Application of mesoporous silica for the oral delivery of poorly water-soluble drugs

The objective of this thesis was to improve the dissolution rate of the poorly waters-soluble drug, fenofibrate by processing it with a high surface area carrier, mesoporous silica. The subsequent properties of the drug – silica composite were studied in terms of drug distribution within the silica matrix, solid state and release properties. Prior to commencing any experimental work, the properties of unprocessed mesoporous silica and fenofibrate were characterised (chapter 3), this allowed for comparison with the processed samples studied in later chapters. Fenofibrate was a highly stable, crystalline drug that did not adsorb moisture, even under long term accelerated storage conditions. It maintained its crystallinity even after SC-CO2 processing. Its dissolution rate was limited and dependent on the characteristics of the particular in vitro media studied. Mesoporous silica had a large surface area and mesopore volume and readily picked up moisture when stored under long term accelerated storage conditions (75% RH, 40 oC). It maintained its mesopore character after SC-CO2 processing. A variety of methods were employed to process fenofibrate with mesoporous silica including physical mixing, melt method, solvent impregnation and novel methods such as liquid and supercritical carbon dioxide (SC-CO2) (chapter 4). It was found that it was important to break down the fenofibrate particulate structure to a molecular state to enable drug molecules enter into the silica mesopores. While all processing methods led to some increase in fenofibrate release properties; the impregnation, liquid and SC-CO2 methods produced the most rapid release rates. SC-CO2 processing was further studied with a view to optimising the processing parameters to achieve the highest drug-loading efficiency possible (chapter 5). In this thesis, it was that SC-CO2 processing pressure had a bearing on drug-loading efficiency. Neither pressure, duration or depressurisation rate affected drug solid state or release properties. The amount of drug that could be loaded onto to the mesoporous silica successfully was also investigated at different ratios of drug mass to silica surface area under constant SC-CO2 conditions; as the drug – silica ratio increased, the drug-loading efficiency decreased, while there was no effect on drug solid state or release properties. The influence of the number of drug-loading steps was investigated (chapter 6) with a view to increasing the drug-loading efficiency. This multiple step approach did not yield an increase in drug-loading efficiency compared to the single step approach. It was also an objective in this chapter to understand how much drug could be loaded into silica mesopores; a method based on the known volume of the mesopores and true density of drug was investigated. However, this approach led to serious repercussions in terms of the subsequent solid state nature of the drug and its release performance; there was significant drug crystallinity and reduced release extent. The impact of in vitro release media on fenofibrate release was also studied (chapter 6). Here it was seen that media containing HCl led to reduced drug release over time compared to equivalent media not containing HCl. The key findings of this thesis are discussed in chapter 7 and included: 1. Drug – silica processing method strongly influenced drug distribution within the silica matrix, drug solid state and release. 2. The silica surface area and mesopore volume also influenced how much drug could be loaded. It was shown that SC-CO2 processing variables such as processing pressure (13.79 – 41.37 MPa), duration time (4 – 24 h) and depressurisation rate (rapid or controlled) did not influence the drug distribution within the SBA- 15 matrix, drug solid state form or release. Possible avenues of research to be considered going forward include the development and application of high resolution imaging techniques to visualise drug molecules within the silica mesopores. Also, the issues surrounding SBA-15 usage in a pharmaceutical manufacturing environment should be addressed.

High-efficiency photovoltaics through mechanically stacked integration of solar cells based on the InP lattice constant

Solar Energy is a clean and abundant energy source that can help reduce reliance on fossil fuels around which questions still persist about their contribution to climate and long-term availability. Monolithic triple-junction solar cells are currently the state of the art photovoltaic devices with champion cell efficiencies exceeding 40%, but their ultimate efficiency is restricted by the current-matching constraint of series-connected cells. The objective of this thesis was to investigate the use of solar cells with lattice constants equal to InP in order to reduce the constraint of current matching in multi-junction solar cells. This was addressed by two approaches: Firstly, the formation of mechanically stacked solar cells (MSSC) was investigated through the addition of separate connections to individual cells that make up a multi-junction device. An electrical and optical modelling approach identified separately connected InGaAs bottom cells stacked under dual-junction GaAs based top cells as a route to high efficiency. An InGaAs solar cell was fabricated on an InP substrate with a measured 1-Sun conversion efficiency of 9.3%. A comparative study of adhesives found benzocyclobutene to be the most suitable for bonding component cells in a mechanically stacked configuration owing to its higher thermal conductivity and refractive index when compared to other candidate adhesives. A flip-chip process was developed to bond single-junction GaAs and InGaAs cells with a measured 4-terminal MSSC efficiency of 25.2% under 1-Sun conditions. Additionally, a novel InAlAs solar cell was identified, which can be used to provide an alternative to the well established GaAs solar cell. As wide bandgap InAlAs solar cells have not been extensively investigated for use in photovoltaics, single-junction cells were fabricated and their properties relevant to PV operation analysed. Minority carrier diffusion lengths in the micrometre range were extracted, confirming InAlAs as a suitable material for use in III-V solar cells, and a 1-Sun conversion efficiency of 6.6% measured for cells with 800 nm thick absorber layers. Given the cost and small diameter of commercially available InP wafers, InGaAs and InAlAs solar cells were fabricated on alternative substrates, namely GaAs. As a first demonstration the lattice constant of a GaAs substrate was graded to InP using an InxGa1-xAs metamorphic buffer layer onto which cells were grown. This was the first demonstration of an InAlAs solar cell on an alternative substrate and an initial step towards fabricating these cells on Si. The results presented offer a route to developing multi-junction solar cell devices based on the InP lattice parameter, thus extending the range of available bandgaps for high efficiency cells.

The application of computer modelling to develop a methodology for ‘existing building’ upgrades to move towards carbon-neutral buildings

The retrofitting of existing buildings for decreased energy usage, through increased energy efficiency and for minimum carbon dioxide emissions throughout their remaining lifetime is a major area of research. This research area requires development to provide building professionals with more efficient building retrofit solution determination tools. The overarching objective of this research is to develop a tool for this purpose through the implementation of a prescribed methodology. This has been achieved in three distinct steps. Firstly, the concept of using the degree-days modelling method as an adequate means of basing retrofit decision upon was analysed and the results illustrated that the concept had merit. Secondly, the concept of combining the degree-days modelling method and the Genetic Algorithms optimisation method is investigated as a method of determining optimal thermal energy retrofit solutions. Thirdly, the combination of the degree-days modelling method and the Genetic Algorithms optimisation method were packaged into a building retrofit decision-support tool and named BRaSS (Building Retrofit Support Software). The results demonstrate clearly that, fundamental building information, simplified occupancy profiles and weather data used in a static simulation modelling method is a sufficient and adequate means to base retrofitting decisions upon. The results also show that basing retrofit decisions upon energy analysis results are the best means to guide a retrofit project and also to achieve results which are optimum for a particular building. The results also indicate that the building retrofit decision-support tool, BRaSS, is an effective method to determine optimum thermal energy retrofit solutions.

Functional application of lactic acid bacteria exopolysaccharide in complex food systems

Lactic acid bacteria expolysaccharides (LAB-EPS), in particular those formed from sucrose have the potential to improve food and beverage rheology and enhance their sensory properties potentially replacing or reducing expensive hydrocolloids currently used as improvers in food and beverage industries. Addition of sucrose not only enables EPS formation but also affects organic acid formation, thus influencing the sensory properties of the resulting food/beverage products. The first part of the study the organoleptic modulation of barley malt derived wort fermented using in situ produced bacterial polysaccharides has been investigated. Weisella cibaria MG1 was capable to produce exopolysaccharides during sucrosesupplemented barley malt derived wort fermentation. Even though the strain dominated the (sucrose-supplemented) wort fermentation, it was found to produce EPS (14.4 g l-1) with lower efficiency than in SucMRS (34.6 g l-1). Higher maltose concentration in wort led to the increased formation of oligosaccharide (OS) at the expense of EPS. Additionally, small amounts of organic acids were formed and ethanol remained below 0.5% (v/v). W. cibaria MG1 fermented worts supplemented with 5 or 10% sucrose displayed a shear-thinning behaviour indicating the formation of polymers. This report showed how novel and nutritious LAB fermented wort-base beverage with prospects for further advancements can be formulated using tailored microbial cultures. In the next step, the impact of exopolysaccharide-producing Weissella cibaria MG1 on the ability to improve rheological properties of fermented plant-based milk substitute plant based soy and quinoa grain was evaluated. W. cibaria MG1 grew well in soy milk, exceeding a cell count of log 8 cfu/g within 6 h of fermentation. The presence of W. cibaria MG1 led to a decrease in gelation and fermentation time. EPS isolated from soy yoghurts supplemented with sucrose were higher in molecular weight (1.1 x 108 g/mol vs 6.6 x 107 g/mol), and resulted in reduced gel stiffness (190 ± 2.89 Pa vs 244 ± 15.9 Pa). Soy yoghurts showed typical biopolymer gels structure and the network structure changed to larger pores and less cross-linking in the presence of sucrose and increasing molecular weight of the EPS. In situ investigation of Weissella cibaria MG1 producing EPS on quinoa-based milk was performed. The production of quinoa milk, starting from wholemeal quinoa flour, was optimised to maximise EPS production. On doing that, enzymatic destructuration of protein and carbohydrate components of quinoa milk was successfully achieved applying alpha-amylase and proteases treatments. Fermented wholemeal quinoa milk using Weissella cibaria MG1 showed high viable cell counts (>109 cfu/mL), a pH of 5.16, and significantly higher water holding capacity (WHC, 100 %), viscosity (> 0. 5 Pa s) and exopolysaccharide (EPS) amount (40 mg/L) than the chemically acidified control. High EPS (dextran) concentration in quinoa milk caused earlier aggregation because more EPS occupy more space, and the chenopodin were forced to interact with each other. Direct observation of microstructure in fermented quinoa milk indicated that the network structures of EPS-protein could improve the texture of fermented quinoa milk. Overall, Weissella cibaria MG1 showed favorable technology properties and great potential for further possible application in the development of high viscosity fermented quinoa milk. The last part of the study investigate the ex-situ LAB-EPS (dextran) application compared to other hydrocolloids as a novel food ingredient to compensate for low protein in biscuit and wholemeal wheat flour. Three hydrocolloids, xanthan gum, dextran and hydroxypropyl methylcellulose, were incorporated into bread recipes based on high-protein flours, low-protein flours and coarse wholemeal flour. Hydrocolloid levels of 0–5 % (flour basis) were used in bread recipes to test the water absorption. The quality parameters of dough (farinograph, extensograph, rheofermentometre) and bread (specific volume, crumb structure and staling profile) were determined. Results showed that xanthan had negative impact on the dough and bread quality characteristics. HPMC and dextran generally improved dough and bread quality and showed dosage dependence. Volume of low-protein flour breads were significantly improved by incorporation of 0.5 % of the latter two hydrocolloids. However, dextran outperformed HPMC regarding initial bread hardness and staling shelf life regardless the flour applied in the formulation.

Delivering enhanced efficiency in the synthesis of α-diazosulfoxides by exploiting the process control enabled in flow

Continuous-flow generation of α-diazosulfoxides results in a two- to three-fold increase in yields and decreased reaction times compared to standard batch synthesis methods. These high yielding reactions are enabled by flowing through a bed of polystyrene-supported base (PS-DBU or PS-NMe2) with highly controlled residence times. This engineered solution allows the α-diazosulfoxides to be rapidly synthesized while limiting exposure of the products to basic reaction conditions, which have been found to cause rapid decomposition. In addition to improved yields, this work has the added advantage of ease of processing, increased safety profile, and scale-up potential.