); Clarochem (Ireland) Ltd

Methyl tetra-O-acetyl-α-d-glucopyranuronate: crystal structure and influence on the crystallisation of the β anomer

Methyl tetra-O-acetyl-β-d-glucopyranuronate (1) and methyl tetra-O-acetyl-α-d-glucopyranuronate (3) were isolated as crystalline solids and their crystal structures were obtained. That of the β anomer (1) was the same as that reported by Root et al., while anomer (3) was found to crystallise in the orthorhombic space group P212121 with two independent molecules in the asymmetric unit. No other crystal forms were found for either compound upon recrystallisation from a range of solvents. The α anomer (3) was found to be an impurity in initially precipitated batches of β-anomer (1) in quantities <3%; however, it was possible to remove the α impurity either by recrystallisation or by efficient washing, i.e. the α anomer is not incorporated inside the β anomer crystals. The β anomer (1) was found to grow as prisms or needles elongated in the a crystallographic direction in the absence of the α impurity, while the presence of the α anomer (3) enhanced this elongation.

Optimisation of chemoenzymatic processes in asymmetric synthesis

This thesis describes the optimisation of chemoenzymatic methods in asymmetric synthesis. Modern synthetic organic chemistry has experienced an enormous growth in biocatalytic methodologies; enzymatic transformations and whole cell bioconversions have become generally accepted synthetic tools for asymmetric synthesis. Biocatalysts are exceptional catalysts, combining broad substrate scope with high regio-, enantio- and chemoselectivities enabling the resolution of organic substrates with superb efficiency and selectivity. In this study three biocatalytic applications in enantioselective synthesis were explored and perhaps the most significant outcome of this work is the excellent enantioselectivity achieved through optimisation of reaction conditions improving the synthetic utility of the biotransformations. In the first chapter a summary of literature discussing the stereochemical control of baker’s yeast (Saccharomyces Cerevisae) mediated reduction of ketones by the introduction of sulfur moieties is presented, and sets the work of Chapter 2 in context. The focus of the second chapter was the synthesis and biocatalytic resolution of (±)-trans-2-benzenesulfonyl-3-n-butylcyclopentanone. For the first time the practical limitations of this resolution have been addressed providing synthetically useful quantities of enantiopure synthons for application in the total synthesis of both enantiomers of 4-methyloctanoic acid, the aggregation pheromone of the rhinoceros beetles of the genus Oryctes. The unique aspect of this enantioselective synthesis was the overall regio- and enantioselective introduction of the methyl group to the octanoic acid chain. This work is part of an ongoing research programme in our group focussed on baker’s yeast mediated kinetic resolution of 2-keto sulfones. The third chapter describes hydrolase-catalysed kinetic resolutions leading to a series of 3-aryl alkanoic acids. Hydrolysis of the ethyl esters with a series of hydrolases was undertaken to identify biocatalysts that yield the corresponding acids in highly enantioenriched form. Contrary to literature reports where a complete disappearance of efficiency and, accordingly enantioselection, was described upon kinetic resolution of sterically demanding 3-arylalkanoic acids, the highest reported enantiopurities of these acids was achieved (up to >98% ee) in this study through optimisation of reaction conditions. Steric and electronic effects on the efficiency and enantioselectivity of the biocatalytic transformation were also explored. Furthermore, a novel approach to determine the absolute stereochemistry of the enantiopure 3-aryl alkanoic acids was investigated through combination of co-crystallisation and X-ray diffraction linked with chiral HPLC analysis. The fourth chapter was focused on the development of a biocatalytic protocol for the asymmetric Henry reaction. Efficient kinetic resolution in hydrolase-mediated transesterification of cis- and trans- β-nitrocyclohexanol derivatives was achieved. Combination of a base-catalysed intramolecular Henry reaction coupled with the hydrolase-mediated kinetic resolution with the view to selective acetylation of a single stereoisomer was investigated. While dynamic kinetic resolution in the intramolecular Henry was not achieved, significant progress in each of the individual elements was made and significantly the feasibility of this process has been demonstrated. The final chapter contains the full experimental details, including spectroscopic and analytical data of all compounds synthesised in this project, while details of chiral HPLC analysis are included in the appendix. The data for the crystal structures are contained in the attached CD.

An evaluation of orogenic kinematic evolution utilizing crystalline and magnetic anisotropy in granitoids

The Silurian-Devonian Galway Granite Complex (GGC ~425-380Ma) is defined here as a suite of granitoid plutons that comprise the Main Galway Granite Batholith and the Earlier Plutons. The Main Batholith is a composite of the Carna Pluton in the west and the Kilkieran Pluton in the east and extends from Galway City ~130km to the west. The Earlier Plutons are spatially, temporally and structurally distinct, situated northwest of the Main Batholith and include the Roundstone, Omey, Inis and Letterfrack Plutons. The majority of isotopic and structural data currently available pertain to the Kilkieran Pluton, several tectonic models have already been devised for this part of the complex. These relate emplacement of the Kilkieran Pluton to extension across a large east-west Caledonian lineament, i.e. the Skird Rocks Fault, during late Caledonian transtension. No chronological data have been published that directly and accurately date the emplacement of the Carna Pluton or any of the Earlier Plutons. There is also a lack of data pertaining to the internal structure of these intrusions. Accordingly, no previous study has established the mechanisms of emplacement for the Earlier Plutons and only limited work is available for the Carna Pluton. As a consequense of this, constituents of the GGC have not previously been placed in a context relative to each other or to regional scale Silurio-Devonian kinematics. The current work focuses on the Omey, Roundstone and Carna Plutons. Here, results of detailed field and Anisotropy of Magnetic Susceptibiliy (AMS) fabric studies are presented. This work is complemented by geological mapping that focuses on fault dynamics and contact relationships. Interpretation of AMS data is aided by rock magnetic experiment data and petrographic microstructural evaluations of representative samples. A new geological map of the the Omey Pluton demonstrates that this intrusion has a defined roof and base which are gently inclined parallel to the fold hinge of the Connemara Antiform. AMS and petrographic data show the intrusion is cross cut by NNW-SSE shear zones that extend into the country rock. These pre-date and were active during magma emplacement. It is proposed that the Omey pluton was emplaced as a discordant phacolith. Pre-existing subvertical D5 faults in the host rock were reactived during emplacement, due to regional sinistral transpression, and served as centralised ascent conduits. A central portion of the Roundstone Pluton was mapped in detail for the first time. Two facies are identified, G1 forms the majority of the pluton and coeval G2 sheets cross cut G1 at the core of the pluton. NNW-SSE D5 faults mapped in the country rock extend across the pluton. These share a geometrical relationship with the distribution of submagmatic strain in the pluton and parallel the majoity of mapped subvertical G2 dykes. These data indicate that magma ascent was controlled by NNW-SSE conduits that are inherently related to those identifed in the Omey Pluton. It is proposed that the Roundstone Pluton is a punched laccolith, the symmetry and structure of which was controlled by pre-exising host rock structures and regional sinistral transpressive stress which presided during emplacement. Field relationships show the long axis of the Carna Pluton lies parallel to mulitple NNW-SSE shear zones. These are represented on a regional scale by the Clifden-Mace Fault which cross cuts the core of this intrusion. AMS and petrographic data show concentric emplacement fabrics were tectonically overprinted as magma cooled from the magmatic state due to this faulting. It is proposed that the Clifden-Mace Fault system was active during ascent and emplacement of the magma and that pluton inflation only terminated as this controlling structure went into compression due to the onset of regional transtension. U-Pb zircon laser ablation inductively coupled mass spectrometry (LA-ICP-MS) data has been compiled from four sample sites. New geochronological data from the Roundstone Pluton (RD1 = ± 3.2Ma) represent the oldest age determination obtained from any member of the GGC and demonstrates that this pluton predates the Carna Pluton by ~10Ma and probably intruded synchronously with the Omey Pluton (~422.5 ± 1.7Ma). Chronological data from the Carna Pluton (CN2 = 412.9 ± 2.5Ma; CN3 = 409.8 ± 7.2Ma; CN4 = 409.6 ± 3.6Ma) represent the first precise magma crystallisation age for this intrusion. This work shows this pluton is 10Ma older than the Kilkieran Pluton and that the supply of magma into the Carna Pluton had terminated by ~409Ma. Chronological, magnetic and field data have been utilised to evaluate the kinematic evolution of the Caledonides of western Ireland throughout the construction of the GGC. It is proposed that the GGC was constructed during four distinct episodes. The style of emplacement and the conduits used for magma transport to the site of emplacement was dependent on the orientation of local structures relative to the regional ambiant stress field. This philosophy is used to critically evaluate and progress existing hypotheses on the transition from regional transpression to regional transtension at the end of the Caledonian Orogeny.

Polymer and metallodielectric based photonic crystals

The bottom-up colloidal synthesis of photonic crystals has attracted interest over top-down approaches due to their relatively simplicity, the potential to produce large areas, and the low-costs with this approach in fabricating complex 3-dimensional structures. This thesis focuses on the bottom-up approach in the fabrication of polymeric colloidal photonic crystals and their subsequent modification. Poly(methyl methacrylate) sub-micron spheres were used to produce opals, inverse opals and 3D metallodielectric photonic crystal (MDPC) structures. The fabrication of MDPCs with Au nanoparticles attached to the PMMA spheres core–shell particles is described. Various alternative procedures for the fabrication of photonic crystals and MDPCs are described and preliminary results on the use of an Au-based MDPC for surface-enhanced Raman scattering (SERS) are presented. These preliminary results suggest a threefold increase of the Raman signal with the MDPC as compared to PMMA photonic crystals. The fabrication of PMMA-gold and PMMA-nickel MDPC structures via an optimised electrodeposition process is described. This process results in the formation of a continuous dielectric-metal interface throughout a 3D inverted photonic crystal structure, which are shown to possess interesting optical properties. The fabrication of a robust 3D silica inverted structure with embedded Au nanoparticles is described by a novel co-crystallisation method which is capable of creating a SiO2/Au NP composite structure in a single step process. Although this work focuses on the creation of photonic crystals, this co-crystallisation approach has potential for the creation of other functional materials. A method for the fabrication of inverted opals containing silicon nanoparticles using aerosol assisted chemical vapour deposition is described. Silicon is a high dielectric material and nanoparticles of silicon can improve the band gap and absorption properties of the resulting structure, and therefore have the potential to be exploited in photovoltaics.

Optimised crystal morphologies for active pharmaceutical ingredients and related studies

The majority of active pharmaceutical ingredients (APIs) are crystalline solids in their pure forms. Crystalline solids have definable morphologies, i.e. shape and size. Crystal morphology is determined by both the internal structure of the crystals and external factors during growth from solution. The morphology of a crystal batch can affect key processes during manufacturing. Companies generally accept whatever morphology the manufacturing process provides and deal with any subsequent problems by costly trouble‒shooting. Rational design of optimised morphologies for crystalline pharmaceutical solids would be a very significant technical and commercial advance. Chapter one introduces the concept of crystal nucleation and growth. The phenomenon of polymorphism alongside the causes and impact is discussed. A summary of the scope of instrumentation used in the investigation of crystal polymorphism and morphology, including crystal size distribution (CSD), is also included. Chapter two examines the research carried out during an exploration of the optimum crystallisation parameters of phenacetin. Following a morphological study, the impact this induces on particle density and flow properties is examined. The impact of impurities on the crystallisation properties of phenacetin is investigated. Significantly, the location of impurities within individual crystals is also studied. The third chapter describes an industrial collaboration looking at the resolution and polymorphic study of trometamol and lysine salts of ketoprofen and 2‒phenylpropionic acid (2‒PPA). Chapter four incorporates a solid state study on three separate compounds: 2‒chloro‒4‒nitroaniline, 4‒hydroxy‒N‒phenylbenzenesulfonamide and N‒acetyl‒D‒glucosamine‒6‒O‒sulfate. 2‒Chloro‒4‒nitroaniline and 4‒hydroxy‒N‒phenylbenzenesulfonamide both produced interesting, extreme morphologies which warranted further investigation as part of a collaborative study. Following a summarisation of results in chapter five, chapter six contains the full experimental details, incorporating spectral and other analytical data for all compounds synthesised during the course of the research.

Stabilisation of dehydrated nanoemulsions using sugar - protein matrices

There are numerous review papers discussing liquid nanoemulsions and how they compare to other emulsion systems. Little research is available on dried nanoemulsions. The objectives of this research were to (i) study the effect of varying the continuous phase of nanoemulsions with different carbohydrate/protein ratios on subsequent emulsion stability, and (ii) compare the physicochemical properties, lactose crystallisation properties, microstructure, and lipid oxidation of spray dried nanoemulsions compared to spray dried conventional emulsions having different water and sugar contents. Nanoemulsions containing sunflower oil (10% w/w), β-casein (2.5–10% w/w) and lactose or trehalose (10–17.5%) were produced following optimisation of the continuous phase by maximising and minimising viscosity and glass transition temperature (Tg’) using mixture design software. Increasing levels of β-casein from caused a significant increase in viscosity, particle size, and nanoemulsion stability, while resulting in a decrease in Tg’. Powders were made from spray drying emulsions/nanoemulsions consisting of lactose or a 70:30 mixture of lactose:sucrose (23.9%), sodium caseinate (5.1%) and sunflower oil (11.5%) in water. Nanoemulsions, produced by microfluidisation (100 MPa), had higher stability and lower viscosity than control emulsions (homogenization at 17 MPa) with lower solvent extractable free fat in the resulting powder. Partial replacement of lactose with sucrose decreased Tg and delayed Tcr. DVS and PLM showed that in powdered nanoemulsions, lactose crystallises faster than in powdered conventional emulsions. Microstructure of both powders (CLSM and cryo-SEM) showed different FGS in powders and different structure post lactose crystallisation. Powdered nanoemulsions had lower pentanal and hexanal (indicators of lipid oxidation) after 24 months storage due to their lower free fat and porosity, measured using a validated GC HS-SPME method, This research has shown the effect of altering the continuous phase of nanoemulsions on microstructure of spray dried nanoemulsions, which affects physical properties, sugar crystallisation, and lipid oxidation.

Home: the foundations of belonging

To be at home means to be embedded in a dense pattern of relationships to people and place which gives rise to an inherently meaningful experience of the world. This order is neither abstract nor imposed from without, but crystallises from the shared experience of people inhabiting a concrete location. Home involves the localisation of meaning in a concrete setting and in the activities of everyday life, and this embodies an ongoing process of ‘cosmicisation’ which is vital for both social life and individual well-being. Home is not a fixed structure, static and frozen, which shuts out the external world; it is a dynamic centre which draws in experience and gives it meaning. It is a constellation of significance rather than a singular and unitary essence. It is produced by localising processes, which work to concentrate and stabilise value around a secure centre. The elaboration of seven interlinked localising processes forms the core of the thesis: The cultivation of place The accumulation of collective memory The crystallisation of life-ways and their evolution into tradition The generation of mutuality of being through sharing in fundamental biological processes which generate and preserve life Social circles of gift exchange and recognition which reinforce this mutuality of being The elaboration of symbolic boundaries The counterparts of localising processes are globalising ones. These involve the dismantling of the taken-for-granted relationships of everyday life and their reconstitution within spatially extended networks, governed by rationalised institutions, within separate spheres of economic production, commercial transactions, political administration and cultural exchange. The global market, the public arena, technological development and the bureaucratic state are all solvents of localised associations, which result in the dissipation and relativisation of value. However globalising processes never entirely displace localising ones. Even today, localising processes shape those areas of our lives which anchor our identities and provide a sense of meaning: the everyday interactions of home, family, community and intimate circles of friendship.

The effects of formulation and processing on surface characteristics and functional properties of dairy powders

The objectives of this thesis were to (i) study the effect of increasing protein concentration in milk protein concentrate (MPC) powders on surface composition and sorption properties; (ii) examine the effect of increasing protein content on the rehydration properties of MPC; (iii) study the physicochemical properties of spraydried emulsion-containing powders having different water and oil contents; (iv) analyse the effect of protein type on water sorption and diffusivity properties in a protein/lactose dispersion, and; (v) characterise lactose crystallisation and emulsion stability of model infant formula containing intact or hydrolysed whey proteins. Surface composition of MPC powders (protein contents 35 - 86 g / 100 g) indicated that fat and protein were preferentially located on the surface of powders. Low protein powder (35 g / 100 g) exhibited lactose crystallisation, whereas powders with higher protein contents did not, due to their high protein: lactose ratio. Insolubility was evident in high protein MPCs and was primarily related to insolubility of the casein fraction. High temperature (50 °C) was required for dissolution of high protein MPCs (protein content > 60 g / 100 g). The effect of different oil types and spray-drying outlet temperature on the physicochemical properties of the resultant fat-filled powders was investigated and showed that increasing outlet temperature reduced water content, water activity and tapped bulk density, irrespective of oil type, and increased solvent-extractable free fat for all oil types and onset of glass transition (Tg) and crystallisation (Tcr) temperature. Powder dispersions of protein/lactose (0.21:1), containing either intact or hydrolysed whey protein (12 % degree of hydrolysis; DH), were spray-dried at pilot scale. Moisture sorption analysis at 25 °C showed that dispersions containing intact whey protein exhibited lactose crystallisation at a lower relative humidity (RH). Dispersions containing hydrolysed whey protein had significantly higher (P < 0.05) water diffusivity. Finally, a spray-dried model infant formula was produced containing hydrolysed or intact whey as the protein with sunflower oil as the fat source. Reconstituted, hydrolysed formula had a significantly (P < 0.05) higher fat globule size and lower emulsion stability than intact formula. Lactose crystallisation in powders occurred at higher RH for hydrolysed formula. In conclusion, this research has shown the effect of altering the protein type, protein composition, and oil type on the surface composition and physical properties of different dairy powders, and how these variations greatly affect their rehydration characteristics and storage stability.