No / An isocratic oil-in-water microemulsion High Performance Liquid Chromatography (MELC) was developed and validated for the determination of terbutaline in urine samples. A solid phase extraction (SPE) method which used Oasis HLB cartridges was optimised to isolate terbutaline from a urine matrix followed by HPLC with fluorescence detection. The urinary assay was performed in accordance with FDA and ICH regulations for the validation of bioanalytical samples. The method uses the isocratic oil-in-water micro emulsion to separate the terbutaline from the endogenous urine components. The chromatographic separation was carried out on C18-Spherisorb (250mm×4.6mm) analytical column maintained at 30 °C. The mobile phase was 94.4% aqueous orthophosphate buffer (adjusted to pH 3 with orthophosphoric acid), 0.5% ethyl acetate, 1.5% Brij35, 2.5% 1-butanol and 1.1% Octanesulfonic acid (OSA), all w/w. The terbutaline peak was detected by fluorescence detection, using excitation and emission wavelengths of 267 and 313 nm, respectively. The linearity of response was demonstrated at six different concentrations of terbutaline which were extracted from spiked urine, ranging from 60 to 1000ng/ml. The terbutaline was extracted from urine by a solid phase extraction clean-up procedure on Oasis HLB cartridges, and the relative recovery was >87.64% (n = 5). The limit of detection (LOD) and limit of quantitation (LOQ) in urine were 20.21 and 61.24ng/ml, respectively. The intra-day and inter-day precisions (in term of % coefficient of variation) were <3.56% and <2.87%, respectively. In the method development the influence of the composition of the microemulsion system was also studied and the method was found to be robust with respect to changes of the microemulsion components.

Microemulsions have gained interest from the pharmaceutical industry due to their ability to co-solubilize hydrophilic and lipophilic drugs, and to provide enhanced drug penetration. In this work, thermosensitive gelatin- and poloxamer 407-stabilized microemulsion-based gels (MBGs) were formulated using alcohol-free, low toxicity and low viscosity lecithin-based linker microemulsions. The addition of gelatin to water-rich bicontinuous microemulsions induced the formation of clear viscoelastic gels containing an oil-rich microemulsion as the gelatin seemed to dehydrate the original microemulsion. The addition of poloxamer 407 to water-continuous microemulsions produced MBGs with different gelation temperatures. High concentrations of lipophilic components in the microemulsion, particularly the oil, reduced sol-gel transition temperature, while hydrophilic components increased sol-gel transition temperature. Gelatin and poloxamer MBGs provided desirable viscoelastic properties for ophthalmic and transdermal applications with minimal impact on the transport properties of the original microemulsions.

Microemulsions have gained interest from the pharmaceutical industry due to their ability to co-solubilize hydrophilic and lipophilic drugs, and to provide enhanced drug penetration. In this work, thermosensitive gelatin- and poloxamer 407-stabilized microemulsion-based gels (MBGs) were formulated using alcohol-free, low toxicity and low viscosity lecithin-based linker microemulsions. The addition of gelatin to water-rich bicontinuous microemulsions induced the formation of clear viscoelastic gels containing an oil-rich microemulsion as the gelatin seemed to dehydrate the original microemulsion. The addition of poloxamer 407 to water-continuous microemulsions produced MBGs with different gelation temperatures. High concentrations of lipophilic components in the microemulsion, particularly the oil, reduced sol-gel transition temperature, while hydrophilic components increased sol-gel transition temperature. Gelatin and poloxamer MBGs provided desirable viscoelastic properties for ophthalmic and transdermal applications with minimal impact on the transport properties of the original microemulsions.

Interest in microemulsions as potential platforms for polymerization stems from the wide range of phase behaviour dependant morphologies and domain sizes that can be generated in a low viscosity environment. By introducing polymerizable components into the oil and aqueous phases of a microemulsion, we may essentially create a low viscosity, low interfacial tension, bicontinuous template with nanostructured morphologies and narrow domain size distributions analogous to those generated through conventional interpenetrating polymer network (IPN) synthesis and spinodal decomposition. The main objective of this dissertation is to test the application of bicontinuous microemulsion templates to the formulation and polymerization of a silicone-hydrogel IPN. In addition, the project expands on the classical definition of IPNs to a scale of entanglement at the level of groups of polymer chains, as opposed to molecular or chain-level entanglement. This study is divided into two main parts. In the first part, silicone microemulsions were developed and characterized according to the Hydrophilic-Lipophilic Difference (HLD) framework. The hydrophobicity of silicone oils, the characteristic curvature of silicone surfactants and the co-surfactant contribution of methacrylic acid (MAA) and hydroxyethyl methacrylate (HEMA) were quantified. These findings led to the successful formulation of bicontinuous microemulsions (μEs) containing silicone oil, silicone alkyl polyether and reactive monomers in aqueous solution. Ternary phase diagrams of these systems revealed the potential for silicone-containing polymer composites with bicontinuous morphologies. In the second part of this study, the formulation and simultaneous polymerization of polydimethylsiloxane-poly(methacrylic acid – hydroxyethyl methacrylate), (PDMS-P(MAA-HEMA) IPNs from bicontinuous microemulsions was demonstrated. Laser scanning confocal microscopy (LSCM) on swollen polymers highlights aqueous pathways, and indicates the formation of bicontinuous morphologies with domain sizes at equilibrium swelling ranging from ~100 nm to 1 μm. Incorporating polymerizable surfactants into the microemulsion aided in stabilizing the initial microemulsion structure during polymerization. The process developed demonstrates a simple, single-step polymerization approach to forming IPNs from low viscosity microemulsion templates, and could potentially be extended to a variety of hydrophilic and hydrophobic monomers.

Interest in microemulsions as potential platforms for polymerization stems from the wide range of phase behaviour dependant morphologies and domain sizes that can be generated in a low viscosity environment. By introducing polymerizable components into the oil and aqueous phases of a microemulsion, we may essentially create a low viscosity, low interfacial tension, bicontinuous template with nanostructured morphologies and narrow domain size distributions analogous to those generated through conventional interpenetrating polymer network (IPN) synthesis and spinodal decomposition. The main objective of this dissertation is to test the application of bicontinuous microemulsion templates to the formulation and polymerization of a silicone-hydrogel IPN. In addition, the project expands on the classical definition of IPNs to a scale of entanglement at the level of groups of polymer chains, as opposed to molecular or chain-level entanglement. This study is divided into two main parts. In the first part, silicone microemulsions were developed and characterized according to the Hydrophilic-Lipophilic Difference (HLD) framework. The hydrophobicity of silicone oils, the characteristic curvature of silicone surfactants and the co-surfactant contribution of methacrylic acid (MAA) and hydroxyethyl methacrylate (HEMA) were quantified. These findings led to the successful formulation of bicontinuous microemulsions (μEs) containing silicone oil, silicone alkyl polyether and reactive monomers in aqueous solution. Ternary phase diagrams of these systems revealed the potential for silicone-containing polymer composites with bicontinuous morphologies. In the second part of this study, the formulation and simultaneous polymerization of polydimethylsiloxane-poly(methacrylic acid – hydroxyethyl methacrylate), (PDMS-P(MAA-HEMA) IPNs from bicontinuous microemulsions was demonstrated. Laser scanning confocal microscopy (LSCM) on swollen polymers highlights aqueous pathways, and indicates the formation of bicontinuous morphologies with domain sizes at equilibrium swelling ranging from ~100 nm to 1 μm. Incorporating polymerizable surfactants into the microemulsion aided in stabilizing the initial microemulsion structure during polymerization. The process developed demonstrates a simple, single-step polymerization approach to forming IPNs from low viscosity microemulsion templates, and could potentially be extended to a variety of hydrophilic and hydrophobic monomers.

Orientador: Rosiane Lopes da Cunha / Texto em inglês e português / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Engenharia de Alimentos / Made available in DSpace on 2018-08-22T16:01:09Z (GMT). No. of bitstreams: 1 Fasolin_LuizHenrique_D.pdf: 4514107 bytes, checksum: cbdb7bfe81fe688fefd10aac2e7238ac (MD5) Previous issue date: 2013 / Resumo: Os sistemas auto-organizáveis como meio para obtenção de produtos com diferentes características têm sido estudados como uma alternativa aos métodos tradicionais de produção de emulsões e gelificação. Todavia, a formação de produtos com ingredientes biocompatíveis ainda é pouco explorada, devido à complexidade e a toxicidade de alguns dos ingredientes geralmente utilizados. Nesse contexto, o objetivo geral desse trabalho foi produzir sistemas com diferentes características a partir do estudo do diagrama de fases de sistemas compostos por água, óleo vegetal, surfactante e co-surfactante biocompatíveis, além de um biopolímero gelificante. Na primeira parte deste estudo, a influência da concentração do co-surfactante (etanol) e da insaturação do óleo (óleo de girassol comum ou óleo de girassol alto oléico, HOSO) foi investigada. Os resultados mostraram que, dependendo da composição do meio, foram obtidas diferentes estruturas (microemulsões ou líquidos cristalinos) com distintos comportamentos reológicos. A formação dessas estruturas foi influenciada pela insaturação do óleo e pela concentração de etanol. Na segunda etapa, a substituição do etanol por ácidos orgânicos (acético e propiônico) foi estudada, bem como sua influência no comportamento reológico-estrutural dos sistemas. Nesse caso, a estruturação dos sistemas foi dependente da combinação entre os ingredientes. O óleo de girassol solubilizou maior quantidade de ácido propiônico devido sua maior hidrofobicidade, enquanto o HOSO apresentou mais afinidade com o ácido acético. Essa diferença de afinidades levou a mudanças no mecanismo de difusão do co-surfactante, bem como sua susceptibilidade à partição. A fim de estudar a viabilidade da adição da goma gelana nas microemulsões para obtenção de sistemas gelificados, uma terceira etapa foi realizada com o intuito de avaliar a interação desse polissacarídeo com o surfactante. Foram observados dois comportamentos predominantes, dependendo da concentração dos componentes. Em baixas concentrações de surfactante, a rede de gelana prevaleceu formando géis fortes com claro ponto de ruptura. Com o aumento da concentração, o surfactante começou a se auto-organizar em estruturas mais complexas até que em altas concentrações sua estrutura se tornou predominante com formação de géis fracos. Na última etapa do trabalho, a goma gelana foi adicionada em alguns sistemas do diagrama de fases formulados com HOSO com ou sem ácido acético. Os géis formulados sem ácido acético foram homogêneos e dependentes da razão água/surfactante. A maior quantidade de água levou a géis mais resistentes devido à formação de uma rede de gelana mais densa. Por outro lado, maiores concentrações de surfactante levaram a géis mais fracos e ao aparecimento de uma temperatura de transição relacionada à estruturação do surfactante. A adição de ácido levou à desestabilização da estrutura cristalina, impedindo a estruturação do surfactante. Além disso, ao invés de géis homogêneos, foram formados géis particulados ou microgéis, que foram auto-sustentáveis apenas em altas concentrações de água. Por fim, este trabalho mostrou que sistemas auto-organizados são de particular utilidade na obtenção de produtos com diferentes características tecnológicas, cujas propriedades podem ser moduladas de acordo com a aplicação / Abstract: Self-assembly systems as a way to obtaining products with different characteristics have been studied as an alternative to traditional emulsification and gelation methods. However, the use of biocompatible ingredients in these systems was scarcely explored due to the complexity or toxicity of the most common ingredients. Thus, the aim of this work was to produce systems with different technological characteristics from the study of phase diagrams composed by water, edible oil, surfactant and biocompatible cosurfactants, as well as a gelling biopolymer. In the first part of this work, the influence of the cosurfactant (ethanol) concentration and oil unsaturation (sunflower oil or high oleic sunflower oil, HOSO) was investigated from the phase-diagrams construction. Results showed that depending on the systems composition different structures could be obtained (microemulsion or liquid crystalline) with different rheological behavior. Moreover, the formation of these structures was influenced by the oil unsaturation and ethanol concentration. In the second step, the replacement of ethanol by organic acids (acetic and propionic) was evaluated, as well as their influence on the rheological-structural behavior. In this case, the systems self-assemble was dependent on the ingredients combination. Sunflower oil solubilized a great amount of propionic acid due to its higher hydrophobicity, whereas HOSO presented more affinity with acetic acid. These affinity differences between oil and cosurfactant changed the diffusion mechanism of the acid through the surfactant and oil tails as well as its susceptibility to the partition phenomenon. In order to study the feasibility of gellan gum addition in the microemulsion to obtain gelled systems, a third step was carried out to evaluate the interactions between this polysaccharide and the surfactant. It was observed two prevailing behavior depending on the components concentration. At low surfactant concentration the gellan network prevailed and formed hard gels were formed with clear rupture point. With the surfactant content increase, its moieties started to self-assembly in highly organized structures until that, at high concentration, these structures became predominant with the formation of weak or soft gels. In the last part of this work gellan gum was added to some systems of the phase diagram formulated with HOSO with or without acetic acid. The gels formulated without acetic acid were homogeneous gels and dependent on the water/surfactant ratio. The higher water content led to harder gels due to the formation of a denser gellan network. On the other hand, higher surfactant concentration led to weaker gels and a transition temperature related to the surfactant structuration was observed. The acid acetic addition led to the liquid crystalline destabilization, hindering the surfactant structuration. Moreover, instead of bulky gels, particulate gels or microgels were formed, which were self-supporting only at high water concentration. Finally, this work showed that self-assembly systems are particularly useful to obtain products with different technological characteristics, whose properties can be modulated according to the application / Doutorado / Engenharia de Alimentos / Doutor em Engenharia de Alimentos

Alkali-Surfactant-Polymer (ASP) or Surfactant-Polymer (SP) flooding are attractive chemical enhanced oil recovery (EOR) methods. However, some reservoir conditions are not favorable for the use of polymers or their use would not be economically attractive due to low permeability, high salinity, or some other unfavorable factors. In such conditions, gas can be an alternative to polymer for improving displacement efficiency in chemical-EOR processes. The co-injection or alternate injection of gas and chemical slug results in the formation of foam. Foam reduces the relative permeability of injected chemical solutions that form microemulsion at ultra-low interfacial tension (IFT) conditions and generates sufficient viscous pressure gradient to drive the foamed chemical slug. We have named this technique of foam assisted enhanced oil recovery as Alkali/Surfactant/Gas (ASG) process. The concept of ASG flooding as an enhanced oil recovery technique is relatively new, with very little experimental and theoretical work available on the subject. This dissertation presents a systematic study of ASG process and its potential as an EOR method. We performed a series of high performance surfactant-gas tertiary recovery corefloods on different core samples, under different rock, fluid, and process conditions. In each coreflood, foamed chemical slug was chased by foamed chemical drive. The level of mobility control in corefloods was evaluated on the basis of pressure, oil recovery, and effluent data. Several promising surfactants, with dual properties of foaming and emulsification, were identified and used in the coreflood experiments. We observed a strong synergic effect of foam and ultra-low IFT conditions on oil recovery in ASG corefloods. Oil recoveries in ASG corefloods compared reasonably well with oil recoveries in ASP corefloods, when both were conducted under similar conditions. We found that the negative salinity gradient concept, generally applied to chemical floods, compliments ASG process by increasing foam strength in displacing fluids (slug and drive). A characteristic increase in foam strength was observed, in nearly all ASG corefloods conducted in this study, as the salinity first changed from Type II(+) to Type III environment and then from Type III to Type II(-) environment. We performed foaming and gas-microemulsion flow experiments to study foam stability in different microemulsion environments encountered in chemical flooding. Results showed that foam in oil/water microemulsion (Type II(-)) is the most stable, followed by foam in Type III microemulsion. Foam stability is extremely poor (or non-existent) in water/oil microemulsion (Type II (+)). We investigated the effects of permeability, gas and liquid injection rates (injection foam quality), chemical slug size, and surfactant type on ASG process. The level of mobility control in ASG process increased with the increase in permeability; high permeability ASG corefloods resulting in higher oil recovery due to stronger foam propagation than low permeability corefloods. The displacement efficiency was found to decrease with the increase in injection foam quality. We studied the effect of pressure on ASG process by conducting corefloods at an elevated pressure of 400 psi. Pressure affects ASG process by influencing factors that control foam stability, surfactant phase behavior, and rock-fluid interactions. High solubility of carbon dioxide (CO₂) in the aqueous phase and accompanying alkali consumption by carbonic acid, which is formed when dissolved CO₂ reacts with water, reduces the displacement efficiency of the process. Due to their low solubility and less reactivity in aqueous phase, Nitrogen (N₂) forms stronger foam than CO₂. Finally, we implemented a simple model for foam flow in low-IFT microemulsion environment. The model takes into account the effect of solubilized oil on gas mobility in the presence of foam in low-IFT microemulsion environment. / text

The aims of this thesis are concerned with the synthesis of layered double hydroxide nanoparticles with controlled morphology and particle size distribution and an investigation of their physical properties. An introduction of layer double hydroxide chemistry, especially existing synthetic approaches, is reviewed in Chapter 1. Structural investigations, characterisation techniques, the properties and the applications of LDHs are discussed consecutively. The first successful synthesis of lithium aluminium nanorods using the hydrothermal treatment of a gibbsite precursor with a rod-like morphology is described in Chapter 2. The rod morphology is depicted using electron microscopy and confirmed by comparing refined X-ray diffraction patterns to a standard sample. Chapter 3 describes the application of reverse microemulsion method to prepare Co-Al and Ni-Al LDH nanoplatelets. The LDH particle sizes can be effectively controlled, and the structures of the nanoplatelets are investigated. The magnetic properties of the LDH nanoplatelets are dependent on the size of the nanoplatelets. A novel single component microemulsion system for the synthesis of LDHs is developed in Chapter 4. Mg-Al LDH nanoplatelets were successfully synthesised with precise particle size control. The factors affecting the formation of the microemulsions and the mechanism of the synthesis are discussed. Chapter 5 focuses on the applications of the novel single component microemulsion methods to prepare a range of LDHs with different metal combinations including Co-Al, Ni-Al, Zn-Al, Li-Al, Ca-Al, and Ni-Fe. This method proves very effective at controlling the particle sizes. The magnetic properties of the LDHs containing paramagnetic transition metal centres have been studied in detail. In Chapter 6, the DIFFaX program has been used to simulate the XRD patterns of layered structures. The factors influencing the XRD patterns in these materials have been systematically investigated including the effects of particle size, stacking faults, and disorder. The XRD patterns of materials described in previous chapters are simulated using the latest DIFFaX+ code in order to estimate the particle sizes and stacking sequences. The characterising techniques and the experimental details are listed in Chapter 7.

Infantile hemangiomas (IHs), benign vascular lesions present on the surface of the skin of children, are treated with systemic or topical beta-adrenergic antagonists (known as “beta-blockers”). However, systemic beta-blocker therapy is associated with serious adverse events in pediatric patients, and there are currently no topical formulations optimized for the skin. The objectives of this work were to 1) evaluate the local skin concentrations and drug permeation through the skin using novel beta-blocker formulations, and 2) characterize the epidermal properties and skin surface inflammatory mediators of IH skin. Skin concentrations and drug permeation through the skin from current topical treatment options were quantified in vitro; these data served as benchmarks to which other treatment paradigms in later studies were compared. Microneedle (MN)-mediated delivery of two beta-blockers, propranolol and timolol, was evaluated in vitro using solid MNs and two dissolving MN array formulations. Solid MNs increased skin concentrations of timolol compared to intact skin, while producing similar skin concentrations of propranolol. Drug permeation through the skin was increased for both drugs after MN pretreatment. Both formulations of dissolving MN arrays were ineffective at increasing local skin concentrations compared to intact skin. This was likely due to the small loading capacity of drug into the array. Drug-loaded microemulsions (ME) of varying composition were formulated and characterized. All ME formulations had solubilization properties, and water rich MEs had the greatest cumulative release through a homogenous membrane compared to surfactant rich MEs. Drug-loaded MEs did not increase local skin concentrations in vitro compared to a drug solution; however, water rich ME formulations produced greater skin-to-receiver ratio of drug concentration, indicating their potential for skin accumulation. MN pretreatment increased the skin-to-receiver ratios for surfactant rich formulations but not for water rich formulations, indicating this enhancement in skin retention after MN pretreatment is formulation dependent. These results demonstrate the potential for topical treatment of IHs upon further optimization of delivery and formulation parameters. The epidermal properties and skin surface mediators of IH skin were compared to normal, unaffected skin. Significant differences in barrier function and color, as well as chemokine and growth factor concentrations, were observed between the two sites. These results provide a greater understanding of the IH properties that have previously not been quantified. Similar changes in lesion color, which correlate to efficacy, were observed after beginning treatment with oral propranolol or topical timolol, while changes in barrier function were similar between the two treatment groups. These results indicate topical timolol may be a safe alternative for systemic treatment for superficial IHs without a loss of efficacy.

A multidisciplinary literature survey revealed that copolymeric nanoparticles could be applied in various technologies such as the production of paint, adhesives, packaging material and lately especially drug delivery systems. The specialized application and investigation of copolymers in drug delivery resulted in the synthesis of two series of copolymeric materials, i.e. poly(styrene-co-methyl methacrylate) (P(St-co-MMA)) and poly(styrene-co-ethyl methacrylate) (P(St-co-EMA)) were synthesized via the technique of o/w microemulsion copolymerization. These copolymers have not as yet been utilized to their full potential in the development of new drug delivery systems. However the corresponding hydrophobic homopolymer poly(styrene) (PS) and the hydrophilic homopolymer poly(methyl methacrylate) (PMMA) are known to be biocompatible. Blending of homopolymers could result in novel applications, however is virtually impossible due to their unfavorable mixing entropies. The immiscibility challenge was overcome by the synthesis of copolymers that combined the properties of the immiscible homopolymers. The synthesized particles were analyzed by gel permeation chromatography combined with multi-angle laser light scattering (GPC-MALLS) and attenuated total reflectance Fourier infrared spectroscopy (ATR-FTIR). These characterizations revealed crucial information to better understand the synthesis process and particle properties i.e. molecular weight, nanoparticle size and chemical composition of the materials. Additionally, GPC-MALLS revealed the copolymer chain conformation. These characterizations ultimately guided the selection of appropriate copolymer nanoparticles to develop a controlled-release drug delivery system. The selected copolymers were dissolved in a pharmaceutically acceptable solvent, tetrahydrofuran (THF) together with a drug, rifampin. Solvent casting of this dispersion resulted in the evaporation of the solvent and assembly of numerous microscale copolymer capsules. The rifampin molecules were captured in these microcapsules through a process of phase separation and coacervation. These microcapsules finally sintered to produce a multi-layer film with an unusual honeycomb structure, bridging yet another size scale hierarchy. Characterization of these delivery systems revealed that both series of copolymer materials produced films capable of controlling drug release and that could also potentially prevent biofilm adhesion. / Thesis (Ph.D. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2008.