Phase equilibrium studies at normal pressures

A total pressure apparatus has been developed to measure vapour-liquid equilibrium data on binary mixtures at atmospheric and sub-atmospheric pressures. The method gives isothermal data which can be obtained rapidly. Only measurements of total pressure are made as a direct function of composition of synthetic liquid phase composition, the vapour phase composition being deduced through the Gibbs-Duhem relationship. The need to analyse either of the phases is eliminated. As such the errors introduced by sampling and analysis are removed. The essential requirements are that the pure components be degassed completely since any deficiency in degassing would introduce errors into the measured pressures. A similarly essential requirement was that the central apparatus would have to be absolutely leak-tight as any leakage of air either in or out of the apparatus would introduce erroneous pressure readings. The apparatus was commissioned by measuring the saturated vapour pressures of both degassed water and ethanol as a function of temperature. The pressure-temperature data on degassed water measured were directly compared with data in the literature, with good agreement. Similarly the pressure-temperature data were measured for ethanol, methanol and cyclohexane and where possible a direct comparison made with the literature data. Good agreement between the pure component data of this work and those available in the literature demonstrates firstly that a satisfactory degassing procedure has been achieved and that secondly the measurements of pressure-temperature are consistent for any one component; since this is true for a number of components, the measurements of both temperature and pressure are both self-consistent and of sufficient accuracy, with an observed compatibility between the precision/accuracy of the separate means of measuring pressure and temperature. The liquid mixtures studied were of ethanol-water, methanol-water and ethanol-cyclohexane. The total pressure was measured as the composition inside the equilibrium cell was varied at a set temperature. This gave P-T-x data sets for each mixture at a range of temperatures. A standard fitting-package from the literature was used to reduce the raw data to yield y-values to complete the x-y-P-T data sets. A consistency test could not be applied to the P-T-x data set as no y-values were obtained during the experimental measurements. In general satisfactory agreement was found between the data of this work and those available in the literature. For some runs discrepancies were observed, and further work recommended to eliminate the problems identified.

Immunoinformatic evaluation of multiple epitope ensembles as vaccine candidates:E coli 536

Epitope prediction is becoming a key tool for vaccine discovery. Prospective analysis of bacterial and viral genomes can identify antigenic epitopes encoded within individual genes that may act as effective vaccines against specific pathogens. Since B-cell epitope prediction remains unreliable, we concentrate on T-cell epitopes, peptides which bind with high affinity to Major Histacompatibility Complexes (MHC). In this report, we evaluate the veracity of identified T-cell epitope ensembles, as generated by a cascade of predictive algorithms (SignalP, Vaxijen, MHCPred, IDEB, EpiJen), as a candidate vaccine against the model pathogen uropathogenic gram negative bacteria Escherichia coli (E-coli) strain 536 (O6:K15:H31). An immunoinformatic approach was used to identify 23 epitopes within the E-coli proteome. These epitopes constitute the most promiscuous antigenic sequences that bind across more than one HLA allele with high affinity (IC50 <50nM). The reliability of software programmes used, polymorphic nature of genes encoding MHC and what this means for population coverage of this potential vaccine are discussed.

An exploratory study of management accounting and control systems in a developing country

This thesis reports on the results of case studies in four commercial banks in Nigeria. The study focuses how management accounting and control systems (MCS) operate in the four banks. The study is motivated by the dearth of literature on management accounting practices in the developing world in general and in Nigeria in specific. The case study approach adopted in conducting the research was useful in exploring the dynamics of the MCS in the organisations. Data was gathered from two sources. First, semi-structured interviews were conducted with managers at the head office, regional office and branches of each bank. The participants were selected from different backgrounds and managerial levels to provide broader understanding of the operations of the MCS. Second, various internal and external documents were reviewed to provide supporting evidence for the interview results. New institutional sociology (NIS) provided the theoretical framework to understand the results. NIS provided explanations for how the MCS in the four banks were shaped by diverse external and internal factors. The key factors identified as shaping the operations of the MCS were the need to comply with the regulatory environment (coercive isomorphism), the need to maintain social and cultural support (normative isomorphism) and the need to imitate successful organisations in order to appear legitimate (mimetic isomorphism). The study also examines the interplay between the institutional forces, market forces and infra-organisational power relations. This analysis is necessary to overcome the criticism of NIS that it downplays the role of market forces, agency and intra-organisational relations. The findings of the study have implications for understanding the operations of MCS in the developing world.

Development of an on-demand beam pulsing system for Pixe-analysis of thick targets

This work concerns the developnent of a proton irduced X-ray emission (PIXE) analysis system and a multi-sample scattering chamber facility. The characteristics of the beam pulsing system and its counting rate capabilities were evaluated by observing the ion-induced X-ray emission from pure thick copper targets, with and without beam pulsing operation. The characteristic X-rays were detected with a high resolution Si(Li) detector coupled to a rrulti-channel analyser. The removal of the pile-up continuum by the use of the on-demand beam pulsing is clearly demonstrated in this work. This new on-demand pu1sirg system with its counting rate capability of 25, 18 and 10 kPPS corresponding to 2, 4 am 8 usec main amplifier time constant respectively enables thick targets to be analysed more readily. Reproducibility tests of the on-demard beam pulsing system operation were checked by repeated measurements of the system throughput curves, with and without beam pulsing. The reproducibility of the analysis performed using this system was also checked by repeated measurements of the intensity ratios from a number of standard binary alloys during the experimental work. A computer programme has been developed to evaluate the calculations of the X-ray yields from thick targets bornbarded by protons, taking into account the secondary X-ray yield production due to characteristic X-ray fluorescence from an element energetically higher than the absorption edge energy of the other element present in the target. This effect was studied on metallic binary alloys such as Fe/Ni and Cr/Fe. The quantitative analysis of Fe/Ni and Cr/Fe alloy samples to determine their elemental composition taking into account the enhancement has been demonstrated in this work. Furthermore, the usefulness of the Rutherford backscattering (R.B.S.) technique to obtain the depth profiles of the elements in the upper micron of the sample is discussed.

Solubility enhancement of poorly water soluble drugs using liposome technology

The aim of this work is to investigate the various parameters that could control the encapsulation of lipophilic drugs and investigate the influence of the physical properties of poorly water-soluble drugs on bilayer loading. Initial work investigated on the solubilisation of ibuprofen, a model insoluble drug. Drug loading was assessed using HPLC and UV spectrophotometric analysis. Preliminary studies focused on the influence of bilayer composition on drug loading to obtain an optimum cholesterol concentration. This was followed up by studies investigating the effect of longer alkyl chain lipids, unsaturated alkyl chain lipids and charged lipids. The studies also focused on the effects of pH of the hydration medium and addition of the single chain surfactant a-tocopherol. The work was followed up by investigation of a range of insoluble drugs including flurbiprofen, indomethacin, sulindac, mefenamic acid, lignocaine and progesterone to investigate the influence of drugs properties and functional group on liposomal loading. The results show that no defined trend could be obtained linking the drug loading to the different drug properties including molecular weight, log P and other drug specific characteristics. However, the presence of the oppositely charged lipids improved the encapsulation of all the drugs investigated with a similar effect obtained with the substitution of the longer chain lipids. The addition of the single chain surfactant a-tocopherol resulted in enhancement of drug loading and possibly is governed by the log P of the drug candidate. Environmental scanning-electron microscopy (ESEM) was used to dynamically follow the changes in liposome morphology in real time during dehydration thereby providing a alternative assay of liposome formulation and stability. The ESEM analysis clearly demonstrated ibuprofen incorporation enhanced the stability of PC:Chol liposomes.

A technique to randomise consecutive codons in a sequence of DNA using MAX oligonucleotides

Randomisation of DNA using conventional methodology requires an excess of genes to be cloned, since with randomised codons NNN or NNG/T 64 genes or 32 genes must be cloned to encode 20 amino acids respectively. Thus, as the number of randomised codons increases, the number of genes required to encode a full set of proteins increases exponentially. Various methods have been developed that address the problems associated with excess of genes that occurs due to the degeneracy of the genetic code. These range from chemical methodologies to biological methods. These all involve the replacement, insertion or deletion of codon(s) rather than individual nucleotides. The biological methods are however limited to random insertion/deletion or replacement. Recent work by Hughes et al., (2003) has randomised three binding residues of a zinc finger gene. The drawback with this is the fact that consecutive codons cannot undergo saturation mutagenesis. This thesis describes the development of a method of saturation mutagenesis that can be used to randomise any number of consecutive codons in a DNA strand. The method makes use of “MAX” oligonucleotides coding for each of the 20 amino acids that are ligated to a conserved sequence of DNA using T4 DNA ligase. The “MAX” oligonucleotides were synthesised in such a way, with an MlyI restriction site, that restriction of the oligonucleotides occurred after the three nucleotides coding for the amino acids. This use of the MlyI site and the restrict, purify, ligate and amplify method allows the insertion of “MAX” codons at any position in the DNA. This methodology reduces the number of clones that are required to produce a representative library and has been demonstrated to be effective to 7 amino acid positions.

The application of monolayer studies in the understanding of liposomal formulations

The study of surfactant monolayers is certainly not a new technique, but the application of monolayer studies to elucidate controlling factors in liposome design remains an underutilised resource. Using a Langmuir-Blodgett trough, pure and mixed lipid monolayers can be investigated, both for their interactions within the monolayer, and for interfacial interactions with drugs in the aqueous sub-phase. Despite these monolayers effectively being only half a bilayer, with a flat rather than curved structure, information from these studies can be effectively translated into liposomal systems. Here we outline the background, general protocols and application of Langmuir studies with a focus on their application in liposomal systems. A range of case studies are discussed which show how the system can be used to support its application in the development of liposome drug delivery. Examples include investigations into the effect of cholesterol within the liposome bilayer, understanding effective lipid packaging within the bilayer to promote water soluble and poorly soluble drug retention, the effect of alkyl chain length on lipid packaging, and drug-monolayer electrostatic interactions that promote bilayer repackaging.

Bound antioxidants in elastomers

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Formulation of immunomodulatory agents

Reversed-phase high-performance liquid chromatography procedures were developed for the analysis of pyrimidine-based drugs bropirimine and its derivatives (2-N-acetyl- and 2-N-propanoyl-) and for pyrimethamine and its 2/4- substituted derivatives (2, N-propanoyl and 2,4-N, N-dipropanoyl-) and its 6- substituted (methyl-, ethyl-, propyl- and isopropyl- carboxylates) analogues. Stability studies indicated that these derivatives were not sufficiently labile to act as potential prodrugs. Solubility-pH profiles were constructed from which the dissociation constants were calculated. The physicochemical properties of these compounds were studied and attempts were made to increase the poor aqueous solubility of bropirimine (35μg/mL) by prodrug synthesis, solvate formation (acetic acid, N, N-dimethylformamide and N-methylformamide) and the use of co-solvents and additives. The first two methods proved to be fruitless whereas the latter method resulted in an intravenous formulation incorporating 32mg/mL of bropirimine. An in-vitro method for the detection of precipitation was developed and the results suggested that by using low injection rates (< 0.24mL/min) and high mobile phase flow rates (> 500mL/hr) precipitation could be minimised. Differential scanning calorimetry showed that bropirimine debrominates in the presence of a number of additives commonly used in formulation work but the temperature at which this occurred were usually > 200oC. In-vitro work gave encouraging results for the possibility of rectal delivery of bropirimine but in-vivo work on rabbits showed considerable variations in the resulting plasma levels and pharmacokinetic parameters.

The impact of ageing on the barriers to drug delivery

Generally, we like to see ageing as a process that is happening to people older than ourselves. However the process of ageing impacts on a wide range of functions within the human body. Whilst many of the outcomes of ageing can now be delayed or reduced, age-related changes in cellular, molecular and physiological functionality of tissues and organs can also influence how drugs enter, distribute and are eliminated from the body. Therefore, the changing profile of barriers to drug delivery should be considered if we are to develop more age-appropriate medicines. Changes in the drug dissolution and absorption in older patients may require the formulation of oral delivery systems that offer enhanced retention at absorption sites to improve drug delivery. Alternatively, liquid and fast-melt dosage systems may address the need of patients who have difficulties in swallowing medication. Ageing-induced changes in the lung can also result in slower drug absorption, which is further compounded by disease factors, common in an ageing population, that reduce lung capacity. In terms of barriers to drug delivery to the eye, the main consideration is the tear film, which like other barriers to drug delivery, changes with normal ageing and can impact on the bioavailability of drugs delivery using eye drops and suspensions. In contrast, whilst the skin as a barrier changes with age, no significant difference in absorption of drugs from transdermal drug delivery is observed in different age groups. However, due to the age-related pharmacokinetic and pharmacodynamic changes, dose adaptation should still be considered for drug delivery across the skin. Overall it is clear that the increasing age demographic of most populations, presents new (or should that be older) barriers to effective drug delivery. © 2012 Elsevier B.V. All rights reserved.

The influence of Arabian Gulf environment on mechanisms of reinforcement corrosion

The reduction in the useful-service life of reinforced concrete construction in the Arabian Gulf is attributed to reinforcement corrosion. While this phenomenon is primarily related to chloride ions, the concomitant pressure of sulfate salts may accelerate the deterioration process. Another factor which might influence reinforcement corrosion is the elevated ambient temperature. While few studies have been conducted to evaluate the individual effect of sulfate contamination and temperature on chloride binding and reinforcement corrosion, the synergistic effect of these factors on concrete durability, viz.-a-viz., reinforcement corrosion, needs to be evaluated. Further, the environmental conditions of the Arabian Gulf are also conducive for accelerated carbonation. However, no data are available on the concomitant effect of chloride-sulfate contamination and elevated temperature on the carbonation behaviour of plain and blended cements.This study was conducted to evaluate the conjoint effect of chloride-sulfate contamination and temperature on the pore solution chemistry and reinforcement corrosion. The effect of chloride-sulfate contamination and elevated temperature on carbonation in plain and blended cements was also investigated. Pore solution extraction and analysis, X-ray diffraction, differential thermal analysis, scanning electron microscopy, DC linear polarization resistance and AC impedance spectroscopy techniques were utilized to study the effect of experimental parameters on chloride binding, reinforcement corrosion and carbonation.The results indicated that the concomitant presence of chloride and sulfate salts and temperature significantly influences the durability performance of concrete by: (i) decreasing the chloride binding, (ii) increasing reinforcement corrosion, and (iii) accelerating the carbonation process. To avoid such deterioration, it is advisable to minimize both chloride and sulfate contamination contributed by the mixture ingredients. Due to the known harmful role of sulfate ions in decreasing the chloride binding and increasing reinforcement corrosion, limits on allowable sulfate contamination in concrete should also be established.