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It is known that a newly formed glass container will only possess a very small fraction of its theoretical strength. This suggests that damage occurs on the surface of the glass melt during the forming process due to glass to mould contact and hot glass handling. It might be expected that any damage inflicted on the surface of a glass article during manufacture would heal at the elevated manufacturing temperatures used, however this does not appear to be true. Therefore, the actual mechanism by which glass strength is reduced during forming needs to be fully understood and the work presented in this thesis addresses this problem. Experiments, therefore, have been carried out here which simulate the formation of glass articles using an experimental pressing rig by systematically altering processing parameters such as the mould material, surface fmish of the mould, pressing temperature and atmosphere. Processing parameters that are used industrially for the formation of glass containers were generally reproduced wherever possible in order to investigate the glass-to-mould interaction. The interaction of both a cast iron mould material and carbon-carbon composite materials with a soda-lime-silica glass were examined using the techniques of scanning electron microscopy, x-ray photoelectron spectroscopy and atomic force microscopy in order to determine the type and extent of surface damage formed. The surfaces of the pressed glass samples made were found to contain defects of embedded particles and indented dimples. The embedded particles found were usually due to bulk material transfer from the plunger material used. The texture found on the surface of the pressed glass samples was found to be directly affected by the surface fmish of the plunger. Pressing glass samples using a cast iron plunger at an initial plunger temperature below 450°C resulted in a randomly rippled 'chilled' surface. As the initial temperature of the plunger was increased, the surface texture of the pressed glass became a closer replica of the plunger surface. The use of vacuum assistance to form the glass samples also resulted in the surface of the pressed glass becoming a closer replica of the original plunger surface, even at lower pressing temperatures. The surfaces of the cast iron and carbon-carbon composite plungers appeared to have been affected by the initial plunger temperatures used. As the initial pressing temperature was increased, the amount of oxidation for both material types increased. In the case of the carbon-carbon composite materials investigated, both the matrix and fibres were found to have broken down at the pressing temperatures used. X-ray photoelectron spectroscopy, of the pressed glass surfaces and the plunger materials indicated that sodium ions had migrated from the glass melt to the plunger surface during forming.

Thesis (M.S.)--Rochester Institute of Technology, 1991. / Typescript. Includes bibliographical references (leaves 54-56).

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / The administration of medication and nutrients via parenteral is very used nowadays. One of the risks of this procedure is the presence of contaminants, which depending on their nature may cause severe damage to the patients due to the direct way of the administration (in the circulatory stream). In this work we investigated the possibility of the containers to be sources of metals for solutions of parenteral nutrition. The investigated containers are made of different kinds of glass and plastic polymers, namely polypropylene, PVC and EVA. The system container/solution (amino acids, salts, glucose and lipids) individually stored, was submitted to the sterilization process and after that stored for a time period of approximately 10 months, since the shelf-life period of these formulations are generally 2 years. After the sterilization and at regular time intervals, aliquots of each solution were collected and their contents on Al, Pb, Cd, Fe, Cr, Mn, Ba, and Zn were measured by graphite furnace atomic absorption spectrometry. The containers were also analyzed for the determination of the amount of each metal they contained. These metals are either constituents of the container material, as Al in glasses, or impurities in the case of plastic polymers. All containers presented the metals investigated. The solutions, depending on their composition (species dissolved) were able to extract the metals either from the glass or the polymers. The highest extraction rates occurred in solutions of the amino acids cysteine and glutamic acid, and in solutions of NaHCO3. The metals released in higher concentration were Ba, Pb and Zn form plastic containers and Al, Pb and Zn form glass containers. A different behavior was observed among the plastic polymers, and the different kinds of glass. While EVA was the most inert polymer, the clear glass ampoule released the highest amount of metals into the solutions. Fifty commercial samples were analyzed as well, and the investigated metals were found in all of them. The commercial formulations presented the same tendency of the individual sample used in the study, either in relation to the behavior of the substance in solution or the container material. / Atualmente a administração parenteral, tanto de medicamentos quanto nutrientes, é uma prática muito difundida. Um dos riscos desta prática é a presença de contaminantes que, dependendo da sua natureza, podem acarretar graves danos aos pacientes devido à forma direta (na corrente circulatória) da administração. Neste trabalho, investigou-se a possibilidade das embalagens serem fontes de contaminação por metais de soluções utilizadas na nutrição parenteral. As embalagens investigadas incluíram vários tipos de vidro e polímeros plásticos mais comumente utilizados (polipropileno, polivinil cloreto (PVC) e etil vinil acetato(EVA)). As embalagens, nas quais foram armazenados individualmente os constituintes das soluções parenterais (aminoácidos, sais, glicose, vitaminas e lipídeos), foram submetidas ao processo de esterilização e de armazenagem a longo prazo, visto que a validade deste tipo de formulação é geralmente de 2 anos. Após a esterilização e em intervalos de tempo regulares, alíquotas das soluções foram retiradas e os teores em Al, Pb, Cd, Fe, Cr, Mn, Ba e Zn foram medidos por espectrometria de absorção atômica forno de grafite (GF AAS) e espectrometria de massa com plasma indutivamente acoplado (ICP-MS). As embalagens utilizadas foram também analisadas para determinar quanto dos metais em estudo elas apresentavam, seja como constituinte, como é o caso do Al no vidro, ou como impureza, no caso de todos os metais nos polímeros plásticos. Todas as embalagens continham os metais em estudo em maior ou menor concentração. As soluções, dependendo dos seus constituintes foram capazes de extrair os metais, tanto do vidro quanto do plástico. As maiores taxas de extração ocorreram com as soluções dos aminoácidos cisteína e acido glutâmico. Os metais extraídos em maiores quantidades foram Ba, Pb e Zn das embalagens plásticas e Al, Pb e Zn das embalagens de vidro. Observou-se diferente comportamento entre os diferentes polímeros e tipos de vidro. O EVA mostrou-se o polímero mais inerte, enquanto que as ampolas transparentes foram as que mais metais liberaram para as soluções. Foram analisadas, também, 50 amostras comerciais, as quais se mostraram contaminadas pelos metais em estudo. Observou-se nas soluções comerciais a mesma tendência das soluções individuais do estudo, tanto com relação ao comportamento da embalagem, quanto ao conteúdo (ação do componente sobre a embalagem) e os metais extraídos.

O problema de dimensionamento e sequenciamento de lotes vem sendo extensivamente estudado por pesquisadores da área de Pesquisa Operacional e há uma tendência de que tais trabalhos passem a cada vez mais integrar aspectos reais dos processos produtivos. Entretanto, percebe-se que os estudos conduzidos em alguns setores industriais negligenciam importantes restrições tecnológicos dos processos de produção e isso afasta esses trabalhos de Pesquisa Operacional de uma aplicação efetiva, como é o caso da indústria de embalagens de vidro. Neste contexto, propõe-se um modelo de programação inteira mista e um método de solução para o problema de dimensionamento e sequenciamentos de lotes na indústria de embalagens de vidro, sendo que este trabalho diferencia-se dos demais existentes na literatura por agregar restrições tecnológicas específicas desse processo produtivo. O modelo proposto, denominado CLSD-GCST, foi amplamente validado com base em um conjunto de testes com 40 instâncias de um problema real de uma grande empresa do setor no pacote comercial IBM ILOG CPLEX Optimization Studio Versão 12.5. A validação do modelo incluiu ainda uma análise de ganhos potenciais para o negócio de baseada no modelo SCOR. Já o método de solução proposto consiste em uma metaheurística de Busca em Vizinhança Variável (VNS) e se mostrou promissor para a solução do problema estudado, proporcionando resultados de qualidade em um baixo tempo computacional. Além disso, o VNS superou o Branch-and-Cut do CPLEX para grandes instâncias, nas quais o pacote comercial encontrou dificuldades. Por fim, o VNS proposto também foi validado por meio da análise de testes computacionais e suas principais características foram avaliadas sistematicamente, gerando um conjunto de informações que pode direcionar a utilização e, até mesmo, a evolução desse método em pesquisas futuras. / Lot sizing and scheduling problem has been extensively studied by Operations Research scientists and there is a tendency of incorporating more production processes real aspects in these researches. However, it can be noticed that studies conducted in some industrial sectors neglect important production process technological constraints and it keeps the Operations Research works away from an effective application, as happens with the glass containers industry. In this context, a mixed integer programming model and a solution method were proposed for glass containers industry lot sizing and scheduling problem, the main difference between this work and the others in literature is the inclusion of process specific technological constraints. The proposed model, named CLSD-GCST, was widely validated by a set of tests performed with 40 instances from a large company real problem using the commercial package IBM ILOG CPLEX Optimization Studio Version 12.5. The model validation also included a potential business earnings analysis based on SCOR framework. About the proposed solution method, it consists of a Variable Neighborhood Search (VNS) metaheuristic and it proved to be promising for the studied problem solution, providing good quality results in low computational time. Moreover, VNS overcame the CPLEX Branch-and-Cut for large instances, in which the commercial package found difficulties. Lastly, the proposed VNS was validated by means of computational tests analysis and its main characteristics were systematically evaluated, generating an information set that may direct this method application and even its evolution in future researches.

O problema de dimensionamento e sequenciamento de lotes vem sendo extensivamente estudado por pesquisadores da área de Pesquisa Operacional e há uma tendência de que tais trabalhos passem a cada vez mais integrar aspectos reais dos processos produtivos. Entretanto, percebe-se que os estudos conduzidos em alguns setores industriais negligenciam importantes restrições tecnológicos dos processos de produção e isso afasta esses trabalhos de Pesquisa Operacional de uma aplicação efetiva, como é o caso da indústria de embalagens de vidro. Neste contexto, propõe-se um modelo de programação inteira mista e um método de solução para o problema de dimensionamento e sequenciamentos de lotes na indústria de embalagens de vidro, sendo que este trabalho diferencia-se dos demais existentes na literatura por agregar restrições tecnológicas específicas desse processo produtivo. O modelo proposto, denominado CLSD-GCST, foi amplamente validado com base em um conjunto de testes com 40 instâncias de um problema real de uma grande empresa do setor no pacote comercial IBM ILOG CPLEX Optimization Studio Versão 12.5. A validação do modelo incluiu ainda uma análise de ganhos potenciais para o negócio de baseada no modelo SCOR. Já o método de solução proposto consiste em uma metaheurística de Busca em Vizinhança Variável (VNS) e se mostrou promissor para a solução do problema estudado, proporcionando resultados de qualidade em um baixo tempo computacional. Além disso, o VNS superou o Branch-and-Cut do CPLEX para grandes instâncias, nas quais o pacote comercial encontrou dificuldades. Por fim, o VNS proposto também foi validado por meio da análise de testes computacionais e suas principais características foram avaliadas sistematicamente, gerando um conjunto de informações que pode direcionar a utilização e, até mesmo, a evolução desse método em pesquisas futuras. / Lot sizing and scheduling problem has been extensively studied by Operations Research scientists and there is a tendency of incorporating more production processes real aspects in these researches. However, it can be noticed that studies conducted in some industrial sectors neglect important production process technological constraints and it keeps the Operations Research works away from an effective application, as happens with the glass containers industry. In this context, a mixed integer programming model and a solution method were proposed for glass containers industry lot sizing and scheduling problem, the main difference between this work and the others in literature is the inclusion of process specific technological constraints. The proposed model, named CLSD-GCST, was widely validated by a set of tests performed with 40 instances from a large company real problem using the commercial package IBM ILOG CPLEX Optimization Studio Version 12.5. The model validation also included a potential business earnings analysis based on SCOR framework. About the proposed solution method, it consists of a Variable Neighborhood Search (VNS) metaheuristic and it proved to be promising for the studied problem solution, providing good quality results in low computational time. Moreover, VNS overcame the CPLEX Branch-and-Cut for large instances, in which the commercial package found difficulties. Lastly, the proposed VNS was validated by means of computational tests analysis and its main characteristics were systematically evaluated, generating an information set that may direct this method application and even its evolution in future researches.

Die Einbrennsilikonisierung wird schon lange verwendet, um spezielle Eigenschaften bei pharmazeutischen Glasbehältnissen zu erzielen. Üblicherweise werden Silikonöle verwendet um Gleitfilme auf den Oberflächen vorgefüllter Glasspritzen zu erzeugen oder die Glaswand zu hydrophobieren damit wäßrige Inhalte sauber ablaufen können. Weiterhin kann durch die hydrophobe Deaktivierung der Glaswände eine Reduktion der Adsorption von Wirk- und Hilfsstoffen sowie eine Erhöhung der hydrolytischen Resistenz erreicht werden. Wegen des parenteralen Verwendungszweckes werden meistens Gläser der Glasart 1 entsprechend dem europäischen Arzneibuch eingesetzt. Die Silikonölfilme (Trimethylsiloxy-endgeblockte Polydimethylsiloxane, PDMS) werden aus verdünnter wäßriger Emulsion auf der inneren Behältnisoberfläche gespreitet und anschließend bei Temperaturen oberhalb von 300°C für ca. 10-30 min hitzebehandelt. Neben der Sterilisation und Entpyrogenisierung wird der Silikonfilm durch das Einbrennen verändert. In der Literatur wurde dieser Prozeß bisher als Hitzefixierung oder -härtung bezeichnet in der Annahme, daß das Silikonöl durch Glasbindung oder Quervernetzung immobilisiert wird. Es wurden weitere Effekte wie Verdampfung oder Zersetzungsreaktionen als Folge der Hitzebehandlung angenommen. Die Dissertation hatte daher zum Ziel diese Vorstellungen analytisch zu belegen. Die Eigenschaften einbrennsilikonisierter Gläser lassen sich durch einfache Experimente beschreiben. Durch organische Extraktion der Gläser (z.B. Toluol, Dichlormethan) läßt sich der überwiegende Silikonanteil (ca. 80%) wiederfinden. Nach erschöpfender Extraktion zeigt sich eine beständige Hydrophobie z.B. durch die Ausbildung hoher Randwinkel von Wasser oder das veränderte Ablaufverhalten von Flüssigkeiten in diesen Behältnissen festgestellt werden. Basierend auf diesen Beobachtungen wurde die Anwesenheit einer gebundenen neben einer löslichen Silikonölfraktion nach dem Einbrennen angenommen. Alle analytischen Studien wurden an dieser zwei Lagen Theorie orientiert und durchgeführt. Dazu wurden einige oberflächensensitive Techniken wie z.B. die kombinierte Röntgenphotoelektronen- und Augerelektronenspektroskopie (XPS/AES) und die Flugzeit-Sekundärionenmassenspektroskopie (TOF-SIMS) eingesetzt. Durch chemische Zustandsdiagramme und massenspektroskopische Strukturanalyse konnte die Ausbildung von Bindungen zwischen Glas und Silikon detektiert werden. Kontaktwinkelmessungen zeigten, daß das gebundene Silikon bis ca. 400°C thermostabil ist und oberhalb von 450°C pyrolysiert wird. Die extrahierbare Silikonfraktion wurde ebenfalls mit einigen analytischen Techniken im Vergleich mit den jeweiligen unbehandelten Ausgangsmaterialien untersucht. Chromatographische Studien mittels Größenausschluß- und Hochtemperatur-Gaschromatographie (SEC,GC) zeigten signifikante Unterschiede in der polymeren Zusammensetzung des PDMS. Die Molekulargewichtsmittel stiegen als Folge von Verlusten von niedermolekularen Siloxanen einer Größe zwischen 0-100 Siloxaneinheiten (SU) an. Diese Defizite können auf Verdampfungs- (0-50 SU) und Zersetzungsreaktionen (50-100 SU) zurückgeführt werden. Die Untersuchung des extrahierbaren eingebrannten Silikonöls mit der Fourier Transform Infrarot Spektroskopie (FTIR) zeigte keine strukturelle Veränderung der PDMS Moleküle, z.B. durch Hydrolyse, Oxidation oder Verzweigung an. Die Emulgatoren werden durch das Einbrennen zerstört. Dies wurde durch die 1H-Kernresonanz Spektroskopie (1H-NMR) nachgewiesen. Die Thermostabilität des PDMS wird durch katalytische Effekte der Emulsionshilfsstoffe und durch die Anwesenheit von Sauerstoff erniedrigt, wie aus thermogravimetrische Analysen (TGA) mit kommerziellen Silikonölen und Ölemulsionen modellhaft abgeleitet wurde. Um die Migration von Silikonölspuren in Arzneimittel in silikonisierten Glasbehältnissen zu bewerten wurde eine Atom Absorptions spektroskopische (AAS) Methode entwickelt und entsprechend den ICH-Richtlinien validiert (Bestimmungsgrenze in Liquida 10 mg/L). Die Schlußfolgerung aus den Analysen ist, daß nach der Einbrennsilikonisierung zwei differenzierbare Silikonfraktionen an der Glasoberfläche anwesend sind. Die kovalent gebundene Dünnschicht ist unlöslich und verliert ihren Ölcharakter, ist aber für die Hydrophobisierung ausreichend. In der löslichen Fraktion, werden die mittleren Molekulargewichte durch den Verlust von niedermolekularen Anteilen erhöht. Der Anteil dieser Schicht hängt von der eingesetzten Ausgangsmenge an Silikonöl ab. Durch die Entfernung der niedermolekularen Anteile und die Zerstörung der Emulgatoren können toxikologische Bedenken zurückgestellt werden. / Heat Curing Siliconization of Pharmaceutical Glass Containers The heat curing siliconization has long since been used to introduce special properties to pharmaceutical glass containers. Silicone oils are usually applied to the containers to form lubricating films on the inner surface of prefilled syringes or to gain hydrophobic container walls for clear draining aqueous solutions, e.g. in injection vials. Furthermore the deactivation of the glass wall reduces adsorption of hydrophilic drug compounds and increases the hydrolytic stability of the glass surface. Due to the parenteral targeting the glass containers are made from glass type 1 according to the European Pharmacopoeia. The silicone oil films (= trimethylsiloxy endcapped polydimethylsiloxane, PDMS) are spread from diluted aqueous silicone oil emulsions on the inner surface and successively heat treated above 300°C for 10-30 minutes. Apart from sterilization and depyrogenation, the silicone layer is changed by the burning-in treatment. In literature the process has previously been designated as heat fixing or heat curing assuming that silicone oil is immobilized by bonding to the glass or branching. Further effects such as vaporization or degradation were suggested along with the heating. Proving these suggestions analytically was therefore the aim of the dissertation. The properties of siliconized glass containers can be characterized by simple experiments. Extraction of the glasses with suitable organic solvents (e.g. toluene, dichloromethane) recovers most of the silicone (approximately 80%) after a typical heat curing process. Still, after exhaustive solvent extraction there are persisting hydrophobic properties of the glasses evidenced by high contact angles of water and changed draining behaviour of fluids in the containers. From this observations it was assumed that a bound and a soluble silicone species is present after the heat curing siliconization. All analytical studies were based on the two-layer hypothesis and thus divided in two parts. Several surface analysis techniques were employed to detect and characterize the fixed silicone layer among them the combined X-ray photoelectron and augerelectron spectroscopy (XPS/AES) and time-of-flight secondary ion mass spectroscopy (TOF-SIMS). The formation of new bonds between silicone and glass was evidenced by chemical state plots and mass spectroscopic structural analysis. Contact angle measurements showed that the bound silicone was thermostable up to 400°C and pyrolyzed at temperatures above 450°C. The extractable silicone was also studied with several analytical techniques in comparison with the respective uncured starting materials. Chromatographic studies using size exclusion (SEC) and high temperature gas chromatography (GC) revealed significant changes in the composition of the silicone polymer. The molecular weight averages increase because low molecular weight siloxanes (LMWS) with 0-100 dimethylsiloxane units are removed through the heat curing process. These deficits can be related to vaporization (molecules from 0-50 units) and degradation (molecules from 0-100 units) effects. A Fourier transform infrared spectroscopic (FTIR) investigation of the molecular structure of the extractable PDMS after heat treatment showed no chemical changes e.g. by hydrolysis, branching or oxidation. The emulsifiers are destroyed in the heating process which was proved by a proton nuclear magnetic resonance (1H-NMR) study. The thermostability of the silicones is decreased by katalytic effects of auxiliary substances in the emulsions and the presence of oxygen. This was concluded from model thermogravimetric studies (TGA) with commercial medical grade silicone oils and emulsions. To evaluate migration of silicone traces to drug formulations in siliconized glass containers a trace analytical method by graphite furnace atomic absorption spectrometry (GF-AAS) was developed and validated according to the ICH guidelines. In liquid formulations levels of 10µg/L can be properly quantified. It was concluded that two main species of silicone can be differentiated on the glass surface after heat curing siliconization. The bonded thin layer is insoluble and sufficient for hydrophobic deactivation. The oil properties are lost. The extractable fraction is altered by removal of LMWS which increases molecular weight and viscosity and determines the lubricating properties. Its amount depends on the used silicone mass. No toxicological concern has to be made about LMWS and emulsifiers in the drug product due to their removal in the curing step.

Assessment of odor thresholds is a widely recognized method of measuring olfactory abilities in humans. To date no attempts have been made to assess whether chemical complexity of odors used can produce more reliable results. To this end, we performed two studies of repeated measures design with 121 healthy volunteers (age 19–62 years). In Study 1, we compared thresholds obtained from tests based on one odor presented in a pen-like odor dispensing device with three odors and six odors mixtures presented in glass containers. In study 2 we compared stimuli of one and three odors, both presented in glass containers. In both studies measurements were performed twice, separated by at least three days. Results indicate that the multiple odor mixtures produced more reliable threshold scores, as compared to thresholds based on a single substance.

Assessment of odor thresholds is a widely recognized method of measuring olfactory abilities in humans. To date no attempts have been made to assess whether chemical complexity of odors used can produce more reliable results. To this end, we performed two studies of repeated measures design with 121 healthy volunteers (age 19–62 years). In Study 1, we compared thresholds obtained from tests based on one odor presented in a pen-like odor dispensing device with three odors and six odors mixtures presented in glass containers. In study 2 we compared stimuli of one and three odors, both presented in glass containers. In both studies measurements were performed twice, separated by at least three days. Results indicate that the multiple odor mixtures produced more reliable threshold scores, as compared to thresholds based on a single substance.