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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
221

Etude de l'influence des paramètres nano et microstructuraux sur les propriétés thermoélectriques des siliciures de magnésium Mg2 (Si, Sn) de type -n / Influence of nano and microstructural parameters on the thermoelectric properties of n-type magnesium silicides Mg2(Si,Sn)

Bellanger, Philippe 28 April 2014 (has links)
Ce travail de thèse porte sur l’étude de l’influence des paramètres nano et microstructuraux pour l’optimisation des propriétés thermoélectriques des siliciures de magnésium Mg2(Si,Sn) de type -n. Ces matériaux thermoélectriques ont été choisis pour leurs compatibilités avec une utilisation en génération de puissance dans le domaine de l’automobile.Par une approche combinatoire utilisant les couples de diffusion, il est premièrement ré investigué le diagramme de phase pseudo-binaire Mg2Si-Mg2Sn dans le but d’interpréter les microstructures observées. Il est ensuite présenté les effets expérimentaux des paramètres de densification par frittage flash (SPS) sur les microstructures et les propriétés thermoélectriques résultantes. Finalement, il est explicité à l’aide de la modélisation l’influence des paramètres microstructuraux sur les propriétés thermoélectriques de l’alliage optimisé et nanostructuré Mg2Si0,3875Sn0,6Sb0,0125. / This study presents the influence of nano and microstructural parameters to optimize thermoelectric properties of n-type magnesium silicides Mg2(Si,Sn). These thermoelectric materials are chosen for their compatibilities with power generation in automotive.From a combinatorial approach using diffusion couples, it is first reinvestigated the pseudo-binary phase diagram Mg2Si-Mg2Sn to rationalize the observed microstructures. Then the experimental effects of sintering parameters (SPS) on resulting microstructures and thermoelectric properties are presented. Finally, the influence of microstructural parameters on the thermoelectric properties of optimized and nanostructured Mg2Si0,3875Sn0,6Sb0,0125 alloys are explained through modelling.
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222

Modelo de ashkin-teller de tr?s cores na rede ponte de wheatstone

Oliveira, Roberto Teodoro Gurgel de 22 February 2010 (has links)
Made available in DSpace on 2014-12-17T15:14:51Z (GMT). No. of bitstreams: 1 RobertoTGO_DISSERT.pdf: 394069 bytes, checksum: fbb8faf7e24cc92335302e442b92ec43 (MD5) Previous issue date: 2010-02-22 / Conselho Nacional de Desenvolvimento Cient?fico e Tecnol?gico / In this work we study the phase transitions of the ferromagnetic three-color Ashkin-Teller Model in the hierarquical lattice generated by the Wheatstone bridge using real space renormalization group approach. With such technique we obtain the phase diagram and its critical points with respective critical exponents v. This model presents four phases: ferromagnetic, paramagnetic and two intermediates. Nine critical points were found, three of which are of Ising model type, three are of four states Potts model type, one is of eight states Potts model type and the last two which do not correspond to any Potts model with integer number of states. iv / Neste trabalho estudamos as transi??es de fase do modelo de Ashkin-Teller de tr?s cores ferromagn?tico na rede hier?rquica ponte de Wheatstone utilizando o m?todo de grupo de renormaliza??o no espa?o real. Com a utiliza??o desta t?cnica obtemos o diagrama de fases e seus pontos cr?ıticos com respectivos expoentes cr?ticos v. O modelo apresenta quatro fases: ferromagn?tica, paramagn?tica e duas intermedi?rias. Nove pontos cr?ıticos foram encontrados, sendo tr?s de classe de universalidade Ising, tr?s Potts de quatro estados, um Potts de oito estados e dois com classe de universalidade n?o correspondente a nenhum Potts com n?mero inteiro de estados
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223

Estudo das propriedades termodinâmicas do modelo de Ashkin-Teller na presença de campo magnético aleatório. / Study of thermodynamics properties of Ashkin-Teller in random magnetic field

Luiz Antonio Bastos Bernardes 27 October 1995 (has links)
A teoria de campo médio para o modelo de Ashkin-Teller com interações ferromagnéticas de longo alcance na presença de campos magnéticos aleatórios foi desenvolvida. Isso foi conseguido através do uso do truque de réplicas para a obtenção da energia livre e do estudo analítico das equações integrais acopladas dos parâmetros de ordem, da estabilidade de suas soluções e das suas expansões para T &#8804 Tc. Inicialmente, foram determinadas as expressões gerais das funções termodinâmicas do modelo no caso em que existiam três campos magnéticos aleatórios com distribuições gaussianas. Em seguida, foi examinado o caso particular do modelo com um só campo magnético aleatório na direção de Z = &#8249 &#948 S &#8250. A estratégia adotada se mostrou poderosa pois possibilitou a caracterização detalhada do diagrama de fases com várias superfícies de coexistência e das linhas de pontos críticos. As equações integrais das funções termodinâmicas desse caso particular foram discutidas e resolvidas numericamente para valores especiais das constantes de interação e da variância. Para o caso particular do modelo na presença de campos magnéticos aleatórios nas direções &#8249 S &#8250 e &#8249 &#948 &#8250, foram determinadas e discutidas as expressões das funções termodinâmicas. Foram também obtidas as equações das superfícies de instabilidade da solução paramagnética. Foi provado que a transição entre as fases paramagnética e de Baxter é sempre de primeira ordem. Outro resultado original da tese foi a verificação da existência da simetria de dilatação e contração do modelo de Potts na presença de campos magnéticos aleatórios. Essa simetria permite que o estudo da energia livre no intervalo q&#8712 (1,2) forneça o comportamento termodinâmico do sistema para todo q>2. / The meanfield theory of the long range Ashkin-Teller model in random fields was developed. This was obtained by using the replica trick and the study of the coupled integral equations for the order parameters, the stability of their solutions, and their expansions for T &#8804 Tc. Inicially, the expressions of the thermodynamic functions for the model in three random fields with Gaussian distributiuons were determined. After this, it was examined the particular case of the model with only one random field in the Z = &#8249 &#948 S &#8250 direction. The strategy revealed itself powerful by the detailed characterization of the phase diagram with several coexistence surfaces and lines of critical points. The integral equations of the thermodynamic functions for this particular case were discussed and numerically solved for special values of the interaction constants and field distribution variance. For the particular case of the model with random fields in the &#8249 S &#8250 and &#8249 &#948 &#8250, directions, the expressions were also determined and discussed. The equations of the instability surfaces for the paramagnetic solution were obtained, and it was proved that the para-Baxter transition line is always of first order. Another original result of the thesis was the verification of the the existence of the dilatation and contration symmetry in the Potts model with random fields. This symmetry permits that the study of the free energy in the q&#8712(1,2) interval supplies the thermodynamics behavior of the system for q>2.
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224

Micro-Mechanisms Associated with Friction Stir Welding of Aluminum with Titanium

Kar, Amlan January 2016 (has links) (PDF)
Out of the known aerospace metal and alloys, Aluminium (Al) and Titanium (Ti) are important due to their unique combination of properties, such as strength, ductility and corrosion resistance etc. For these reasons, welding of these two materials, especially in the butt and lap configuration, has a significant impact for structural applications. However, welding of Al to Ti is a challenge due to wide differences in their physical properties and properties of the brittle intermetallic that are formed. Such problems in Ti-Al weld can be minimized if the temperature of welding is reduced. Therefore, many solid-state welding processes have been introduced for this system in the past few decades. Amongst these processes, Friction Stir Welding (FSW) is among the most appropriate for dissimilar materials in the butt and lap configuration, as this process involves lower temperature of processing. The present thesis is an attempt to address the issues pertaining to the friction stir welding of commercially pure Al and Ti. Though these commercially pure materials are seldom used in actual applications, where alloys such as Ti-6Al-4V and Al 2219 (and their variants) are used, this work is done to get a fundamental understanding of the underlying mechanisms during Friction Stir Welding (FSW). The study has been extended to the effect of using a thin strip of other metallic materials between Al and Ti. These inserts are likely to play a role in the formation of intermetallic and control the after effects of the formation of these intermetallic. Two metals have been chosen for this purpose, namely Zinc (Zn) and Niobium (Nb). The thesis has 8 chapters that attempts to systematically understand the process of FSW of cp-Al to cp-Ti. In Chapter 1 of the thesis, the FSW process is introduced with an emphasis on important parameters that control the welding process. In addition, a brief introduction of Al-Ti binary system is also given. Literature related to conventional solid state welding processes and friction stir welding process is presented in Chapter 2. In this chapter, previous works on the FSW of various materials is reviewed, with more emphasis on welding of aluminium to titanium. At the end of the chapter the scope and motivation of the present investigation has been outlined Chapter 3 includes the experimental details involved in the present study. In addition to the details of the processes and various characterization techniques used in the present investigation, the basic principles involved in various techniques, names as X-ray tomography, Scanning Electron Microscopy (SEM) with Electron Back-Scattered Diffraction (EBSD), X-Ray Diffraction (XRD) and Electron Probe Micro-Analysis (EPMA) have also been given. Micro-hardness and tensile tests results are also reported in this chapter. A detailed study on FSW of Al and Ti is presented in chapter 4 of the thesis. The effect of process parameters on the evolution of microstructure and mechanical properties has been reported. A bottom-up approach on experimentally determining the “process window” is presented. The results emphasises on the distribution of titanium fragments and intermetallic particles in the nugget zone and their influence on mechanical properties of the weld. The microstructural evolution in the matrix is also detailed. The most noteworthy observation is substantial grain refinement in the nugget zone due to the presence of fine fragments of titanium and intermetallic. Cross-tensile tests of the samples welded under the optimised conditions fail in the retreating side of the aluminium material and has strength more than the parent material. The last section in this chapter deals with thermal stability of the microstructures. Chapter 5 deals with the use of Zn as interlayer between Al and Ti. The microstructural evolution and its effect on the mechanical properties have been examined. The investigations clearly show that FSW of Al and Ti with Zn interlayer has superior mechanical properties compared to Al-Ti welds without interlayer. The resulting microstructure has a better thermal stability. The use of Nb as interlayer has been studied in chapter 6. The microstructural investigation of the nugget zone reveals that Nb interlayer does not readily form solid solution with any of the base materials and Nb gets distributed more heterogeneously compared to Ti itself. This has led to a reduction in the strength of the weld, however, the ductility increases The thermal stability of the microstructure is poor compared to FSW of Al to Ti with Zn interlayer. In chapter 7, salient features of the different micro-mechanism operating during FSW of the investigated combinations has been discussed in detail. Finally, the outcome of the thesis has been summarized and scope for future investigation is outlined in chapter 8.
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225

Traitement d’eaux usées industrielles par congélation sur paroi froide / Treatment of industrial wastewaters by freezing on cold surface

Htira, Thouaiba 23 September 2016 (has links)
Ce travail vise à étudier un procédé de traitement d'eaux usées industrielles par cristallisation en milieu fondu sur paroi froide. Deux effluents modèles sont choisis : un mélange eau/acétone et un mélange eau/acide propanoïque. Dans un premier temps, l'équilibre solide-liquide du mélange est étudié pour connaitre les limites de l'étude en température et en concentration. Le procédé de traitement de l'eau est alors conduit, selon un mode opératoire précis. Deux modes de fonctionnement sont mis en œuvre, un mode statique et un mode dynamique avec une circulation en boucle de la solution. La concentration en impuretés dans la glace est analysée après chaque cycle de congélation. L'étude paramétrique, conduite suivant un plan d'expériences, a mis en avant les effets importants de la concentration initiale de la solution et de la rampe de refroidissement. La microstructure de la glace est également analysée par microscopie en chambre froide pour interpréter les mécanismes d'incorporation d'impuretés au sein de la glace. Les inclusions de liquide sont sous la forme de poches de solution à faible vitesse de croissance et sont localisées dans les joints de grain à plus forte vitesse. Enfin, la modélisation du procédé fonctionnant en mode statique, par les éléments finis et en 2D axisymétrique avec frontière mobile, montre la présence de mouvements de convection. En mode dynamique, l'hydrodynamique de l'écoulement dans l'espace annulaire est décrite par une modélisation 3D prenant en compte la position de l'entrée et de la sortie. Les résultats démontrent la faisabilité du procédé et permettent des avancées significatives dans la compréhension des phénomènes mis en jeu / This work aims to study a process of industrial wastewater treatment by melt crystallization on a cold wall. Two effluent model solutions are chosen: water/acetone and water/propionic acid binary mixtures. First, the solid liquid phase diagrams are determined experimentally in order to delimit the operating range of temperature and concentration. Then, a parametric study of the wastewater treatment process by freezing is performed, by means of an experimental design, for two working modes, static mode and dynamic mode by adding a recirculation loop, respectively. The impurity concentration in the ice is analyzed after each freezing cycle. The process requires applying very precise conditions and the ice concentration mainly depends on the initial solution concentration and on the applied cooling rate. The ice microstructure is also characterized by optical microscopy in a cold chamber and gives insights into the mechanism of impurity incorporation: the liquid inclusions are localized under the form of solution pockets at low growth rate or between the polycrystals at higher growth rate. Lastly, 2D axisymmetric modelling of the process in static mode, based on finite elements and taking into account the moving boundary, shows the presence of buoyancy loops in relation with the density dependence of the solution with temperature. In dynamic mode, the hydrodynamics in the annular space is described by a 3D model to account for the positions of the inlet and outlet pipes. All the results demonstrate the process feasibility and allow better understanding of the occurring phenomena
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226

Optilmisation de l'utilisation du gadolinium comme poison consommable dans le combustible nucléaire : Vers une REP sans bore / Optimizing the use of gadolinium as burnable poison in nuclear fuel : towards a boron free PWR

Pieck, Dario 22 October 2013 (has links)
L’excès de réactivité neutronique dans les centrales nucléaires est compensé par des sys-tèmes actifs de contrôle du réacteur : acide borique et barres de contrôle. L’apport d’antiréactivité peut se faire passivement avec des poisons consommables, c'est-à-dire des absorbants de neutrons, en particulier du gadolinium (Gd).Dans le cadre d’une augmentation de l’enrichissement en U²³⁵ et de réduction de l’utilisation d’acide borique, cette thèse a pour objectif d’optimiser la distribution du ga-dolinium dans des céramiques d’UO₂ afin d’obtenir un apport optimisé d’antiréactivité dans un Réacteur à Eau sous Pression.Dans ce sens, le travail est orienté à trouver des nouveaux matériaux riches en gadolinium. Le diagramme de phase U-O-Gd a donc été exploré dans le domaine des fortes teneurs en Gd. Deux phases cubiques ont été trouvées et caractérisées : les phases C1 et C2. En vue d’une application industrielle, la phase C1 a été retenue comme candidate pour l’ajout du Gd dans les pastilles d’UO₂.La distribution optimale de cette phase C1 dans les assemblages de combustible nucléaire a été étudiée avec le code de calcul neutronique APOLLO2.8. Des études paramétriques ont été réalisées. Ces études neutroniques ont aboutit à un concept performant de pastille empoisonnée. Finalement, des pastilles prototype ont été fabriquées en laboratoire suivant ce concept. L’ensemble des résultats obtenus montre qu’un concept de pastille avec un dépôt superficiel neutrophage de phase C1 est une manière d’apporter de l’antiréactivité de manière optimisée dans le cadre de cycles longs. Ceci pourrait potentiellement être appliquée à l‘échelle industrielle. Un brevet a été déposé en ce sens. / Reactivity excess in Nuclear Power Plants is controlled by reactor’s active systems: boric acid dilution and control rods. Alternatively, negative reactivity insertion can be made in a passive way using burnable poisons, i.e. neutron absorbers, this is the case of gadolinium (Gd).In the industrial framework of U²³⁵ enrichment increase and boric acid restraint, the goal of this thesis is to optimize the distribution of gadolinium in UO₂ ceramics to obtain a high-performance provision of negative reactivity in Pressurized Water Reactors.In this sense, the work is focus on new gadolinium-rich materials. Thus, U-Gd-O phase diagram was explored in the field of high Gd contents. Two cubic phases were found and characterized: the C1 and C2 phases. With the aim of an industrial application, C1 phase was selected as candidate for Gd addition into UO₂ pellets.The optimal distribution of C1 phase within a nuclear fuel assembly was studied using APOLLO 2.8 neutron transport code. Parametrical calculations were performed. These neutronic studies have ends in a successful “concept of poisoned pellet”.Finally, some prototype pellets following this concept were made in laboratory to proof it feasibility.All the obtained results shows that the proposed concept of a neutrophage C1-phase coating on UO₂ pellets is a convenient way to reduce reactivity excess within the framework of long irradiation cycles. This concept could be potentially applied in industrial scale. Consequently a patent application process was initiated.
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227

Synthèse de (co)polymères à base de Poly(3-hexylthiophène) pour le photovoltaïque organique

Nicolet, Célia 12 December 2011 (has links)
L’optimisation de la morphologie de la couche active est primordiale pour l’augmentation des rendements des cellules solaires photovoltaïques organiques. Nous avons montré l’influence du ratio de matériaux donneur (P3HT) et accepteur (PCBM) d’électrons ainsi que de la masse molaire du P3HT sur la morphologie de la couche active. Afin de contrôler la séparation de phases entre les matériaux donneur et accepteur d’électrons, il est possible d’utiliser des copolymères à blocs afin d’aider la compatibilisation entre le P3HT et le PCBM. Nous avons choisi de synthétiser des copolymères à blocs P3HT-b-polystyrène et des P3HT-b-polyisoprène présentant une certaine compatibilité avec les matériaux de la partie active. L’ajout optimisé de P3HT-b-polyisoprène permet une augmentation de 30% des rendements et de 90% de durée de vie des cellules solaires. / Active layer morphology optimization is fundamental to achieve high efficiency in organic photovoltaic solar cells. We showed the influence of the donor (P3HT) and acceptor (PCBM) material ratio and the impact of the P3HT molecular weight on the active layer morphology. We demonstrated the possibility of using well-designed block copolymers to help P3HT and PCBM compatibilization and to control their phase separation. We chose to synthesize P3HT-b-polystyrene and P3HT-b-polyisoprene for which each block is compatible with the active materials. Optimal addition of P3HT-b-polyisoprene enables to get a 30%-improved efficiency and a 90%-enhanced lifetime of the solar cells.
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228

Synthèse des clathrates dans le système silicium-sodium sous haute pression et haute température / Synthesis of clathrates in the silicon-sodium system under high pressure and high temperature

Jouini, Zied 30 March 2018 (has links)
Cette thèse porte sur l’étude de la synthèse et des données thermodynamiques des clathrates intermétalliques du système Na-Si, qui sont des matériaux pertinents pour les applications thermoélectriques et qui sont les précurseurs pour de nouvelles formes de Si prometteuses pour des applications photovoltaïques et photoniques. Dans ce travail la formation de clathrates Na-Si a été étudiée in situ et ex situ sous haute pression et haute température. Un nombre de nouvelles formes de silicium a été observé en chauffant des clathrates sous vide. Sous pression inférieure à 3 GPa les clathrates ne se forment pas par l’interaction des éléments. A la place, le siliciure Na4Si4 se forme et reste stable jusqu’à la fusion. Au-dessus de 3 GPa, Na4Si4 formé au début du chauffage, réagit avec l’excès de Si et donne Na30Si136 (structure II) et ensuite, si Na30Si136 réagit avec l’excès de Si pour former Na8Si46 (structure I) au dessous de 7 GPa et le clathrate NaSi6 au-dessus de 7 GPa. Des expériences ont été réalisées en utilisant des cellules standard Paris-Edimbourg (enclumes opposées) jusqu'à 6 GPa et la presse multi-enclumes pour les pressions au-dessus de 6 GPa. La forte sensibilité des produits de cristallisation à la concentration en sodium a été observée. Un schéma de transformations de clathrate pour les pressions entre 0 à 10 GPa et températures entre 300 et 1500 K a été proposé. Le diagramme de phase (concentration – température sous 4 GPa) qui représente les transformations observées et les domaines de stabilité a également été proposé et suggère l’existence de trois équilibres eutectiques : entre Si et structure I, entre structures I et II, et entre structure II et Na4Si4. Pour comprendre la thermodynamique et les interactions dans le système Na-Si, on a également effectué la modélisation du diagramme de phase à pression ambiante, ce que nous a permis de trouver les caractéristiques thermodynamiques de fusion et les équations des liquidus observés. Pour prendre en compte l’impact de la pression sur la thermodynamique, les équations d’état p-V-T de Si à structure diamant, structure I et la forme haute pression de structure II ont été utilisés. / The objective of this thesis is to study the synthesis and thermodynamics of intermetallic clathrates of the Na-Si system, which are the important materials for thermoelectric applications and are the promising precursors for new forms of Si for the photovoltaic and photonic applications. In this work the formation of the Na-Si clathrates have been studied in situ and ex situ at high pressure and high temperature. A number of new forms of silicon have been observed while heating the clathrates under vacuum. Under pressures below 3 GPa the clathrates does not form by the interaction of elements. Instead, the silicide Na4Si4 forms and remains stable up to melting. Above 3 GPa, Na4Si4 formed in the beginning of the heating, react with the excess of Si and gives Na30Si136 (structure II) and after that, if Na30Si136 react with the excess of Si, to form Na8Si46 (structure I) below 7 GPa and the clathrate NaSi6 above 7 GPa. The experiments have been performed by using the standard Paris-Edinburg cell (opposite anvils) up to 6 GPa and multianvil press for pressures above 6 GPa. The strong sensibility of the crystallization product to the concentration of sodium has been observed. The diagram of transformations in clathrates for pressures between 0 and 10 GPa and temperatures between 300 and 1500 K has been proposed. The phase diagram (concentration – temparature at 4 GPa) that represents the observed transformations and stability domains has been also proposed and suggests the existence of three eutetic equilibria: between Si and structure I, between structures I and II, and between structure II and Na4Si4. To understand the thermodynamics and interactions in the system Na-Si, the modelisation of phase diagram at ambient pressure has also been performed that allowed us to establish the thermodynamic characteristics of melting and the equations of observed liquidi. To take into account the impact of pressure on the thermodynamics, the p-V-T equations of state of diamond Si, structure I and high-pressure form of structure II have been used.
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229

Metabolická a biofyzikální charakterizace bakteriálních buněk schopných akumulace PHA / Metabolic and biophysical characterization of bacterial cells capable of PHA accumulation

Slaninová, Eva January 2021 (has links)
This thesis deals with the characterization of bacterial cells capable of polyhydroxyalkanoates (PHA) accumulation. The dissertation thesis is written in the form of a discussed published publications which are attached to the thesis as appendixes. The work develops a study of the current topic of the protective functions of PHA and clarifies protective mechanisms against selected stressors. Firstly, we focused on the protective effects of PHA granules against UV radiation and osmotic stress, specifically hypotonic conditions. In the case of UV exposition, the cells protected themselves by scattering UV radiation on the intracellular granules protecting especially nucleoid. When exposed to osmotic stress, the amorphous state of PHA granules is very important since it is capable of stabilization of cell membranes under hypertonic stress, afterwards, bacterial cells can maintain their integrity during the subsequent hypotonic challenge. In general, the amorphous state of PHA granules is key to ensure the proper biological functions of PHA whether as storage or protective polymer. Therefore, in the next part of this work, we focused on the core of the stabilization mechanism that protects native PHA granules from crystallization and thus the intracellular polymer maintains in a thermodynamically unfavorable amorphous phase state. Based on experimental work, we applied selected stresses because we proposed a new model of stabilization of the amorphous state of PHA granules in vivo. It consists of two mechanisms, where small volumes of PHA granules reduce the rates of crystallization and at the same time the water present in the granules plays the role of a low molecular plasticizer. Due to the metabolic apparatus of bacterial cells, PHA are simultaneously synthesized and degraded which leads to an increment of intracellular concentration of monomers that also figure in the protective effect of PHA. In this context, we aimed at the description of the mechanism of cryoprotective effects of 3-hydroxybutyrate, the monomer of the most common of PHA, poly(3-hydroxybutyrate). Hence, we constructed an equilibrium and non-equilibrium phase diagram of the 3HB-water system to prove that 3HB is a very effective cryoprotectant. This fundamental understanding of the protective properties of PHA monomers could be also used in the food industry or cryopreservation of biological samples.
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230

Strategic pre-clinical development of Riminophenazines as resistance circumventing anticancer agents

Koot, Dwayne Jonathan 26 April 2013 (has links)
Cancer is responsible for upward of 13% of human deaths. Contemporary chemotherapy of disseminated cancer is often thwarted by dose limiting systemic toxicity and by multi-drug resistance (MDR). Riminophenazines are a novel class of potential anticancer agents that possess a potent multi-mechanistic antineoplastic action. Apart from their broad action against intrinsic, non-classical resistance, Riminophenazines inhibit the action of Pgp and hypothetically all ABC transporters demonstrating their great utility against classical MDR. Considering that combination chemotherapy is the norm, the vision directing R&D efforts was that Riminophenazines could be used with benefit within many standard chemotherapeutic regimes. The strategic intent of this project was to attain improved therapeutic benefit for patients through gains in both pharmaco dynamic and pharmacokinetic specificity for cancer cells over what is currently available. Tactically, this was driven through the use of synergistic Fixed-Ratio Drug Combinations (FRDC) encapsulated within tumour-targeting Nanoparticulate Drug Delivery Systems (NDDS). Long-term aims of this R&D project were to: 1) Screen FRDC of clofazimine (B663) and the lead derivative (B4125) with etoposide, paclitaxel and vinblastine for synergistic drug interactions in vitro. 2) Design, assemble and characterize a novel nanoparticulate, synergistic, anticancer co-formulation. 3) Evaluate the in vivo safety and efficacy of the developed product/s in accordance with international regulatory guidelines. Using the median effect and combination index equations, impressive in vitro synergistic drug interactions (CI<1) were shown for various FRDC of the three standard chemotherapeutics tested (etoposide, paclitaxel and vinblastine) in combination with either B663 or B4125 against MDR neoplastic cell cultures. Considering in vitro results and with the view to advance quickly to clinical studies, the already approved clofazimine (B663) was elected as the combination partner for paclitaxel (PTX). Considering the potency and wide action of PTX, a novel coformulation (designed to circumvent drug resistance) has the potential to greatly impact upon virtually all cancer types, particularly if selectively delivered through innovative delivery systems and loco-regional administration. A passively tumour targeting, micellular NDDS system called Riminocelles™ that encapsulates a synergistic FRDC of B663 and PTX has been designed, assembled using thin film hydration methods and characterized in terms of drug loading, particle size, zeta potential, CMC and drug retention under sink conditions. An acute toxicity and a GLP repeat dose toxicity study confirmed Riminocelles to be well tolerated and safe at clinically relevant dosages whilst Taxol® (QDx7) produced statistically significant (P<0.05) weight loss within 14 days. The same study demonstrated statistically significant (P<0.05) tumour growth delays superior to that of Taxol at an equivalent PTX dosage of 10 mg/kg. Importantly, all components (amphiphiles and drugs) used in assembly of Riminocelles are already individually approved for medicinal use - this promotes accelerated development towards advanced clinical trials and successful registration. Although these results are very promising (outperforming Taxol), this system was however found in a pharmacokinetic study to suffer from in vivo thermodynamic instability due to the high concentration (abundance) of albumin present in plasma. For this reason, in vivo longevity within circulation, permitting passive tumour accumulation was not fully realized. A second NDDS called the RiminoPLUS™ imaging system was additionally developed. This lipopolymeric nanoemulsion system has successfully entrapped Lipiodol® Ultra fluid (an oil based contrast agent) within the hydrophobic core of a monodisperse particle population with a size of roughly 100 nm and a stability of one week. This formulation is therefore thought capable of CT imaging of tumour tissue and drug targeting after either intravenous or loco-regional injection. In vivo proof of the imaging concept is warranted. The results of this study serve to highlight the great potential of in vitro optimized synergistic FRDC against drug resistant cancers. Lipopolymeric micelles are an effective way to formulate multiple hydrophobic drugs for intravenous administration and present a means by which cancer can be readily targeted; provided that the delivery system possess the prerequisite in vivo stability and surface attributes. Further experiments exploring synergistic drug and biological combinations as well as “intelligent” NDDS actively guided through specific molecular recognition are called for. / Thesis (PhD)--University of Pretoria, 2012. / Pharmacology / unrestricted
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