[pt] A escassez de recursos de água doce está ameaçando nossa sociedade. A urbanização, a industrialização, o crescimento populacional e as alterações climáticas estão a representar um grande desafio para a segurança dos recursos hídricos humanos. Com base nessa situação crítica, os cientistas estão prestando cada vez mais atenção à dessalinização. Os métodos tradicionais de dessalinização empregam o processo de destilação. Esses métodos desempenham um papel importante no serviço de abastecimento de água em alguns locais carentes de água. No entanto, devido ao alto consumo de energia desses métodos, o preço da água produzida é elevado. Portanto, desenvolver novas tecnologias de dessalinização com baixo consumo de energia é de grande interesse e uma delas tem atraído a atenção dos pesquisadores, que é a osmose reversa (OR). O RO utiliza a membrana semipermeável como filtro, o que permite que a água ou moléculas relativamente pequenas passem por si mesmas, mas impede que as grandes moléculas ou íons penetrem. Esta tecnologia reduziu significativamente o consumo de energia em comparação com os métodos de destilação e rapidamente ocupa mais de 60 por cento da capacidade total de dessalinização instalada. O desempenho da tecnologia RO depende fortemente do material das membranas desempenha um papel importante. Nas últimas décadas, polímeros, por exemplo, poliamida e acetato de celulose, dominaram a indústria de RO de membrana semipermeável por sua boa eficiência de rejeição de sal e baixo custo de consumo de energia. No entanto, mesmo com as vantagens das membranas poliméricas, o custo final da água produzida ainda é alto. É por isso que os recursos de água doce ainda continuam sendo a preocupação. Desde a primeira vez que o grafeno foi produzido a partir do grafite, chamou a atenção de pesquisadores em todo o mundo por sua estrutura 2D ultrafina, excelente condutividade e transparência etc. Logo depois, o grafeno e seus derivados, como óxido de grafeno e óxido de grafeno reduzido, exibem potencial na dessalinização devido à sua estrutura 2D fina e expansibilidade. Este trabalho explora a possibilidade de aplicação de derivados de grafeno em um processo de dessalinização relativamente prático. No prsente projeto foram produzidos tanto GO (pelo método de Hammer) e RGO (a partir de aquecimento em atmosfera inerte) e de membranas a partir de acetato de celulose com GO e RGO. Ensaios de dessalinação também foram realizados para amostras produzidas variando de modo sistemático diferentes parâmetros de síntese de GO e RGO e de fabricação das membranas de acetato de celulose. / [en] Fresh-water resource scarcity is threatening our society. Urbanization, industrialization, population growth and climate change are making big challenge to human s water resource security. Based on this critical situation, scientists are paying more and more attention to desalination. Traditional desalination methods employ distillation process. These methods play an important role in water supply service in some water-lacked places. However, due to high energy consumption of these methods, the price of produced water is very high. Therefore, developing new desalination technologies with low energy consumption is of high interest and one of them has attracted researchers attention, which is reverse osmosis (RO).(1) RO utilizes the semi-permeable membrane as a filter, which allows the water or relatively small molecules pass through itself, but prevents the large molecules or ions from penetrate. This technology significantly reduced the energy consumption compared to the distillation methods and quickly takes more than 60 percent of the total installed desalination capacity.(2) The performance of RO technology strongly depends on the material of membranes plays an important role. In the past decades, polymers, for instance polyamide and cellulose acetate, dominate the semi-permeable membrane RO industry for their good salt rejection efficiency and low cost of energy consumption. However, even with the advantages of polymer membranes, the final cost of produced water is still high. That s why fresh-water resource still remain the concern. Since the first time that graphene was produced from graphite, it caught researcher’s attention all over the world for its ultra-thin 2D structure, excellent conductivity and transparency, etc. Soon after, graphene and its derivatives, such as graphene oxide and reduced graphene oxide, exhibit potential in desalination due to their thin 2D structure and expandability.(3) This work explores the possibility of application of graphene derivatives in a relatively practical desalination process. In the present project, GO (by the Hammer method), RGO (from heating in air atmosphere) and cellulose acetate membranes with GO and RGO were produced. Desalination tests were also performed for samples produced by systematically varying different parameters of GO, RGO and fabrication of cellulose acetate membranes.

Die Gläsernen Figuren sind die bekanntesten Ausstellungsobjekte des Deutschen Hygiene-Museums, die im 20. Jahrhundert in unterschiedlichsten Ausstellungsformaten einem Millionenpublikum präsentiert wurden. Die transparenten Modelle wurden vorwiegend aus dem Kunststoff Celluloseacetat gefertigt, der starken Alterungsprozessen unterworfen ist. Im konservierungswissenschaftlichen Forschungsprojekt »Gläserne Figuren – Ausstellungsikonen des 20. Jahrhunderts« wurden die Körpermodelle untersucht und ein Konzept für ihren langfristigen Erhalt erstellt. Die gewonnenen Erkenntnisse zur Produktions- und Materialgeschichte sowie zu den Alterungsprozessen und Konservierungsmöglichkeiten werden in dieser Publikation vorgestellt. Empfehlungen zum Umgang mit dreidimensionalen Celluloseacetatobjekten in Museen und Sammlungen schließen sich an. Darüber hinaus werden mehr als 60 historische Objekte aus dem Sammlungskonvolut »Gläserne Figuren« vorgestellt. Im Mittelpunkt stehen dabei die Lebensläufe der im Deutschen Hygiene-Museum befindlichen zwölf Ganzfiguren, die zwischen 1935 und 2000 hergestellt wurden und alle die Transformation vom Anschauungsmodell zum historisch bedeutsamen Objekt durchlaufen haben. Zudem werden die Auswertungspotenziale weiterer Objektgruppen zur Herstellungstechnik und Ausstellungsgeschichte der Figuren sowie zu den Präsentations- und Werbestrategien beleuchtet. / The Transparent Figures are the most well-known exhibition objects of the Deutsches Hygiene-Museum and were presented to millions of people in the 20th century in the most varied exhibition formats. The transparent models were primarily made of the plastic cellulose acetate, which is subject to pronounced ageing processes. The body models were examined and a concept for their long-term preservation was created in the conservation science research project “Transparent Figures – Exhibition Icons of the 20th Century”. The knowledge concerning the production and material history acquired, as well as of ageing processes and possibilities for conservation are presented in this publication. This is joined by recommendations for dealing with three-dimensional cellulose acetate objects in museums and collections. In addition to this, more than 60 historical objects from the “Transparent Figures” collection set will be presented. The focus is thereby on the curricula vitae of the twelve complete figures found in the Deutsches Hygiene-Museum, which were manufactured between 1935 and 2000 and have all undergone the transformation from the display model to the historically important object. The evaluation potential of other object groups with regard to manufacturing technology and the exhibition history of the figures, as well as to the presentation and advertising strategies are also illuminated.

Die Gläsernen Figuren sind die bekanntesten Ausstellungsobjekte des Deutschen Hygiene-Museums, die im 20. Jahrhundert in unterschiedlichsten Ausstellungsformaten einem Millionenpublikum präsentiert wurden. Die transparenten Modelle wurden vorwiegend aus dem Kunststoff Celluloseacetat gefertigt, der starken Alterungsprozessen unterworfen ist. Im konservierungswissenschaftlichen Forschungsprojekt »Gläserne Figuren – Ausstellungsikonen des 20. Jahrhunderts« wurden die Körpermodelle untersucht und ein Konzept für ihren langfristigen Erhalt erstellt. Die gewonnenen Erkenntnisse zur Produktions- und Materialgeschichte sowie zu den Alterungsprozessen und Konservierungsmöglichkeiten werden in dieser Publikation vorgestellt. Empfehlungen zum Umgang mit dreidimensionalen Celluloseacetatobjekten in Museen und Sammlungen schließen sich an. Darüber hinaus werden mehr als 60 historische Objekte aus dem Sammlungskonvolut »Gläserne Figuren« vorgestellt. Im Mittelpunkt stehen dabei die Lebensläufe der im Deutschen Hygiene-Museum befindlichen zwölf Ganzfiguren, die zwischen 1935 und 2000 hergestellt wurden und alle die Transformation vom Anschauungsmodell zum historisch bedeutsamen Objekt durchlaufen haben. Zudem werden die Auswertungspotenziale weiterer Objektgruppen zur Herstellungstechnik und Ausstellungsgeschichte der Figuren sowie zu den Präsentations- und Werbestrategien beleuchtet. / The Transparent Figures are the most well-known exhibition objects of the Deutsches Hygiene-Museum and were presented to millions of people in the 20th century in the most varied exhibition formats. The transparent models were primarily made of the plastic cellulose acetate, which is subject to pronounced ageing processes. The body models were examined and a concept for their long-term preservation was created in the conservation science research project “Transparent Figures – Exhibition Icons of the 20th Century”. The knowledge concerning the production and material history acquired, as well as of ageing processes and possibilities for conservation are presented in this publication. This is joined by recommendations for dealing with three-dimensional cellulose acetate objects in museums and collections. In addition to this, more than 60 historical objects from the “Transparent Figures” collection set will be presented. The focus is thereby on the curricula vitae of the twelve complete figures found in the Deutsches Hygiene-Museum, which were manufactured between 1935 and 2000 and have all undergone the transformation from the display model to the historically important object. The evaluation potential of other object groups with regard to manufacturing technology and the exhibition history of the figures, as well as to the presentation and advertising strategies are also illuminated.

Additives, incorporated in film coating formulations, and their process parameters are generally selected using a trial-and-error approach. However, coating problems and defects, especially those associated with aqueous coating systems, indicate the necessity of embracing a quality-by-design approach to identify the optimum coating parameters. In this study, the feasibility of using thermal and rheological measurements to help evaluate and design novel coating formulations has been investigated. Hydroxypropyl methylcellulose acetate succinate (HPMCAS), an enteric coating polymer, was used as the film forming polymer. Differential Scanning Calorimetry (DSC), Dynamic Mechanical Analysis (DMA), and Parallel Plate Shear Rheometery (PPSR) were used to evaluate the effect of different plasticisers on the performance of HPMCAS. The results illustrate that, for identical formulations, the DSC and DMA methods yielded up to 40% differences in glass transition temperature (Tg) values. Moreover, Tg measured using loss modulus signals were always 20-30 oC less than those measured using tan delta results in DMA testing. Absolute and relative Tg values can significantly vary depending on the geometry of the samples, clamp size, temperature ramping rate and the frequency of the oscillations. Complex viscosity data for different formulations demonstrated a variable shear thinning behaviour and a Tg independent ranking. It is, therefore, insufficient to rely purely on Tg values to determine the relative performance of additives. In addition, complex viscosity results, obtained using both the DMA and PPSR techniques at similar temperatures, are shown to be comparable. The results from both techniques were therefore used to produce continuous master curves for the HPMCAS formulations. Additionally, step strain tests showed that HPMCAS chains do not fully III disentangle after 105 seconds as predicted by the Maxwell model. Finally, in situ aqueous-based coating experiments proved that mixtures of triethyl acetyl citrate and acetylated monoglyceride (TEAC/AMG), even without cooling of the suspension, do not cause blocking of the spray nozzle whereas triethyl citrate (TEC) based formulae did. TEAC (alone or in a combination with AMG) exhibits superior wettability to HPMCAS than TEC/AMG formulations and can be used to enhance the efficiency and film quality of the dry coating process.

Applications of Hot Melt Extrusion (HME) in pharmaceuticals have become increasingly popular over the years but nonetheless a few obstacles still remain before wide scale implementation. In many instances these improvements are related to both processing and product performance. It is observed that HME process optimisation is majorly focused on the active pharmaceutical ingredient's (API) properties. Characterising polymeric properties for their suitability in HME should be equally studied since the impact of excipients on both product and process performance is just as vital. In this work, two well-established cellulose ester derivatives: Hydroxy Propyl Methyl Cellulose Acetate Succinate (HPMCAS) and Hydroxy Propyl Methyl Cellulose Phthalate (HPMCP) are studied for their HME suitability. Their thermal, thermodynamic, rheological, thermo-chemical and degradation kinetic properties were evaluated with model plasticisers and APIs. It was found the thermal properties of HPMCP are severely compromised whereas HPMCAS is more stable in the processing zone of 150 to 200 °C. Thermodynamic properties revealed that both polymers share an important solubility parameter range (20-30 MPa P1/2P) where the majority of plasticisers and BCS class II APIs lie. Thus, greater miscibility/solubility can be expected. Further, the processability of these two polymers investigated by rheometric measurements showed HPMCAS possesses better flow properties than HPMCP because HPMCP forms a weak network of chain interactions at a molecular level. However, adding plasticisers such as PEG and TEC the flow properties of HPMCP can be tailored. The study also showed that plasticisers have a major influence on thermo-chemical and kinetic properties of polymers. For instance, PEG reduced polymer degradation with reversal in kinetic parameters whereas blends of CA produced detrimental effects and increased polymer degradation with reduction in onset degradation temperatures. Further, both polymers are observed to be chemically reactive with the APIs containing free -OH, -SOR2RN- and -NH2 groups. Finally, these properties prove that suitability of HPMCP is highly debated for HME and demands great care in use while that of HPMCAS is relatively better than HPMCP in many instances.

Face à la diminution croissante des ressources d'origine fossile, une attention particulière est portée depuis plusieurs années envers l'utilisation de ressources renouvelables. Dans ce contexte, beaucoup de recherches sont orientées vers l'utilisation de polysaccharides tels que la cellulose. L'intérêt de ces composés est qu'ils sont abondants, peu chers et biodégradables. A l'inverse, ces polymères possèdent une faible résistance mécanique limitant ainsi leurs applications. De manière à moduler les propriétés de ces polymères, une alternative consiste à les modifier chimiquement par greffage de chaînes de polymères synthétiques. Néanmoins, les stratégies de greffage décrites dans la littérature présentent certaines limitations notamment sur la facilité de mise en oeuvre, la toxicité des méthodes employées, le nombre d'étapes de synthèses ou encore le contrôle des masses molaires. Par ailleurs, la caractérisation de ces architectures complexes reste délicate notamment pour prouver le greffage covalent des chaînes de polymère sur le polysaccharide. C'est précisément dans cet axe de recherche que s'insère ce sujet de thèse. Plus particulièrement, l'objectif principal consiste à mettre au point une méthode de greffage de l'acétate de cellulose robuste et facile à mettre en oeuvre, en vue d'une utilisation potentielle en tant que compatibilisant de mélange de polystyrène et d'acétate de cellulose. Afin d'atteindre cet objectif, notre stratégie a consisté à utiliser la polymérisation radicalaire contrôlée par les nitroxydes (NMP) où une attention particulière a été portée sur la caractérisation structurale des matériaux synthétisés (RMN du solide et DOSY, RPE, CES, DLS et DSC). / In order to respond to the fossil resources depletion, a particular attention was paid to the use of renewable resources since several years. In this context, many researches focus on the use of polysaccharides such as cellulose. These compounds are attractive because of their abundance, low cost and biodegradability. On the other hand, these polymers suffer from weak mechanical resistance limiting their practical applications. Grafting synthetic polymers chains on these natural polymers is an alternative to this problem. Nevertheless, grafting strategies described in the literature involve certain limitations such as the difficulty of implementation, the toxicity of the used methods, the great number of synthesis steps or the control of molar mass. Moreover, the characterization of these complex architectures remains delicate in order to prove the covalent grafting of chains on the polysaccharide. In line with this research context, the topic of this thesis concerns the development of a robust method for cellulose acetate polymer grafting. Moreover, the selected method has to be easy to implement, with a possible application as a compatibilizer for blending of polystyrene and cellulose acetate. In order to achieve this purpose, our strategy is based on the use of Nitroxide-Mediated Polymerization (NMP) where particular attention was paid to the structural characterization of synthesized materials (solid state NMR, DOSY NMR, ESR, SEC of grafts, DLS and DSC).

Cetoconazol é um fármaco antimicótico largamente utilizado e veiculado por diversas formas farmacêuticas. Apesar de ser comprovadamente eficaz, é uma substância muito hepatotóxica quando administrado por via oral. Por esse motivo justifica-se o seu emprego em preparações tópicas e sistemas transdérmicos. Essa substância apresenta razoáveis níveis de penetração elou permeação cutânea, mas esses níveis podem ser melhorados através da incorporação, às formulações, de substâncias denominadas promotores de permeação/penetração (enhancers). Essas substâncias têm a função de modificar a difusão dos fármacos através da pele. Neste trabalho, foi estudada a liberação/permeação do cetoconazol de cremes O/A contendo os promotores de permeação/penetração, propilenoglicol e uma solução alcóolica de mentol, empregados em associação e isoladamente na concentração de 0 a 5% p/p. O estudo foi conduzido in vitro, utilizando célula de Franz modificada com o emprego de membrana sintética de acetato de celulose. Foram preparadas e testadas dez formulações, a partir de uma fórmula de creme O/A não-iônico. Dentre as dez formulações estudadas aquela que apresentou melhores resultados quanto aos parâmetros de fluxo e coeficiente de permeabilidade, após uma hora do início do experimento, foi uma formulação que apresenta 1% p/p de propilenoglicol e 1% p/p de solução alcoólica de mentol. / Ketoconazole is an antifungal drug and is largely employed in many delivery systems and dosage forms. Oral administration is not recommended because of its hepatotoxic effects, so topical preparations are employed. This drug shows skin penetration and/or permeation levels, but these levels may be enhanced by the addition of enhancers. These substances modify the diffusion of drugs through skin. In this work, the liberation/permeation of ketoconazole from, O/W creams was studied. These creams have propylene glycol and na alcoholic menthol solution as enhancers, in a range from 0 to 5%w/w. It was an in-vitro experiment, employing Franz modified cells and synthetic cellulose membrane Ten nonionic O/W creams were made and tested. Among the ten tested formulations the one which showed best results in flux and permeability coefficient, after 1 hour, was a formulation which has 1 % w/w of menthol alcoholic solution concentrations.

Cetoconazol é um fármaco antimicótico largamente utilizado e veiculado por diversas formas farmacêuticas. Apesar de ser comprovadamente eficaz, é uma substância muito hepatotóxica quando administrado por via oral. Por esse motivo justifica-se o seu emprego em preparações tópicas e sistemas transdérmicos. Essa substância apresenta razoáveis níveis de penetração elou permeação cutânea, mas esses níveis podem ser melhorados através da incorporação, às formulações, de substâncias denominadas promotores de permeação/penetração (enhancers). Essas substâncias têm a função de modificar a difusão dos fármacos através da pele. Neste trabalho, foi estudada a liberação/permeação do cetoconazol de cremes O/A contendo os promotores de permeação/penetração, propilenoglicol e uma solução alcóolica de mentol, empregados em associação e isoladamente na concentração de 0 a 5% p/p. O estudo foi conduzido in vitro, utilizando célula de Franz modificada com o emprego de membrana sintética de acetato de celulose. Foram preparadas e testadas dez formulações, a partir de uma fórmula de creme O/A não-iônico. Dentre as dez formulações estudadas aquela que apresentou melhores resultados quanto aos parâmetros de fluxo e coeficiente de permeabilidade, após uma hora do início do experimento, foi uma formulação que apresenta 1% p/p de propilenoglicol e 1% p/p de solução alcoólica de mentol. / Ketoconazole is an antifungal drug and is largely employed in many delivery systems and dosage forms. Oral administration is not recommended because of its hepatotoxic effects, so topical preparations are employed. This drug shows skin penetration and/or permeation levels, but these levels may be enhanced by the addition of enhancers. These substances modify the diffusion of drugs through skin. In this work, the liberation/permeation of ketoconazole from, O/W creams was studied. These creams have propylene glycol and na alcoholic menthol solution as enhancers, in a range from 0 to 5%w/w. It was an in-vitro experiment, employing Franz modified cells and synthetic cellulose membrane Ten nonionic O/W creams were made and tested. Among the ten tested formulations the one which showed best results in flux and permeability coefficient, after 1 hour, was a formulation which has 1 % w/w of menthol alcoholic solution concentrations.

Charakteristisch für Perlcellulose als Regenerat vom Typ Cellulose II sind sphärisch geformte, poröse Partikel mit einer hohen spezifischen Oberfläche und einer guten Bioverträglichkeit. Aufgrund ihrer Eigenschaften sind diese Cellulosemikropartikel besonders gut für medizinische Anwendungen geeignet. Im Mittelpunkt der Arbeit standen Herstellung, Charakterisierung und Modifizierung von Perlcellulosen mit Partikelgrößen von etwa 1 bis10 µm. Im Rahmen der Arbeit wurden zunächst sieben technische Cellulose-2,5-acetate mit vergleichbaren molekularen Eigenschaften auf ihre Eignung zur Herstellung von Perlcellulose nach dem in EP0750007 beschriebenen Acetatverfahren untersucht. Dabei erfolgte der Vergleich verschiedener Eigenschaften. Aus allen untersuchten Celluloseacetaten können Perlcellulosen synthetisiert werden. Als besonders geeignet erwies sich ein Produkt mit einer Molmasse von über 100.000, einem Verhältnis der Molmasse zur numerischen Molmasse von etwa 1,5 und einer guten Löslichkeit in Ethylacetat / Methanol (100:17,5). Die hergestellte Perlcellulose hat eine geringe Partikelgröße und eine relativ enge Größenverteilung. Damit erfüllt dieses Cellulose-2,5-acetat alle Anforderungen für die Synthese von Perlcellulose. Der entscheidende Verfahrensschritt zur Herstellung von Perlcellulose ist das Dispergieren der Emulsion mittels Inline-Ultraturrax. Die Partikelgrößenverteilung hängt im Wesentlichen von den Bedingungen während des Dispergierens ab. Im Rahmen der Arbeit gelang die reproduzierbare Herstellung von Cellulosemicrospheres mit einer Partikelgröße unter 5 µm. Für die Herstellung von Cellulosemikropartikeln mit definierten Eigenschaften ist neben den Synthesebedingungen auch die Charakterisierung der Perlcellulosen von entscheidender Bedeutung. Dafür wurden zunächst etablierte Verfahren verwendet (Partikelgrößenmessung, REM und Quecksilberporosimetrie). Parallel dazu erfolgte die Entwicklung bzw. Einführung neuer Methoden. Im Vordergrund stand die Untersuchung des Sedimentationsverhaltens der Perlcellulosen durch analytisches Zentrifugieren. Davon ausgehend konnte ein Verfahren zur Berechnung der Porosität aus dem Sedimentationsvolumen entwickelt werden. Zum Nachweis der kompletten Deacetylierung der Proben wurde die Ramanspektroskopie genutzt. Durch die Anwendung vorhandener und die Entwicklung neuer Methoden wird die genaue Einstellung von Eigenschaften der Perlcellulosen (z. B. Partikelgröße und deren Verteilung, Morphologie sowie Porosität) ermöglicht und deren Reproduzierbarkeit gewährleistet. Weitere Versuche hatten die Entwicklung von Endotoxinadsorbermaterial auf Basis von Perlcellulose und Polymyxin-B-sulfat (PMB) zum Ziel. Die Kopplung des PMB erfolgte meist nach Aktivierung der Proben mit Epichlorhydrin. Zunächst wurde die eingesetzte Epichlorhydrinmenge variiert, um das Optimum für die Aktivierung der Perlcellulosen zu finden. Weiterhin wurden unterschiedliche Mengen PMB angebunden und die Anbindung an nicht aktivierte Proben untersucht. Die Planung aller Versuche erfolgte jeweils nach Auswertung der an der Donau-Universität Krems durchgeführten Limulus- Amöbocyten- Lysat (LAL)-Tests. Mittels dieser Batchtests wurde die Wirksamkeit des Endotoxinadsorbermaterials sowohl im Vergleich zu unbehandeltem Blutplasma und als auch zu kommerziell erhältlichen Adsorbern auf Polystyrenbasis getestet. Endotoxinadsorber, die bei diesen Tests besonders gut bewertet wurden, konnten in einem up-scale- Versuch erstmals in größeren Mengen synthetisiert werden. Auch die direkte Herstellung von Endotoxinadsorbermaterial aus Perlcelluloseacetat konnte realisiert werden. Bei diesem neu entwickelten Verfahren erfolgen Deacetylierung und Aktivierung in einem Schritt. Damit kann die Herstellung vereinfacht werden. Zur Gewährleistung der Erstfehlersicherheit in extrakorporalen Blutreinigungssystemen sollen magnetisierte Perlcellulosepartikel als bioverträgliche Marker eingesetzt werden. Versuche zur Magnetisierung von Cellulosemikropartikeln während des Herstellungsprozesses zeigten, dass die Einbindung von Magnetit bei Erhalt der sphärischen Partikelstruktur prinzipiell auch auf diesem homogenen Syntheseweg möglich ist.:1. EINLEITUNG 3 2. THEORETISCHE GRUNDLAGEN 5 2.1 CELLULOSE 5 2.1.1 Molekulare Struktur 7 2.1.2 Morphologische Struktur 9 2.1.3 Polymorphie 9 2.1.3.1 Native Cellulose 11 2.1.3.2 Weitere Cellulosemodifikationen 12 2.1.3.3 Umwandlung von Cellulose I in Cellulose II 13 2.1.4 Aktivierung 15 2.2 CELLULOSEACETAT 17 2.2.1 Herstellung 17 2.2.1.1 Technische Herstellung 18 2.2.1.2 Homogene Herstellungsmethoden 19 2.2.2 Eigenschaften und Charakterisierung 20 2.2.3 Verwendung 21 2.3 PERLCELLULOSE 22 2.3.1 Herstellung 23 2.3.1.1 Sprühverfahren 23 2.3.1.2 Suspensionsverfahren 24 2.3.1.3 Acetatverfahren 24 2.3.2 Charakterisierung 26 2.3.2.1 Partikelgröße und Partikelgrößenverteilung 26 2.3.2.2 Porosität 27 2.2.2.3 Quellwert 28 2.3.2.4 Weitere Methoden 28 2.3.3 Verwendung 30 2.3.3.1 Perlcellulose als Adsorbermaterial 30 2.3.3.2 Adsorption von Endotoxinen 31 2.3.4 Magnetisierung 36 2.3.4.1 Einsatz und Herstellung magnetischer Partikel 36 2.3.4.2 Einbindung von Magnetit in Perlcellulose 39 3. HERSTELLUNG VON PERLCELLULOSE 41 3.1 CELLULOSEACETAT ALS AUSGANGSSTOFF FÜR DIE SYNTHESE VON PERLCELLULOSE 41 3.1.1 Charakterisierung von Celluloseacetaten 41 3.1.1.1 Löslichkeit 41 3.1.1.2 Trübungsmessungen 42 3.1.1.3 Molmassenverteilung 44 3.1.1.4 Verteilung der Substituenten 45 3.1.1.5 Bestimmung des Substitutionsgrades mittels NMR und SEC 46 3.1.2 Einfluss der Celluloseacetate auf die Eigenschaften der Perlcellulose 47 3.1.2.1 Herstellung der Perlcellulosen 47 3.1.2.2 Messung der Partikelgröße 48 3.1.2.3 Charakterisierung der Perlcellulosen mittels Rasterelektronenmikroskopie 49 3.1.3 Schlussfolgerungen 51 3.2 HERSTELLUNG VON PERLCELLULOSE MIT DEFINIERTEN EIGENSCHAFTEN 52 3.2.1 Bildung der Celluloseperlen 52 3.2.2 Dispergieren im Inline- Ultraturrax 54 3.2.2.1 Einfluss der Drehzahl 54 3.2.2.2 Mehrfaches Dispergieren 56 3.2.2.3 Geschwindigkeit der Schlauchpumpe 58 3.2.2.4 Vergleich der Ergebnisse 59 3.2.3 Zusammensetzung der Emulsion 60 3.2.3.1 Salzgehalt 61 3.2.3.2 Methylcellulosekonzentration 62 3.2.3.3 Ethylacetatkonzentration 63 3.2.3.4 Tensidgehalt 65 3.2.3.5 Gleichzeitige Veränderung mehrerer chemischen Parameter 66 3.2.4 Aufbereitung des Perlcelluloseacetats 68 3.2.4.1 Abrotieren der Lösungsmittel 68 3.2.4.2 Reinigung und Deacetylierung 69 3.2.5 Standardbedingungen 69 4. CHARAKTERISIERUNG VON PERLCELLULOSEN 70 4.1 PARTIKELGRÖßENMESSUNG 70 4.2 RASTERELEKTRONENMIKROSKOPIE 70 4.3 QUECKSILBERPOROSIMETRIE 71 4.4 SEDIMENTATIONSVERHALTEN 73 4.4.1 Sedimentationsgeschwindigkeit 73 4.4.2 Berechnung der mittleren Teilchengröße 79 4.4.3 Sedimentationsvolumen 82 4.5 BESTIMMUNG DER POROSITÄT AUS DEM SEDIMENTATIONSVOLUMEN 83 4.5.1 Porositätsuntersuchungen an einer analytischen Multiprobenzentrifuge 83 4.5.2 Porositätsuntersuchungen an einer Laborzentrifuge 84 4.5.3 Vergleich der ermittelten Porositätswerte 85 4.6 RAMANSPEKTROSKOPIE 87 5. PERLCELLULOSE ALS ENDOTOXINADSORBERMATERIAL 88 5.1 ENTWICKLUNG VON ENDOXINADSORBERN AUF BASIS VON PERLCELLULOSE 88 5.1.1 Aktivierung von Perlcellulose 88 5.1.2 Anbindung von Polymyxin-B-Sulfat 90 5.2 CHARAKTERISIERUNG UND OPTIMIERUNG DES ENDOTOXINADSORBERMATERIALS 90 5.3 UP- SCALE- VERSUCH 96 5.4 WEITERE VERSUCHE MIT PERLCELLULOSE 98 5.5 ANBINDUNG VON PMB AN PERLCELLULOSEACETAT 102 5.6 BEWERTUNG UND AUSBLICK 107 6. MAGNETISCHE MARKERPARTIKEL AUF BASIS VON PERLCELLULOSE 109 6.1 HOMOGENE EINBINDUNG VON MAGNETIT IN PERLCELLULOSE 109 6.1.1 Auswahl des Dispergiergerätes 111 6.1.2 Optimierung der BUT- Drehzahl und der Dispergierzeit 112 6.1.3. Versuche mit Methylcellulose als Schutzkolloid 120 6.2 CHARAKTERISIERUNG DER MAGNETISIERTEN PERLCELLULOSEPARTIKEL 122 6.2.1 Partikelgröße 122 6.2.2 Rasterelektronenmikroskopie 124 6.2.3 Energiedispersive Röntgenmikroanalyse 126 6.2.4 Bestimmung des Eisengehaltes mittels AAS 128 6.2.5 Magnetische Messungen 129 6.3 BEWERTUNG DER BISHERIGEN ERGEBNISSE 130 7. ZUSAMMENFASSUNG UND AUSBLICK 132 8. EXPERIMENTELLES 135 8.1 CHEMIKALIEN 135 8.2 METHODISCHES 135 8.3 PRÄPARATIONSVORSCHRIFTEN UND ARBEITSANLEITUNGEN 136 8.3.1 Herstellen der Ausgangslösungen 136 8.3.2 Herstellung der Perlcellulosen 137 8.3.2.1 Herstellung des Perlcelluloseacetates 137 8.3.2.2 Deacetylierung des Perlcelluloseacetates 138 8.3.3 Aktivierung von Perlcellulosen 138 8.3.4 Herstellung von Endotoxinadsorbermaterial 138 8.3.5 Magnetitanbindung 139 LITERATUR 140 ABKÜRZUNGSVERZEICHNIS 152 ABBILDUNGSVERZEICHNIS 154 TABELLENVERZEICHNIS 158 / Bead cellulose is regenerated cellulose II characterized by spherically shaped, porous particles with a high specific surface and a good biocompatibility. Because of their properties these cellulose microspheres are especially suited for medical applications. The focus of this work was the synthesis, characterization and modification of bead cellulose with particle sizes between 1 to 10 µm. In the frame of this work seven technical cellulose-2.5-acetates were investigated with regard to their suitability for making bead cellulose according to the process described in EP0750007. These cellulose acetates have comparable molecular characteristics. Different properties were compared. Bead celluloses can be synthesized from all investigated cellulose acetates. A product with a molecular weight of more than 100,000 and with a ratio between molecular weight and numeric molecular weight of about 1.5 is special suited. This cellulose-2.5-acetate has a good solubility in ethyl acetate / methanol (100:17.5). The bead cellulose made from it has a low particle size and a relative narrow size distribution. Thus this cellulose acetate complies with the requirements for making bead cellulose. The most important process step for making bead cellulose is the dispersing of the emulsion using an inline-ultraturrax. The distribution of particle size depends mainly on the conditions during dispersing. A reproducible synthesis of cellulose microspheres with a particle size range below 5 µm was successfully achieved. In addition to determining conditions for manufacturing bead cellulose the characterization of the microspheres is essential to obtain bead cellulose with well defined properties. At first well-established methods of characterization were used (particle size measurement, SEM and mercury porosimetry). In parallel new methods were developed and implemented. The main focus was the investigation of sedimentation behaviour of bead cellulose using analytical centrifugation. Based on this knowledge of the sedimentation volume a new method to calculate the porosity was designed. Raman spectroscopy was used for detecting the complete deacetylation of the samples. By using well-established and newly developed methods properties of bead cellulose such as particle size and distribution, morphology and porosity can be accurately adjusted. In this way the reproducible synthesis of cellulose microspheres can be ensured. The aim of further experiments was to develop an endotoxin adsorber material based on a coupling of bead cellulose with Polymyxin B sulfate (PMB). The coupling with PMB was carried out after activation of the samples by using epichlorohydrin. At first the added epichlorohydrin amount was diversified in order to find the optimum for the activation of bead cellulose. Later the coupling of different amounts of PMB took place and the linking of PMB to non activated samples was investigated too. The planning of all experiments occurred after evaluation of Limulus amebocyte lysate (LAL) tests at Danube-University Krems. Using these batch tests the effectiveness of the endotoxin adsorber material was tested compared to untreated blood plasma as well as commercial available adsorbers based on polystyrene. Endotoxin adsorbers showing the best adsorption rate were then synthesized for the first time in larger quantities. Also the direct synthesis of endotoxin adsorber material based on bead cellulose acetate could be realized. Using this newly developed method, deacetylation and activation occur during the same step. This means manufacturing process can be simplified. Using magnetized bead cellulose as biocompatible marker particles is planned to achieve first fault safety in case of a membrane rupture during extracorporeal blood purification. Initial tests have shown that the magnetization of cellulose microspheres is possible during the manufacturing process. The incorporation of magnetite can be realized while keeping the spherical shape of the particles using this homogenous synthesis pathway.:1. EINLEITUNG 3 2. THEORETISCHE GRUNDLAGEN 5 2.1 CELLULOSE 5 2.1.1 Molekulare Struktur 7 2.1.2 Morphologische Struktur 9 2.1.3 Polymorphie 9 2.1.3.1 Native Cellulose 11 2.1.3.2 Weitere Cellulosemodifikationen 12 2.1.3.3 Umwandlung von Cellulose I in Cellulose II 13 2.1.4 Aktivierung 15 2.2 CELLULOSEACETAT 17 2.2.1 Herstellung 17 2.2.1.1 Technische Herstellung 18 2.2.1.2 Homogene Herstellungsmethoden 19 2.2.2 Eigenschaften und Charakterisierung 20 2.2.3 Verwendung 21 2.3 PERLCELLULOSE 22 2.3.1 Herstellung 23 2.3.1.1 Sprühverfahren 23 2.3.1.2 Suspensionsverfahren 24 2.3.1.3 Acetatverfahren 24 2.3.2 Charakterisierung 26 2.3.2.1 Partikelgröße und Partikelgrößenverteilung 26 2.3.2.2 Porosität 27 2.2.2.3 Quellwert 28 2.3.2.4 Weitere Methoden 28 2.3.3 Verwendung 30 2.3.3.1 Perlcellulose als Adsorbermaterial 30 2.3.3.2 Adsorption von Endotoxinen 31 2.3.4 Magnetisierung 36 2.3.4.1 Einsatz und Herstellung magnetischer Partikel 36 2.3.4.2 Einbindung von Magnetit in Perlcellulose 39 3. HERSTELLUNG VON PERLCELLULOSE 41 3.1 CELLULOSEACETAT ALS AUSGANGSSTOFF FÜR DIE SYNTHESE VON PERLCELLULOSE 41 3.1.1 Charakterisierung von Celluloseacetaten 41 3.1.1.1 Löslichkeit 41 3.1.1.2 Trübungsmessungen 42 3.1.1.3 Molmassenverteilung 44 3.1.1.4 Verteilung der Substituenten 45 3.1.1.5 Bestimmung des Substitutionsgrades mittels NMR und SEC 46 3.1.2 Einfluss der Celluloseacetate auf die Eigenschaften der Perlcellulose 47 3.1.2.1 Herstellung der Perlcellulosen 47 3.1.2.2 Messung der Partikelgröße 48 3.1.2.3 Charakterisierung der Perlcellulosen mittels Rasterelektronenmikroskopie 49 3.1.3 Schlussfolgerungen 51 3.2 HERSTELLUNG VON PERLCELLULOSE MIT DEFINIERTEN EIGENSCHAFTEN 52 3.2.1 Bildung der Celluloseperlen 52 3.2.2 Dispergieren im Inline- Ultraturrax 54 3.2.2.1 Einfluss der Drehzahl 54 3.2.2.2 Mehrfaches Dispergieren 56 3.2.2.3 Geschwindigkeit der Schlauchpumpe 58 3.2.2.4 Vergleich der Ergebnisse 59 3.2.3 Zusammensetzung der Emulsion 60 3.2.3.1 Salzgehalt 61 3.2.3.2 Methylcellulosekonzentration 62 3.2.3.3 Ethylacetatkonzentration 63 3.2.3.4 Tensidgehalt 65 3.2.3.5 Gleichzeitige Veränderung mehrerer chemischen Parameter 66 3.2.4 Aufbereitung des Perlcelluloseacetats 68 3.2.4.1 Abrotieren der Lösungsmittel 68 3.2.4.2 Reinigung und Deacetylierung 69 3.2.5 Standardbedingungen 69 4. CHARAKTERISIERUNG VON PERLCELLULOSEN 70 4.1 PARTIKELGRÖßENMESSUNG 70 4.2 RASTERELEKTRONENMIKROSKOPIE 70 4.3 QUECKSILBERPOROSIMETRIE 71 4.4 SEDIMENTATIONSVERHALTEN 73 4.4.1 Sedimentationsgeschwindigkeit 73 4.4.2 Berechnung der mittleren Teilchengröße 79 4.4.3 Sedimentationsvolumen 82 4.5 BESTIMMUNG DER POROSITÄT AUS DEM SEDIMENTATIONSVOLUMEN 83 4.5.1 Porositätsuntersuchungen an einer analytischen Multiprobenzentrifuge 83 4.5.2 Porositätsuntersuchungen an einer Laborzentrifuge 84 4.5.3 Vergleich der ermittelten Porositätswerte 85 4.6 RAMANSPEKTROSKOPIE 87 5. PERLCELLULOSE ALS ENDOTOXINADSORBERMATERIAL 88 5.1 ENTWICKLUNG VON ENDOXINADSORBERN AUF BASIS VON PERLCELLULOSE 88 5.1.1 Aktivierung von Perlcellulose 88 5.1.2 Anbindung von Polymyxin-B-Sulfat 90 5.2 CHARAKTERISIERUNG UND OPTIMIERUNG DES ENDOTOXINADSORBERMATERIALS 90 5.3 UP- SCALE- VERSUCH 96 5.4 WEITERE VERSUCHE MIT PERLCELLULOSE 98 5.5 ANBINDUNG VON PMB AN PERLCELLULOSEACETAT 102 5.6 BEWERTUNG UND AUSBLICK 107 6. MAGNETISCHE MARKERPARTIKEL AUF BASIS VON PERLCELLULOSE 109 6.1 HOMOGENE EINBINDUNG VON MAGNETIT IN PERLCELLULOSE 109 6.1.1 Auswahl des Dispergiergerätes 111 6.1.2 Optimierung der BUT- Drehzahl und der Dispergierzeit 112 6.1.3. Versuche mit Methylcellulose als Schutzkolloid 120 6.2 CHARAKTERISIERUNG DER MAGNETISIERTEN PERLCELLULOSEPARTIKEL 122 6.2.1 Partikelgröße 122 6.2.2 Rasterelektronenmikroskopie 124 6.2.3 Energiedispersive Röntgenmikroanalyse 126 6.2.4 Bestimmung des Eisengehaltes mittels AAS 128 6.2.5 Magnetische Messungen 129 6.3 BEWERTUNG DER BISHERIGEN ERGEBNISSE 130 7. ZUSAMMENFASSUNG UND AUSBLICK 132 8. EXPERIMENTELLES 135 8.1 CHEMIKALIEN 135 8.2 METHODISCHES 135 8.3 PRÄPARATIONSVORSCHRIFTEN UND ARBEITSANLEITUNGEN 136 8.3.1 Herstellen der Ausgangslösungen 136 8.3.2 Herstellung der Perlcellulosen 137 8.3.2.1 Herstellung des Perlcelluloseacetates 137 8.3.2.2 Deacetylierung des Perlcelluloseacetates 138 8.3.3 Aktivierung von Perlcellulosen 138 8.3.4 Herstellung von Endotoxinadsorbermaterial 138 8.3.5 Magnetitanbindung 139 LITERATUR 140 ABKÜRZUNGSVERZEICHNIS 152 ABBILDUNGSVERZEICHNIS 154 TABELLENVERZEICHNIS 158