O ambiente produtivo denominado job shop representa empresas manufatureiras com características como: alta variedade de produtos, volume baixo de produção e uma fábrica dividida em áreas funcionais. O problema abordado neste trabalho trata da determinação do programa de produção (scheduling) de cada lote de produtos no ambiente job shop, com a premissa de que cada produto a ser elaborado surge através de um pedido realizado pelo cliente com especificações e particularidades próprias. O objetivo do trabalho é apresentar e examinar de forma detalhada as formulações matemáticas do tipo linear inteira mista (PLIM), encontradas na literatura para o ambiente que consideram a função objetivo do makespan. Além disso, se estabelece uma nova formulação matemática que auxilia a simulação do ambiente. Todas as formulações foram comparadas através de suas dimensões e testes computacionais. Adicionalmente são apresentadas três diferentes estratégias de resolução que permitem a exploração de soluções obtidas através de diferentes metodologias. A primeira estratégia estabelece para cada instância uma solução inicial que promove uma redução do número de combinações a serem avaliadas pelo software, a segunda estratégia combina duas formulações tornando uma formulação unificada, e a terceira estratégia, estabelece um processo que utiliza duas formulações de forma consecutiva compondo um procedimento sistemático. Experimentos computacionais indicam que a formulação com melhor desempenho para o problema de job shop é a formulação de Manne (1960) por obter o melhor limitante superior (upper bound). A formulação proposta apresenta o melhor limitante inferior (lower bound). Todas as formulações melhoram seus resultados através do uso das estratégias propostas. / The operational job shop environment, represents manufacturing companies with high product variety, low volume production and an organization divided into functional areas. The problem addressed in this work determines the production schedule of each batch production, with the premise that each product results from a request made by the client with specifications and its own particularities. The main objective here is to present and to examine in detail the mathematical integer - linear program formulations (MILP) from the literature for the job shop classic environment, which considers the makespan objective. Furthermore, a new mathematical formulation is provided to help with the simulation of the environment. All the formulations were compared by mathematical dimensions and computational tests. In addition, three different strategies are presented to promote the exploration of solutions obtained from new methodologies. The first strategy defines an initial solution for each problem and promotes a reduction of the combination number to be evaluated by the software. The second strategy considers the combination of two mathematical formulations under one objective function. The third strategy establishes a procedure in which two mathematical formulations are used consecutively, creating a systematic procedure. Computational experiments demonstrate that the best formulation for the job shop problem is the Manne (1960) formulation, since it obtains the best upper bound. The proposal formulation obtains the best lower bound. All of the formulations improve their results through the use of the proposed strategies.

The research described in this thesis began with a single long-term objective: modelling of the vertebral artery during chiropractic manipulation of the cervical spine. Although chiropractic treatment has become prevalent, the possible correlation between neck manipulation and subsequent stroke in patients has been the subject of debate without resolution. Past research has been qualitative or statistical, whereas resolution demands a fundamental understanding of the associated mechanics.<p> Analysis in the thesis begins with a study of the anatomy and properties pertinent to the chiropractic problem. This indicates that the complexity of the problem will necessitate a long-term multidisciplinary effort including a nonlinear finite element formulation effective in analysing image data for soft tissue modelled as nearly incompressible. This leads to an assessment of existing finite element methods and the conclusion that new equation solving techniques are needed to ensure numerical stability.<p> Three techniques for effectively eliminating the source of numerical instability are developed and demonstrated with the aid of original finite element codes. Two of the methods are derived as modifications of matrix decomposition algorithms, while the third method constitutes a new finite element formulation. In addition, the understanding gained in developing these methods is used to produce a theorem for assessing a different but related problem: deformation of a nearly incompressible material subjected to a single concentrated force. Throughout the thesis, an interdisciplinary path from chiropractic problem to numerical algorithms is outlined, and results are in the form of mathematical proofs and derivations of both existing and new methods.

This master thesis considers an investigation of protective formulations (ointment, cream) containing enzyme inhibitors. Model experiments have been made on the enzyme trypsin. It is well accepted that feces and urine are an important causing factor for skin irritation (dermatitis) while using diaper. A protective formulation is a physical barrier that separates the harmful substances from the skin. It can also be an active barrier containing active substances, which can be active both towards the skin, and the substances from feces and urine. By preventing contact from these substances the skin will not be harmed, at least for a period of time. A number of different inhibitors were tested towards trypsin and they all showed good inhibition, two of the inhibitors were selected to be immobilized with the help of NHS-­activated Sepharose. Immobilization of these two inhibitors leads to a lesser extent of the risk of developing allergy and also that the possible toxic effect can be minimized.

The research described in this thesis began with a single long-term objective: modelling of the vertebral artery during chiropractic manipulation of the cervical spine. Although chiropractic treatment has become prevalent, the possible correlation between neck manipulation and subsequent stroke in patients has been the subject of debate without resolution. Past research has been qualitative or statistical, whereas resolution demands a fundamental understanding of the associated mechanics.<p> Analysis in the thesis begins with a study of the anatomy and properties pertinent to the chiropractic problem. This indicates that the complexity of the problem will necessitate a long-term multidisciplinary effort including a nonlinear finite element formulation effective in analysing image data for soft tissue modelled as nearly incompressible. This leads to an assessment of existing finite element methods and the conclusion that new equation solving techniques are needed to ensure numerical stability.<p> Three techniques for effectively eliminating the source of numerical instability are developed and demonstrated with the aid of original finite element codes. Two of the methods are derived as modifications of matrix decomposition algorithms, while the third method constitutes a new finite element formulation. In addition, the understanding gained in developing these methods is used to produce a theorem for assessing a different but related problem: deformation of a nearly incompressible material subjected to a single concentrated force. Throughout the thesis, an interdisciplinary path from chiropractic problem to numerical algorithms is outlined, and results are in the form of mathematical proofs and derivations of both existing and new methods.

The shock compression of Reactive Particle Metal Mixtures (RPMMs) is studied at the microscale by direct numerical simulation. Mixture microstructures are rendered explicitly, providing spatial resolution of the coupled thermal, mechanical, and chemical responses at the particle level during shock compression. A polymer-bonded aluminum-iron oxide thermite system is the focus of this work; however, the computational methods developed here may be extended to other reactive particle systems. Shock waves are propagated through the mixtures in finite element simulations, where Eulerian formulations are used to handle the highly-dynamic nature of particulate shock compression. Thermo-mechano-chemical responses are computed for a set of mixture classes (20% and 50% epoxy content by weight) subjected to a range of dynamic loading conditions (particle velocities ranging from 0.300??00 km/s). Two critical sub-problems are addressed: (i) the calculation of Hugoniot data for variable mixture compositions and (ii) the prediction of sites that experience microscale reaction initiation. Hugoniot calculations are in excellent agreement with experimental data. Microscale reaction initiation sites are predicted in certain load cases for each mixture class, although such predictions cannot currently be validated by experimental methods.

Developments in high throughput screening and combinatorial chemistry have contributed to the unprecedented success of the pharmaceutical industry over the last twenty years, leading to a multitude of blockbuster compounds that revolutionized treatment for a variety of clinical indications. This success, particularly in drug discovery, has been tempered by an increased number of moieties exhibiting delivery limitations due to molecular structure. One of the most pressing areas of pharmaceutical research today is addressing the reduced aqueous solubility of developmental chemical entities in pharmaceutical pipelines, which has been estimated to affect up to 90% of such compounds. Current technologies have focused on maximizing dissolution rates or equilibrium solubilities of such compounds using platforms such as microemulsions, polymorph engineering, particle size reduction, and complexation. While these technologies have been shown to improve oral bioavailability for a number of compositions, further improvement can be achieved by developing new production and formulation technologies for amorphous systems. Within the frame work of this dissertation, two unique technologies for bioavailability enhancement were investigated; formulation with concentration enhancing polymers to provide extended durations of supersaturation and the development of a novel fusion based solid dispersion production process based on thermo-kinetic mixing, termed KinetiSol® Dispersing, for the production of amorphous solid dispersions. Studies of solid dispersions containing concentration enhancing polymers prepared by ultra rapid freezing showed the ability of these formulations to provide improved oral bioavailability of itraconazole when compared to the currently marketed product, which is a conventional hydrophilic solid dispersion. KinetiSol® Dispersing was also extensively studied within this work and shown to be a viable platform for the production of hydrophilic solid dispersions, plasticizer free solid dispersions and solid dispersions containing heat sensitive active ingredients. In a culminating study, KinetiSol® Dispersing was utilized for the production of amorphous solid dispersions containing concentration enhancing polymers for improved oral bioavailability of itraconazole. Ultimately, this body of work demonstrated that concentration enhancing polymers could provide improved oral bioavailability for poorly water soluble compounds, while KinetiSol® Dispersing could be used for the production of such compositions, thereby presenting novel technologies for addressing future development of poorly water soluble active ingredients. / text

Pressurized metered dose inhalers (pMDIs) are widely utilized to manage diseases of the lungs, such as asthma and chronic obstructive pulmonary disease. They can be formulated such that the drug and/or nonvolatile excipients are dissolved or dispersed in the formulation, rendering a solution or suspension formulation, respectively. While the formulation process for solution pMDIs is well defined, the formulation process of pMDIs with any type of suspended entity can be lengthy and empirical. The use of suspended drug or the addition of a second drug or excipient in a suspension pMDI formulation may non-linearly impact the product performance of the drug of interest in the formulation; this requires iterative testing of a series of pMDIs in order to identify a formulation with the most potential for success. One of the primary attributes used to characterize the product performance and quality control of inhaled medications is the residual aerodynamic particle size distribution (APSD) of the aerosolized drug. Along with clinical factors, formulation and device parameters have a significant impact on APSD. In this study, a computational model was developed using the principles of statistics and physical chemistry to predict the residual APSD generated by suspension pMDIs based on formulation, device, and raw drug or excipient substance considerations. The formulations modeled and experimentally evaluated consist of a suspended drug or excipient with/without a dissolved drug or excipient in a cosolvent-propellant system. The in silico model enables modeling a process that is difficult to delineate experimentally and contributes to understanding the link between pMDI formulation and device to product performance. The ability to identify and understand the variables that affect atomization and/or aerosol disposition , such as initial droplet size, suspended micronized drug or excipient size, and drug or excipient concentration, facilitates defining the design space for suspension pMDIs during development and improves recognizing the sensitive of the APSD is on each hardware and formulation variable. This model can later be applied to limit batch-to-batch variation in the manufacturing process and selecting plausible suspension pMDI formulations with quality design as the end goal.

We consider the design of finite element methods for inverse problems with full-field data governed by elliptic forward operators. Such problems arise in applications in inverse heat conduction, in mechanical property characterization, and in medical imaging. For this class of problems, novel finite element methods have been proposed (Barbone et al., 2010) that give good performance, provided the solutions are in the H^1(Ω) function space. The material property distributions being estimated can be discontinuous, however, and therefore it is desirable to have formulations that can accommodate discontinuities in both data and solution. Toward this end, we present a mixed variational formulation for this class of problems that handles discontinuities well. We motivate the mixed formulation by examining the possibility of discretizing using a discontinuous discretization in an irreducible finite element method, and discuss the limitations of that approach. We then derive a new mixed formulation based on a least-square error in the constitutive equation. We prove that the continuous variational formulations are well-posed for applications in both inverse heat conduction and plane stress elasticity. We derive a priori error bounds for discretization error, valid in the limit of mesh refinement. We demonstrate convergence of the method with mesh refinement in cases with both continuous and discontinuous solutions. Finally we apply the formulation to measured data to estimate the elastic shear modulus distributions in both tissue mimicking phantoms and in breast masses from data collected in vivo.

Made available in DSpace on 2016-03-15T14:17:05Z (GMT). No. of bitstreams: 2 2.pdf: 2354876 bytes, checksum: b870b9f5322d8473f9ec787dd8eaf90b (MD5) license.txt: 1748 bytes, checksum: 8a4605be74aa9ea9d79846c1fba20a33 (MD5) Previous issue date: 2013 / Fundação Oswaldo Cruz. Instituto de Tecnologia em Fármacos/Farmanguinhos. Rio de Janeiro, RJ, Brasil. / As espécies do gênero Passiflora são ricas em flavonóides que apresentam atividade ansiolítica, dentre outras. P. incarnata L. é a espécie mais estudada tanto por sua composição química quanto por seus efeitos farmacológicos. Contudo, atividades biológicas semelhantes às de P. incarnata tem sido relatadas para espécies brasileiras deste gênero botânico, constituindo uma fonte alternativa para a formulação de fitoterápicos. Um estudo preliminar comparativo dos aspectos macroscópicos e microscópicos de quatro espécies nativas, P. pedata L., P. nitida Kunth e P. quadriglandulosa Rodschield, associado à morfologia da folha de P. edulis Sims descrita na Farmacopéia Brasileira, foi realizado para a avaliação de possíveis problemas na identificação da espécie de interesse, ou mesmo pela adulteração da droga vegetal proveniente de P. incarnata. Os resultados demonstraram grande diversidade morfológica entre P. pedata, P. nitida e P. quadriglandulosa, entretanto foi observada semelhança entre as folhas de P. edulis e P. incarnata, pois ambas apresentaram limbo trilobado. Não obstante, elas foram diferenciadas pela análise de suas principais características anatômicas. O objetivo deste trabalho foi desenvolver uma formulação fitoterápica contendo como ingrediente ativo extrato de P. incarnata e identificar o marcador da espécie, vitexina, segundo a legislação vigente. Amostras de extratos desta espécie, obtidas de fornecedores comerciais, foram analisadas por espectrofotometria e cromatografia a fim de identificar e quantificar o marcador. Concomitantemente, foram preparadas formulações farmacêuticas isentas de sacarose a partir destes extratos. As amostras de extratos e formulações foram processadas e analisadas por cromatografia em camada delgada. O cromatograma, após a revelação com reagente químico característico, apresentou manchas relacionadas à vitexina e outras bandas características de flavonóides. As análises obtidas por cromatografia líquida de alta e ultra eficiência (CLAE e CLUE) mostraram diferenças significativas no que tange a quantidade de amostra, sensibilidade, rapidez, delineamento dos sinais e dos respectivos espectros UV. Por meio da CLUE foi possível verificar a presença do principal marcador (vitexina, M-1 de 431 daltons) no produto contendo extratos de Passiflora e uma amostra padrão deste flavonóide. / Species of Passiflora are rich in flavonoids which have anxiolytic activity, among other activities. P. incarnata L. is the most studied species by its chemical composition and its pharmacological effects. However, biological activities similar to those described for P. incarnata have been reported to other Brazilian species of the same genus, providing an alternative source for the formulation of herbal medicines. A comparative preliminary study on macroscopic and microscopic aspects about four native species, P. pedata L., P. nitida Kunth and P. quadriglandulosa Rodschield, associated to the leaf morphology of P. edulis Sims described in the Brazilian Pharmacopoeia, was performed to evaluate possible difficulties in the identification of the species of interest, or even adulteration of the vegetal drug P. incarnata. Results showed important morphological differences among P. pedata, P. nitida and P. quadriglandulosa, however there was similarity in the trilobed lamina of P. incarnata and P. edulis leaves. On the other hand, both species can be distinguished by the analysis of its main anatomical characteristics. The aim of this work was to develop an herbal formulation containing extract of P. incarnata as active ingredient, and to identify the marker of the species, vitexin, according to actual law of Brazil. Sample extracts of P. incarnata obtained from commercial suppliers were analyzed in order to identify and quantify the marker. Concomitantly, pharmaceutical formulations free of sucrose were prepared with these extracts. Extracts and formulations were processed and analyzed by thin layer chromatography. The chromatogram, revealed by characteristic chemical reagent, showed bands of vitexin and other flavonoids. The high and ultra performance liquid chromatography (HPLC and ULPC) analysis presented significative differences about the sample amount, sensibility, quickness, peaks delineation and respective UV spectra. Using UPLC, it was possible to verify the presence of the main marker (vitexin, M-1 of 431 daltons) in the product obtained with the extracts of P. incarnata and vitexin standard.

Made available in DSpace on 2014-06-11T19:31:35Z (GMT). No. of bitstreams: 0 Previous issue date: 2009-12-11Bitstream added on 2014-06-13T18:42:24Z : No. of bitstreams: 1 oliveira_map_dr_botfca.pdf: 804551 bytes, checksum: 700238b1422e359e397bc2e36724e08e (MD5) / Outros / O presente trabalho teve por objetivos verificar o efeito da remoção pela chuva de diferentes formulações de flutriafol, em condições de laboratório, aplicadas com e sem a adição de óleo na calda de pulverização, assim como verificar a influencia do óleo no espectro de gotas. O experimento considerou dez caldas resultantes da interação de cinco tratamentos contendo o flutriafol (quatro formulações de flutriafol isolado e uma mistura de flutriafol com tebuconazole), todas aplicadas com e sem óleo mineral. As dez caldas foram aplicadas sobre plantas de soja que receberam posteriormente lavagem por chuva simulada em laboratório com quatro intervalos de tempo entre a aplicação e a chuva. As chuvas foram simuladas em duas etapas, sendo uma lâmina inicial de 5 mm seguida de uma lâmina complementar de 15 mm. As coletas foram realizadas com quatro repetições, sendo cada uma delas constituída de um vaso com quatro plantas. A avaliação da concentração de flutriafol nas soluções resultantes da lavagem das plantas foi realizada através da quantificação dos resíduos do fungicida na água pelo método de cromatografia gasosa e espectrometria de massa (GCMS). Após a aplicação das caldas, as plantas foram retiradas do laboratório e deixadas à temperatura ambiente, a espera do tempo decorrido para a simulação da chuva, de acordo com cada tratamento. Após a simulação das lâminas de chuva as plantas foram cortadas dos vasos e lavadas em saco plástico contendo 200 mL de água destilada. Todas as lavagens foram realizadas em 4 intervalos: 0 h (no momento da aplicação), 1 h, 2 h e 48 h após a aplicação. Para o cálculo do percentual extraído, as quantidades de flutriafol nas soluções de lavagem foram comparadas à quantidade total depositada nas plantas, a qual foi representada... / The present study had for objectives to verify the effect of rainfastness of different flutriafol formulations, in laboratory conditions, applied with and without the oil adjuvant in the spray solution, as well as to verify the influence of the oil on the droplet spectrum. The experiment considered ten spray solutions related to five treatments containing flutriafol (four formulations of flutriafol and a flutriafol mixture with tebuconazole), all applied with and without mineral oil. The ten solutions were applied on soybean plants that were washed by simulated rainfall in laboratory with four time intervals between the application and the rainfall. Rainfall was simulated by one initial precipitation of 5 mm followed by a complementary 15 mm rainfall. Each vase with four plants was considered one replication. The washing solutions from the vases were collected and the flutriafol concentration on those solutions was evaluated through the quantification of the residues of the fungicide in the water using the Gas Chromatography-Mass Spectrometry (GC-MS). After the spray application the plants were removed of the laboratory and left to room temperature, the wait of the time elapsed for the simulation of the rain, in agreement with each treatment.After the simulated rain the plants were cut out of the vases and washed by immersion in plastic sack containing 200 mL of distilled water. All of the washing solutions (from the rain and the immersion process) were accomplished in 4 intervals: 0 h (in the moment of the spray application), 1 h, 2 h and 48 h after the application. For the calculation of the flutriafol extracted, the amounts of fungicide in the wash solutions were compared to the total amount deposited in the plants, which was represented by the sum of the amounts of the assets recovered in the washing... (Complete abstract click electronic access below)