The potential applications of dispersed and self-assembled nanoparticles depend critically on accurate control and prediction of their phase behavior. The chemical potential is essential in describing the equilibrium distribution of all components present in every phase of a system and is useful as a building block for constructing phase diagrams. Furthermore, the chemical potential is a sensitive indicator of the local environment of a molecule or particle and is defined in a mathematically rigorous manner in both classical and statistical thermodynamics. The goal of this research is to use simulations and experiments to understand how particle size and composition affect the particle chemical potential of attractive nanoparticle-polymer mixtures. The expanded ensemble Monte Carlo (EEMC) simulation method for the calculation of the particle chemical potential for a nanocolloid in a freely adsorbing polymer solution is extended to concentrated polymer mixtures. The dependence of the particle chemical potential and polymer adsorption on the polymer concentration and particle diameter are presented. The perturbed Lennard-Jones chain (PLJC) equation of state (EOS) for polymer chains1 is adapted to calculate the particle chemical potential of nanocolloid-polymer mixtures. The adapted PLJC equation is able to predict the EEMC simulation results of the particle chemical potential by introducing an additional parameter that reduces the effects of polymer adsorption and the effective size of the colloidal particle. Osmotic pressure measurements are used to calculate the chemical potential of nanocolloidal silica in an aqueous poly(ethylene oxide) (PEO) solution at different silica and PEO concentrations. The experimental data was compared with results calculated from Expanded Ensemble Monte Carlo (EEMC) simulations. The results agree qualitatively with the experimentally observed chemical potential trends and illustrate the experimentally-observed dependence of the chemical potential on the composition. Furthermore, as is the case with the EEMC simulations, polymer adsorption was found to play the most significant role in determining the chemical potential trends. The simulation and experimental results illustrate the relative importance of the particles size and composition as well as the polymer concentration on the particle chemical potential. Furthermore, a method for using osmometry to measure chemical potential of nanoparticles in a nanocolloid-mixture is presented that could be combined with simulation and theoretical efforts to develop accurate equations of state and phase behavior predictions. Finally, an equation of state originally developed for polymer liquid-liquid equilibria (LLE) was demonstrated to be effective in predicting nanoparticle chemical potential behavior observed in the EEMC simulations of particle-polymer mixtures.

Cancer is the second leading cause of death in the United States and its onset is highly incident in the lungs, with very low long-term survival rates. Chemotherapy plays a significant role for lung cancer treatment, and pulmonary delivery may be a potential route for anticancer drug delivery to treat lung tumors. Coenzyme Q₁₀ (CoQ₁₀) is a poorly-water soluble compound that is being investigated for the treatment of carcinomas. In this work, we hypothesize that formulations of CoQ10 may be developed for pulmonary delivery with a satisfactory pharmacokinetic profile that will have the potential to improve a pharmacodynamic response when treating lung malignancies. The formulation design was to use a vibrating-mesh nebulizer to aerosolize aqueous dispersions of CoQ₁₀ stabilized by phospholipids physiologically found in the lungs. In the first study, a method was developed to measure the surface tension of liquids, a physicochemical property that has been shown to influence the aerosol output characteristics from vibrating-mesh nebulizers. Subsequently, this method was used, together with analysis of particle size distribution, zeta potential, and rheology, to further evaluate the factors influencing the capability of this nebulizer system to continuously and steadily aerosolize formulations of CoQ₁₀ prepared with high pressure homogenization. The aerosolization profile (nebulization performance and in vitro drug deposition of nebulized droplets) of formulations prepared with soybean lecithin, dimyristoylphosphatidylcholine (DMPC), dipalmitoylphosphatidylcholine (DPPC) and distearoylphosphatidylcholine (DSPC) were evaluated. The rheological behavior of these dispersions was found to be the factor that may be indicative of the aerosolization output profile. Finally, the pulmonary deposition and systemic distribution of CoQ₁₀ prepared as DMPC, DPPC, and DSPC dispersions were investigated in vivo in mice. It was found that high drug amounts were deposited and retained in the mouse lungs for at least 48 hours post nebulization. Systemic distribution was not observed and deposition in the nasal cavity occurred at a lower scale than in the lungs. This body of work provides evidence that CoQ₁₀ may be successfully formulated as dispersions to be aerosolized using vibrating-mesh nebulizers and achieve high drug deposition in the lungs during inhalation. / text

Cancer is the second leading cause of death in the United States and its onset is highly incident in the lungs, with very low long-term survival rates. Chemotherapy plays a significant role for lung cancer treatment, and pulmonary delivery may be a potential route for anticancer drug delivery to treat lung tumors. Coenzyme Q₁₀ (CoQ₁₀) is a poorly-water soluble compound that is being investigated for the treatment of carcinomas. In this work, we hypothesize that formulations of CoQ10 may be developed for pulmonary delivery with a satisfactory pharmacokinetic profile that will have the potential to improve a pharmacodynamic response when treating lung malignancies. The formulation design was to use a vibrating-mesh nebulizer to aerosolize aqueous dispersions of CoQ₁₀ stabilized by phospholipids physiologically found in the lungs. In the first study, a method was developed to measure the surface tension of liquids, a physicochemical property that has been shown to influence the aerosol output characteristics from vibrating-mesh nebulizers. Subsequently, this method was used, together with analysis of particle size distribution, zeta potential, and rheology, to further evaluate the factors influencing the capability of this nebulizer system to continuously and steadily aerosolize formulations of CoQ₁₀ prepared with high pressure homogenization. The aerosolization profile (nebulization performance and in vitro drug deposition of nebulized droplets) of formulations prepared with soybean lecithin, dimyristoylphosphatidylcholine (DMPC), dipalmitoylphosphatidylcholine (DPPC) and distearoylphosphatidylcholine (DSPC) were evaluated. The rheological behavior of these dispersions was found to be the factor that may be indicative of the aerosolization output profile. Finally, the pulmonary deposition and systemic distribution of CoQ₁₀ prepared as DMPC, DPPC, and DSPC dispersions were investigated in vivo in mice. It was found that high drug amounts were deposited and retained in the mouse lungs for at least 48 hours post nebulization. Systemic distribution was not observed and deposition in the nasal cavity occurred at a lower scale than in the lungs. This body of work provides evidence that CoQ₁₀ may be successfully formulated as dispersions to be aerosolized using vibrating-mesh nebulizers and achieve high drug deposition in the lungs during inhalation.

Foram produzidas dispersões aquosas não-poluentes e inovadoras de poli(uretano-uréia) à base de poli(glicol propilênico) (PPG) e de copolímeros em bloco, poli(glicol etilênicob-glicol propilênico), (EG-b-PG) com teor de 7% de unidades de glicol etilênico. Os poli(uretano-uréia)s foram preparados, em duas etapas, pelo método do prepolímero. Na primeira etapa, foram obtidos anionômeros, sintetizados em massa, à base do copolímero EG-bPG, PPG, ácido dimetilol propiônico (DMPA) (gerador dos sítios aniônicos) e diisocianato de isoforona (IPDI). Ainda na primeira etapa, os grupos carboxílicos do DMPA foram submetidos à neutralização com trietilamina (TEA). Na segunda etapa, foi realizada a dispersão do prepolímero anionômero e, em seguida, foi conduzida a reação de extensão de cadeia com a hidrazina (HYD). Nas diferentes formulações, foram variadas a razão NCO/OH e as proporções de PPG e do copolímero em bloco EG-b-PG. Além disso, foram obtidas dispersões aquosas programadas para teores de sólidos de 40 e 50%. As dispersões foram avaliadas quanto ao teor de sólidos totais, tamanho médio de partícula e viscosidade. Os filmes, obtidos por vazamento das dispersões, foram avaliados quanto à absorção de água, termogravimetria (TG) e propriedades mecânicas (ensaio de tração). Os filmes vazados e os monômeros foram caracterizados por espectrometria na região de infravermelho (FTIR) As dispersões obtidas se mostraram adequadas para serem aplicadas como revestimento para madeira, metais e vidro / Non-polluting and poly(urethane-urea) aqueous dispersions based on poly(propylene glycol) (PPG) and block copolymers of poly(ethylene glycol-b-propylene glycol) (EG-b-PG) containing 7% of ethylene glycol repeating units, were produced in an innovative way. The poly(urethane-urea)s were prepared, in two steps, by the prepolymer method. In the first step, anionomers, synthesized in bulk, based on EG-b-PG, PPG, dimethylolpropionic acid (DMPA) (anionomer sites generator) and isophorone diisocyanate (IPDI) were obtained. Still in the first step, the DMPA carboxylic groups were neutralized with triethylamine (TEA), generating the anionomer groups. In the second step, the anionomer prepolymer was dispersed in water under vigorous stirring and afterwards was chain extended with hydrazine. Different formulations were obtained by varying the NCO/OH ratio, and the proportions of PPG and EG-b-PG. Besides, poly(urethane-urea) aqueous dispersions with 40% and 50% of solid contents were obtained. The dispersions were evaluated in terms of their solid-contents, particle size and viscosity. The cast films, obtained from the dispersions concernig of water absorption, thermogravimetry (TG) and mechanical properties (stress and elongation at break). The films and monomers were characterized by infrared spectrometry (FTIR). The obtained dispersions were suitable when applied as for wood, metals and glass surfaces

Materiais nanoestruturados têm recebido destaque na comunidade científica, destacando-se, dentre eles, os nanocompósitos à base de polímeros e argila. Quando esses materiais são obtidos no estado líquido, ressalta-se também o uso de água em substituição a solventes orgânicos, devido a questões ambientais. Neste trabalho foram sintetizadas dispersões aquosas à base de poliuretanos (WPUs) e argila hidrofílica do tipo montimorilonita (MMT) de natureza sódica, com o objetivo de avaliar as propriedades de barreira a gases conferidas pela presença de argila e pela variação nas proporções entre os segmentos flexíveis poli(glicol propilênico) (PPG) e o copolímero em bloco à base de poli(glicol etilênico) e poli(glicol propilênico) (EG-b-PG). Os monômeros empregados na síntese foram: poli(glicol propilênico) (PPG); copolímero em bloco à base de poli(glicol etilênico) e poli(glicol propilênico) (EG-b-PG), com teor de 7% de EG; ácido dimetilolpropiônico (DMPA), diisocianato de isoforona (IPDI) e etilenodiamina (EDA), como extensor de cadeia. Foram sintetizadas dispersões aquosas com e sem a presença de argila, fixando-se a razão entre o número de equivalentes-grama de grupos diisocianato e hidroxila (razão NCO/OH) em 1,5. Nas formulações foi variado também o teor de argila em relação à massa de prepolímero em 0,5% e 1%. Foi adicionada uma etapa de agitação adicional com dispersor Turrax em algumas formulações. A argila foi previamente deslaminada em água deionizada e incorporada à formulação na etapa da dispersão do prepolímero. As dispersões foram avaliadas, quanto ao teor de sólidos totais, tamanho médio de partícula e viscosidade aparente. Os filmes vazados a partir das dispersões foram caracterizados por espectrometria na região do infravermelho (FTIR) e permeabilidade ao CO2. A resistência térmica dos filmes foi determinada por termogravimetria (TG). Foram observadas modificações nas propriedades dos filmes obtidos com a inserção da argila e com a variação no teor de segmentos à base de poli(glicol etilênico). A inserção da argila promoveu uma melhoria na resistência térmica das membranas bem como uma redução na permeabilidade das mesmas. Foi observado um aumento na permeabilidade das membranas obtidas a partir das formulações com maior percentual de copolímero (EG-b-PG), com e sem argila. / Nanostructured materials have been receiving increasing attention of scientific community, especially systems of nanocomposites based on polymer and clay. These materials can be obtained in aqueous state and the use of water, replacing organic solvents, is an important line of research due to environmental issues. In this work, dispersions based on waterbone polyurethanes and sodic hydrophilic clay montmorillonite (MMT) were synthesized, in order to evaluate the possible formation of nanocomposites (NWPUs). The monomers employed in the synthesis were: poly (propylene glycol) (PPG), block copolymer based on poly (ethylene glycol) and poly (propylene glycol) (EG-b-PG), containing 7% ethylene glycol; dimethylolpropionic acid (DMPA); isophorone diisocyanate (IPDI); and ethylenediamine (EDA) as chain extender. Aqueous dispersions with and without clay were synthesized by fixing the ratio between the equivalent-grams of diisocyanate and hydroxyl groups (NCO/OH ratio) in 1.5. The clay content also varied from 0.5% to 1% related to prepolymer initial mass. An additional stirring step with Turrax disperser was made in some formulations. The clay was previously delaminated in deionized water and incorporated at prepolymer dispersion in water-addition step. The dispersions were then evaluated in terms of solids content, particle size and apparent viscosity. The films cast from dispersions were characterized by infrared spectrometry (FTIR), thermogravimetry (TG) and permeability to CO2. Cast films were obtained and the gas barrier properties imparted by the clay were analyzed as well as the influence of poly (ethylene glycol) segments content. The insertion of clay imparted an improvement in thermal resistance properties and a decrease in membrane permeability. It was also observed an increase in permeability to CO2 of membranes obtained from formulations containing the higher amount of copolymer (EG-b-PG), independent of clay content.

Foram produzidas dispersões aquosas não-poluentes e inovadoras de poli(uretano-uréia) à base de poli(glicol propilênico) (PPG) e de copolímeros em bloco, poli(glicol etilênicob-glicol propilênico), (EG-b-PG) com teor de 7% de unidades de glicol etilênico. Os poli(uretano-uréia)s foram preparados, em duas etapas, pelo método do prepolímero. Na primeira etapa, foram obtidos anionômeros, sintetizados em massa, à base do copolímero EG-bPG, PPG, ácido dimetilol propiônico (DMPA) (gerador dos sítios aniônicos) e diisocianato de isoforona (IPDI). Ainda na primeira etapa, os grupos carboxílicos do DMPA foram submetidos à neutralização com trietilamina (TEA). Na segunda etapa, foi realizada a dispersão do prepolímero anionômero e, em seguida, foi conduzida a reação de extensão de cadeia com a hidrazina (HYD). Nas diferentes formulações, foram variadas a razão NCO/OH e as proporções de PPG e do copolímero em bloco EG-b-PG. Além disso, foram obtidas dispersões aquosas programadas para teores de sólidos de 40 e 50%. As dispersões foram avaliadas quanto ao teor de sólidos totais, tamanho médio de partícula e viscosidade. Os filmes, obtidos por vazamento das dispersões, foram avaliados quanto à absorção de água, termogravimetria (TG) e propriedades mecânicas (ensaio de tração). Os filmes vazados e os monômeros foram caracterizados por espectrometria na região de infravermelho (FTIR) As dispersões obtidas se mostraram adequadas para serem aplicadas como revestimento para madeira, metais e vidro / Non-polluting and poly(urethane-urea) aqueous dispersions based on poly(propylene glycol) (PPG) and block copolymers of poly(ethylene glycol-b-propylene glycol) (EG-b-PG) containing 7% of ethylene glycol repeating units, were produced in an innovative way. The poly(urethane-urea)s were prepared, in two steps, by the prepolymer method. In the first step, anionomers, synthesized in bulk, based on EG-b-PG, PPG, dimethylolpropionic acid (DMPA) (anionomer sites generator) and isophorone diisocyanate (IPDI) were obtained. Still in the first step, the DMPA carboxylic groups were neutralized with triethylamine (TEA), generating the anionomer groups. In the second step, the anionomer prepolymer was dispersed in water under vigorous stirring and afterwards was chain extended with hydrazine. Different formulations were obtained by varying the NCO/OH ratio, and the proportions of PPG and EG-b-PG. Besides, poly(urethane-urea) aqueous dispersions with 40% and 50% of solid contents were obtained. The dispersions were evaluated in terms of their solid-contents, particle size and viscosity. The cast films, obtained from the dispersions concernig of water absorption, thermogravimetry (TG) and mechanical properties (stress and elongation at break). The films and monomers were characterized by infrared spectrometry (FTIR). The obtained dispersions were suitable when applied as for wood, metals and glass surfaces

O escoamento líquido-líquido, em especial o escoamento óleo-água, vem atraindo a atenção de pesquisadores devido à alta demanda pelo combustível fóssil no atual cenário petrolífero mundial e nacional. Os desafios tecnológicos colocados pelas descobertas de reservas de óleos pesados e altamente viscosos consideram, em especial, a preocupação por minimizar as perdas energéticas nas linhas. Emulsões inversas ou dispersões óleo-em-água, na qual o óleo se encontra disperso de maneira uniforme em água, caracteriza-se pela baixa viscosidade aparente, tornando-se um tipo de emulsão desejável em algumas etapas do transporte de petróleo. Esses fatos tornam essencial o estudo deste tipo de padrão para o dimensionamento e operação ótima de dutos de produção de petróleo. Contudo, não existe ainda um número abrangente de trabalhos sobre padrão disperso líquido-líquido, ao comparar com escoamento em fases separadas. Trabalhos sobre dispersões têm reportado redução de atrito sem a adição de substâncias químicas em regime turbulento. No entanto, não há ainda um entendimento satisfatório do fenômeno. Na maioria dos trabalhos, sendo quase todos realizados com óleos leves e pouco viscosos, a redução é reportada em dispersões água-em-óleo, com escassos trabalhos reportando o fenômeno em dispersões óleo-em-água. A pesquisa realizada tratou do estudo experimental e teórico de dispersões óleo-em-água em tubulações. O escoamento foi caracterizado a partir da obtenção de dados de holdup, gradiente de pressão por fricção, distribuição das fases e padrão de escoamento. Uma teoria foi proposta para explicar a redução de atrito detectada neste trabalho, baseada na existência de um filme fino de água que escoa em contato com a parede do tubo, a baixos números de Reynolds, evitando o contato direto do núcleo turbulento (mistura bifásica) com a parede do tubo. O referido filme líquido foi detectado e quantificado utilizando-se técnica visual. Além disso, um modelo dinâmico baseado na teoria de lubrificação hidrodinâmica foi desenvolvido como tentativa de explicar a formação do filme líquido parietal no escoamento turbulento de dispersões óleo-água. / Liquid-liquid flow, especially oil-water flow, has attracted the attention of researchers due to the high demand for petroleum in the current global scenario. The discovery of reserves of heavy and highly viscous oils creates new challenges which are mainly concerned with reducing the significant pressure drop in pipes. Inverse emulsion or oil-in-water dispersions in which the oil is dispersed in water is characterized by its low effective viscosity, making it a desirable type of emulsion in some steps of oil production. These facts make the study of dispersed liquid-liquid flow essential for the design and optimal operation of oil pipelines. However, the studies on such flow pattern are scanty in comparison to those on separate flows, as stratified and annular flow patterns. Drag reduction in oil-water turbulent flow without the addition of any chemical substance has been reported in some studies. This phenomenon has received increasing attention in recent years, because there is not a satisfactory understanding of its dynamics yet. Most studies, almost all using light oils, report drag reduction in dispersion of water-in-oil, with few studies reporting the phenomenon in oil-in-water dispersions. This research comprises an experimental and theoretical study on oil-in-water dispersions in pipes. Pressure gradient, holdup, phase distribution and flow patterns data were obtained to characterize the two-phase flow. A theory was proposed to explain the drag reduction detected in this work, based on the existence of a thin water film flowing in contact with the pipe wall at low Reynolds numbers, avoiding contact between the turbulent core (mixture) and the pipe wall. The liquid film was detected and quantified using visual technique. In addition, a dynamic model based on the hydrodynamic lubrication theory was developed as an attempt to explain the formation of the liquid film.

La Béringie, un vaste territoire qui s’étend de la Sibérie orientale au Territoire du Yukon, est perçue comme le point d’entrée des populations humaines en Amérique. A la fin du Pléistocène, ce territoire déglacé aurait constitué un refuge aux premières populations préhistoriques se dispersant hors d’Asie. Selon les données génétiques et paléo-génétiques, la Béringie fut occupée au cours du Dernier Maximum Glaciaire (19 000-23 000 cal BP, années calibrées Before Present) par une population humaine qui demeura génétiquement isolée durant près de 8000 à 9000 ans, donnant ainsi naissance à la lignée des Natifs Américains qui allaient se disperser, plus tard, au sud des masses glaciaires nordaméricaines et jusqu’en Amérique du Sud. Cette « Beringian standstill hypothesis », toutefois, ne trouva aucun soutien dans le registre archéologique : en Sibérie orientale, le plus ancien site est daté à 32 000 cal BP, tandis qu’en Alaska et au Yukon, la présence humaine ne remonte pas au-delà de 14 000 cal BP. Dans les années 70-80’s, le site des Grottes du Poisson-Bleu (Yukon) livra des outils en pierre et des ossements supposés modifiés par les humains, enfouis dans un dépôt loessique pléistocène ; les découvertes encouragèrent les archéologues J. Cinq-Mars et R. Morlan à évoquer l’hypothèse d’une occupation humaine sporadique dans le nord du Yukon entre 11 000 et 30 000 cal BP environ. La nature anthropogénique des échantillons osseux soumis aux datations radiocarbones ainsi que l’intégrité de la stratigraphie furent toutefois remises en question par une majorité d’archéologues. La présente dissertation propose une analyse archéozoologique et taphonomique rigoureuse et systématique des assemblages fauniques de mammifères des Grottes I et II dans le but d’appréhender les facteurs responsables de l’accumulation et de la modification du matériel osseux. De nouvelles datations radiocarbones effectuées par le laboratoire Oxford Radiocarbon Accelerator Unit sur des ossements portant des traces indéniablement culturelles permettent une datation précise de l’occupation humaine du site. Les résultats illustrent plusieurs traces de découpe sur des os de cheval, caribou, wapiti et possiblement bison et mouflon, tandis que des ossements de mammouth pourraient avoir été collectés pour l’industrie osseuse. Les nouvelles datations AMS suggèrent que les Grottes du Poisson-Bleu étaient occupées de façon sporadique entre 12 000 et 24 000 cal BP, soit pendant et après le Dernier Maximum Glaciaire. Le site offre ainsi un soutien archéologique à l’hypothèse de l’isolation génétique des populations béringiennes à l’origine des premières dispersions en Amérique. L’histoire taphonomique des Grottes du Poisson-Bleu rejoint celle des sites karstiques béringiens qui illustrent des occupations interspécifiques alternées entre carnivores et des fréquentations humaines de courte durée pour des activités de chasse. En outre, les altérations anthropiques sur des os de cheval des Grottes I et II ravivent le débat sur les extinctions de la mégafaune à la fin du Pléistocène (ca. 14 000 cal BP). Le site souligne l’incomplétude du registre archéologique et invite à multiplier les efforts de recherche en Béringie si l’on veut être à même de comprendre la préhistoire du peuplement des Amériques. / Beringia, a vast landscape stretching from eastern Siberia to the Yukon Territory, is thought to be the initial entry point of humans into North and South America. At the end of the Pleistocene, this unglaciated region constituted a refugium for the first prehistoric populations dispersing out of Asia. According to genetic and palaeogenetic data, Beringia was occupied during the Last Glacial Maximum (19 000-23 000 cal BP, calibrated years before present) by a human population that remained genetically isolated for about 8000 to 9000 years, leading to the divergence of the Native American lineage that would eventually disperse south of the ice-sheets into North and South America. The « Beringian standstill hypothesis » is not well supported in the archaeological record, however: in eastern Siberia, the oldest archaeological site is dated to 32 000 cal BP while in Alaska and the Yukon, evidence for a human presence doesn’t exceed 14 000 cal BP. Excavated in the 70s-80s, the Bluefish Caves site (Yukon) yielded stone tools and bone remains thought to have been culturally modified, buried in a Pleistocene loess deposit; the discovery encouraged archaeologists J. Cinq-Mars and R. Morlan to propose that humans occupied the caves sporadically between about 11 000 and 30 000 cal BP. The anthropogenic nature of the bone samples submitted for radiocarbon analysis and the stratigraphic integrity of the site didn’t convince the scientific community, however. The current dissertation proposes a rigorous archaeozoological and taphonomic analysis of the mammal bone assemblages of Caves I and II in order to identify the agents responsible for the accumulation and modification of the bone material. The results show several cut marks on bone specimens belonging to horse, caribou, wapiti and possibly bison and Dall sheep, while mammoth skeletal remains may have been collected for bone industry. New radiocarbon dates obtained by an Oxford laboratory (Oxford Radiocarbon Accelerator Unit) on bone bearing indisputable evidence of cultural modification allow the precise dating of the human occupation at the site. The AMS dates suggest that the Bluefish Caves were occupied sporadically between 12 000 to 24 000 cal BP, i.e., during and after the Last Glacial Maximum. The site, therefore, offers archaeological support for the Beringian standstill hypothesis. The taphonomic history of the Bluefish Caves, as well as other Beringian karstic sites, shows use of the caves by various carnivores and short-term human occupations for hunting activities. Moreover, cultural modifications on horse bone from Caves I and II enhance the debate surrounding the megafaunal extinctions at the end of the Pleistocene (ca. 14 000 cal BP). The site underlines the incompleteness of the archaeological record and invites us to expand research efforts in Beringia if we are to understand the prehistory of the first people of the Americas.

<p>Supersaturating drug delivery systems are an attractive solubility enabling formulation strategy for poorly soluble drugs due to their potential to significantly enhance solubility and hence, bioavailability. Compendial dissolution testing is commonly used a surrogate for assessing the bioavailability of enabling formulations. However, it increasingly fails to accurately predict <i>in vivo</i> performance due its closed-compartment characteristics and the lack of absorptive sink conditions. <i>In vivo</i>, drug is continually removed due to absorption across the gastrointestinal membrane, which impacts the luminal concentration profile, which in turn affects the dissolution kinetics of any undissolved material, as well as crystallization kinetics from supersaturated solutions. Thus, it is critical to develop an improved methodology that better mimics <i>in vivo</i> conditions. An enhanced approach integrates dissolution and absorption measurements. However, currently-used two-compartment absorptive apparatuses, employing a flat-sheet membrane are limited, in particular by the small membrane surface area that restricts the mass transfer, resulting in unrealistic experimental timeframes. This greatly impacts the suitability of such systems as a formulation development tool. The goal of this research is two-fold. First, to develop and test a high surface area, flow-through, absorptive dissolution testing apparatus, designed to provide <i>in vivo</i> relevant information about formulation performance in biologically relevant time frames. Second, to use this apparatus to obtain mechanistic insight into physical phenomenon occurring during formulation dissolution. Herein, the design and construction of a coupled dissolution-absorption apparatus using a hollow fiber membrane module to simulate the absorption process is described. The hollow fiber membrane offers a large membrane surface area, improving the mass transfer rates significantly. Following the development of a robust apparatus, its application as a formulation development tool was evaluated in subsequent studies. The dissolution-absorption studies were carried out for supersaturated solutions generated via anti-solvent addition, pH-shift and by dissolution of amorphous formulations. The research demonstrates the potential of the apparatus to capture subtle differences between formulations, providing insight into the role of physical processes such as supersaturation, crystallization kinetics and liquid-liquid phase separation on the absorption kinetics. The study also explores dissolution-absorption performance of amorphous solid dispersions (ASDs) and the influence of resultant solution phase behavior on the absorption profile. Residual crystalline content in ASDs is a great concern from a physical stability and dissolution performance perspective as it can promote secondary nucleation or seed crystal growth. Therefore, the risk of drug crystallization during dissolution of ASDs containing some residual crystals was assessed using absorptive dissolution measurements and compared to outcomes observed using closed-compartment dissolution testing. Mesoporous silica-based formulations are another type of amorphous formulations that are gaining increased interest due to higher physical stability and rapid release of the amorphous drug. However, their application may be limited by incomplete drug release resulting from the adsorption tendency of the drug onto the silica surface. Thus, the performance of mesoporous silica-based formulations was also evaluated in the absorptive dissolution testing apparatus to determine the impact of physiological conditions such as gastrointestinal pH and simultaneous membrane absorption on the adsorption kinetics during formulation dissolution. Overall, the aim of this research was to demonstrate the potential of the novel <i>in vitro</i> methodology and highlight the significance of a dynamic absorptive dissolution environment to enable better assessment of complex enabling formulations. <i>In vivo</i>, there are multiple physical processes occurring in the gastrointestinal lumen and the kinetics of these processes strongly depend on the absorption kinetics and <i>vice-a-versa</i>. Thus, using this novel tool, the interplay between solution phase behavior and the likely impacts on bioavailability of supersaturating drug delivery systems can be better elucidated. This approach and apparatus is anticipated to be of great utility to the pharmaceutical industry to make informed decisions with respect to formulation optimization.</p>

Les travaux de recherche décrits dans cette thèse s’intéressent aux conditions environnementales qui ont vu les premières dispersions humaines du technocomplexe de l’Aurignacien en Europe, au début du Paléolithique supérieur. En d’autres mots, ce projet contribue aux discussions sur la transition entre le Paléolithique moyen et le Paléolithique supérieur, une période qui a vu le remplacement des populations néanderthaliennes d’Europe par les populations d’humains anatomiquement modernes (HAM) arrivantes. Ce tournant de l’histoire de notre espèce s’est déroulé durant le stade isotopique marin 3 (MIS 3), une période de changements climatiques répétés et cycliques entre 60 000 et 24 000 années avant aujourd’hui. L’impact de ces changements climatiques sur les dynamiques populationnelles est un sujet vivement discuté chez les chercheurs. Cette recherche fait une contribution certaine à ce discours par l’évaluation de la sensibilité des HAM aux changements climatiques et au risque écologique, ainsi que par l’investigation des impacts des différentes conditions climatiques du MIS 3 sur leurs comportements spatiaux et sur leurs dispersions initiales en Europe. La thèse s’articule autour de trois articles de recherche. Le premier article fait office de collecte de données et vise la sélection d’un corpus d’assemblages archéologiques fiables et bien contrôlés chronologiquement. En effet, un obstacle de l’étude des interactions humain- environnement durant le MIS 3 est l’association claire entre les occupations archéologiques et les événements climatiques millénaires. Une revue critique des datations publiées pour la culture archéologique de l’Aurignacien, un recensement des études environnementales reliées aux niveaux datés et une classification bayésienne de ces datations et occupations archéologiques dans les différents cycles froids et chauds de cette période ont été réalisés. La base de données ainsi produite a servi, dans le cadre du second article, à la production de modèles d’habitat propice (habitat suitability) pour les interstadiaires et les stadiaires du MIS 3. Ces modèles utilisent des données paléoclimatiques de fine résolution (15km, interpolées à 1km) qui représentent les tendances de précipitation et de température, ainsi que la variabilité interannuelle de celles-ci (une cinquantaine de prédicteurs sont ainsi testés). L’approche utilisée 4 pour la production des modèles est l’algorithme d’apprentissage automatique (machine learning) Random Forest, lequel a permis de sélectionner des prédicteurs forts de l’occupation humaine selon les conditions climatiques en place. Le troisième article décrit une étude exploratoire qui bâtit sur les modèles d’adéquation de l’habitat produits ci-avant dans la réalisation d’analyses mixtes de chemins de moindre coût (least-cost path analysis). Grâce à ces modèles, il a été possible de comparer les routes potentielles pour l’entrée des HAM en Europe selon les conditions climatiques chaude ou froide, en plus d’étudier l’impact de ces oscillations sur les axes de mobilité au sein du continent et sur l’interconnexion des différentes régions habitables. Les analyses effectuées dans le cadre de cette thèse montrent que les HAM du début du Paléolithique supérieur étaient bel et bien sensibles aux changements climatiques et au risque écologique. Les détériorations environnementales associées aux périodes stadiaires ont considérablement réduit la taille de leur espace vital en Europe, en plus d’avoir limité la connectivité entre les régions habitables. Dans le même ordre d’idées, la prise de décision spatiale était sensible à la variabilité climatique, et donc à la prédictibilité des ressources dans le paysage. Cette gestion du risque écologique chez Homo sapiens, en plus de sa capacité à s’adapter aux changements climatiques, s’inscrit parmi les capacités adaptatives qui ont plausiblement joué un rôle important dans la survie et le succès de l’espèce. Finalement, selon les résultats, les HAMs ont probablement profité d’une extension de leur habitat durant un épisode stadiaire pour se disperser en Europe. / The research described in this thesis focuses on the environmental conditions that saw the first human dispersal from the Aurignacian technocomplex in Europe, at the beginning of the Upper Paleolithic. In other words, this project contributes to discussions on the transition from the Middle Paleolithic to the Upper Paleolithic, a period that saw the replacement of Europe’s Neanderthal populations by incoming populations of anatomically modern humans (AMHs). This turning point in the history of our species took place during Marine Isotope Stage 3 (MIS 3), a period of repeated and cyclical climate change between 60,000 and 24,000 years before present. The impact of these climatic changes on population dynamics is a widely discussed topic among researchers. This research makes a definite contribution to this discourse by assessing the sensitivity of HAMs to climate change and ecological risk, as well as investigating the impacts of the different MIS 3 climatic conditions on their spatial behaviour and initial dispersal in Europe. The thesis is structured around three research articles. The first article acts as a data collection step and aims to select a corpus of reliable, chronologically controlled archaeological assemblages. Indeed, an obstacle to the study of human-environment interactions during MIS 3 is the clear association between archaeological occupations and millennial climatic events. A critical review of published dates for the Aurignacian archaeological culture, a survey of environmental studies related to dated levels and a Bayesian classification of these dates and archaeological layers within the different cold and warm cycles of this period were carried out. In the second article, the resulting database was used to produce habitat suitability models for the interstadials and stadials of MIS 3. These models use fine-resolution paleoclimatic reconstructions(15 km, interpolated to 1 km) representing precipitation and temperature trends, as well as their interannual variability (some 50 predictors were tested). The models were produced using the Random Forest machine learning algorithm, which was used to select strong predictors of human occupation based on prevailing climatic conditions. The third article describes an exploratory study that builds on the habitat suitability models produced above in carrying out least-cost path analysis. Thanks to these models, it was 6 possible to compare potential routes for HAMs to enter Europe under warm and cold climatic conditions, and to study the impact of these oscillations on mobility routes within the continent and on the interconnection of different habitable regions. The analyses carried out as part of this thesis show that early Upper Palaeolithic HAMs were indeed sensitive to climate change and ecological risk. Environmental deterioration associated with stadial periods considerably reduced the size of their suitable landmassin Europe, in addition to limiting connectivity between habitable regions. Similarly, spatial decision-making was sensitive to climatic variability, and therefore to the predictability of resources in the landscape. This ecological risk management in Homo sapiens, as well as their ability to adapt to climate change, are plausibly part of the adaptive capacities that played an important role in the survival and success of the species. Finally, according to the results, HAMs probably took advantage of an extension of their habitat during a stadial episode to disperse across Europe.