Neste trabalho foi desenvolvida uma metodologia para a determinação da capacidade anti-radicalar de substâncias hidrofílicas e lipofílicas baseada na quimiluminescência do luminol em meio micelar. A reação de luminol, hemina e peróxido de hidrogênio foi estudada na presença de tensoativos carregados (CTAB/CTAC e SDS). Variou-se independentemente a concentração de cada reagente de forma a avaliar seu papel sobre a intensidade inicial de emissão (I0), que é proporcional à velocidade inicial da reação. Em solução aquosa de SDS, a I0 apresentou correlação linear com a concentração de H2O2 entre 5,0 10-6 e 6,0 10-5 mol/L e com a concentração de hemina no intervalo de 8,0 10-9 a 4,0 10-7 mol/L. O aumento da concentração de luminol no intervalo de 5,0 10-7 a 1,0 10-3 provocou aumento na I0 até 5,0 10-5 mol/L, permanecendo constante para concentrações maiores. Na presença de CTAB, o valor de I0 variou linearmente com a concentração de H2O2 no intervalo estudado (2,0 10-5 a 6,7 10-4 mol/L). A I0 aumentou com o aumento da concentração da hemina entre 8,0 10-8 e 8,0 10-6 mol/L. A variação da concentração de luminol de 5,0 10-7 a 5,0 10-5 também provocou aumento na I0, a qual ficou constante para concentrações maiores. Para este tensoativo foram realizadas também medidas de cmc nas condições de reação (tampão fosfato pH 11,6 e µ = 0,1), obtendo-se um valor de 2 10-4 mol/L, cinco vezes menor do que a cmc em água. As mudanças espectrais de hemina e luminol em diferentes concentrações de CTAB foram avaliadas, obtendo-se evidências da interação destes reagentes com o tensoativo. Destes estudos, foi possível compreender melhor o comportamento do sistema e foram encontradas condições nas quais se obtêm decaimento lento da intensidade de emissão e I0 alto. Estas condições são ideais para a realização de um ensaio de determinação da capacidade anti-radicalar. O efeito do antioxidante trolox, utilizado como padrão, foi avaliado nestas condições nos sistemas baseados nos três tensoativos. Em todos os casos, observou-se correlação linear entre a concentração de trolox e a área suprimida na cinética de emissão, a qual é proporcional ao número de radicais seqüestrados pelo antioxidante. Os limites de detecção para trolox ficaram abaixo de 1,0 10-7 mol/L, e a faixa de linearidade é de no mínimo uma ordem de grandeza (não foram testadas concentrações superiores a 2,0 10-6 mol/L). No meio de reação com CTAB foram determinadas as capacidades anti-radicalares (n) dos seguintes antioxidantes: vitamina E (n=3,5 ± 0,1), rutina (n=4,0 ± 0,2), quercetina (n=3,8 ± 0,4) e ácido úrico (n=1,3 ± 0,1). Os valores de n determinados com este método foram muito similares com aqueles medidos utilizando-se o ensaio com o radical estável DPPH. Portanto, o ensaio desenvolvido com luminol em meio micelar se mostrou adequado para testar tanto substâncias hidrossolúveis como lipossolúveis. Foram testadas condições para a realização de ensaios consecutivos com injeções repetidas de várias alíquotas de antioxidante na presença de CTAB. Os valores encontrados com o ensaio realizado desta forma foram iguais aos obtidos com o ensaio onde as injeções são feitas individualmente. Este método permite automação e resulta na economia de reagentes e redução do tempo de ensaio / In this work, a methodology to evaluate the anti-radical capacity of hydrophilic and lipophilic compounds based on luminol chemiluminescence in micellar media was developed. The reaction of luminol, hemin and hydrogen peroxide was studied in the presence of charged surfactants (CTAB/CTAC and SDS). The concentration of each reagent was independently varied in order to evaluate its influence on the initial emission intensity (I0), which is proportional to the initial reaction rate. In aqueous SDS solution, I0 showed a linear correlation with the H2O2 concentration between 5,0 10-6 and 6,0 10-5 mol/L, and with the hemin concentration between 8,0 10-9 and 4,0 10-7 mol/L. An increase in the luminol concentration between 5,0 10-7 and 1,0 10-3 mol/L led to an increase in I0 up to 5,0 10-5 mol/L, higher luminol concentrations do not further increased I0. In the presence of CTAB, I0 increased linearly with the H2O2 concentration in the interval studied (2,0 10-5 to 6,7 10-4 mol/L). An increase in I0 was also observed on increasing the hemin concentration from 8,0 10-8 to 8,0 10-6 mol/L. An increase of the luminol concentration from 5,0 10-7 to 5,0 10-5 increased the observed I0, which did not change for higher luminol concentrations. The cmc of CTAB was measured in the reaction conditions (phosphate buffer pH 11,6 and µ= 0,1), and the value determined, 2 10-4 mol/L, was five times lower than the cmc in water. The absorption spectra of hemin and luminol in different CTAB concentrations showed significant variation with the surfactant concentration, indicating an interaction between these reagents and the surfactant. With these studies it was possible to understand well the behavior of the system and to establish experimental conditions which lead to kinetic curves with a slow emission intensity decay and relatively high I0, ideal conditions for the performance of the anti-radical capacity assay. The effect of trolox, the antioxidant used as reference, was evaluated in this conditions in the systems based on the three surfactants. In all the cases a linear correlation between the trolox concentration and the suppressed area in the emission kinetics was observed. This area is proportional to the number of radicals trapped by the antioxidant. Detection limits for trolox were below 1,0 10-7 mol/L, and the linear range was at least one order of magnitude (concentrations higher than 2,0 10-6 mol/L were not evaluated). The antioxidant capacity (n) was determined in the reaction medium containing CTAB for vitamin E (n= 3,5 ± 0,1), rutin (n=4,0 ± 0,2), quercetin (n=3,8 ± 0,4) and uric acid (n=1,3 ± 0,1). The n values determined by this method were very similar to those measured with the DPPH assay. Hence, the assay developed with luminol in micelar media was adequate to evaluate the anti-radical capacity of hidrosoluble as well as liposoluble compounds. The assay conditions established in the presence of CTAB allowed the consecutive injection of antioxidant samples during the same kinetic run. The values determined in this consecutive injection assay proved to be very similar to those obtained in the assay where injections were made individually. This method allows automation, economy of reagents and reduction of assay time

Uma nova rota de síntese via metodo sol-gel para óxido de titânio (titânia) e óxido misto titânio/zircônio (zircônia) é proposta neste trabalho. As amostras foram submetidas ao tratamento hidrotérmico e obteve-se compostos mesoestruturados e de elevada área superficial. Algumas amostras foram submetidas à calcinação a 450°C para a verificação da estabilidade a altas temperaturas. As amostras foram analisadas por difratometria de raios-x (DRX), espalhamento de raios-x de baixo ângulo (SAXS), área superficial através do método BET, por microscopia eletrônica de varredura por emissão de campo (FE-SEM), além de serem testadas na fotodegradação de corantes. Foram testados diferentes alcóxidos precursores, isopropóxido de titânio e n-butóxido de titânio; ácidos, clorídrico e nítrico; e surfactantes, Pluronic® P123, Brij® 700 e Brij® 98; e também variadas as quantidades de surfactantes utilizadas, para que fosse possível analisar como estas variações afetam a síntese dos compostos e se estabelecer uma nova rota padronizada utilizando-se os melhores precursores em quantidades ideais. Para efeito de comparação, foi testada uma rota alcalina de síntese, que levou ao material com área superficial mais elevada. Como resultado deste trabalho, foi desenvolvida uma nova rota de síntese para óxidos mesoestruturados de titânio e titânio/zircônio corn elevada área superficial, na qual a etapa de calcinação para remoção do surfactante foi eliminada. Algunas dos materiais preparados mostraram excelente desempenho na degradação fotocatalítica de um corante comercial. / A new sol-gel based synthetic route for titania and mixed titania-zirconia ceramic powders is proposed in this contribution. This route combines a surfactant-template strategy with hydrothermal treatment, yielding mesostructured compoundes with a high surface area. Some samples were calcined at 450 °C in order to verify the stability of the structures at these temperatures. The materials were characterized by x-ray diffraction (XRD), small angle x-ray scattering (SAXS), surface area (BET method), field emission scanning electron microscopy (FE-SEM), and were also tested in the photocatalytic degradation of selected dyes. Different precursor alcóxidos were used: titanium isopropoxide and titanium n-butoxide. Two different acids were used to catalyze the hydrolysis reaction, HCl and HNO3. Three surfactants were used as templating agents: Pluronic P123®, Brij 700®, and Brij 98®. The amount of surfactant was also changed in order to verify how these variations affect the surface area and morphology of the resulting compounds. For comparison, an alkaline route was also tested, in which the highest surface area was observed. As a result of this work, a new synthetic route for mesostructured titania and titania-zirconia mixed oxides was developed, in which the surfactant is removed without a calcinations step, resulting in compounds with high surface areas and, in some cases, excellent photocatalytic properties for the degradation of a dye.

Nanoparticulate drug delivery systems (NDDS) such as nanocrystals, nanosuspensions, solid-lipid nanoparticles often formulated for the bioavailability enhancement of poorly soluble drug candidates are stabilized by a mixture of excipients including surfactants and polymers. Most literature studies have focused on the interaction of excipients with the NDDS surfaces while ignoring the interaction of excipients in solution and the extent to which the solution-state interactions influence the affinity and capacity of adsorption. Mechanisms by which excipients stabilize NDDS and how this information can be utilized by formulators a priori to make a rational selection of excipients is not known. The goals of this dissertation work were (a) to determine the energetics of interactions between HPMC and model surfactants and the extent to which these solution-state interactions modulate the adsorption of these excipients onto solid surfaces, (b) to determine and characterize the structures of various aggregate species formed by the interaction between hydroxypropyl methylcellulose (HPMC) and model surfactants (nonionic and ionic) in solution-state, and (c) to extend these quantitative relationships to interpret probable mechanisms of mixed adsorption of excipients onto the model NDDS surface. A unique approach utilizing fluorescence, solution calorimetry and adsorption isotherms was applied to tease apart the effect of solution state interactions of polymer and surfactant on the extent of simultaneous adsorption of the two excipients on a model surface. The onset of aggregation and changes in aggregate structures were quantified by a fluorescence probe approach with successive addition of surfactant. In the presence of HPMC, the structures of the aggregates formed were much smaller with an aggregation number (Nagg) of 34 as compared to micelles (Nagg ~ 68) formed in the absence of HPMC. The strength of polymer-surfactant interactions was determined to be a function of ionic strength and hydrophobicity of surfactant. The nature of these structures was characterized using their solubilization power for a hydrophobic probe molecule. This was determined to be approximately 35% higher in the polymer-surfactant aggregates as compared to micelles alone and was attributed to a significant increase in the number of aggregates formed and the increased hydrophobic microenvironment within these aggregates at a given concentration of surfactant. The energetics of the adsorption of SDS, HPMC, and SDS-HPMC aggregate onto nanosuspensions of silica, which is the model solid surface were quantified. A strong adsorption enthalpy of 1.25 kJ/mol was determined for SDS adsorption onto silica in the presence of HPMC as compared to the negligible adsorption enthalpy of 0.1 kJ/mol for SDS alone on the silica surface. The solution depletion and HPMC/ELSD methods showed a marked increase in the adsorption of SDS onto silica in the presence of HPMC. However, at high SDS concentrations, a significant decrease in the adsorbed amount of HPMC onto silica was determined. This was further corroborated by the adsorption enthalpy that showed that the silica-HPMC-SDS aggregation process became less endothermic upon addition of SDS. This suggested that the decrease in adsorption of HPMC onto silica at high SDS concentrations was due to competitive adsorption of SDS-HPMC aggregates wherein SDS is displaced/desorbed from silica in the presence of HPMC. At low SDS concentrations, an increase in adsorption of SDS was due to cooperative adsorption wherein SDS is preferentially adsorbed onto silica in the presence of HPMC. This adsorption behavior confirmed the hypothesis that the solution-state interactions between pharmaceutical excipients such as polymers and surfactants would significantly impact the affinity and capacity of adsorption of these excipients on NDDS surfaces.

Conscients de la raréfaction progressive et l’augmentation continue du coût du pétrole et aussi des volumes importants des tensioactifs produits et éliminés chaque année, l’industrie chimique s’intéresse de plus en plus aux ressources issues de la biomasse. Cependant, dans le marché européen des tensioactifs, la part des produits d’origine végétale par rapport aux dérivés pétrochimiques est estimée à seulement 20%. Compte-tenu de ces enjeux, de nouvelles stratégies de synthèse pour produire des tensioactifs ayant des structures originales issus d’agro-ressources sont nécessaires. Dans le cadre d’une collaboration de recherche, l’ITERG (Pessac) et l’ICBMS (équipe COB-INSA) de Lyon se sont associées pour développer la synthèse de nouveaux glycolipides amphiphiles obtenus par fonctionnalisation d’huiles végétales époxydées. Les enjeux synthétiques ont concerné la compétition entre les deux fonctions réactives des huiles époxydées (ester et époxyde) et la multifonctionnalité des sucres et autres polyols utilisés comme substrats nucléophiles. Plusieurs séries de composés originaux ont été préparées, et leurs propriétés physico-chimiques ont été évaluées en regard des applications industrielles visées. Parmi les produits synthétisés, quelques uns ont également été évalués en tant que monomères biosourcés. / Aware of the irreversible scarcity and graving increase in oil prices, as well as large amounts of surfactants produced and disposed of each year, the chemical industry more and more focuses on resources from biomass. However in Europe, plant derived from plants only represent 20%. New strategies to produce surfactants with novel structures derived produced of the surfactants from agricultural resources are thus synthetic challenges.. As part of a research collaboration, ITERG (Pessac) and ICBMS (COB-INSA in Lyon) have joined forces to develop the synthesis of new amphiphilic glycolipids obtained by functionalization of epoxidized vegetable oils. Synthetic issues concerned the competition between the two reactive groups of epoxidized oils (ester and oxirane) and multifunctionality of sugars and other polyols used as nucleophilic substrates. Several series of novel compounds were prepared and their physicochemical properties were assessed for targeted industrial applications. Among the synthesized products, some were also evaluated as biobased monomers.

Les premiers stades de la croissance du NiO/Cu(111) ont été caractérisés du point de vue chimique, morphologique et structurale à une échelle microscopique. Pour cela, nous avons utilisé différentes méthodes d'élaboration et combiné différentes techniques de laboratoire in situ ainsi que le rayonnement synchrotron. Les bicouches à couplage d'échange NiO/FeNi/Cu(111) ont aussi été étudiées. L'interface Ni/Cu(111) a été étudié en mettant en évidence les liens entre la morphologie, la structure et les propriétés magnétiques. Les valeurs réduites du moment de spin sont reliées à l'hybridation 3d à l'interface Ni-Cu et au recouvrement de Cu. Dans toute la gamme des épaisseurs étudiées l'anisotropie du moment orbital est dans le plan, déterminant l'orientation de l'axe de facile aimantation. Cette axe peut être reliée à la tétragonalisation du réseau cristallin du Ni. Des couches ultraminces de NiO ont été obtenues par évaporation à partir de pépites de NiO à température ambiante ainsi qu'à 250°C. Les couches minces peuvent être décrite par une bicouche NiO/Ni/Cu(111). Le GISAXS permettent de confirmer les observations STM et de mettre en évidence l'auto-organisation des îlots de NiO. Due à la faible efficacité d'oxydation, les couches minces de NiO déposées à partir du Ni métallique sous oxygène, présentent quelques différences par rapport aux couches déposées à partir des pépites. Le mécanisme de formation des îlots proposé est basé sur un processus de nucléation/agrégation de clusters. Les résultats structurales (LEED et GIXD) peuvent être attribués soit à la formation d'une phase hexagonale alpha-Ni2O3, soit à une distorsion structurale de la maille NiO(111)(sqrt(3)xsqrt(3))R30°. Le système à couplage d'échange NiO/FeNi/Cu(111) a été élaboré en utilisant les deux méthodes d'élaboration du NiO. L'interface NiO/FeNi est très abrupte, présentant une texturation suivant les axes cristallographiques. Les analyses structurales montrent une bonne épitaxie du NiO sur les films d'alliage FeNi.

<p>The focus of this thesis has been on the effects of segregation in mixtures of amphiphilic molecules. Two different systems were investigated: fluorocarbon-hydrocarbon surfactant mixtures and lipid-surfactant mixtures.</p><p>In fluorocarbon-hydrocarbon surfactant mixtures the repulsive interactions between the chains can lead to a demixing into different types of coexisting micelles, fluorocarbon rich and hydrocarbon rich. From NMR self-diffusion measurements such a demixing was found to occur in the mixture of the partially fluorinated surfactant HFDePC and C₁₆TAC. We furthermore suggested a demixing also within the micelles to explain ¹⁹F-NMR line width data and results from neutron scattering.</p><p>In lipid-surfactant mixtures, a segregation of the molecules may instead be caused by a difference in the preferred curvature of the lipid and the surfactant residing within the same aggregate. Using a surfactant selective electrode, binding isoterms of four different cationic surfactants (C₁₂TAC, C₁₄TAC, C₁₆TAC and HFDePC) to preformed lipid (GMO) vesicles were determined. Perforated vesicles were observed by cryo-TEM in the mixture with C₁₆TAC. To explain the results from the binding isoterms, the formation of pores in the bilayer was regarded as a cooperative process, similar to micelle formation. The surfactant accumulates at the edges of the pores, and increasing the surfactant concentration results in an increased number of pores with a constant surfactant/lipid ratio at the edges.</p><p>The lipid-surfactant mixtures were also studied at the solid/solution interface using AFM. An adsorbed mesh structure, a counterpart to the bulk perforated lamellar phase, was observed for the first time.</p>

<p>The breathing pattern of preterm infants is immature and is associated with a variety of reflexes. In a patient on the ventilator these reflexes interfere with spontaneous breathing. A better understanding of the immature control of breathing could lead to further improvements in ventilatory techniques. This thesis concerns studies of pulmonary stretch receptor (PSR) and phrenic nerve activity as part of the regulation of breathing in an animal model. </p><p>During assist/control ventilation with three different inspiratory pressure waveforms in animals with healthy lungs, squarewave pressure waveform<b> </b>strongly inhibits spontaneous inspiratory activity.</p><p>During partial liquid ventilation (PLV) in animals with healthy lungs, all PSRs studied maintained their phasic character, with increased impulse frequency during inspiration. PSR activity was not higher during PLV than during gas ventilation (GV), indicating that there was no extensive stretching of the lung during PLV.</p><p>During proportional assist ventilation (PAV) the applied airway pressure is servo-controlled proportionally to the ongoing breathing effort, thereby interacting with the activity of PSRs. Peak PSR activity was higher and occurred earlier during PAV than during CPAP. The regulation of breathing is maintained during PAV in surfactant-depleted animals before and early after surfactant instillation, with a higher ventilatory response and a lower breathing effort than during CPAP in both conditions.</p><p>Both lung mechanics and gas exchange influence the regulation of breathing. Inhibition of inspiratory activity occurred at a lower arterial pH and a higher PaCO₂ during PLV than during GV in animals with surfactant-depleted lungs, which might be related to recruitment of a larger number of pulmonary stretch receptors during PLV.</p><p>In summary, selected aspects of the regulation of breathing were studied in an animal model with different ventilatory techniques under different lung conditions similar to those that can occur in infants.</p>

<p>When drug molecules are passively absorbed through the cell membrane in the small intestine, the first key step is partitioning of the drug into the membrane. Partition data can therefore be used to predict drug absorption. The partitioning of a solute can be analyzed by drug partition chromatography on immobilized model membranes, where the chromatographic retention of the solute reflects the partitioning. The aims of this thesis were to develop the model membranes used in drug partition chromatography and to study the effects of different membrane components and membrane structures on drug partitioning, in order to characterize drug–membrane interactions.</p><p>Electrostatic effects were observed on the partitioning of charged drugs into liposomes containing charged detergent, lipid or phospholipid; bilayer disks; proteoliposomes and porcine intestinal brush border membrane vesicles (BBMVs), and on the retention of an oligonucleotide on positive liposomes. Biological membranes are naturally charged, which will affect drug partitioning in the human body.</p><p>Proteoliposomes containing transmembrane proteins and cholesterol, BBMVs and bilayer disks were used as novel model membranes in drug partition chromatography. Partition data obtained on proteoliposomes and BBMVs demonstrated how cholesterol and transmembrane proteins interact with drug molecules. Such interactions will occur between drugs and natural cell membranes. In the use of immobilized BBMVs for drug partition chromatography, yet unsolved problems with the stability of the membrane were encountered. A comparison of partition data obtained on bilayer disks with data on multi- and unilamellar liposomes indicated that the structure of the membrane affect the partitioning. The most accurate partition values might be obtained on bilayer disks.</p><p>Drug partition data obtained on immobilized model membranes include both hydrophobic and electrostatic interactions. Such partition data should preferably be used when deriving algorithms or computer programs for prediction of drug absorption.</p>

<p>The aim of this thesis was to identify some functionality related characteristics of pharmaceutically relevant solid materials and to study the effect of their variation on processing behaviour and product performance. For this purpose, particles with different characteristics were prepared under a variety of conditions by crystal agglomeration, wet granulation and spray drying. The effect of particle size distribution on the evolution of the tablet microstructure during and after compression was investigated. The compression behaviour of particles with different nominal strength and degrees of agglomeration was studied and the influence of the surfactant concentration of amorphous particles on the compression behaviour was examined. The response of the powders to compression was described with the help of various techniques characterising the microstructure and tensile strength of the tablets produced. </p><p>Furthermore, a method suitable for observing drug release from single matrix granules was developed and used to study the effect of granule porosity and compaction pressure on the drug release process. </p><p>The particle size distribution did not influence the evolution of the tablet porosity or the tensile strength during compression, but it could have an effect on the evolution of the tablet microstructure during short-term storage, depending on the instability mechanism. The compression behaviour of particles prepared by crystal agglomeration and wet granulation was dependent on their degree of agglomeration and their failure strength. For particles with similar solid state properties and compression behaviour, the surface energy appears to have an effect on the bonding strength of adsorption bonds acting at interparticulate junctions. Using the method developed to observe the drug release from single matrix granules, reproducible data was obtained enabling the drug release process to be characterised. Depending on the type of matrix and the compaction pressure, the drug release rate could be enhanced or retarded. </p>

<p>The interactions between anionic, crosslinked gels and cationic surfactants have been investigated. When exposed to oppositely charged surfactant, the gel collapses into a dense complex of polyion and micelles. During deswelling, the gel phase separates into a micelle-rich, collapsed surface phase, and a swollen, micelle-free core, both still part of the same network. As more surfactant is absorbed, the surface phase grows at the expense of the core, until the entire gel has collapsed. Polyacrylate (PA) gels with dodecyl- (C₁₂TAB), and cetyltrimethylammonium bromide (C₁₆TAB), as well as hyaluronate gels with cetylpyridinium chloride, have been studied. </p><p>Kinetic experiments have been performed on macro- as well as microgels, using micromanipulator assisted light microscopy for the latter. A surfactant diffusion controlled deswelling model has been employed to describe the deswelling. The deswelling kinetics of PA microgels have been shown to be controlled by surfactant diffusion through the stagnant layer surrounding the gel, as the surface phase is relatively thin for the major part of the deswelling. For macroscopic PA gels the surface phase is thicker, and the kinetics with C₁₂TAB were therefore also influenced by diffusion through the surface phase, while for C₁₆TAB they were dominated by it. </p><p>Relevant parameters have also been determined using equilibrium experiments. An irregular, balloon-forming deswelling pattern, mainly found for macrogels, as well as unexpectedly long lag times and slow deswelling for microgels, are reported and discussed. </p><p>The microstructure of fully collapsed PA/C₁₂TAB complexes has been studied using small-angle X-ray scattering. A cubic <i>Pm3n</i> structure was found at low salt concentration, which melted into a disordered micellar phase as the salt concentration was increased. Further increasing the salt concentration dissolved the micelles, resulting in no ordering.</p>