Phase equilibrium studies at moderate pressures

The theory of vapour-liquid equilibria is reviewed, as is the present status or prediction methods in this field. After discussion of the experimental methods available, development of a recirculating equilibrium still based on a previously successful design (the modified Raal, Code and Best still of O'Donnell and Jenkins) is described. This novel still is designed to work at pressures up to 35 bar and for the measurement of both isothermal and isobaric vapour-liquid equilibrium data. The equilibrium still was first commissioned by measuring the saturated vapour pressures of pure ethanol and cyclohexane in the temperature range 77-124°C and 80-142°C respectively. The data obtained were compared with available literature experimental values and with values derived from an extended form of the Antoine equation for which parameters were given in the literature. Commissioning continued with the study of the phase behaviour of mixtures of the two pure components as such mixtures are strongly non-ideal, showing azeotopic behaviour. Existing data did not exist above one atmosphere pressure. Isothermal measurements were made at 83.29°C and 106.54°C, whilst isobaric measurements were made at pressures of 1 bar, 3 bar and 5 bar respectively. The experimental vapour-liquid equilibrium data obtained are assessed by a standard literature method incorporating a themodynamic consistency test that minimises the errors in all the measured variables. This assessment showed that reasonable x-P-T data-sets had been measured, from which y-values could be deduced, but that the experimental y-values indicated the need for improvements in the design of the still. The final discussion sets out the improvements required and outlines how they might be attained.

The chromatographic separation of carbohydrate mixtures

The separation performance of a semicontinuous counter-current chromatographic refiner (SCCR7), consisting of twelve 5.4 cm id x 75cm long columns packed with calcium charged cross-linked polysytrene resin (KORELA VO7C), was optimised. An industrial barley syrup was used containing 42% fructose, 52% glucose and 6% maltose and oligosaccharides. The effects of temperature, flow rates and concentration on the distribution coefficients were evaluated and quantified by deriving general relationships. The effects of flow rates, feed composition and concentration on the separation performance of the SCCR7 were identified and general relationships between them and the switch time, which was found to be the controlling parameter, were developed. Fructose rich (FRP) and glucose rich (GRP) product purities of 99.9% were obtained at 18.6% w/v feed concentrations. When a 66% w/v feed concentration was used and product splitting technique was employed, the throughput was 32.1 kg sugar solids/m3 resin/hr. The GRP contained less than 4.5% fructose, the FRP was over 95% pure, and the respective concentrations were 22.56 and 11.29% w/v. Over 94% of the glucose and 95.78% of the fructose in the feed were recovered in the GRP and FRP respectively. By recycling the dilute product split fractions, the GRP and FRP concentrations were increased to 25.4 and 12.96% w/v; the FRP was 90.2% pure and the GRP contained 6.69% w/v fructose. A theoretical link between batch and semicontinuous chromatographic equipments has been determined. A computer simulation was developed predicting successfully the purging concentration profiles at `pseudo-equilibrium', and also certain system design parameters. An important further aspect of the work has been to study the behaviour of chromatographic bioreactor-separators. Such batch systems of 5.4cm id and lengths varying between 30 and 230cm, were used to investigate the effect of scaling up on the conversion of sucrose into dextran and fructose in the presence of the dextransucrase enzyme. Conversions of over 80% were achieved at 4 hr sucrose residence times. The crude dextransucrase was purified using centrifugation, ultrafiltration and cross-flow microfiltration techniques. Better enzyme stability was obtained by first separating the non-solid impurities using cross-flow microfiltration, and then removing the cells from the enzyme immediately before use by continuous centrifugation.

The effects of varying forms and degrees of government intervention upon the effective competitiveness of UK small businesses

This doctoral thesis responds to the need for greater understanding of small businesses and their inherent unique problem-types. Integral to the investigation is the theme that for governments to effectively influence small business, a sound understanding of the factors they are seeking to influence is essential. Moreover, the study, in its recognition of the many shortcomings in management research and, in particular that the research methods and approaches adopted often fail to give adequate understanding of issues under study, attempts to develop an innovative and creative research approach. The aim thus being to produce, not only advances in small business management knowledge from the standpoints of government policy makers and `lq recipient small business, but also insights into future potential research method for the continued development of that knowledge. The origins of the methodology lay in the non-acceptance of traditional philosophical positions in epistemology and ontology, with a philosophical standpoint of internal realism underpinning the research. Internal realism presents the basis for the potential co-existence of qualitative and quantitative research strategy and underlines the crucial contributory role of research method in provision of ultimate factual status of the assertions of research findings. The concept of epistemological bootstrapping is thus used to develop a `lq partial research framework to foothold case study research, thereby avoiding limitations of objectivism and brute inductivism. The major insights and issues highlighted by the `lq bootstrap, guide the researcher around the participant case studies. A novel attempt at contextualist (linked multi-level and processual) analysis was attempted in the major in-depth case study, with two further cases playing a support role and contributing to a balanced emphasis of empirical research within the context of time constraints inherent within part-time research.

Delivery and stability of antisense oligonucleotide conjugates in vitro

The efficacy of antisense oligonucleotide (ODN) therapy is dependent on four major parameters: delivery to cells, intracellular stability and localisation and efficient action at the target site.The aim of this project was to study the delivery of ODNs to macrophages and to assess the stability of two ODN conjugates, in vitro. The first conjugate aimed to improve uptake of ODNs via mannose receptor mediated delivery, the second investigated the improved delivery of ODN conjugates via non-specific lipophilic interaction with the cell membrane. A mono-mannose phosphoramidite derivative was designed and synthesised and a mono-mannose ODN conjugate synthesised by standard phosphoramidite chemistry. Delivery of this conjugate was enhanced to RAW264.7 and J774 macrophage cell lines via a mechanism of receptor mediated endocytosis. The delivery of three lipophilic ODN conjugates, cholesterol (cholhex), 16-carbon alkyl chain (C16) and hexa-ethylene glycol (HEG) moieties and an unconjugated ODN were assessed in RAW264.7 macrophages. All three conjugates increased the lipophilicity of the ODN as assessed from partition coefficient data. Both the cholhex and unconjugated ODNs were found to have higher degrees of cellular association than the C16 and HEG conjugates. Cellular uptake studies implicated internalisation of these ODNs by an adsorptive endocytosis mechanism. Following endocytosis, ODNs must remain stable during their residence in endosomal/lysosomal compartments prior to exiting and exerting their biological action in either the cytosol or nucleus. Assessment of in vitro stability in a lysosomal extract revealed the cholhex conjugate and unconjugated ODNs to have a longer half-life than the C16 and HEG conjugated ODNs, highlighting the influence of conjugate moieties on lysosomal stability. The effects of base composition and length on stability in a lysosomal extract revealed the longest half-life for homo-cytidine ODNs and ODNs over 20 nucleotides in length. These studies suggest that the above conjugates can enhance cellular association and delivery of antisense ODNs to cultured macrophages. This may lead to their use in treating disorders such as HIV infection, which affects this cell type.

Non-Linear oil firm force coefficients for a journal bearing operating under aligned and misaligned conditions

It is well established that hydrodynamic journal bearings are responsible for self-excited vibrations and have the effect of lowering the critical speeds of rotor systems. The forces within the oil film wedge, generated by the vibrating journal, may be represented by displacement and velocity coefficient~ thus allowing the dynamical behaviour of the rotor to be analysed both for stability purposes and for anticipating the response to unbalance. However, information describing these coefficients is sparse, misleading, and very often not applicable to industrial type bearings. Results of a combined analytical and experimental investigation into the hydrodynamic oil film coefficients operating in the laminar region are therefore presented, the analysis being applied to a 120 degree partial journal bearing having a 5.0 in diameter journal and a LID ratio of 1.0. The theoretical analysis shows that for this type of popular bearing, the eight linearized coefficients do not accurately describe the behaviour of the vibrating journal based on the theory of small perturbations, due to them being masked by the presence of nonlinearity. A method is developed using the second order terms of Taylor expansion whereby design charts are provided which predict the twentyeight force coefficients for both aligned, and for varying amounts of journal misalignment. The resulting non-linear equations of motion are solved using a modified Newton-Raphson method whereby the whirl trajectories are obtained, thus providing a physical appreciation of the bearing characteristics under dynamically loaded conditions.

The influence of the chemical nature of dispersed phase on stability in oil-in-water emulsions

Some of the problems arising from the inherent instability of emulsions are discussed. Aspects of emulsion stability are described and particular attention is given to the influence of the chemical nature of the dispersed phase on adsorbed film structure and stability, Emulsion stability has been measured by a photomicrographic technique. Electrophoresis, interfacial tension and droplet rest-time data were also obtained. Emulsions were prepared using a range of oils, including aliphatic and aromatic hydrocarbons, dispersed In a solution of sodium dodecyl sulphate. In some cases a small amount of alkane or alkanol was incorporated into the oil phase. In general the findings agree with the classical view that the stability of oil-in-water emulsions is favoured by a closely packed interfacial film and appreciable electric charge on the droplets. The inclusion of non-ionic alcohol leads to enhanced stability, presumably owing to the formation of a "mixed" interfacial film which is more closely packed and probably more coherent than that of the anionic surfactant alone. In some instances differences in stability cannot he accounted for simply by differences in interfacial adsorption or droplet charge. Alternative explanations are discussed and it is postulated that the coarsening of emulsions may occur not only hy coalescence but also through the migration of oil from small droplets to larger ones by molecular diffusion. The viability of using the coalescence rates of droplets at a plane interface as a guide to emulsion stability has been researched. The construction of a suitable apparatus and the development of a standard testing procedure are described. Coalescence-time distributions may be correlated by equations similar to those presented by other workers, or by an analysis based upon the log-normal function. Stability parameters for a range of oils are discussed in terms of differences in film drainage and the natl1re of the interfacial film. Despite some broad correlations there is generally poor agreement between droplet and emulsion stabilities. It is concluded that hydrodynamic factors largely determine droplet stability in the systems studied. Consequently droplet rest-time measurements do not provide a sensible indication of emulsion stability,

The stability and formulation of topical analgesics

High-performance liquid chromatographic methods are developed for the simultaneous determination of various salicylates, their p-hydroxy isomers and nicotinic acid esters. The method is sensitive enough to detect trace amounts (~µM/L)of the product generated from cross reactivity between the drugs and the vehicle. The developed method also allows analysis of various topical products containing salicylate and nicotinate esters in their formulations. Applying this method, the degradation profiles of salicylates, nicotinates, p-hydroxy benzoate, o-methoxy benzoate and aspirin prodrugs in alkaline media are determined. The profile for alkyl salicylate degradation is found to be first order (A---? B) When the alcoholic radical is similar to that of the ester. In alcohol having a radical different from that of the ester function, the degradation is found to proceed through competitive transesterification and hydrolysis. The intermediates are identified following synthesis and isolation. The rate and extent of transesterification depends on the proportion of alcohol present in the system. Equations are presented to model the time profiles of reactant and product concentration. The reactions are base catalysed and the predominant pathway involves a concerted solvent attack upon the salicylate anion. Competitive hydrolysis of both ester components also follows this mechanism at moderate pH values but rates increase under strongly alkaline conditions as direct hydroxide attack becomes significant. In contrast, transesterification is independent of base concentration once full ionization is accomplished. The competitive hydrolysis is modelled using equations involving the dielectric constant of the medium. A range of other esters are also shown to undergo base-catalysed transesterification. In non-alcoholic solution phenyl salicylate undergoes a concentration-dependent oligomerisation which yields salsalate among the products. Competitive transesterification and hydrolysis also occur in products for topical use which have vehicles based upon alcohol, glycol or glycol polymers. Such reactions may compromise stability assessments, pharmaceutical integrity and delivery profiles.

Formulation of topical non-steroidal anti-inflammatory agents

Reversed-pahse high-performance liquid chromatographic (HPLC) methods were developed for the assay of indomethacin, its decomposition products, ibuprofen and its (tetrahydro-2-furanyl)methyl-, (tetrahydro-2-(2H)pyranyl)methyl- and cyclohexylmethyl esters. The development and application of these HPLC systems were studied. A number of physico-chemical parameters that affect percutaneous absorption were investigated. The pKa values of indomethacin and ibuprofen were determined using the solubility method. Potentiometric titration and the Taft equation were also used for ibuprofen. The incorporation of ethanol or propylene glycol in the solvent resulted in an improvement in the aqueous solubility of these compounds. The partition coefficients were evaluated in order to establish the affinity of these drugs towards the stratum corneum. The stability of indomethacin and of ibuprofen esters were investigated and the effect of temperature and pH on the decomposition rates were studied. The effect of cetyltrimethylammonium bromide on the alkaline degradation of indomethacin was also followed. In the presence of alcohol, indomethacin alcoholysis was observed and the kinetics of decomposition were subjected to non-linear regression analysis and the rate constants for the various pathways were quantified. The non-isothermal, sufactant non-isoconcentration and non-isopH degradation of indomethacin were investigated. The analysis of the data was undertaken using NONISO, a BASIC computer program. The degradation profiles obtained from both non-iso and iso-kinetic studies show that there is close concordance in the results. The metabolic biotransformation of ibuprofen esters was followed using esterases from hog liver and rat skin homogenates. The results showed that the esters were very labile under these conditions. The presence of propylene glycol affected the rates of enzymic hydrolysis of the ester. The hydrolysis is modelled using an equation involving the dielectric constant of the medium. The percutaneous absorption of indomethacin and of ibuprofen and its esters was followed from solutions using an in vitro excised human skin model. The absorption profiles followed first order kinetics. The diffusion process was related to their solubility and to the human skin/solvent partition coefficient. The percutaneous absorption of two ibuprofen esters from suspensions in 20% propylene glycol-water were also followed through rat skin with only ibuprofen being detected in the receiver phase. The sensitivity of ibuprofen esters to enzymic hydrolysis compared to the chemical hydrolysis may prove valuable in the formulation of topical delivery systems.

Remote sensing applied to slope stability in mountainous roads in Iran

The Alborz Mountain range separates the northern part of Iran from the southern part. It also isolates a narrow coastal strip to the south of the Caspian Sea from the Central Iran plateau. Communication between the south and north until the 1950's was via two roads and one rail link. In 1963 work was completed on a major access road via the Haraz Valley (the most physically hostile area in the region). From the beginning the road was plagued by accidents resulting from unstable slopes on either side of the valley. Heavy casualties persuaded the government to undertake major engineering works to eliminate ''black spots" and make the road safe. However, despite substantial and prolonged expenditure the problems were not solved and casualties increased steadily due to the increase in traffic using the road. Another road was built to bypass the Haraz road and opened to traffic in 1983. But closure of the Haraz road was still impossible because of the growth of settlements along the route and the need for access to other installations such as the Lar Dam. The aim of this research was to explore the possibility of applying Landsat MSS imagery to locating black spots along the road and the instability problems. Landsat data had not previously been applied to highway engineering problems in the study area. Aerial photographs are better in general than satellite images for detailed mapping, but Landsat images are superior for reconnaissance and adequate for mapping at the 1 :250,000 scale. The broad overview and lack of distortion in the Landsat imagery make the images ideal for structural interpretation. The results of Landsat digital image analysis showed that certain rock types and structural features can be delineated and mapped. The most unstable areas comprising steep slopes, free of vegetation cover can be identified using image processing techniques. Structural lineaments revealed from the image analysis led to improved results (delineation of unstable features). Damavand Quaternary volcanics were found to be the dominant rock type along a 40 km stretch of the road. These rock types are inherently unstable and partly responsible for the difficulties along the road. For more detailed geological and morphological interpretation a sample of small subscenes was selected and analysed. A special developed image analysis package was designed at Aston for use on a non specialized computing system. Using this package a new and unique method for image classification was developed, allowing accurate delineation of the critical features of the study area.

An investigation into the wavelength stability of polymer optical fibre Bragg gratings

The inscription of Bragg gratings has been demonstrated in PMMA-based polymer optical fibre. The water affinity of PMMA can introduce significant wavelength change in a polymer optical fibre Bragg grating (POFBG). In polymer optical fibre losses are much higher than with silica fibre. Very strong absorption bands related to higher harmonics of vibrations of the C-H bond dominate throughout the visible and near infrared. Molecular vibration in substances generates heat, which is referred to as the thermal effect of molecular vibration. This means that a large part of the absorption of optical energy in those spectral bands will convert into thermal energy, which eventually drives water content out of the polymer fibre and reduces the wavelength of POFBG. In this work we have investigated the wavelength stability of POFBGs in different circumstances. The experiment has shown that the characteristic wavelength of a POFBG starts decreasing after a light source is applied to it. This decrease continues until equilibrium inside the fibre is established, depending on the initial water content inside the fibre, the surrounding humidity, the optical power applied, and the fibre size. Our investigation has shown that POFBGs operating at around 850 nm show much smaller wavelength reduction than those operating at around 1550 nm in the same fibre; POFBGs with different diameters show different changes; POFBGs powered by a low level light source, or operating in a very dry environment are least affected by this thermal effect.

Bifurcation contrasts between plane Poiseuille flow and plane Magnetohydrodynamic flow

The stability characteristics of an incompressible viscous pressure-driven flow of an electrically conducting fluid between two parallel boundaries in the presence of a transverse magnetic field are compared and contrasted with those of Plane Poiseuille flow (PPF). Assuming that the outer regions adjacent to the fluid layer are perfectly electrically insulating, the appropriate boundary conditions are applied. The eigenvalue problems are then solved numerically to obtain the critical Reynolds number Rec and the critical wave number ac in the limit of small Hartmann number (M) range to produce the curves of marginal stability. The non-linear two-dimensional travelling waves that bifurcate by way of a Hopf bifurcation from the neutral curves are approximated by a truncated Fourier series in the streamwise direction. Two and three dimensional secondary disturbances are applied to both the constant pressure and constant flux equilibrium solutions using Floquet theory as this is believed to be the generic mechanism of instability in shear flows. The change in shape of the undisturbed velocity profile caused by the magnetic field is found to be the dominant factor. Consequently the critical Reynolds number is found to increase rapidly with increasing M so the transverse magnetic field has a powerful stabilising effect on this type of flow.

Investigating the role of cholesterol in the formation of non-ionic surfactant based bilayer vesicles:thermal analysis and molecular dynamics

The aim of this research was to investigate the molecular interactions occurring in the formulation of non-ionic surfactant based vesicles composed monopalmitoyl glycerol (MPG), cholesterol (Chol) and dicetyl phosphate (DCP). In the formulation of these vesicles, the thermodynamic attributes and surfactant interactions based on molecular dynamics, Langmuir monolayer studies, differential scanning calorimetry (DSC), hot stage microscopy and thermogravimetric analysis (TGA) were investigated. Initially the melting points of the components individually, and combined at a 5:4:1 MPG:Chol:DCP weight ratio, were investigated; the results show that lower (90 C) than previously reported (120-140 C) temperatures could be adopted to produce molten surfactants for the production of niosomes. This was advantageous for surfactant stability; whilst TGA studies show that the individual components were stable to above 200 C, the 5:4:1 MPG:Chol:DCP mixture show ∼2% surfactant degradation at 140 C, compared to 0.01% was measured at 90 C. Niosomes formed at this lower temperature offered comparable characteristics to vesicles prepared using higher temperatures commonly reported in literature. In the formation of niosome vesicles, cholesterol also played a key role. Langmuir monolayer studies demonstrated that intercalation of cholesterol in the monolayer did not occur in the MPG:Chol:DCP (5:4:1 weight ratio) mixture. This suggests cholesterol may support bilayer assembly, with molecular simulation studies also demonstrating that vesicles cannot be built without the addition of cholesterol, with higher concentrations of cholesterol (5:4:1 vs 5:2:1, MPG:Chol:DCP) decreasing the time required for niosome assembly. © 2013 Elsevier B.V.

Consideration of the efficacy of non-ionic vesicles in the targeted delivery of oral vaccines

The fundamentals of this research were to exploit non-ionic surfactant technology for delivery and administration of vaccine antigens across the oral route and to gain a better understanding of vaccine trafficking. Using a newly developed method for manufacture of non-ionic surfactant vesicles (niosomes and bilosomes) lower process temperatures were adopted thus reducing antigen exposure to potentially damaging conditions. Vesicles prepared by this method offered high protection to enzymatic degradation, with only ~10 % antigen loss measured when vesicles incorporating antigen were exposed to enzyme digestion. Interestingly, when formulated using this new production method, the addition of bile salt to the vesicles offered no advantage in terms of stability within simulated gastro-intestinal conditions. Considering their ability to deliver antigen to their target site, results demonstrated that incorporation of antigen within vesicles enhanced delivery and targeting of the antigen to the Peyer's Patch, again with niosomes and bilosomes offering similar efficiency. Delivery to both the Peyer's patches and mesentery lymphatics was shown to be dose dependent at lower concentrations, with saturation kinetics applying at higher concentrations. This demonstrates that in the formulation of vaccine delivery systems, the lipid/antigen dose ratio is not only a key factor in production cost, but is equally a key factor in the kinetics of delivery and targeting of a vaccine system. © 2013 Controlled Release Society.

Consideration of the efficacy of non-ionic vesicles in the targeted delivery of oral vaccines

The fundamentals of this research were to exploit non-ionic surfactant technology for delivery and administration of vaccine antigens across the oral route and to gain a better understanding of vaccine trafficking. Using a newly developed method for manufacture of non-ionic surfactant vesicles (niosomes and bilosomes) lower process temperatures were adopted thus reducing antigen exposure to potentially damaging conditions. Vesicles prepared by this method offered high protection to enzymatic degradation, with only ~10 % antigen loss measured when vesicles incorporating antigen were exposed to enzyme digestion. Interestingly, when formulated using this new production method, the addition of bile salt to the vesicles offered no advantage in terms of stability within simulated gastro-intestinal conditions. Considering their ability to deliver antigen to their target site, results demonstrated that incorporation of antigen within vesicles enhanced delivery and targeting of the antigen to the Peyer's Patch, again with niosomes and bilosomes offering similar efficiency. Delivery to both the Peyer's patches and mesentery lymphatics was shown to be dose dependent at lower concentrations, with saturation kinetics applying at higher concentrations. This demonstrates that in the formulation of vaccine delivery systems, the lipid/antigen dose ratio is not only a key factor in production cost, but is equally a key factor in the kinetics of delivery and targeting of a vaccine system. © 2013 Controlled Release Society.

Formation of Singularities for Weakly Non-Linear N×N Hyperbolic Systems

We present some results on the formation of singularities for C^1 - solutions of the quasi-linear N × N strictly hyperbolic system Ut + A(U )Ux = 0 in [0, +∞) × Rx . Under certain weak non-linearity conditions (weaker than genuine non-linearity), we prove that the first order derivative of the solution blows-up in finite time.