A pesquisa tem por objeto de estudo as dispersões das racionalidades formativas: o modo como, em nossa época, a ideia de formação, compreendida como ato de interferência educativa nos modos de existir individuais e/ou coletivos, tem-se difundido em espaços e relações cada vez mais cotidianas que em muito ultrapassam o ambiente escolar. Levando em conta o contexto dos estudos de base pós-estruturalista realizados, sobretudo, a partir das análises foucaultianas, o trabalho se pauta no mapeamento de saturações discursivas em torno da questão da formação, encarando-a como um elemento fundamental das razões biopolíticas que encontraram na vida individual, principalmente a partir da emergência do liberalismo, algumas possibilidades efetivas de se governar. De inspirações cartográficas e a partir de uma releitura do conceito de mitologia de Roland Barthes, o estudo focaliza, em um primeiro momento, a identificação do que foram considerados mitos formativos fundamentais representações de representações que constroem figuras socialmente naturalizadas associadas, no caso, à formação docente. A partir dessas reflexões, donde derivaram seis mitos formativos essenciais a formação complexa, a formação múltipla, a formação mensurável, a formação competente, a formação aconselhável, a formação reformável , busca-se na segunda etapa de pesquisa definir a maneira como tal mitologia se dispersa, por um lado, em discursos oficiais, tomados de dispositivos da legislação educacional e produções de organismos internacionais e, por outro, em falas cotidianas dispersas, voltadas à formação para a vida e para o trabalho, mediante a análise de exemplares de um periódico semanal de grande circulação nacional e de transcrições de discussões promovidas no âmbito de um evento pautado na formação do trabalhador. As análises permitiram a construção de um mapa de operações discursivas capazes de integrar a formatividade a questões associadas à laboralidade e aos modos de existir. Do que resulta a construção de um amálgama que, se por determinados movimentos promove a valorização de um sentido moral da formatividade já presente na noção iluminista de bildung, atualizando-a e imprimindo-lhe algumas inversões, por meio de outros integra tais produções em um caminho de preparo pessoal. Esse caminho termina por imprimir ao ato de formar(-se) uma ênfase acima de tudo instrumental, convertendo o bom homem em um bom trabalhador e garantindo a sua própria existência um sentido, acima de tudo, funcional. A viabilização das racionalidades que possibilitam tal configuração se dá a partir de processos dispersivos inerentes ao dispositivo da formação atual: há dispersões pela complexidade, pela chancela social, pela liquidez das aquisições, pelo engajamento individual, pela qualificação de saberes e pela parceria coletiva. Tais modos de espalhamento terminam por dar à questão formativa contemporânea traços epidêmicos, capazes de englobar a cotidianidade a partir de razões que estão, antes de tudo, associadas a formas de consumir e de permanecer mercadologicamente viável: uma hiperformatividade, portanto, capaz de converter a própria vida em um processo constante de preparação para algo. / This research has as its object of study the dispersions of the formative rationalities: the way in which, in our time, the idea of formation, understood as act of educative interference in the individual and/or collective modes of being, has spread towards ever more quotidian spaces and relations that reach far beyond the school sphere. Taking into account the context of post-structuralist studies chiefly based on Foucauldian analyses, this work is based on mapping out discursive saturations around the issue of formation, seeing it as a fundamental element of the biopolitical rationale that has found in the individual life, mainly since the emergence of liberalism, effective possibilities of governing. Of cartographical inspiration, and based on a rereading of Roland Barthes concept of mythology, the study focuses firstly on identifying what have been regarded as fundamental formative myths representations of representations that construct socially naturalized images associated, in the present case, to teacher formation. From these reflections, whence six social formative myths were derived the complex formation, the multiple formation, the measurable formation, the competent formation, the advisable formation, the reformable formation , one seeks, during the second stage of the research, to define the way in which such mythology is dispersed, on the one hand, in official discourses laden with educational legislation and productions of international organisms and, on the other hand, in dispersed daily discourses focused on the formation for life and for work, through the analysis of issues of a weekly periodical of large national circulation and of transcriptions of discussions promoted within an event targeted at the formation of workers. The analyses allowed the construction of a map of discursive operations capable of integrating formativity and questions associated to the sphere of labor and to the modes of being. From that results the construction of an amalgam which, if through some movements promotes the valuation of a moral sense of formativity already present in the Enlightenment notion of Bildung, bringing it up to date and giving it some inversions, through other movements integrates such productions into a path of personal preparation. This path ends up conferring to the act of forming (oneself) an emphasis which is above all instrumental, converting the good man into a good worker, and endowing his very existence with a meaning which is above all functional. The coming into being of the rationalities that allow such configuration takes place from dispersive processes inherent to the device of modern formation: there are dispersions through complexity, through the social seal of approval, through the liquidity of acquisitions, through individual commitment, through the qualification of knowledges and through collective partnership. Such modes of spreading eventually give to the contemporary formative question rather epidemic contours, capable of encompassing the daily life through reasons that are, above all, associated to forms of consuming and of remaining viable in market terms: a hyperformativity, therefore, capable of converting life itself in a process of constant preparation for something.

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Este trabalho visou obter extratos secos padronizados de Curcuma longa L., e sua otimização visando o aumento da solubilidade dos curcuminóides e melhoria nas suas atividades biológicas. No estudo de extração, os curcuminóides foram extraídas utilizando dois solventes, etanol e solução etanólica alcalina e dois processos microondas e ultrassom seguindo planejamentos fatoriais completos 24, e com pH do solvente, teor de etanol, tempo de extração, potência do microondas ou temperatura no ultrassom, e proporção massa da droga pela massa do solvente como variáveis independentes. Os extratos foram caracterizados quanto ao rendimento de sólidos totais, teor de curcuminóides totais, rendimento de curcuminóides totais, teor de curcumina, rendimento de curcumina e atividade antioxidante por difenil-picril-hidrazila. A condição de extração com melhor resultado foi o ultrassom a 20 ºC, solvente etanol 96 ºGL, 1 parte de planta para 7 de solvente, pH 10 e duração de 5 min., pois, nesta condição, obteve-se maior teor de curcumina e maior atividade antioxidante. O estudo visando aumento da solubilidade da curcumina constou da preparação de dispersões sólidas pelos métodos de spray drying e hot melt coating. Ambos os métodos foram estudados com os polímeros hidrofílicos Gelucire® 44:14 e 50:13, e aplicando-se planejamento fatorial tipo Box-Behnken. As dispersões sólidas particuladas foram avaliadas pela morfologia, densidade aparente e de compactação, fator de Hausner, índice de Carr, ângulo de repouso, umidade residual, atividade de água, calorimetria diferencial de varredura, termogravimetria, difração de raio-X, espectrometria de infravermelho, solubilidade em água e teste de dissolução. A maior solubilidade foi obtida com secagem no spray drying a 40 ºC, proporção Gelucire®44/14:curcumina 1:1 e proporção 1:5 de Aerosil:dispersão (DS16). No hot melt coating, a melhor solubilidade foi obtida com maior quantidade de Gelucire 50/13 e menor de Lactose (DS 3). Dispersões sólidas particuladas foram preparadas também com o Gelucire® 50/13 por spray drying (DS 17). Considerando-se os fatores solubilidade e teor de curcumina nas partículas, a dispersão DS 17 foi escolhida como a mais adequada para os ensaios biológicos posteriores. A mesma condição de preparo da DS17 foi usada para produzir dispersões sólidas com o extrato obtido por ultrassom (DSE). Nesta dispersão a solubilidade dos curcuminóides demonstrou ser 330 vezes maior do que o extrato seco nas mesmas condições porém sem a adição de carreador. No ensaio de avaliação da atividade antitumoral in vitro, foram avaliadas a citotoxicidade da curcumina pura, DS 17, DS 3 e a DSE, em diferentes linhagens tumorais, leucemia T (jurkat), melanona (C8161), adenocarcinoma coloretal (HT29), carcinoma hepatocelular (HepG2) e de célula não tumoral (PBMC). A curcumina apresentou atividade citotóxica para células tumorais e esta não foi afetada pelo processo de produção da dispersão sólida. Além disso, a DS do extrato apresentou maior citotoxicidade, o que pode ser devido ao sinergismo de outros compostos. O extrato também foi mais seletivo para células tumorais que a curcumina e as dispersões. O estudo de atividade anti-inflamatória in vivo usando o modelo de edema de pata, demonstrou que a dispersão DS 17 apresentou maior atividade do que a curcumina na mesma dose, indicando que o aumento da solubilidade possibilita uma maior absorção e consequentemente maior biodisponibilidade. / The aim of this work was to obtain standardized dried extracts of Curcuma longa L. and to develop pre-formulations and capsules with improved curcuminoids solubility and higher biological activities. In the extraction study, the powdered roots of Curcuma longa L. were extracted using ethanol and an aqueous alkaline ethanol solution by microwave and ultrasound assisted methods, together with the application of 24 full factorial designs of experiments to better understand the effects of solvent pH, ethanol concentration, microwave power, ultrasound temperature and ratio of drug to solvent (w/w) on the extract. The extracts were characterized by solids yield, curcuminoid content and yield, curcumin content and yield and antioxidant activity by the diphenylpycril hydrazil method. The best extraction resulted from the ultrasound assisted using ethanol 96 oGL at pH 10, 20oC, 1:7 drug to solvent ratio (w/w), during 5 minutes. This condition was chosen because it resulted in the best yields and antioxidant activities. The work developed to improve curcumin and curcuminoid solubilities was based on the preparation of solid dispersions by spray drying and hot melt coating using the hydrophilic carriers Gelucire® 44:14 and 50:13. Applying Box-Behnken designs the effect of process conditions on microparticulate solid dispersions properties, like morphology, bulk and tapped densities, Hausner factor, Carr index, angle of repose, moisture content, water activity, differential scanning calorimetry, thermogravimetric analysis, X-ray powder diffraction, infrared spectrometry, curcuminoid solubility in water and dissolution rate. The highest improvement in drug solubility was obtained by dispersion prepared by spray drying at 40oC, Gelucire® 44:14/curcumin 1:1 ratio, and adding 16,7% Aerosil (DS16). On the other hand, the hot melt granules with best solubility were prepared with higher Gelucire® 50:13 and lower substrate (lactose) contents (DS3). Additional solid dispersion, DS17, was prepared by spray-drying in the same conditions applied to DS16 but using Gelucire® 50:13 as carrier. Considering the aspects drug solubility and content in solid dispersions, DS17 showed the best performance and the same set of conditions used for its preparation was also applied to produce a solid dispersion containing the raw extract obtained by ultrasound extraction. This solid dispersion increased curcumin solubility by a 330-fold factor. In the in vitro antitumor assays pure curcumin, DS3, DS17 and DSE cytotoxicities were evaluated in several tumor cell lines, leukemia T (jurkat), melanona (C8161), adenocarcinoma coloretal (HT29), hepatic carcinoma (HepG2) and in one non tumor (PBMC). The antitumor activities were not influenced by the thermal processes and the extract presented higher cytotoxicity and better selectivity to tumor cells. The in vivo antinflammatory study was performed by the rat paw edema method and showed that solid dispersion DS17 resulted in antinflammatory effect higher than pure curcumin and indomethacin at some doses. The results are an indicative that the increase in drug solubility may incur in an increase oral bioavailability and that the process proposed herein are adequate for preparation of pre-formulations containing less soluble herbal drugs.

Among the different pulmonary fungal infections, aspergillosis, and in particular invasive pulmonary aspergillosis (IPA), are becoming the most worrying diseases in immunocompromised patients. This is due to their high incidence and mortality. Indeed, invasive aspergillosis manifests as invasive pulmonary disease accounting for 50/60% of all cases, with a mortality of 50-90% in severely immunocompromised patients. Triazoles act by inhibiting 14-α demethylase, a fungal cytochrome P450 enzyme implicated in the synthesis of ergosterol, an essential constituent of fungal cell walls. Moreover, they interact with the same cytochrome present in large quantities in the human liver, inducing possible drug-drug interactions in IPA patients. Consequently, interactions resulting from inhibitors, inductors, or substrates of cytochromes can modify the plasmatic concentrations of triazoles or other drugs administered concomitantly. To overcome these important issues, pulmonary delivery of triazoles could be an interesting alternative to conventional routes.The aim of this work was to develop triazole-based dry powders for inhalation able to be deposited adequately in the lungs, with a release of drug and a lung retention that can optimize its pharmacological action. This work focused on two active pharmaceutical ingredients (API): itraconazole (ITZ), for which improved solubility was needed, and voriconazole (VCZ), for which slow release was required.Concerning ITZ, solid dispersions for inhalation (SDIs) comprising ITZ and mannitol were previously developed in our laboratory. The selected SDI showed interesting results in terms of improved dissolution and lung retention in vivo in mice during a pharmacokinetic study. Therefore, this SDI was tested in a murine preclinical model of IPA and showed promising results in terms of prophylaxis efficacy. One aim of this work was to continue the pharmaceutical development of this promising SDI by making a scaling-up study. These methods were intended to improve the SDI’s ecological footprint and productivity by increasing the production yield and decreasing the amount of solvents and time used in its manufacture. During the first step of this study, the obtained SDI showed interesting results obtaining similar powder characteristics (i.e. amorphous content, aerodynamic performance, and dissolution profiles) from concentrated solutions using a laboratory-scale spray-dryer B-290 (Büchi, Switzerland) before using a pilot-scale spray-dryer (GEA Niro, Denmark). Then, the upscaling was performed on the pilot spray-dryer allowing the production of SDIs with increased productivity (yield and process duration). These SDIs had similar powder characteristics than the optimized lab-scale SDIs. During the second part of this work we developed VCZ based dry powder for inhalation. The aim was to slow down the release of this highly permeable and very slightly soluble API and to prolong its lung residence. To this end, various lipidic excipients were chosen. The selection took into account the potential good pulmonary tolerance of the lipids and their hydrophobicity to evaluate their ability to slow down the VCZ release (FPFs 20-25%, slowed release up to 24h, burst effect of ± 58% of VCZ dissolved within 30min). Immediate-release SDIs were also developed to have a comparator reference for the pharmacokinetic and efficacy studies (FPFs of 40%).Then, a pharmacokinetic study in mice was performed following the pulmonary administration of one immediate-release and two sustained-release SDIs (with or without PEG excipient). With an 80-fold higher pulmonary exposure over 24 hours, the slow-release SDIs presented a real interest compared to the immediate-release SDI. Moreover, in accordance with these results, VCZ plasma exposure following the administration of the SDI with PL90-H was more than 1.5-fold higher than its pulmonary exposure (AUC0-24 of 8.70 µg.h/g in the lungs and 14.70 µg.h/mL in the plasma). The slow-release formulations presented plasma exposures at least 15 times lower than their pulmonary exposures (AUC0-24 in lung of 741.40 and 686.85 µg.h/g vs plasmatic AUC0-24 of 37.44 and 42.81 µg.h.mL, respectively with and without PEG excipient). Moreover, the presence of PEG excipient did not influence the residence time and the exposure of the VCZ within the lungs. Finally, the sustained-release SDIs administration by inhalation led to VCZ lung and plasma concentrations higher than the minimal inhibitory concentration (MIC) of VCZ against Aspergillus fumigatus (1 μg/mL) over 24 h. Finally, a murine model of IPA was developed in our lab. The immunosuppression model was fixed and performed by the intraperitoneal (IP) injection of corticosteroids to induce a neutropenia state. Then, different doses of spores (from 1.10^4 to 5.10^6 spores) were inoculated to the neutropenic mice via an endotracheal instillation and the survival rate of each group was observed. Unfortunately, the survival rate resulting from the different infections were not reproducible. Therefore, these models were not suitable to conduct the efficacy study. This underlined the link between the immunosuppressive model and the infection. Indeed, the IPA murine model should be developed according to the immune state of the animal, the Aspergillus conidia species and its concentration to be used. / Doctorat en Sciences biomédicales et pharmaceutiques (Pharmacie) / info:eu-repo/semantics/nonPublished

[pt] Este trabalho apresenta a análise das características de dispersão temporal do canal de propagação banda ultra larga (UWB) feitas a partir da técnica de sondagem em freqüência na banda de 850MHz em sete diferentes ambientes Indoor. Nestes ambientes os parâmetros de dispersão temporal dados pelo retardo médio, retardo RMS e banda de coerência são obtidos. Uma análise adicional sobre a perda de propagação e sobre a robustez do sinal UWB a desvanecimento de pequena escala é também realizada. / [en] This work presents an analysis of the ultra wideband (UWB) channel temporal dispersion characteristics evaluated from the frequency sounding technique over a bandwidth of 850MHz at seven different indoor environment. In each environment, the channel temporal dispersions parameters were assessed in terms of mean delay, delay spread and coherence bandwidth. An additional analysis related to path loss and UWB robustness was also evaluated.

[pt] O escoamento trifásico na indústria do petróleo é caracterizado pela presença das fases gás, óleo e água. A presença da terceira fase (água) traz complexidade a esse processo, visto que pode provocar a formação de diversos novos padrões de escoamento, além dos já conhecidos para escoamento bifásico. Adicionalmente, a presença de uma fase líquida dispersa na outra pode formar uma emulsão, alterando significativamente a viscosidade e, assim, influenciando diretamente na perda de carga. O foco do presente trabalho é na previsão do padrão de golfadas com dispersões de água e óleo utilizando um modelo transiente unidimensional de Dois Fluidos. A presença da água é modelada através da solução da equação de conservação de massa para a fase água. Visando prever com precisão a queda de pressão, assim como a distribuição das frações volumétricas de cada fase ao longo do domínio, desenvolveu-se um modelo de fechamento algébrico para avaliar o escorregamento entre as fases líquidas. Com o modelo proposto, os resultados obtidos para a velocidade de escorregamento no escoamento água/óleo foram comparados com dados experimentais e de outros modelos, apresentando um excelente desempenho. O modelo foi então utilizado para analisar o escoamento trifásico no padrão de golfadas. As previsões para a queda de pressão e características das golfadas (comprimento, frequência e velocidade de translação) foram comparadas com dados experimentais da literatura e os resultados são promissores. / [en] The three-phase flow in the oil industry is characterized by the presence of the gas, oil and water phases. The presence of the third phase (water) adds complexity to this process, since it can cause the formation of several new flow patterns in addition to those already known for two-phase flow. Additionally, the presence of a dispersed phase into another can form an emulsion, altering significantly the viscosity and consequently influencing directly the pressure drop. The focus of this job is in the prediction of the slug flow with dispersions of water and oil using a one-dimensional transient Two Fluid model. The presence of water in the flow is modelled with the solution of an equation of conservation of mass. Intending to predict with precision the pressure drop, as the volumetric phase distribution of each phase throw the domain, an algebraic closure model was inserted to assess the slip between the liquid phases. With the proposed model, the results obtained for the slip velocity of the water/oil flow were compared with experimental data and other models, showing excellent performance. The model was then used to analyze the three-phase flow in the slug pattern. The predictions for pressure drop and characteristics of the slugs (length, frequency and translation velocity) have been compared with experimental data from the literature and the results are promising.

The pharmaceutical industry is at a critical juncture. With little remnants of the “Golden Age of the Pharmaceuticals” and applied pressure from large companies experiencing a dissipation of proprietary compounds, trends indicate a transition from a decade of stagnant productivity to one in which high throughput screening technologies and computational chemistry have diversified the discovery of new chemical entities (NCE). Despite these advances, drug discovery has been challenged by chemical entities that present delivery limitations due to the properties of their molecular structure. A recent evaluation of development pipelines indicated that approximately 70% of drug candidates exhibit poor aqueous solubility; thereby, resulting in erratic dissolution and insufficient bioavailability. Due to intrinsic physical properties, these compounds are known by the biopharmaceutics classification system (BCS) as class II compounds and are amendable to solubility and bioavailability enhancement platforms. Approaches such as pH adjustment, micronization, nanosuspensions, co-solvent solubilization, cyclodextrin inclusion complexation, salt formation, emulsified drug formulations and amorphous solid dispersions (ASD) are commonly utilized to maximize bioavailability and enrich in vivo absorption by prolonging exposure to high concentrations of dissolved drug in the gastrointestinal tract (GIT). Single-phase amorphous systems, such as solid dispersions, have been the focal point of the aforementioned practices as a result of their ability to promote a state of drug supersaturation over an extended duration of time. Within the structure of this dissertation, the application of concentration enhancing polymers for bioavailability enhancement of low solubility compounds was evaluated using solvent and fusion-based solid dispersion technologies. Exploiting a variety of analytical methodologies and tools, formulations produced by spray drying and hot melt extrusion (HME) techniques were investigated for sufficient dissolution enhancement. Studies revealed the selected formulation approaches provided a viable platform for manufacturing solid dispersions by illustrating systems that offered rapid and prolonged periods of supersaturation. While of the applications of single-phase amorphous solid dispersions are continuously expanding, their dissolution behavior is not as well understood. The overarching objective of dissolution testing during formulation development is to achieve biological relevance and predict in vivo performance. Proper in vitro dissolution testing can convey the influence of key in vivo performance parameters and be implemented for assessment and comparison of ASD formulations. Studies suggest that existing research fails to accurately address the intricacies associated with the supersaturated state. Upon solvation and during transit in the GIT, several high-energy drug-containing species are present in addition to free drug. Although these species are not absorbed in vivo, they play a pivotal role in generating and maintaining the supersaturation of a drug substance and function to replenish the supply of free drug as it permeates across the gastrointestinal membrane. Established dissolution apparatuses and methodologies in the United States Pharmacopeia (USP) focus on evaluation of total dissolved drug and may not be physiologically relevant for determining the amount of drug absorbed in vivo. Within the framework of this dissertation, a dissolution methodology was designed to reflect the physiochemical, physiological and hydrodynamic conditions that transpire throughout dissolution and absorption of an ASD during transit in the GIT. The apparatus and model present the ability to understand the kinetics and mechanisms of dissolution, supersaturation and nucleation. To support this hypothesis, analytical methods including high pressure liquid chromatography (HPLC) with ultraviolet (UV) detection were developed and fully validated. In parallel, a novel plasma membrane treatment was established to fabricate biomimetic membranes that possessed a hydrophilic and hydrophobic surface. The treated membranes are comprised of applied surface chemistries that emulate the unstirred aqueous layer created by microvilli protruding from the intestinal epithelial membrane as well as lipophilic constituents corresponding to the epithelial lipid membrane. Calculated in vitro similarity (f2) and difference (f1) factors support the hypotheses that plasma treated microporous polymer membranes exhibit biorelevant properties and demonstrate adequate biorelevance for in vitro dissolution studies. The described dissolution methodology has been applied as a tool for selection of candidates to move forward to pharmacokinetic studies. In a culminating study, in vitro – in vivo correlations (IVIVC) were performed employing the universal membrane-permeation non-sink dissolution method for formulations of Carbamazepine. To demonstrate the utility of the methodology, multiple level C correlations were established. The membrane-permeation model enables quantitative assessment of drug dissolution and absorption and offers a means to predict the relative in vivo performance of amorphous solid dispersions for BCS class II drug substances. / Chemistry

Amorphous solid dispersion (ASD) is a popular method to increase drug solubility and consequently poor drug bioavailability. Cellulose ω-carboxyesters were designed and synthesized specifically for ASD preparations in Edgar lab that can meet the ASD expectations such as high Tg, recrystallization prevention and pH-triggered release due to the free -COOH groups. Rifampicin (Rif), Ritonavir (Rit), Efavirenz (Efa), Etravirine (Etra) and Quercetin (Que) cellulose ester ASDs were investigated in order to increase drug solubility, prevent release at low pH and controlled release of the drug at small intestine pH that can improve drug bioavailability, decrease needed drug content and medication price to make it affordable in third world countries, and extent pill efficiency period to improve patient quality of life and adherence to the treatment schedule. The studies were compared with cellulose based commercial polymers to prove the impact of the investigation and potential for the application. Furthermore, the in vitro results obtained were further supported by in vivo studies to prove the significant increase in bioavailability and show the extended release. The need of new cellulose derivatives for ASD applications extended the research area, the design and synthesis of a new class of polymers, alkyl cellulose ω-carboxyesters for ASD formulations investigated and the efficiency of the polymers were summarized to show that they have the anticipated properties. The polymers were synthesized by the reaction of commercial cellulose alkyl ethers with benzyl ester protected, monofunctional hydrocarbon chain acid chlorides, followed by removal of protecting group using palladium hydroxide catalyzed hydrogenolysis to form the alkyl cellulose wcarboxyalkanoate. Having been tested for ASD preparation, it was proven that the polymers were efficient in maintaining the drug in amorphous solid state, release the drug at neutral pH and prevent the recrystallization for hours, as predicted. / Ph. D.

Nous étudions expérimentalement l'effondrement d'une colonne granulaire dans un liquide visqueux. Contrairement au cas sec, la morphologie des dépôts n'est principalement plus contrôlée par le rapport d'aspect initial du tas mais par la fraction volumique initiale de la masse granulaire. Deux régimes différents sont identifiés selon l'empilement initial. L'empilement lâche donne lieu à des dépôts minces et longs et la dynamique est rapide. Une surpression du liquide est mesurée sous de la colonne. Pour l'empilement dense, l'étalement final est deux fois moindre, le mouvement est lent et une dépression interstitielle est mesurée. Ces observations suggèrent que la dynamique de l'effondrement granulaire dans un fluide est fortement affectée par le comportement de la dilatance du milieu granulaire.Nous développons ensuite un modèle théorique basé sur des équations diphasiques moyennées dans l’épaisseur prenant en compte les mécanismes de dilatance. L’étude dimensionnelle de notre modèle permet de montrer que l’effondrement d’une colonne est contrôlé par trois paramètres sans dimension : le rapport d’aspect de la colonne, la fraction volumique initiale, et le nombre de grains dans l’épaisseur. On montre également que le temps caractéristique met en compétition le frottement visqueux et la gravité.De ce modèle, nous développons un algorithme de résolution lagrangien. Cette approche, grossière mais robuste, permet d’implanter s sans trop de difficulté. Le code est validé sur des configurations simples sur plan incliné avant de simuler l’effondrement de colonnes granulaires immergées dans la même gamme de paramètres que nos expériences. / Nous étudions expérimentalement l'effondrement d'une colonne granulaire dans un liquide visqueux. Contrairement au cas sec, la morphologie des dépôts n'est principalement plus contrôlée par le rapport d'aspect initial du tas mais par la fraction volumique initiale de la masse granulaire. Deux régimes différents sont identifiés selon l'empilement initial. L'empilement lâche donne lieu à des dépôts minces et longs et la dynamique est rapide. Une surpression du liquide est mesurée sous de la colonne. Pour l'empilement dense, l'étalement final est deux fois moindre, le mouvement est lent et une dépression interstitielle est mesurée. Ces observations suggèrent que la dynamique de l'effondrement granulaire dans un fluide est fortement affectée par le comportement de la dilatance du milieu granulaire.Nous développons ensuite un modèle théorique basé sur des équations diphasiques moyennées dans l’épaisseur prenant en compte les mécanismes de dilatance. L’étude dimensionnelle de notre modèle permet de montrer que l’effondrement d’une colonne est contrôlé par trois paramètres sans dimension : le rapport d’aspect de la colonne, la fraction volumique initiale, et le nombre de grains dans l’épaisseur. On montre également que le temps caractéristique met en compétition le frottement visqueux et la gravité.De ce modèle, nous développons un algorithme de résolution lagrangien. Cette approche, grossière mais robuste, permet d’implanter s sans trop de difficulté. Le code est validé sur des configurations simples sur plan incliné avant de simuler l’effondrement de colonnes granulaires immergées dans la même gamme de paramètres que nos expériences.

Highly-exact structural characterization is the crucial step in the development and manufacturing process of pharmaceutical materials. Their structural composition is, however, often very complex and hardly identifiable. The eligible way for obtaining definite structural interpretation of these systems appears the high-resolution solid-state nuclear magnetic resonance (ssNMR) spectroscopy. For this purpose the reliable tool - the ssNMR toolbox for comprehensive characterization of various pharmaceutical solids is described. The rigorous optimization of ssNMR techniques is carried out on enormous number of measured samples containing active pharmaceutical ingredients (APIs) with systems ranging from APIs formulated in solid dispersions to pure forms revealing extensive molecular disorder. In this study the influence of polymeric matrix on the creation of solid dispersion type susceptible for finely tuned controlled drug release is likewise discussed. The distinction between variable structural alignments of API molecules in 3D dimension of complicated pharmaceutical solids is allowed via simple strategy - factor analysis applied to hardly describable ssNMR spectra (13 C CP/MAS NMR and 19 F MAS NMR). The results of this ssNMR investigation contribute to better understanding of solid dispersion...