Dissertations / Theses on the topic 'Salt formulation'

An equivalent material approach is presented for the computation of the elastic properties of brick masonry and for the assessment of salt crystallization in masonry structures. A stacked brick-mortar system consisting of a series of parallel layers which behave elastically is introduced. This is extended such that masonry with two sets of mortar joints (bed and head joints) can be represented by an equivalent homogeneous orthotropic elastic material. It is then extended to salt deteriorated brick masonry by including salt crystals induced within the pores. In terms of the elastic properties of the brick and mortar, as well as relative thicknesses, expressions for the equivalent material's elastic properties are derived. The mechanical properties of salt deteriorated masonry are computed in terms of effective porosity and saturation ratio. Using this derivation, the stresses in the brick-and-mortar joints are calculated for a masonry wall partial deteriorated by salt and subjected to thermal stress variation.

The synthetic antimicrobial peptide SET-M33 is being developed as a possible new antibacterial candidate for the treatment of multi-drug resistant bacteria. SET-M33 is a branched peptide featuring higher resistance and bioavailability than its linear analogues. SET-M33 shows antimicrobial activity against different species of multi-resistant Gram-negative bacteria, including clinically isolated strains of Pseudomonas aeruginosa, Klebsiella pneumoniae, Acinetobacter baumanii and Escherichia coli. In this thesis are repoted strategies to improve the biopharmaceutical development and manufacturing process of this peptide. First, the secondary structure of SET-M33 was investigated by NMR to fully characterize the product in the framework of preclinical studies. Since the final formulation of SET-M33 will be strictly defined in terms of counter-ions and additives, It is also reported the studies on a new salt formulation, SET-M33 chloride, that retains its activity against Gram-negative bacteria and gains in solubility, with a possible improvement in the pharmacokinetic profile. The opportunity of using a chloride counter-ion is very convenient to decrease the manufacturing peptide cost and did not increase the toxicity of the antimicrobial drug. In addition, to identify back-up molecules, a panel of modified versions of SET-M33 was tested in order to produce new molecules with better performance in terms of pharmaceutical profile and manufacturing costs. Amongst them, the opportunity of using SET-M33D-L-Ile and SET-M33D-Leu/Ile will allow to decrease the costs in the synthesis process and SET-M33-Gly/Ala, to eliminate the degradation site for bacterial proteases, without altering the strong antimicrobial activity of the original peptide. Finally cloning strategies, expression systems, purifications and structural characterizations of various proteins of mammalian inflammasomes performed at Boston Children's Hospital, affiliated with Harvard Medical School, are described.

Une nouvelle ère dans la conception des biomatériaux devrait émerger pour traiter simultanément les problèmes liés à la toxicité des produits de dégradation, aux infections et à la libération contrôlée. Les matériaux à base d'albumine suscitent un intérêt croissant en raison de leur biocompatibilité, biodégradabilité, biofonctionnalité et manufacturabilité. Dans la présente étude, une nouvelle famille de matériaux à base d'albumine est conçue. Ces matériaux sont obtenus par compaction assistée par le sel, où des solutions d'albumine bovine (BSA) sont évaporées à 37 °C en présence de sel. Après l'élimination de ce dernier par lavage, des matériaux solides, stables, insolubles en milieu aqueux et entièrement constitués d’albumine sont produits. Ces matériaux présentent de nombreux avantages tels que leur bonne résistance mécanique, leur coût de production réduit et leur facilité de fabrication et de mise en forme. De plus, ils ne sont pas cytotoxiques, n'induisent pas d'inflammation et permettent l'adhésion et la prolifération des cellules épithéliales sans fonctionnalisation additionnelle. En outre, des éponges poreuses d'albumine sont facilement produites en utilisant la compaction assistée par le sel. Ces matériaux sont donc des candidats prometteurs pour le développement de dispositifs implantables biodégradables et d'échafaudages pour l'ingénierie tissulaire
A new era in the design of biomaterials should emerge to deal simultaneously with issues related to toxicity of degradation products, infections and controlled release. Albumin-based materials are arousing growing interest due to their biocompatibility, biodegradability, biofunctionality and manufacturability. In the present study, a new class of materials based exclusively on albumin is designed. These materials are obtained by a salt-assisted compaction, where albumin solutions are mixed with salts and evaporated at 37 °C. After salt removal through washing, stable and water-insoluble solid albumin materials are produced. These materials present many advantages such as stability, good mechanical properties, reduced cost and ease of production and manufacture. Furthermore, biological evaluation shows that they are not cytotoxic, do not induce inflammation and allow the adhesion and proliferation of epithelial cells without additional surface functionalization. In addition, porous albumin sponges are easily produced using salt-assisted compaction. Therefore, these new materials are promising candidates for the development of biodegradable implantable devices and scaffolds for tissue engineering

Ce projet de thèse porte sur la recherche de nouveaux électrolytes et additifs dans le but d’améliorer la cyclabilité d’une électrode négative composite de formule Si0.32Ni0.14Sn0.17Al0.04C0.35 et d’obtenir une interface électrode|électrolyte stable. En effet, comme la plupart des matériaux à base de silicium, ce composite de grande capacité (plus de 600 mA.h.g-1) souffre actuellement d’une faible durée de vie provenant essentiellement des expansions volumiques qu’il subit lors de sa lithiation et de sa SEI défaillante. Deux types d'électrolytes ont été évalués : (i) un mélange de carbonates d’alkyles EC/PC/3DMC auquel a été ajouté un sel de lithium (LiPF6, LiTFSI, LiFSI ou LiDFOB) ainsi que des additifs aidant à la formation de la SEI tels que le carbonate de vinylène (VC) ou le carbonate de fluoroéthylène (FEC), (ii) des liquides ioniques (LI) contenant un cation ammonium quaternaire (N1114+), imidazolium (EMI+) ou pyrrolidinium (PYR+), associé à un anion à charge délocalisée comme le bis(trifluorométhanesulfonyl)amidure (TFSI-) ou le bis(fluorosulfonyl)amidure (FSI-). L’analyse du diagramme d’ionicité de Walden a permis de mettre en évidence la bonne dissociation de LiFSI et LiPF6 dans EC/PC/3DMC assurant ainsi des conductivités ioniques supérieures à 12 mS.cm-1. Bien que possédant des propriétés de transport a priori moins intéressantes dans ce mélange ternaire que les autres sels, LiDFOB forme en réduction une SEI permettant au composite de fournir les meilleures performances en cyclage sans additif avec 560 mA.h.g-1 pour un rendement coulombique de 98,4%. L’ajout d’additif est cependant nécessaire pour atteindre les objectifs fixés par le projet en termes de rendement coulombique (>99,5%). Dans ce cas, l’ajout de 2%VC+10%FEC au mélange ternaire est le plus intéressant avec LiPF6. Le matériau fourni ainsi des capacités de 550 mA.h.g-1 durant une centaine de cycles à un régime de C/5 avec un rendement coulombique de 99,8%. En milieu LI, les performances optimales sont atteintes avec le [EMI][FSI] et 1 mol.L-1 de LiFSI. Le composite atteint alors une capacité de 635 mA.h.g-1 durant 100 cycles à un régime de C/5 avec un rendement coulombique très proche de 100%, tout en s’affranchissant de l’ajout d’additifs. Malgré une viscosité bien plus élevée que celles des mélanges de carbonates d’alkyles, cette formulation permet de générer une SEI plus stable dont la nature, principalement minérale, est issue majoritairement des produits de réduction de FSI-
This study focuses on new electrolytes and additives in order to improve the cyclability of a Si0.32Ni0.14Sn0.17Al0.04C0.35 negative composite electrode (Si-Sn) and to obtain a stable electrolyte|electrolyte interface. Indeed, like most silicon-based materials, this high-capacity Si-Sn composite (over 600 mA.hg-1) currently suffers from a short cycle life due to volume expansion during charge-discharge processes leading to the degradation of the SEI. To improve the quality of the interface, two kinds of electrolytes were evaluated: (i) mixtures of alkyl carbonates EC/PC/3DMC in which a lithium salt (LiPF6, LiTFSI, LiFSI or LiDFOB) and additives like SEI builder (vinylene carbonate (VC) or fluoroethylene carbonate (FEC)) were added, (ii) ionic liquids (IL) based on quaternary ammonium (N1114+), imidazolium (EMI+) or pyrrolidinium (PYR+) cation, associated with delocalized charge anions such as bis(trifluoromethanesulfonyl)imide (TFSI-) or bis(fluorosulfonyl)imide (FSI-). The Walden diagram confirms the efficient dissociation of LiFSI and LiPF6 in EC/PC/3DM ensuring ionic conductivities as high as 12 mS.cm-1. Although possessing limited transport properties in such a ternary mixture compared to other salts, LiDFOB forms, without additional additives, an high quality SEI allowing the composite to provide the best performances in half cells (560 mA.hg-1 and 98.4% coulombic efficiency). The use of additive is however necessary to reach the objectives fixed by the ANR research project in terms of coulombic efficiency (>99.5%). In this case, the addition of 2%VC+10%FEC to the ternary mixture is the most interesting composition with LiPF6 as lithium salt. So, the Si-Sn nanocomposite material reaches 550 mA.h.g-1 during 100 cycles at C/5 with 99.8% efficiency. In IL, the best performances are achieved in [EMI][FSI]/LiFSI (1 mol.L-1). The performances of the Si-Sn composite reaches 635 mA.h.g-1 for 100 cycles at C/5 with coulombic efficiency close to 100%, without additives. This electrolyte formulation generates a stable SEI which the mainly mineral composition, is predominantly derived from the reduction products of FSI-

La plupart des batteries Li-ion aujourd’hui utilisent des électrolytes à base de LiPF6 un sel de lithium connu pour son instabilité chimique au-delà de 60°C car il se dégrade en libérant PF5 et LiF. En présence de traces d’eau il génère en plus des composés oxyfluorophosphorés et du HF qui peut être dommageable à la fois pour les performances et pour le vieillissement de l’accumulateur. Plusieurs sels sont candidats au remplacement de LiPF6, notamment ceux basés sur les anions fluorosulfonylamidures et les anions de Hückel. Ce travail concerne l’étude des propriétés physico-chimiques et de transport des électrolytes à base de 4,5-dicyano-2- (trifluoromethyl)imidazolide de lithium (LiTDI) et bis(fluorosulfonyl)amidure de lithium (LiFSI) pour une utilisation au sein d’accumulateurs de type Li-ion. Dans ce travail il a d’abord été montré que LiTDI n’est que faiblement dissocié dans les mélanges de carbonates d’alkyles utilisés dans les batteries Li-ion tels que le binaire (EC/DMC) ce qui limite sa conductivité. Pour pouvoir remédier à cet inconvénient, une étude des phénomènes de solvatation et d’associations ioniques a été menée et a conduit à proposer un mélange ternaire de solvants (EC/GBL/MP) dans lequel LiTDI est plus dissocié. Le mélange ternaire proposé améliore à la fois les propriétés de transport et les caractéristiques thermiques de l’électrolyte sans compromettre le domaine de stabilité chimique et électrochimique. Enfin, le nouvel électrolyte EC/GBL/MP contenant LiTDI, a été testé en accumulateurs dans les conditions opératoires usuelles (régime C/10 et température ambiante) et sévères (régime 10C et des températures allant de -20 °C à 60 °C). Le problème de corrosion de l’aluminium de LiFSI a aussi été pris en compte. Un électrolyte prometteur à base d’un mélange LiTDI/LiFSI montrant de meilleures performances que chaque sel utilisé séparément dans EC/DMC a été présenté. Les conclusions de cette thèse prouvent que LiTDI ou LiFSI peuvent être utilisés comme sels de lithium dans les électrolytes pour accumulateurs Li-ion
Most of the Li-ion batteries used in electrical devices contain a solution of LiPF6 in alkylcarbonate solvents with the risk of releasing PF5 at elevated temperatures and HF in the presence of water. Several salts are candidates for the replacement of LiPF6, including those based on fluorosulfonylamides and Hückel anions. This work concerns the study of physicochemical and transport properties of lithium 4,5-dicyano-2- (trifluoromethyl)imidazolide (LiTDI) and lithium bis(fluorosulfonyl)amide (LiFSI) based electrolytes and their use in Li-ion battery. First it was revealed that LiTDI is only weakly dissociated in alkylcarbonate mixtures used in Li-ion batteries such as EC/DMC limiting its conductivity. To overcome this disadvantage, a study of the solvation phenomena and of ionic association within the electrolytes was conducted. This study led to a ternary mixture of solvents (EC/GBL/MP) in which LiTDI is more dissociated. This new solvent mixture improves both the transport properties and the thermal stability of the LiTDI based electrolyte without compromising its chemical and electrochemical stability. Finally, the new LiTDI in EC/GBL/MP electrolyte was tested in NMC/graphite batteries under normal (C/10 rate and room temperature) and severe (10C rate and temperatures varying from - 20 ° C to 60 °C) operating conditions. The aluminium corrosion problem encountered by LiFSI based electrolytes was taken into account and a LiTDI/LiFSI salt mixture based electrolyte showing promising results was presented. The findings of this thesis show that LiTDI or LiFSI can be used as lithium salts in electrolytes for Li-ion batteries

Los fluidos de transferencia de calor, y en particular los nanofluidos, se pueden considerar un elemento esencial en diversos sectores industriales y su rendimiento es clave para una adecuada aplicación en tecnologías que van desde la gestión térmica y la refrigeración, a la generación de energía solar térmica y eléctrica mediante el uso de intercambiadores de calor. Estas industrias necesitan fluidos de transferencia de calor con un rango de temperatura del líquido más amplio y mejores prestaciones en la transferencia de calor que los fluidos convencionales. Todos los fluidos parecen beneficiarse de la dispersión de nanopartículas sólidas, tanto aquellos usados en aplicaciones de baja temperatura y temperatura ambiente, como aquellos que funden a más alta temperatura (p. ej. sales fundidas). La dispersión de nanopartículas conduce a la obtención de nanofluidos que con frecuencia presentan mejores conductividades térmicas y/o calores específicos en comparación con los fluidos base. Sin embargo hay algunas excepciones. En la bibliografía podemos encontrar resultados contradictorios acerca de la mejora de las propiedades térmicas en nanofluidos, lo cual hace que sea necesario un estudio de estos materiales en mayor profundidad. Por otra parte, la naturaleza líquida de estos materiales plantea un verdadero desafío, tanto desde el punto de vista experimental como en relación al marco conceptual. El trabajo que se presenta en esta tesis ha abordado dos retos diferentes relacionados con los fluidos de transferencia de calor y los nanofluidos. En primer lugar, se llevó a cabo un estudio riguroso y sistemático de las propiedades térmicas, morfológicas, reológicas, de estabilidad, acústicas y vibracionales de nanofluidos de grafeno en disolventes orgánicos. Observamos un gran aumento de la conductividad térmica de hasta un 48% y un aumento del 18% en la capacidad calorífica de los nanofluidos de grafeno en N,N-dimetilacetamida (DMAc). También se observó una mejora significativa en los nanofluidos de grafeno en N,N-dimetilformamida (DMF) del orden del 25% y 12% para la conductividad térmica y la capacidad calorífica, respectivamente. El desplazamiento de varias bandas del espectro Raman de DMF y DMAc hacia altas frecuencias (máx. ~ 4 cm-1) al aumentar la concentración de grafeno, sugirió que éste tiene la capacidad de afectar a las moléculas de disolvente a larga distancia, en términos de energía vibracional. En paralelo, las simulaciones numéricas basadas en la teoría funcional de la densidad (DFT) y dinámica molecular (MD) mostraron una orientación paralela de DMF hacia el grafeno, favoreciendo la interacción π-π y contribuyendo a la modificación de los espectros de Raman. Además, se observó un orden local de las moléculas de DMF alrededor del grafeno, lo que sugiere que tanto este tipo especial de interacción como el orden local inducido pueden contribuir a la mejora de las propiedades térmicas del fluido. También se realizaron estudios similares en nanofluidos de grafeno disperso en 1-metil-2-pirrolidona, sin embargo, no se observó ninguna modificación de la conductividad térmica o de los espectros de Raman. Todas estas observaciones juntas sugieren que existe una correlación entre la modificación de los espectros vibracionales y el aumento de la conductividad térmica de los nanofluidos. En vista de los resultados, se discutieron y descartaron algunos de los mecanismos propuestos para explicar la mejora de la conductividad térmica en nanofluidos. La segunda línea de investigación se centró en el desarrollo y caracterización de nuevas formulaciones de sales fundidas con baja temperatura de fusión y alta estabilidad térmica. Con este propósito, se sintetizaron dos nuevas formulaciones de seis componentes basadas en nitratos con una temperatura de fusión de 60-75 °C y una estabilidad térmica de aprox. 500 °C. Por otro lado, la complejidad de las muestras llevó a establecer una serie de métodos experimentales que se proponen para la detección del punto de fusión de estos materiales como una alternativa a la calorimetría convencional, estas técnicas son: espectroscopia Raman, técnica 3ω y transmisión óptica.
Heat transfer fluids and nanofluids constitute an important element in the industry and their performance is key to the successful application in technologies that go from heat management and cooling to heat exchangers in thermal-solar energy and electricity generation. These industries demand heat transfer fluids with a wider liquid temperature range and better thermal performance than the conventional fluids. From low-temperature fluids to high-temperature molten salts, these fluids seem to benefit from the dispersion of solid nanoparticles, leading to nanofluids which frequently feature improved thermal conductivities and/or specific heats as compared with the bare fluids. However, there are some exceptions. Contradictory reports make it necessary to study these materials in greater depth than has been usual. Yet, the liquid nature of these materials poses a real challenge, both from the experimental point of view and from the conceptual framework. The work reported in this thesis has tackled two different challenges related to heat transfer fluids and nanofluids. In the first place, a careful and systematic study of thermal, morphological, rheological, stability, acoustic and vibrational properties of graphene-based nanofluids was carried out. We observed a huge increase of up to 48% in thermal conductivity and 18% in heat capacity of graphene-N,N-dimethylacetamide (DMAc) nanofluids. A significant enhancement was also observed in graphene-N,N-dimethylformamide (DMF) nanofluids of approximately 25% and 12% for thermal conductivity and heat capacity, respectively. The blue shift of several Raman bands (max. ~ 4 cm-1) with increasing graphene concentration in DMF and DMAc nanofluids suggested that graphene has the ability to affect solvent molecules at long-range, in terms of vibrational energy. In parallel, numerical simulations based on density functional theory (DFT) and molecular dynamics (MD) showed a parallel orientation of DMF towards graphene, favoring π–π stacking and contributing to the modification of the Raman spectra. Furthermore, a local order of DMF molecules around graphene was observed suggesting that both this special kind of interaction and the induced local order may contribute to the enhancement of the thermal properties of the fluid. Similar studies were also performed in graphene-N-methyl-2-pyrrolidinone nanofluids, however, no modification of the thermal conductivity or the Raman spectra was observed. All these observations together suggest that there is a correlation between the modification of the vibrational spectra and the increase in the thermal conductivity of the nanofluids. In light of these results, the mechanisms suggested in the literature to explain the enhancement of thermal conductivity in nanofluids were discussed and some of them were discarded. The second line of research focused on the development and characterization of novel molten salts formulations with low-melting temperature and high thermal stability. In this regard, two novel formulations of six components based on nitrates with a melting temperature of 60-75 °C and a thermal stability up to ~ 500 °C were synthesized. Moreover, the complexity of the samples led to establish a series of experimental methods which are proposed for the melting temperature detection of these materials as an alternative to conventional calorimetry. These methods are Raman spectroscopy, three-omega technique, and optical transmission.

Most individuals are influenced by pain at some stage in their lives. It can either be of acute or chronic nature. An acute pain condition initiates and is treated within a time span of 12 weeks. Chronic pain can, however, take substantially longer to treat. Chronic pain may last up to 6 months after the original injury was sustained. The after effects of chronic pain can, however, take years to heal, but physical and emotional scars may even last much longer than the initial chronic ailment. In this study the skin was chosen as an area for delivery of non-steroidal anti-inflammatory drugs for the treatment of pain at the joint and muscle tissue regions. The stratum corneum (the topmost horny layer of the skin), however bars the effective movement of chemical substances across the skin as it forms part of the skin's function to protect the superficial tissue of the body against the external environment. It furthermore plays an important role in regulation of the movement of chemicals across the skin. Sweat pores and hair follicles can be utilised as pathways for the movement of chemical substances through the stratum corneum. Physical deformation ie, hydration of the top layer of the skin, may also enhance the movement of chemicals The non-steroidal anti-inflammatory drug, diclofenac, has been evaluated for transdermal diffusion. Three different diclofenac salts were evaluated, namely diclofenac diethylamine, diclofenac hydroxyethyl pyrrolidine and diclofenac sodium. These salts have the potential to relieve systemic pain conditions. Diclofenac salts, however, possess physicochemical characteristics that are unfavourable for transdermal diffusion. Pheroid™ delivery technology, as patented by the Northwest-University, was implemented as a method to enhance transdermal delivery of the diclofenac salts. During the study each of the diclofenac salts was formulated in a Pheroid™ and non-Pheroid™ formulation. All the formulations as well as corresponding retail products containing similar diclofenac salts were evaluated in order to determine which preparation had the most effective transdermal diffusion. High performance liquid chromatograhphy was implemented in order to determine the concentration of each salt in their various preparations. The Pheroid™ and non-Pheroid™ formulations were also compared to retail products currently available. An active ingredient flux was determined by means of Franz cell diffusion studies. Membrane diffusion studies were utilised in order to determine whether the active ingredients were effectively released from the formulated preparations and market products. Membrane diffusion studies determined that Arthruderm (the retail product containing diclofenac sodium) had the most potential to effectively release the active ingredient from the formulation (median flux 28.36 ± 0.26 ug/cm2.h"1). Franz cell diffusion studies showed no flux values for any of the evaluated preparations, including the retail products. Concentrations obtained within the epidermis and dermis were determined through tape stripping of these areas. The largest concentration of active ingredient within the epidermis was obtained from the studies done on Voltaren® (the retail product containing diclofenac diethylamine) which was 7.27 |ig/cm2.h"1 the largest value in the dermis was obtained from a non-Pheroid™ formulation containing diclofenac sodium (4.47 ug/ml). Confocal laser scanning microscopy was utilised and the micrographs where evaluated to ensure that the diclofenac salts were effectively entrapped in the Pheroid™ delivery system.
Thesis (M.Sc. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2010.

Cette étude s’intéresse aux procédés d’ignifugation d’un thermoplastique, le PolyButylène Téréphthalate (PBT), et plus particulièrement à l’ajout en masse de retardateurs de flamme à base de phosphore. L’objectif de ce projet consiste à mettre au point une formulation PBT renforcée avec des fibres de verre et ignifugée en vue d’application dans le domaine électrique et électronique. Dans un premier temps, les propriétés au feu de différents additifs combinés à un sel de diethylphosphinate d’aluminium commercial sont évaluées. Différents sels de phosphinate dérivés de l’acide carboxyethyl(methyl)phosphinique ont par ailleurs été synthétisés puis testés, soit seuls ou combinés à des additifs retardateurs de flamme. Deux systèmes retardateurs de flamme, l’un consistant en un mélange RDP bentonite - diethylphosphinate d’aluminium, l’autre en un mélange RDP bentonite - phenyl amide carboxyethyl(methyl)phosphinate d’aluminium, se sont avérés particulièrement efficaces en terme d’amélioration du comportement au feu du PBT renforcé. Les mécanismes d’ignifugation de ces systèmes ont été étudiés et comparés. Il a été démontré que les deux sels de phosphinate présentaient un mode d’action essentiellement en phase gaz, en libérant des espèces acides phosphiniques agissant comme inhibiteurs des réactions de combustion. Concernant le sel de phosphinate commercial, la libération d’acides phosphiniques s’effectue par interaction chimique entre l’additif et le PBT. A l’inverse, le sel de phosphinate synthétisé au laboratoire semble n’interagir que modérément avec le polymère
This study deals with the formulation of an innovative flame retardant material based on glass fiber reinforced PolyButylene Terephthalate (PBT/GF) used in Electronic and Electrical Equipments (EEE). In a first approach, the flame retardant properties of various additives in combination with the commercial aluminium diethylphosphinate are evaluated in PBT/GF. In a second approach, a variety of phosphinate salts derived from carboxyethyl(methyl)phosphinic acids are synthesized and then tested alone or in combination with FR additives. Two innovative flame retardant systems, namely the combination of Resorcinol bis-Diphenyl Phosphate (RDP) modified bentonite clay with either the aluminium diethylphosphinate or the aluminium phenyl amide of carboxyethyl(methyl)phosphinate, were found to greatly improve the fire behavior of PBT/GF. The FR mechanism of flame retardants were investigated and compared. Both phosphinate salts from the innovative systems mainly act through a gas phase mode of action by releasing phosphinic acids. Regarding the commercial product, the release of phosphinic acid occurs due to chemical interaction between the phosphinate salt and the PBT matrix while the synthesized product only moderately interacts with the polymer

This research work was aimed at the characterization in vitro, ex vivo and in vivo of nanostructured systems which independently contain a natural flavanone extracted from Eysenhardtia platycarpa and another four flavanones obtained through semi-synthesis of the first flavanone with the objective of providing evidence of their efficaciousness as anti-inflammatory cutaneous agents. Initially the flavanone was isolated from its natural source, and following on from this, the derivatives were obtained through chemical reactions of acetylation, methylation, cyclization and vinyl cyclization. Calculations were made in silico using computational programs like Molinspiration and PASS Online. These gave the theoretical physio-chemical properties of the flavanones and estimated the profile of their probable anti-inflammatory activity. An analytical methodology was used for the quantification of the flavanones with High Performance Liquid Chromatography (HPLC) in samples that crossed human skin in an ex vivo study. The objective was to demonstrate that an analytical method had been selected that did not cause any interference from the biological components due to the tissue with which we worked. The results showed that the method was lineal, exact and precise in the assayed concentrations interval (1.56 - 200 µg/mL). Afterwards, nano-structured formulations were prepared individually: they contained each flavanone at 0.5 % and the excipients were: Labrasol®, Labrafac® lipophile, Propylene glycol and Plurol Oleic®. These formulations were morphologically and physio-chemically characterized. The results obtained revealed that the flavanones formulations (FF) were suitable for topical administration. An in vitro assay was carried out of the liberation of the flavanones from their individual formulation, using a dialysis membrane with a system of Franz type cells to guarantee that the formulation liberated the flavanones and allowed there to be a sufficient quantity of each component susceptible to being permeated in human skin. Immediately afterwards, ex vivo studies were realized using human skin with the objective of evaluating the permeation profile of the flavanones contained in dissolution individually and in the formulations. The study demonstrated that the quantity of flavanone permeated and retained in the skin was different, depending on the flavanone assayed. This was probably due to the different molecular interactions of the functional groups with the tissue components. The flavanones derived were retained in the skin in greater quantity than natural flavanone. Finally, an in vivo assay was carried out on the anti-inflammatory efficaciousness in a model of rat’s auricular edema induced by arachidonic acid. The results demonstrated that the flavanones were capable of reducing the edema (swelling) and the formulation excipients did not influence in the biological activity. The formulations turned out to be more effective than the reference pharmaceutical drug used in this study (sodium diclofenac gel). It was shown that the structural modification of the natural flavanone improved the therapeutic activity in which the derived methylated and cyclized vinyl stood out. These results are in concordance with the results obtained in the evaluation of the cytokines expression (IL-1β, IL-6 y TNF-α) carried out, and moreover allowed the advantage of the use of nano-structured systems in making the flavanones more effective to be shown in comparison with flavanones assayed in dissolution.
El presente trabajo de investigación versa sobre la caracterización in vitro, ex vivo e in vivo de sistemas nanoestructurados que contienen de forma independiente una flavanona natural extraída de Eysenhardtia platycarpa y cuatro flavanonas obtenidas mediante semi-síntesis de la primera, con el objetivo de evidenciar su eficacia como agentes antiinflamatorios cutáneos. Inicialmente se aisló la flavanona de su fuente natural seguida de la obtención de los derivados mediante las reacciones químicas acetilación, metilación, ciclación y vinilo ciclación. Se realizaron cálculos in silico utilizando programas computacionales como Molinspiration y PASS Online para obtener las propiedades fisicoquímicas teóricas de las flavanonas y estimar su probable perfil de actividad antiinflamatoria. Se validó una metodología analítica para la cuantificación de las flavanonas por cromatografía líquida de alta eficacia (HPLC) en muestras que atravesaron piel humana en un estudio ex vivo. Lo anterior con el objeto de demostrar una selectividad del método analítico planteado sin que hubiese ninguna interferencia provocada por los componentes biológicos propios del tejido con el que se trabajaría. Los resultados mostraron que el método es lineal, exacto y preciso en el intervalo de concentraciones ensayadas (1.56 - 200 µg/mL). Posteriormente, se prepararon individualmente las formulaciones nanoestructuradas que contenían al 0.5 % cada flavanona y como excipientes: Labrasol®, Labrafac®, Propilenglicol y Plurol Oleico®. Dichas formulaciones fueron caracterizadas morfológica y fisicoquímicamente. Los resultados obtenidos revelaron que las formulaciones de las flavanonas (FF) eran adecuadas para su administración tópica. Se llevó a cabo un ensayo in vitro de liberación de las flavanonas desde su formulación individual, utilizando una membrana de diálisis en sistemas de celdas tipo Franz para garantizar que la formulación libera las flavanonas y permite disponer de cantidad suficiente de cada compuesto susceptible de ser permeado en piel humana. Seguidamente, se realizaron estudios ex vivo utilizando piel humana con el propósito de evaluar el perfil de permeación de las flavanonas contenidas en disolución de forma individual y en las formulaciones. El estudio demostró que la cantidad de flavanona permeada y retenida en la piel fue diferente dependiendo de la flavanona ensayada; probablemente debida a las diferentes interacciones molecular de sus grupos funcionales con los componentes del tejido. Las flavanonas derivadas se retuvieron en mayor cantidad en piel que la flavanona natural. Finalmente, se desarrolló un ensayo in vivo de eficacia antiinflamatoria en un modelo de edema auricular de rata inducido por ácido araquidónico. Los resultados demostraron que las flavanonas fueron capaces de reducir el edema y los excipientes de las formulaciones no influyeron en la actividad biológica. Las formulaciones resultaron ser más efectivas que el fármaco de referencia usado en este estudio (gel de diclofenaco sódico). Se comprobó que la modificación estructural de la flavanona natural mejoró la actividad terapéutica destacando los derivados metilados y vinilo ciclizados. Estos resultados se encuentran en concordancia con los obtenidos de la evaluación de expresión de las citosinas (IL-1β, IL-6 y TNF-α) realizado y además, permitió evidenciar la ventaja del uso de sistemas nanoestructurados para disponer las flavanonas, en comparación con las flavanonas ensayadas en disolución.

Els virus de la influença tipus A (VIAs), han estat implicats en cinc pandèmies i ocasionen, any rere any, epidèmies estacionals. Tenen un elevat potencial zoonòtic, afectant un ampli ventall d’hostes. Els seus principals reservoris són les aus salvatges aquàtiques que poden transmetre el virus a aus domèstiques, i aquestes, a porcs i humans. A més, els porcs són considerats hostes intermediaris, susceptibles d’infecció tant per virus humans com aviars. La mesura preventiva més efectiva contra els VIAs són les vacunes. La majoria són vacunes inactivades que contenen soques dels subtipus circulants més comuns de VIAs. No obstant, presenten inconvenients, com una limitada capacitat de cross-protecció. Aquestes limitacions requereixen una reformulació de les vacunes per tal que s’ajustin als canvis genètics del virus i exigeixen continua vigilància davant possibles pandèmies. Per superar aquests obstacles, la investigació actual cerca una vacuna universal, implementant diverses estratègies de vacuna/immunització utilitzant immunomodul·ladors i epítops altament conservats dels VIAs. Aquesta tesi doctoral avalua diverses estratègies enfocades en la millora de les formulacions vacunals, com en la seva aplicació/avaluació en hostes naturals de VIAs i consta de tres parts: La primera part descriu la introducció general (Capítol I) i l’objectiu general i específics (Capítol II). La introducció explica (i) els virus de la grip (ii) els VIAs (iii) la resposta immune de l'hoste contra els VIAs (iv) les vacunes comercials disponibles en humans, aviar i porcí contra la grip (v) estratègies per obtenir una vacuna universal i (vi) l’ISM, una eina in silico utilitzada en la tesi per predir pèptids conservats. El capítol II descriu l’objectiu:. crear un prototip de vacuna universal contra diferents subtipus de VIAs utilitzant tècniques que incorporen epítops conservats de la hemaglutinina (HA-epítops), predits in silico, introduïts en plàsmids o en forma soluble amb adjuvants diferents. La part II (Capítols III-V), inclou els tres estudis on el disseny de prototips vacunals amb possible caràcter multivalent i la seva aplicació en porcs i aus és avaluada. En el primer estudi, un HA-epítop: el NF-34, predit per ISM, va ser modificat i formulat en un plàsmid amb CTLA-4 (pCMV-CTLA4-Ig-NG34), promotor de la resposta adaptativa. El pCMV-CTLA4-Ig-NG34 es va utilitzar en porcs seronegatius i seropositius contra la grip porcina i es van desafiar contra el virus heteròleg H3N2. Els vacunats van secretar menys virus, van eliminar el virus a les vies respiratòries, van presentar resposta humoral als subtipus circulants més rellevants i anticossos neutralitzants. No obstant, no hi va haver diferències en el grau de lesions pulmonars ni en els signes clínics. Els anticossos materns no van interferir amb l’efecte de la vacuna. En el segon estudi, es va utilitzar un còctel d’HA-epítops combinats amb flagel·lina (VC-4-flagellin), promotor de la resposta innata, en porcs seronegatius i seropositius i es van desafiar amb soques homòlogues i heteròlogues de VIAs. Els porcs vacunats van reduir l'excreció del virus, van produir resposta humoral front els subtipus H1 i H3 i, anticossos neutralitzants contra ambdós virus. Els anticossos materns no varen ser un obstacle, no obstant, els signes clínics i la patologia dels pulmons no es van reduir. Finalment, en el tercer estudi, es va utilitzar el sistema vectorial d’expressió de baculovirus (BEVS) per obtenir extractes de proteïnes que contenien HA-epítops units a la flagel·lina. La formulació es va utilitzar per immunitzar pollastres que es van desafiar amb H7N1, un virus altament patogènic. Els vacunats van sobreviure sense mostrar signes clínics i sense secretar o, en menor quantitat, el virus. El mecanisme de protecció està sota investigació. La part III (capítols VI-VII), descriu la discussió general i les conclusions. També, inclou les referències bibliogràfiques (Capítol VIII) i els annexos.
Influenza viruses (IAVs) have been implicated in five pandemics and are the cause of seasonal epidemics year after year. They are characterized for their high zoonotic potential, affecting a wide range of hosts. Wild aquatic birds are their main reservoirs that transmit the virus to domesticated birds and may spread further to pigs and humans. Moreover, pigs are considered intermediate hosts, susceptible to infection for both humans and avian IAVs. The most effective countermeasure against IVs are the vaccines. Most of them are inactivated vaccines containing strains of the most common circulating subtypes of IVs. However, they present several inconveniences like limiting cross-protection capacity. These limitations require reformulation of vaccines matched to the genetic changes of the virus and demand continuous vigilance for possible pandemics. To overcome these hurdles, current research focuses on seeking for a universal influenza vaccine, implementing several vaccine strategies by using different immunomodulators and highly-conserved IV epitopes in vaccine formulations. This doctoral thesis evaluates distinct approaches both in improving vaccine formulation and its application/evaluation to different IV natural hosts and has been divided into 3 parts: In the Part I, the general introduction (Chapter I) and the general and specific objectives (Chapter II), are described. The introduction explains (i) influenza viruses (ii) the viruses of the genus A (iii) host's immune response against IVs; (iv) the commercial vaccines available against influenza in human, avian and porcine (v) approaches to obtain a universal vaccine and the (vi) ISM, an in silico tool which has been used in the thesis to predict conserved peptides. Chapter II describes the objective of this thesis. Overall, it is intended to create a universal prototype vaccine against different subtypes of IVs using techniques that incorporate in silico predicted conserved HA-epitopes introduced in plasmid or soluble form along with different adjuvants. In Part II (Chapters III-V), three studies that are either published/submitted to international peer-reviewed scientific journals, are included. The design of vaccine prototypes with possible multivalent character and its subsequent application in pigs and birds is evaluated. In the first study, one conserved HA-epitope NF-34, predicted by ISM, was modified and formulated in a plasmid with CTLA-4 (pCMV-CTLA4-Ig-NG34), promoter of the adaptive response. The vaccine approach was used in swine influenza seronegative and seropositive pigs and challenged against heterologous H3N2. Vaccinated pigs secreted fewer viruses, cleared the virus in the respiratory airways, presented humoral response to the most relevant circulating subtypes and elicited neutralizing antibodies. However, there were no differences in the degree of pulmonary lesions and clinical signs. Maternal antibodies did not interfere with the effect of the vaccine. In the second study, a cocktail of HA-epitopes combined with flagellin (VC-4 flagellin), a promoter of the innate response, was used in SIV seronegative and seropositive pigs and were challenged with homologous and heterologous IAV strains. Vaccinated pigs reduced virus excretion, produced humoral response to subtypes H1 and H3, and neutralizing antibodies against both viruses. Maternal antibodies were not an obstacle but, clinical signs and pathology in the lungs were not reduced. Finally, in the third study, baculovirus expression vector system (BEVS) was used to obtain protein extracts containing HA-peptides linked with flagellin. The formulation was used to immunize chickens that were challenged with H7N1, a highly pathogenic virus. Vaccinated animals survived without showing any clinical sign and fewer or no virus secretion. The protection mechanism is under investigation. The general discussion is described in part III (Chapters VI-VII) with possible significance of the results obtained and the relation of conclusions drawn from each study. The bibliographical references (Chapter VIII) and appendices are also included.

Esta pesquisa tem como objetivo investigar a prática de formulação na fala-em-interação de uma sala de aula de inglês como língua adicional na Educação de Jovens e Adultos (EJA). Os conceitos teóricos e a fundamentação metodológica estão embasados na Análise da Conversa Etnometodológica (ACE). O conjunto de dados se constitui de cerca de 14 horas de gravações audiovisuais realizadas em uma escola estadual situada na periferia geográfica e econômica de Porto Alegre. Houve trabalho colaborativo entre a pesquisadora e a professora de inglês da escola que produziram em conjunto o material didático utilizado nas aulas. A análise dos dados evidenciou que a prática da formulação foi uma prática recorrente utilizada pela professora para conduzir a aula. As formulações auxiliaram no destaque e na exposição da construção de conhecimento realizada no grupo, bem como na checagem de entendimento e na resolução dos problemas de intersubjetividade através do reparo em terceira posição. Também foi observada e analisada a relação entre a prática de formular e a cognição socialmente compartilhada e a relação das formulações com o ensino-aprendizagem. A análise detalhada das interações revelou o engajamento dos participantes com a construção conjunta de conhecimento, revelou também essa construção sendo tornada explícita por eles na interação.
This research aims at investigating the formulating practice in talk-in-interaction at an young and adults’ (EJA) classroom in which English is taught as an additional language. The theoretical and methodological concept underlying the research is the Conversation Analysis (CA). The research collection is comprised of a fourteen-hour video recording of interactions carried out at a state school situated in Porto Alegre geographic and economics’ suburb. There was a collaborative work between the researcher and the school English teacher, they elaborated the didactic material used in class. The data analysis provided evidence that the formulating practice was a recurrent practice used by the teacher to conduct the class. The formulations helped in pointing out and explicit the construction of knowledge which was being done by the group, to check understanding and to solve intersubjectivity problems by the third position repair. It was also observed and analyzed the relation between the formulating practice and the socially shared cognition and the relation between formulation and learning-teaching. A detailed analysis of the interactions reveals the participants’ engagement to the joint construction of knowledge and it also shown this construction being made explicit by them in the course of their interaction.

O objetivo desta tese é relacionar análises de segmentos transcritos de fala-em-interação de sala de aula de língua adicional e orientações acerca de metodologia de ensino. Em especial, esta pesquisa propõe colocar em discussão as orientações presentes em manuais de metodologia de ensino de línguas adicionais (Brown, 2007; Hall, 2001a; Harmer, 2009; Schlatter & Garcez, 2012; Scrivener, 2012) acerca do planejamento de tarefas pedagógicas e do gerenciamento interacional da participação dos alunos durante a realização de atividades pedagógicas. Para a realização do estudo, foram geradas 20 horas de registros audiovisuais em uma sala de aula de nível básico 2 de português como língua adicional que adota pedagogia de projetos em um curso em extensão de uma instituição federal de ensino superior. A partir do enquadre teórico-metodológico da Análise da Conversa, analiso neste relatório cinco ocorrências transcritas (de um total de dezoito) de fala-em-interação de sala de aula em que o status epistêmico de conhecedor da língua adicional de algum participante é posto em risco durante a realização de atividades pedagógicas. A realização de atividades pedagógicas foi analisada como constituída de três etapas: convite à participação (Ramos, 2010), produção e continuidade. Observou-se que as ações realizadas na etapa de continuidade da realização da atividade pedagógica foram centrais para a concretização de diferentes objetivos pedagógicos. Quando essas ações estavam implicadas sequencialmente em relação ao que fora feito imediatamente antes na etapa de produção da atividade pedagógica, o objetivo concretizado se relacionava ao uso da língua adicional para a realização de ações. Por outro lado, quando essas ações não exibiam essa implicatividade sequencial, o objetivo realizado dizia respeito à produção de elocuções com acurácia. Verificou-se que as ações realizadas pela professora que rebaixavam o outro participante epistemicamente com relação à língua adicional foram ofertas de reelaboração de elocuções. Já as práticas e ações mobilizadas pela professora que trabalhavam no sentido de assegurar o status epistêmico dos demais participantes como conhecedores da língua adicional foram a formulação (Garfinkel & Sacks, 1970) e a verificação de entendimento (Schegloff, Jefferson, & Sacks, 1977, pp. 379). Tais achados recomendam que manuais de metodologia de ensino de línguas atentem para a importância de a) antever, quando do planejamento de tarefas, a interação projetada na etapa de continuidade da tarefa de modo a maximizar a chance de que os objetivos projetados se concretizem e b) considerar as ações de formulação e verificação de entendimento como centrais para a materialização da atribuição do professor como ratificador do conhecimento produzido pelo aluno.
This thesis is aimed at relating classroom talk-in-interaction transcripts to guidelines on teaching methodology. This research discusses guidelines from additional languague teaching methodology handbooks (Brown, 2007; Hall, 2001a; Harmer, 2009; Schlatter & Garcez, 2012; Scrivener, 2012) on task planning and interactional management of students’ participation while carrying out pedagogical activities. Twenty hours of audiovisual data were generated in a Portuguese-as-an-additional language extension program at a Higher Education institution. The classes registered were a basic 2 level group, whose curriculum followed a progect-based methodology. Following Conversation Analysis framework, I analyse five transcribed segments (from a corpus of eighteen occurances) that portray participants’ epistemic status K+ concerning the additional language at risk during the accomplishment of pedagogical activities. The accomplishment of the pedagogical activity was constituted in three stages: invite for participation (Ramos, 2010), production and follow up. The actions co-constructed during the follow up stage were crucial to reach different pedagogical goals. When such actions were sequentially implied in relation to the action previously done in the production stage of the pedagogical activity, the goal reached was connected to a concept of language as doing social actions. On the other hand, when these actions did not display such sequential implication, the pedagogical goal was connected to accurate language production. The actions produced by the instructor that downgraded the other participant epistemic status in relation to the additional language were offers of reformulated utterances. The practices and actions that ratified the other participants’ epistemic status as K+ in relation to the additional langauge were formulations (Garfinkel & Sacks, 1970) and comprehension checks (Schegloff, Jefferson, & Sacks, 1977, pp. 379). Such findings suggest that additional language teaching handbooks take notice of a) the importance of predicting and projecting the actions to be done during the follow up stage so as to maximize the chances of reaching the pedagogical goals previously planned and b) the actions of formulating and checking understanding as central resources to enable the additional language instructor to ratify others’ production (and knowledge) in the additional language at hand.

Capteur électrochimique basé sur des matériaux carbonés fonctionnalisés, pour la détection de deux micropolluants faisant partie des substances prioritaires de la Directive Cadre européenne sur l’Eau (DCE2000/60/CE) : le plomb et l’anthracène. Les capteurs électrochimiques permettent d’atteindre des limites de détection et une sélectivité adéquates pour l’analyse de micropolluants dont les concentrations sont de l’ordredu μg/L, et sont simples d’utilisation pour des analyses in situ à moindre coût comparés aux appareils d’analyses conventionnels. Leur robustesse est un paramètre important afin de permettre des mesures en continu ou semi-continu dans les eaux. Cette thèse propose tout d’abord le développement du capteur pour la détection du plomb. La formulation d’une encre conductrice de carbone est étudiée pour la sérigraphie de ’électrode réceptrice, permettant ainsi de contrôler la composition de l’encre et d’étudier l’influence de la phase carbonée sur les propriétés électrocatalytiques des électrodes. La fonctionnalisation des électrodes par greffage électrochimique d’un sel de diazonium est également étudiée afin de maîtriser la sensibilité et la reproductibilité des électrodes greffées, en contrôlant l’épaisseur et la qualité des couches. Avec cet objectif, la fonctionnalisation dans un liquide ionique protique qui permet le contrôle de la monocouche en modulant la viscosité de ce milieu a été étudiée. Les électrodes greffées montrent des performances analytiques améliorées notamment en termes de répétabilité et de reproductibilité. Enfin ce travail de thèse porte également sur le développement du capteur pour la détection électrochimique de l’anthracène, molécule sans fonctions chimiques. Les électrodes sont, dans ce cas, fonctionnalisées par un polymère à empreinte moléculaire, matériau connu pour sa très grande sélectivité. Les performances de ce capteur, dont la sélectivité est basée uniquement sur le facteur de forme de la molécule, pour la détection de l’anthracène sont alors mises en évidence
Electrochemical sensor based on functionalized carbon materials, for the detection of two micropollutants, lead and anthracene, which are among of the priority substances of the European Framework Directive on Water(DCE 2000/60 / EC). Electrochemical sensors allow to achieve detection limits and selectivities for the analysis of micropollutants whose concentrations are of the order of μg/L. They are easy to use for in situ analyzes at lower costs compared to those of the conventional analysis equipment. Their robustness is an important parameter in order to allow continuous or semi-continuous measurements in water. First of all, this thesis proposes the development of a sensor for lead detection. The conductive carbon ink formulation is studied for the screen-printing of the receiving electrode, thus allowing to control the ink composition and to study the influence of the carbon phase on the electrocatalytic properties of electrodes. Functionalization of electrodes by electrochemical grafting of a diazonium salt is also studied in order to control the sensitivity and reproducibility of grafted electrodes, by controlling the thickness and the quality of the layers. With this aim it has been studied the functionalization in a protic ionic liquid in order to allow the control of the monolayer bymodulating the viscosity of this medium. The grafted electrodes show improved analytical performance especially in terms of repeatability and reproducibility. Finally, this work reports the development of a sensor for the electrochemical detection of anthracene, a molecule without chemical functions. In this case, a molecularly imprinted polymer, a material known for its very high selectivity, functionalizes the electrodes.Having a selectivity is only based on the form factor of the molecule, the performance of the sensor developed for the detection of anthracene is also highlighted

Salt formation is a routinely used strategy for poorly water-soluble drugs and traditionally performed with small inorganic counterions. High energy crystal lattices as well as effects on the local pH within the aqueous boundary layer during dissolution drive the increased dissolution rate and apparent solubility. Ionic liquids however, by definition low melting ionic salts with often large organic counterions, combine an increased dissolution rate with solubilization of the drug by the counterion itself. Long lasting supersaturation profiles of increased kinetic solubility were reported for several drugs formulated as ionic liquids increasing their overall bioavailability. Furthermore, aggregation and micellization between highly lipophilic compounds and amphiphilic bile acids was described before, demonstrating the capabilities of the human body itself to utilize solubilization of poorly water-soluble compounds. Development of novel counterions not only tailoring the desired physicochemical properties e.g. dissolution rate of the parent drug but adding – in a best-case scenario synergistic – pharmacological activity has been driven forward in the last years. However, salt formation can only be applied for ionizable i.e. acidic or basic compounds. While co-crystals can be used as a nonionized alternative, their formation is not always successful leading to an urgent need for other formulation strategies. In these lines, development of 2D and 3D printing techniques has been ongoing for the last decades and their pharmaceutical application has been demonstrated. The versatile nature and commercial availability allow a decentralized production further elaborating this technique for a highly flexible and patient-oriented supply with medication. This thesis focuses on the theoretical background and potential application of salt formation in the pharmaceutical development of a drug candidate. The first section presents the current knowledge and state of the art in preparation of low melting ionic liquids i.e. salts and is translated to the in vitro investigation of molecular interaction between the poorly water-soluble drug imatinib and components of the human intestinal fluid in the second section. Development of novel antibiotic counterions and assessment of their potential use in pharmaceutical formulations with fluoroquinolones is described in the last two sections. Chapter I describes the application of low melting ionic liquids in pharmaceutical formulation and details their development in the last two decades from versatile organic solvents in chemical synthesis towards amorphous strategies for drug delivery. The chapter gives a general overview on molecular structure and physicochemical properties of several drug containing ionic liquids and details the mechanisms which attribute to a typically fast dissolution, increased aqueous solubility as well as enhanced permeation which was reported in several publications. Chapter II translates the increased aqueous solubility of drugs by an organic counterion to the human gastrointestinal tract with taurocholate and lecithin as main drivers for the solubilization of highly lipophilic and poorly water-soluble drugs. Investigation of the interaction of imatinib – a poorly water-soluble weak base – with fasted- and fed state simulated intestinal fluids revealed a complex interplay between the components of the intestinal fluid and the drug. Mixed vesicles and micelles were observed in concentration dependent aggregation assays and revealed differences in their size, molecular arrangement as well as composition, depending on the tested drug concentration. Overall, the study outlines the effective interaction of weakly basic drugs with taurocholate and lecithin to minimize recrystallization during intestine passage finally leading to favorable supersaturation profiles. Chapter III focuses on the development of novel antibiotic counterions which potentially move the evolution of ionic liquids from a pharmaceutical salt with tailored physicochemical properties to a synergistic combination of two active pharmaceutical ingredients. The natural occurring anacardic acid derived from the cashew nut shell inspired a series of antibacterial active acidic compounds with increasing alkyl chain length. Their physicochemical properties, antibacterial activity, bacterial biofilm inhibition and cytotoxicity were detailed and in vivo activity in a Galleria mellonella model was assessed. This group of anacardic acid derivatives is synthetically accessible, easily modifiable and yielded two compounds with favorable activity and physicochemical profile for further drug development. Chapter IV outlines the potential application of anacardic acid derivatives in pharmaceutical formulations by salt formation with fluoroquinolone antibiotics as well as novel techniques such as 2D/3D printing for preparation of drug imprinted products. Despite anacardic acid derivatives demonstrated promising physicochemical properties, salt formation with fluoroquinolone antibiotics was not feasible. However, 2D/3D printed samples with anacardic acid derivative alone or in combination with ciprofloxacin demonstrated physical compatibility between drug and matrix as well as antibacterial activity against three S. aureus strains in an agar diffusion assay. Conclusively, drug printing can be applied for the herein tested compounds, but further process development is necessary. In summary, preparation of low melting ionic liquids, salts or co-crystals is an appropriate strategy to increase the aqueous solubility of poorly water-soluble drugs and tailor physicochemical properties. The counterion itself solubilizes the drug and furthermore potentially interferes with the complex micellar environment in the human intestine. However, salt formation as routinely used formulation strategy is not feasible in every case and development of alternative techniques is crucial to hurdle challenges related to unfavorable physicochemical properties. The outlined techniques for 2D/3D drug printing provide versatile production of drug products while extending the design space for novel drug development
Die Salzbildung mit pharmazeutischen Wirkstoffen – als routinemäßig durchgeführte Strategie für schlecht wasserlösliche Substanzen – wird traditionell mit kleinen, anorganischen Gegenionen durchgeführt. Eine tragende Rolle spielen hierbei ein hochenergetisches Kristallgitter sowie die Beeinflussung des pH-Wertes in der ruhenden Grenzschicht während des Auflösungsprozesses. Diese treiben eine beschleunigte Auflösungsrate sowie eine Erhöhung der scheinbaren Löslichkeit an. Ionische Flüssigkeiten stellen per Definition niederschmelzende ionische Salze mit oftmals großen, organischen Gegenionen dar. Sie kombinieren, aufgrund ihrer hohen Gitterenergie, eine beschleunigte Auflösungsratemit der Solubilisierung des Wirkstoffs durch das Gegenion. Langanhaltende Übersättigungen mit erhöhter kinetischer Löslichkeit und eine damit einhergehende, verbesserte Bioverfügbarkeit, wurden bereits bei verschiedenen Wirkstoffen beobachtet, die als ionische Flüssigkeiten formuliert wurden. Auch der menschliche Körper nutzt diesen Effekt und solubilisiert schlecht wasserlösliche Substanzen durch Aggregation und Mizellisierung lipophiler Substanzen mit amphiphilen Gallensäuren. Die Entwicklung neuartiger – meist kationischer – Gegenionen wurde in den letzten Jahren vorangetrieben. Vor allem Gegenionen, die nicht nur die gewünschten physikochemischen Eigenschaften (z.B. Auflösungsrate) hervorbringen, sondern einen eigenen – im besten Fall synergistischen – pharmakologischen Effekt aufweisen. Jedoch kommt eine Salzbildung nur für ionisierbare Substanzen respektive Säuren und Basen in Frage. Während Co-Kristalle als Alternative für nicht-ionisierbare Substanzen dienen können, ist deren Herstellung nicht immer erfolgreich und neue Formulierungsstrategien werden notwendig. Deshalb wurde unter anderem die Entwicklung von 2D- und 3D-Druckverfahren in den letzten Jahrzehnten vorangetrieben und deren Relevanz für pharmazeutische Fragestellungen aufgezeigt. Die vielseitige Natur und kommerzielle Verfügbarkeit des 2D/3D-Drucks erlaubt eine dezentrale Produktion und ermöglicht eine flexible und patientenorienterte Medikamentenversorgung. Diese Dissertation beschäftigt sich vorrangig mit den theoretischen Hintergründen und den praktischen Anwendungsmöglichkeiten der Salzbildung in der pharmazeutischen Entwicklung eines potenziellen Wirkstoffes. Das erste Kapitel präsentiert den gegenwärtigen Stand der Technik zur Verwendung von niederschmelzenden ionischen Flüssigkeiten. Diese Erkenntnisse werden im Anschluss auf eine Untersuchung der Interaktionen des schlecht wasserlöslichen Wirkstoffs Imatinib und den Bestandteilen der menschlichen Verdauungssäfte übertragen. Die Entwicklung neuartiger, antibiotisch wirksamer Gegenionen und deren potenzielle Verwendung in pharmazeutischen Formulierungen mit Fluorchinolonen ist Gegenstand der letzten zwei Kapitel. Kapitel I beschreibt niederschmelzende ionische Flüssigkeiten in pharmazeutischen Formulierungen und führt deren Entwicklung in den letzten drei Jahrzehnten aus: Vom vielfältig anwendbaren, organischen Lösemittel für die chemische Synthese hin zur amorphen Darreichungsform. Das Kapitel gibt einen Überblick über die molekularen Strukturen und physikochemischen Eigenschaften verschiedener wirkstoffbeinhaltender, ionischer Flüssigkeiten. Hierbei werden die zugrundeliegenden Mechanismen dargelegt, was im Besonderen die rasche Auflösung, eine erhöhte Löslichkeit in wässrigen Medien sowie eine Beeinflussung der Permeation meint. Kapitel II überträgt die Beobachtung einer erhöhten Löslichkeit in Gegenwart eines organischen Gegenions auf den menschlichen Verdauungstrakt, in dem Taurocholat und Lecithin hauptverantworlich für die Solubilisierung von liphilen und schlecht wasserlöslichen Substanzen sind. Untersuchungen der Interaktion von Imatinib, einer schlecht wasserlöslichen, schwachen Base, mit simulierten, intestinalen Flüssigkeiten zeigten ein komplexes System aus Bestandteilen der intestinalen Flüssigkeit und dem Wirkstoff. Gemische aus Vesikel und Mizellen, die mithilfeeines Aggregationsassays untersucht wurden, zeigten, in Abhängigkeit von momentanen Wirkstoffkonzentrationen, Unterschiede in ihrer Größe sowie der molekularen Anordnung und Zusammensetzung. Zusammenfassend beschreibt dieses Kapitel die effektive Interaktion von schwachen Basen mit Taurocholat und Lecithin sowie eine Möglichkeit zur Minimierung von Rekristallisation und damit der Aufrechterhaltung von übersättigten Zuständen während der Wirkstoff den Verdauungstrakt passiert. Kapitel III befasst sich mit der Entwicklung neuartiger antibiotischer Gegenionen. Diese treiben möglicherweise die Weiterentwicklung von ionischen Flüssigkeiten mit optimierten physikochemischen Eigenschaften zu synergistischen Kombinationen aus zwei pharmakologisch aktiven Substanzen voran. Die natürlich vorkommende Anacardsäure, welche sich aus der Schale der Cashewnuss gewinnen lässt, hat eine Reihe von antibakteriellen, sauren Substanzen inspiriert, die sich allein in der Länge ihrer Alkylkette unterschieden. Physikochemische Eigenschaften, antibakterielle Aktivität, Inhibition des bakteriellen Biofilms sowie Zytotoxizität wurden untersucht und anschließend in vivo mittels Galleria mellonella-Modell beleuchtet. Diese Gruppe aus Anacardsäurederivaten ist synthetisch zugänglich, einfach chemisch modifizierbar und brachte zwei Substanzen mit vorteilhafter Aktivität und physikochemischen Eigenschaften zur weiteren Entwicklung hervor. Kapitel IV beschreibt die potenzielle Anwendung der Anacardsäurederivate in pharmazeutischen Formulierungen. Durch Salzbildung mit Fluorchinolon-Antibiotika sowie Nutzung neuerer Techniken, wie dem 2D/3D-Druck, wurden wirkstoffbedruckte Darreichungsformen hergestellt. Obwohl die Anacardsäurederivate vielversprechende physikochemische Eigenschaften zeigten, eigneten sie sich nicht für eine Salzbildung mit Fluorchinolonen. Trotzdem war es möglich Anacardsäurederivate allein oder in Kombination mit Ciprofloxacin auf Oberflächen zu drucken, wobei keine physische Inkompatibilität zwischen Wirkstoff und Matrix erkennbar war jedoch eine antibakterielle Wirkung gegen drei S. aureus Stämme gezeigt werden konnte. Abschließend stellte sich der Druck von Wirkstoffen, mit den untersuchten Techniken, als machbar heraus, wobei eine Weiterentwicklung des Prozesses sicherlich notwendig ist. Zusammenfassend stellt die Herstellung von niederschmelzenden, ionischen Flüssigkeiten, Salzen oder Co-Kristallen eine geeignete Strategie dar, die Löslichkeit schlecht wasserlöslicher Substanzen zu verbessern und deren physikochemische Eigenschaften zu optimieren. Das Gegenion kann dabei dazu beitragen den Wirkstoff zu solubilisieren, wobei es sehr wahrscheinlich ist, dass er auch mit dem komplexen mizellaren System des menschlichen Verdauungstrakts interagiert. Trotzdem ist eine routinemäßige Salzbildung nicht in allen Fällen zielführend und alternative Technologien müssen entwickelt werden, um die Herrausforderungen mit unvorteilhaften physikochemischen Eigenschaften zu meistern. Die beschriebenen 2D/3D-Druckverfahren bieten hierbei eine Produktion variabler und vielfältiger Darreichungsformen und erweitern den Gestaltungsraum für neuartige Wirkstoffentwicklungen

Nowadays, shale gas is the fastest growing natural unconventional gas resource worldwide, as a result of the combination between major technological developments and geopolitical events. Despite the great potential in terms of exploitable reservoirs, several environmental issues have been associated to shale gas extraction and hydraulic fracturing, like induced seismicity, greenhouse gas emissions, and water contamination. In this perspective, the formulation of environmentally-safe fracturing fluids plays a crucial role in the minimization of the environmental footprint of shale gas exploitation. In this work we proposed two completely green and eco-compatible fracturing fluid formulations specific for the shale gas formations in Europe. These formulations must possess well-defined properties in terms of composition and operative performances, including the absence of controlled or toxic substances, an appropriate viscosity for proppant transport, the effectiveness in high pressure, temperature and salinity conditions and the presence of specific additives to limit the extraction of Naturally Occuring Radioactive Materials (NORM). The first formulation we developed is a linear gel based on four different green polysaccharides, namely guar gum, sodium hyaluronate, sodium alginate and hydroxpropylcellulose. The second is a viscoelastic surfactant-based (VES) fluid, composed by an eco-compatible surfactant, sodium oleate, and a inorganic salt, KCl. Rheological measurements, Optical Microscopy, Differential Scanning Calorimetry (DSC) and Small Angle X-Ray Scattering experiments were performed in order to assess the main physico-chemical properties of the formulations and their fluid behaviour. All the formulations show a very high viscosity (optimal to avoid proppant sedimentation), a high shear resistance and a good thermal stability. Moreover, we tested their effectiveness at high temperature, high pressure and salinity content, demonstrating that the variation in these geochemical parameters can be effectively used to modulate the fluid rheological behaviour. The polysaccharide-based and the VES formulations were then implemented by the inclusion of two specific additives, Carbon Black and Azorubine, which induces a fluid responsiveness to specific external stimuli, namely an applied electrical voltage and UV light. Rheological, DSC and SAXS experiments demonstrated that in both cases the fluid viscosity can be modulated using an applied input. The addition of Carbon black brings about also an enhanced thermal resistance and the possibility to recover and re-use the fluid. In the last part of the work we developed two completely safe and environmental friendly approaches to limit the amount of NORM in the flowback water and for the treatment of wastewaters after the extraction of the shale gas. The first method is a physical treatment consisting in the exposure of the fracfluid to a weak static magnetic field before being pumped in the pipelines (Magnetic Water Treatment, MWT). The second method is based on the use of green innovative scale inhibitors, polyglutammate and polyaspartate, to replace the non-ecocompatible polyacrilates in fracfluid formulations. Optical microscopy, Fluorescence Spectroscopy and X-Ray Diffraction experiments showed that the combined effect of an external magnetic field and high temperature reduces the amount of insoluble alkali earth metals scales (CaCO3, BaCO3, SrCO3and CaSO4) and limits NORM extraction, since the formation of fewer scales of larger dimensions makes more difficult the flowback of NORM ions. Qualitative precipitation and solubility experiments demonstrated the effectiveness of the green antiscalant agents in reducing the precipitate and controlling the crystals size of CaSO4 and SrSO4. The high temperature does not affect the anti-scaling performances, which are even enhanced when added to a polysaccharide-based formulation. For this reason, the use of very small amounts of these green additives could be a simple way to limit the formation al of mineral scales, also in the presence of radioactive materials, such as radium salts.

Many vaccines require an adjuvant to induce a strong immune response. Aluminum–containing adjuvants have been approved by the United States Food and Drug Administration for human use for many years. There are two main aluminum-containing adjuvants, aluminum hydroxide and aluminum phosphate. Due to their favorable safety profile, aluminum-containing adjuvants have been widely used in human vaccines for decades. Many currently licensed and commercially available vaccines contain aluminum-containing adjuvants. However, aluminum-containing vaccine adjuvants suffer from two major limiting factors: (1) aluminum-containing adjuvants can only weakly or moderately potentiate antigen-specific antibody responses and are generally considered incapable of inducing cellular immune responses; (2) vaccines that contain aluminum-containing adjuvants require cold-chain refrigeration for storage and distribution, and may not be frozen, because freezing of the vaccine in dispersion causes irreversible coagulation that damages vaccines (e.g., loss in potency and stability). In this dissertation, the first limitation was addressed by reducing the size of the aluminum hydroxide from micrometers (3-10 micrometer) to nanometers of less than 200 nm, and the second limitation mentioned above was addressed by freeze-drying vaccines that contain aluminum salts as adjuvants into a dry powder using thin-film freeze-drying. In addition, using an improved experimental design, the vaccine adjuvant activities of nanoparticles of around 200 nm was compared to that of the nanoparticles of around 700 nm. The smaller 200 nm nanoparticles showed a more potent adjuvant activity than the larger nanoparticles. When dispersed in an aqueous medium, both aluminum hydroxide and aluminum phosphate are physically 1–20 micrometer particulates. There are data showing that particulate vaccine carriers of around 200 nm (or less) may be optimal in potentiating the immunogenicity of vaccines. Based on this finding, aluminum hydroxide nanoparticles of 112 nm were synthesized, and its adjuvant activity was compared to that of the traditional aluminum hydroxide adjuvant, which have particulates of 3-20 micrometer. Using ovalbumin and Bacillus anthracis protective antigen protein as model antigens, it was found that protein antigens adsorbed on the aluminum hydroxide nanoparticles induced stronger antigen-specific antibody responses than the same protein antigens adsorbed on the traditional aluminum hydroxide microparticles of around 9.3 µm. Importantly, the inflammation reactions induced by aluminum hydroxide nanoparticles in the injection sites were milder than that induced by microparticles. Simply reducing the particle size of the traditional aluminum hydroxide adjuvant in suspension from micrometers into nanometers represents a novel and effective approach to improve its potency. The second limitation was addressed by converting vaccines that contain an aluminum salt as an adjuvant from an aqueous dispersion into a dried powder using thin-film freeze-drying. There is evidence that aluminum-containing vaccines can be lyophilized to dry powders using high speed freezing methods. Thin-film freezing is a high speed freezing method with a freezing rate between 100 to 10,000 K/s, but the feasibility of using thin-film freeze-drying to freeze-dry vaccines that contain aluminum salts as adjuvants has not been tested before. In this dissertation, Using ovalbumin as a model protein antigen and aluminum hydroxide or aluminum phosphate as an adjuvant, it was confirmed that vaccines that are adjuvanted with aluminum hydroxide or aluminum phosphate can be freeze-dried with as low as 2% (w/v) of trehalose as a cryoprotectant by thin-film freeze-drying without causing vaccine aggregation while preserving the immunogenicity of the vaccine. Finally, the feasibility of using the thin-film freeze-drying method to freeze-drying vaccines that contain aluminum salts as adjuvants was further confirmed by drying a commercial aluminum salt-adjuvanted tetanus toxoid vaccine. Vaccines that contain aluminum salts as adjuvants may be converted to a dry powder using the thin-film freeze-drying method to avoid loss of potency due exposure to freezing conditions during transport and storage.
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Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used in the treatment of inflammation and pain (Escribano et al., 2003:203). Diclofenac, a classical NSAID, is considerably more effective as an analgesic, antipyretic and anti-inflammatory drug than other traditional NSAIDs, like indomethacin and naproxen (Grosser et al., 2011:986). However, the use of diclofenac is known for its many side effects, such as gastric disorders, while fluid and sodium retention are also commonly observed (Rossiter, 2012:391). Since topical diclofenac offers a more favourable safety profile, it is a valuable substitute for oral NSAID therapy in the treatment of osteoarthritis (Roth & Fuller, 2011:166). The benefits of topically applied NSAIDs, compared to oral administration and systemic delivery, include the easy cessation of treatment, should effects become troublesome (Brown et al., 2006:177), the avoidance of extensive, first-pass metabolism (Cleary, 1993:19; Kornick, 2003:953; Prausnitz & Langer, 2008:1261; Lionberger & Brennan, 2010:225), reduced systemic side effects (Colin Long, 2002:41), convenience of application and improved patient compliance (Cleary, 1993:19; Prausnitz & Langer, 2008:1261). An approach that is often applied in optimising the solubility and dissolution rate of poorly water soluble, weak electrolytes is to prepare a salt of the active pharmaceutical ingredient (API) (Minghetti et al., 2007:815; O’Connor & Corrigan, 2001:281-282). Diclofenac is frequently administered as a salt, due to the high partition coefficient and very low water solubility of this molecule (Fini et al., 1999:164). Formulating for efficacy (FFETM) is a software programme designed by JW Solutions to facilitate the formulation of cosmetic ingredients or solvents into a product that would optimally deliver active ingredients into the skin. The notion is built upon solubility, i.e. solubility of the active ingredient in the formulation and solubility of the formulation in the skin. This programme could also be employed to optimise amounts of predetermined ingredients, to propose formulations that would ensure optimal drug delivery, to calculate the skin delivery gap (SDG) and to demonstrate transdermal permeation of active ingredients and excipients (JW Solutions Software, 2013a). When the SDG is known, it mathematically indicates the optimal active ingredient and topical delivery vehicle to use (JW Solutions, 2013b). In this study, diclofenac sodium (DNa), diclofenac diethylamine (DDEA) and diclofenac N-(2- hydroxyethyl) pyrrolidine (DHEP) were each formulated in the following emulgels: * An emulgel optimised towards the stratum corneum (SC) (enhancing drug delivery into this layer and deeper tissues) (oily phase ~30%), * A more hydrophilic emulgel (oily phase ~15%), and * A more lipophilic emulgel (oily phase ~45%). Components of the oily phase and its respective amounts, as well as the SDG of formulations were determined by utilising the FFETM software of JW Solutions (2013a). The aqueous solubilities of DNa, DDEA and DHEP were determined and their respective values were 11.4 mg/ml, 8.0 mg/ml and 11.9 mg/ml, all indicative of effortless percutaneous delivery (Naik et al., 2000:319). Log D (octanol-buffer distribution coefficient) (pH 7.4) determinations for DNa, DDEA and DHEP were performed and their values established at 1.270 (DNa), 1.291 (DDEA) and 1.285 (DHEP). According to these values, diclofenac, when topically applied as a salt in a suitable vehicle, should permeate transdermally without the aid of radical intervention (Naik et al., 2000:319; Walters, 2007:1312). Membrane release studies were also carried out in order to determine the rate of API release from these new formulations. Results confirmed that diclofenac was indeed released from all nine of the formulated emulgels. The more hydrophilic DNa formulation released the highest average percentage of diclofenac (8.38%) after 6 hours. Subsequent transdermal diffusion studies were performed to determine the diclofenac concentration that permeated the skin. The more hydrophilic DNa emulgel showed the highest average percentage skin diffusion (0.09%) after 12 hours, as well as the highest average flux (1.42 ± 0.20 μg/cm2.h). The concentrations of diclofenac in the SC-epidermis (SCE) and epidermis-dermis (ED) were determined through tape stripping experiments. The more lipophilic DNa emulgel demonstrated the highest average concentration (0.27 μg/ml) in the ED, while the DNa emulgel that had been optimised towards the SC, had the highest concentration in the SCE (0.77 μg/ml).
MSc (Pharmaceutics), North-West University, Potchefstroom Campus, 2014

碩士
國立臺中教育大學
科學應用與推廣學系科學教育碩士班
101
In this study, a total of 383 9th graders’ ability in formulating and transferring representations regarding “acid” and “acid-base neutralization” was investigated. Also, this study explored if high achievers and low achievers varied in their ability in formulating and transferring representations. Two instruments for assessing student ability in formulating and transferring representations regarding acid and acid-base neutralization were developed in this study. The participants’ responses on the questionnaires were analyzed qualitatively, and then this study categorized the students’ ability in formulating and transferring representations into different levels. The major findings of the current study are: 1. regarding ability in formulating representations of “acid” and “acid-base neutralization”, the students showed better ability in formulating macro representations, followed by symbolic representations and micro representations; 2. the students had difficulties transferring from the micro representation of“acid” and “acid-base neutralization” to the other two levels of representations; 3. The students’ ability in ability in formulating representations regarding “acid” and “acid-base neutralization” was significantly correlated with that in transferring representations; 4. The students’ ability in formulating and transferring representations regarding “acid” and “acid-base neutralization” was associated with their chemical achievement. Implications for educational practices and future research were also discussed in this study.