Dissertations / Theses on the topic 'Simulated moving bed (SMB)'

La chromatographie à lit mobile simulé (procédé SMB) est une technique de séparation bien maîtrisée dans certains secteurs traditionnels tels que la séparation de sucres et d’hydrocarbures. Cependant, son application à la séparation de composés à haute valeur ajoutée dans l’industrie pharmaceutique pose de nouveaux problèmes liés à la nature des produits à séparer ainsi qu'aux exigences plus strictes en matière de pureté et de quantités produites. Les principaux problèmes ouverts sont notamment la détermination des conditions de fonctionnement optimales, la conception de structures robustes de régulation, et le développement d’un système de supervision permettant la détection et la localisation de dégradations de fonctionnement. Ces tâches requièrent l’usage d’un modèle mathématique du procédé ainsi qu’une méthodologie d’estimation paramétrique. L’étude et le développement des modèles mathématiques pour ce type d’installation ainsi que l’estimation des paramètres des modèles sur base de mesures expérimentales constituent précisément l’objet de nos travaux de doctorat.

Les modèles mathématiques décrivant les procédés SMB consistent en les bilans massiques des composés à séparer. Ce sont des modèles à paramètres distribués (décrit par des équations aux dérivées partielles). Certains ont un comportement dynamique de type hybride (c'est-à-dire faisant intervenir des dynamiques à temps continu et des événements discrets). Quelques modèles ont été développés dans la littérature. Il s’agit de sélectionner ceux qui paraissent les plus intéressants au niveau de leur temps de calcul, de leur efficacité et du nombre de paramètres à déterminer. En outre, de nouvelles structures de modèles sont également proposées afin d’améliorer le compromis précision / temps de calcul.

Ces modèles comportent généralement certains paramètres inconnus. Ils consistent soit, en des grandeurs physiques mal définies au départ des données de base, soit, en des paramètres fictifs, introduits à la suite d'hypothèses simplificatrices et englobant à eux seuls un ensemble de phénomènes. Il s’agit de mettre au point une procédure systématique d’estimation de ces paramètres requérant le moins d’expériences possible et un faible temps de calcul. La valeur des paramètres est estimée, au départ de mesures réelles, à l'aide d'une procédure de minimisation d'une fonction de coût qui indique l’écart entre les grandeurs estimées par le modèle et les mesures. La sensibilité du modèle aux écarts sur les paramètres, ainsi que l’identifiabilité du modèle (possibilité de déterminer de manière univoque les paramètres du modèle) sur la base de mesures en fonctionnement normal sont étudiées. Ceci fournit un critère de comparaison supplémentaire entre les différents modèles et permet en outre de déterminer les conditions expérimentales optimales (choix du type d’expérience, choix des signaux d’entrée, choix du nombre et de la position des points de mesures…) dans lesquelles les mesures utilisées lors de l’estimation paramétrique doivent être relevées. De plus, les erreurs d’estimation sur les paramètres et les erreurs de simulation sont estimées. La procédure choisie est ensuite validée sur des données expérimentales recueillies sur un procédé pilote existant au Max-Planck-Institut für Dynamik komplexer technischer systeme (Magdebourg, Allemagne).

Doctorat en Sciences de l'ingénieur
info:eu-repo/semantics/nonPublished

Simulated moving bed chromatography process (SMBCP) is the technical realisation of a countercurrent adsorption process through the cyclic port switching. SMB technology reduces the cost of packing material with high loading capacity and provides high purity and high recovery in a very short time. Major commodity applications have been found in the petroleum, food, biotechnology, pharmaceutical and fine chemical industries. The industrial applications bring an emergent demand to improve the SMBCP operation for higher product quality, productivity, efficiency and robustness. However, for this particular process, we encounter several challenges. Firstly, the interplay of the effects of strong nonlinearities, competition of solutes, mass transfer resistance and fluid dynamic dispersion produces steep concentration fronts. Mathematical model accounted for this particular property constitutes a serious difficulty for the solution procedure. Secondly, a dynamic SMB model consists of a set of partial differential, ordinary differential and algebraic equations, which are highly coupled. The large size is a problem due to its intensive computation when on-line optimisation and real-time control are necessary. Thirdly, the SMB unit operation exhibits complex dynamics. Process metrics for design and operation can be determined only when a cyclic steady state is reached after a certain number of switching. Achieving this steady state by solving the PDE models cycle after cycle involves expensive calculation. Studies have been carried out to solve these problems through process analysis, investigation on spatial discretisation techniques, and development of an accelerated integration scheme.
Through a systematic study on the advances of SMB modelling, design and control, a set of functionally equivalent models for SMBCP are identified and summarized for their practical applications. The limitations of the existing modelling techniques in industrial applications are also identified. Furthermore, structural analysis of the existing models is conducted for a better understanding of the functionality and suitability of each model. Suggestions are given on how to choose an appropriate model with sufficient accuracy while keeping the computational demand reasonably low for real time control.
Effort is made on to the systematic investigation of different numerical methods for the solution of PDEs to circumvent the steep gradients encountered in chromatographic separation. Comprehensive studies are conducted on a single column chromatographic process represented by a transport-dispersive-equilibrium linear model. Numerical solutions from the upwind-1 finite difference, wavelet-collocation, and high resolution methods are evaluated by quantitative comparisons with the analytical solution for a range of Peclet numbers. It reveals that for a PDE system with a low Peclet number, all existing numerical methods work well, but the upwind finite difference method consumes the most time for the same degree of accuracy of the numerical solution. The high resolution method provides an accurate numerical solution for a PDE system with a medium Peclet number. The wavelet collocation method is capable of catching up steep changes in the solution, and thus can be used for solving PDE models with high singularity.
The advantages and disadvantages of the wavelet based approaches are further investigated through several case studies on real SMBCP system. A glucose-fructose separation process is firstly chosen with its relatively simple isotherm representations. Simulations are conducted using both wavelet collocation and upwind finite difference methods. For more complicated applications, an enantiomers separation process is selected. As the PDEs model exhibit a certain degree of singularity, wavelet collocation and high resolution methods are adopted for spatial discretisation. It is revealed that both the wavelet based approaches and high resolution methods are good candidates in terms of computation demand and prediction accuracy on the steep front. This is the first time that these two frontier numerical methods are used for such a complex SMB system models and our results are encouraging for the development of model-based online control scheme.
In developing a new scheme to rapidly obtain the solution at steady state for any arbitrary initial condition, the concept of Quasi-Envelope (QE) is adopted under the consideration that a SMBCP can be treated as a pseudo-oscillatory process because of a large number of continuous switching. The scheme allows larger steps to be taken to predict the slow change of starting state within each switching. Combined with previously developed wavelet-based technique, this method is successfully applied to the simulation of a SMB sugar separation process. Investigations are also carried out on the location of proper starting point for the algorithm and on the effect of changing stepsize to the convergence of iteration method. It is found that if the starting state of Quasi-Envelope is chosen to be the same as the original function, the multivalue algorithm would require similar computational effort to achieve the steady state prediction, regardless of the integration stepsize. If using constant stepsize, launching QE later is helpful when quasi-envelope displays steep change at the start-up period. A changing stepsize produces slow convergence compared to the constant stepsize strategy, thus increasing the work load where the stepsize change is occurring. Other iteration method is required to be imposed to achieve faster convergence right from the beginning. Potential applications can be seen for other chemical engineering processes with inherent cyclic behaviour.

S'han creat les eines necessàries per a estudiar la viabilitat de dur a terme la separació de mescles de dos i tres components basats en un mètode de separació en continu tipus SMB. Amb aquesta finalitat, s'ha creat un sistema per al disseny ràpid i econòmic de separadors SMB que permet simular el comportament d'una columna qualsevol integrada en un sistema SMB. Aquest sistema, està constituït per una sola columna cromatogràfica que pot treballar en qualsevol de les quatre zones en què es pot dividir un SMB.

El sistema de control de l'instrument permet simular cicles complets de separadors SMB. A més, el programa també permet treballar amb separacions formalment binàries o ternàries, en conformacions de SMB de 4, 6 i 8 columnes i combinació d'elles agrupades en 4 zones de treball. El sistema també integra un programa de simulació numèrica i optimització de separadors SMB.

La combinació del programa i el sistema de disseny de SMB permet establir la variació de la concentració de cada substància amb el temps podent així determinar: el nombre de columnes per zona, el temps de canvi de cada columna, el cabal d'operació a cada zona i la concentració de cada substància per cada sortida de l'SMB.

Per tal de verificar el correcte funcionament de l'equip complet s'ha dut a terme la separació de dos components, fenol i triclorofenol, determinant-ne les condicions òptimes de separació. Tot i que la retenció entre aquestes dues substàncies és molt similar, el prototipus ha permès estudiar el comportament de la unitat SMB complerta. També s'ha estudiat la separació del p-aminofenol i l'o-aminofenol com a part integrant del procés de fabricació del paracetamol i se n'han trobat les condicions òptimes d'operació. En treballar amb aquest procés s'ha buscat la màxima puresa del p-aminofenol en detriment de la puresa de l'o-aminofenol aconseguint una puresa de p-aminofenol a la sortida refinat del 97%.

Finalment, i des del punt de vista del canvi d'escala, s'han determinat els valors de la longitud no utilitzada de rebliment i del coeficient global de transferència de matèria per tal de poder extrapolar els resultats del prototipus a escala industrial.
Se han creado las herramientas necesarias para estudiar la viabilidad de desarrollar separaciones de mezclas de 2 y 3 componentes basados en un método de separación en continuo tipo SMB. Con esta finalidad se ha creado un sistema para el diseño rápido y económico de separadores SMB que permite simular el comportamiento de una columna cualquiera integrada en un sistema SMB. Este sistema está constituido por una única columna cromatográfica que puede trabajar en cualquiera de las cuatro zonas en que se puede dividir un SMB.

El sistema de control del instrumento permite simular ciclos completos de separadores SMB. Además, el programa también permite trabajar con separaciones formalmente binarias o ternarias, en conformaciones de SMB de 4, 6 y 8 columnas y combinación de ellas agrupadas en 4 zonas de trabajo. El sistema también integra un programa de simulación numérica y optimización de separadores SMB.

La combinación del programa y el sistema de diseño de SMB permite establecer la variación de la concentración de cada sustancia con el tiempo pudiendo así determinar: el número de columnas por zona, el tiempo de cambio de cada columna, el caudal de operación en cada zona y la concentración de cada sustancia por cada salida del SMB.

Para verificar el correcto funcionamiento del equipo completo se ha separado una mezcla de dos compuestos, fenol y triclorofenol, determinando las condiciones óptimas de separación. Aunque la retención entre estas dos sustancias es muy similar, el prototipo ha permitido estudiar el comportamiento de la unidad SMB completa. También se ha estudiado la separación del p-aminofenol y el o-aminofenol como parte integrante del proceso de fabricación del paracetamol y se han determinado las condiciones óptimas de operación. Al trabajar con este proceso se ha buscado la máxima pureza del p-aminofenol con menoscabo de la pureza del o-aminofenol consiguiendo una pureza de p-aminofenol a la salida de refinado del 97%.

Finalmente se han determinado los valores de la longitud de lecho no utilizada y del coeficiente global de transferencia de materia para extrapolar los resultados del prototipo a escala industrial.
The necessary tools to study the viability of developing separations of mixtures of 2 and 3 components using a continuous method like the SMB have been developed. A fast and non-expensive system to design such separations has been developed. This system can simulate the behaviour of a single column integrated in the SMB. This system is composed by a single column capable to work in every one of the four zones into which an SMB can be divided.

The control system gives the possibility of simulate complete cycles of an SMB separator. In addition the program also can work with binary or ternary separations, in SMB conformations of 4, 6 and 8 columns and its combinations grouped together in 4 working zones. The system also integrates a numerical simulation and optimization program of SMB separators.

The combination of program and SMB design system establishes the concentration of each substance within the time. It gives the following parameters: the number of columns per zone, the column switch time, the flow in each zone and the concentration at the SMB outlet.

In order to check the correct operation of the whole unit the separation of phenol and trichlorophenol have been done determining the best operation conditions. However the retention of this substances is very similar, the prototype has studied the complete separation. It also has been studied the separation of p-aminophenol and o-aminophenol as a part of the sysntesis process os paracetamole and the best separation condition have been stablished. While working with this process the maximum purity of p-aminophenol has been searched. The purity of p-aminophenol at the raffinate outlet is about 97%.

Finally the values of unused bed lenght and overall mass transfer coefficient have been calculated to extrapolate the results to the industrial scale.

La séparation des C8 aromatiques par Lit Mobile Simulé (LMS) permet d'obtenir du paraxylène (PX) pur. Les autres composés du mélange sont recyclés dans un réacteur afin d'être isomérisés puis séparés à nouveau. La charge du LMS est composée à environ 75% par ce flux de recyclage. L'intégration de la réaction dans le LMS, réalisée en intercalant des réacteurs d'isomérisation entre les lits d'adsorbant de la zone 3 (procédé LMS Réactif, LMSR), doit permettre une réduction de ce flux de recyclage.L'objectif de cette thèse est de développer une méthodologie d'étude des procédés de type Lit Mobile Simulé (LMS) et Lit Mobile Simulé Réactif (LMSR) basée sur :-un outil expérimental simplifié : le pilote One-column réactif (OCR)-des simulateurs One-column réactif ou non qui seront validés par les résultats expérimentaux du pilote-des simulateurs LMS et LMSR permettant d'accéder aux résultats des procédés industriels.Les simulations de One-column (OC) montrent une bonne sensibilité aux paramètres clés de la séparation des C8 aromatiques (sélectivité PX/EB et diffusion intracristalline). Les résultats expérimentaux font ressortir des difficultés importantes à mettre en œuvre le OC expérimentalement. Plusieurs hypothèses sont exposées pour expliquer les résultats obtenus mais les difficultés rencontrées limitent, en l'état, l'utilisation du pilote pour l'étude de la séparation (réactive ou non) des C8 aromatiques.L'étude du LMSR effectuée par simulation montre l'importance du nombre et de l'emplacement des réacteurs ainsi que de l'intégration du LMSR dans la boucle de production de PX. L'usage du LMSR pour la production de PX permet une réduction importante du débit de recyclage
Today, pure paraxylene (PX) is mainly obtained from a mix of C8 aromatics by a separation process based on adsorption: the Simulated Moving Bed (SMB). The other components of the blend are sent to an isomerisation reactor and are recycled to the SMB. 75% of the SMB feed flow rate come from this recycle flow. Coupling reaction and separation by inserting isomerisation reactors between the adsorption beds of the third zone (Simulated Moving Bed Reactor, SMBR) should allow a reduction of this recycling flow rate.The main objective of this thesis is to develop a new methodology for studying SMB and SMBR processes based on:- a simplify experimental tool : the One-column reactive (OCR) pilot unit- simulators of the OCR which will be validated by the experimental results obtain on the pilot unit- simulators of SMB and SMBR processes which give access to industrial processes results.Simulation results show that OC system seem to be sensitive to key parameters of C8 aromatics separation (PX/EB selectivity and micropore diffusivity). Results on the pilot unit highlight the difficulties to implement an experimental OC. Hypothesis are given to explain those results but, without modification, OCR pilot unit cannot be used to study xylene separation (with or without reaction).SMBR study done by simulation shows the impact of the placement and the number of reactors. Integration of SMBR in the global PX production scheme is also essential. SMBR allows an important reduction of recycling flow rate (up to 50%)

Doutoramento em Engenharia Química
A exploração de compostos, subprodutos e resíduos naturais é um passo chave para a obtenção de um futuro sustentável. A valorização e comercialização destes materiais dependem da aplicação de técnicas adequadas de conversão e separação/purificação que permitam obter os níveis desejados de pureza e produtividade. Os ácidos triterpénicos, particularmente os ácidos betulínico, oleanólico e ursólico, são compostos de elevado valor que têm atraído interesse devido às suas já reportadas propriedades nutraceuticas e farmacológicas. Estes triterpenoides estão presentes em diversas fontes vegetais mas podem ser encontrados com abundâncias consideráveis na casca do eucalipto (decídua e externa), um resíduo comum da indústria da pasta e papel. O isolamento dos ácidos triterpénicos é uma tarefa difícil devido às suas semelhantes estruturas moleculares, especialmente no caso dos ácidos oleanólico e ursólico, que são isómeros de posição. O leito móvel simulado (simulated moving bed, SMB) é uma técnica cromatográfica de separação contínua e em contracorrente que maximiza a força diretriz de transferência de massa permitindo a separação de moléculas mesmo quando as seletividades se aproximam de um. Por exemplo, é frequentemente utilizada no isolamento de enantiómeros. No SMB clássico a separação de dois componentes é efetuada em quatro zonas, os caudais e concentrações de alimentação são fixos e as portas de entrada/saída são comutadas simultaneamente. Recentemente, novas implementações tais como a modificação da concentração ou caudais da alimentação, a utilização de tempos de comutação variáveis e a introdução de novas zonas para separação multicomponente, têm permitido a obtenção de maior flexibilidade e melhor performance. Uma revisão profunda destes modos de operação foi feita durante esta tese. A modelação e otimização são passos essenciais no dimensionamento e desenvolvimento de qualquer processo e particularmente importantes no SMB. Como ponto de partida para o estudo do fracionamento de ácidos triterpénicos por leito móvel simulado, modelos fenomenológicos conhecidos foram aplicados para desenvolver de um simulador SMB. Durante este trabalho uma estratégia de otimização de unidades de SMB foi desenvolvida combinando as metodologias de desenho de experiências e respostas de superfície com simulações computacionais, com o objetivo de obter condições de operação ótimas com baixa complexidade e um esforço computacional reduzido. Esta técnica de otimização foi aplicada ao estudo da separação dos enantiómeros de óxido de trans-estilbeno, usando informação da literatura, e posteriormente comparada com outros procedimentos de determinação de condições de operação ótimas. Esta técnica permitiu purezas acima de 99.5 % para ambos enantiómeros, necessitando de um baixo número de simulações. A separação de ácidos triterpénicos foi inicialmente estudada à escala analítica, através de uma série de ensaios cromatográficos em diferentes condições para seleção de fase móvel e estacionária apropriada. Os melhores resultados foram obtidos com uma coluna Apollo C18 usando metanol/água 95/5 (%,v/v) e os parâmetros de equilíbrio e transporte foram determinados através de experiências de rutura com os compostos puros. Esta informação foi utilizada com sucesso na simulação da separação de uma mistura ternária, cujos resultados foram validados com experiências de rutura ternárias. A separação em SMB de uma mistura representativa de um extrato natural contendo os ácidos betulínico, oleanólico e ursólico foi desenhada utilizando um processo em dois passos: inicialmente o ácido betulínico foi isolado dos ácidos oleanólico e ursólico e, de seguida, os ácidos oleanólico e ursólico foram fracionados. Esta separação foi otimizada usando a metodologia de desenho de experiências e respostas de superfície combinada com simulações rigorosas e permitiu demonstrar que é possível produzir os ácidos betulínico, oleanólico e ursólico com purezas de 99.4 %, 99.1 %, e 99.4 %. Os polímeros molecularmente impressos (molecularly imprinted polymers, MIPs) são sintetizados para possuírem centros ativos altamente seletivos para moléculas alvo, tornando-os adsorventes muito promissores. Vários MIPs foram sintetizados por polimerização por precipitação usando diferentes formulações. Após a preparação, estes polímeros foram caracterizados por microscopia eletrónica de varrimento e os mais promissores, em termos de características morfológicas, foram diretamente testados através de experiências de adsorção. Os resultados revelam que o material “MIP1b” exibe selectividade infinita para o ácido oleanólico, a molécula alvo usada na sua síntese. Em conjunto com a sua capacidade de adsorção – superior à da previamente estudada fase C18 – estes resultados demonstram o elevado potencial do polímero “MIP1b” para aplicação na separação dos ácidos triterpénicos. Investigação adicional é necessária neste tópico onde diferentes técnicas de separação podem ser antecipadas. Este trabalho culminou com o dimensionamento e montagem de uma unidade laboratorial de leito móvel verdadeiro baseada num sistema de uma-válvula-ST por coluna recentemente patenteado, que permite à unidade operar sobre diferentes estratégias de operação e configurações.
The exploitation of natural compounds, by-products and residues is a key strategy for the pursuit of a sustainable future. The effective valorization and commercialization of these materials depends on the application of adequate conversion and separation/purification techniques that can provide desired levels of purity and productivity. Triterpenic acids, particularly betulinic, oleanolic, and ursolic acids, are high value molecules that have attracted considerable interest due to their reported nutraceutical and pharmacological properties. These triterpenoids are present in diverse vegetable sources but significant abundances are found in Eucalyptus bark (deciduous and external), a common residue from the paper and pulp industry. The isolation of triterpenic acids is a difficult task due to their similar molecular structures, particularly in the case of oleanolic and ursolic acids, which are positional isomers. The simulated moving bed (SMB) technology is a countercurrent continuous chromatographic technique that maximizes the mass transfer driving force, thus allowing the separation of compounds even when selectivities approach one. For instance, it is often used for enantiomers isolation. In a classic SMB, the separation of two components is accomplished across four zones, the flow rates and feed concentrations are fixed, and the inlet/outlet ports are switched synchronously. Recently, new implementations and modifications, such as the modulation of feed concentration or flow rates, variable switch times and additional zones for multicomponent separations, enabled better flexibility and performances to be achieved. A thorough review of these modes of operation was performed in this thesis. Modeling and optimization are necessary steps for the design and development of any process, being particularly important in SMB. As the starting point for the study of the fractionation of triterpenic acids by simulated moving bed, well know phenomenological models were applied to develop a SMB simulator. During this work, an optimization strategy of SMB units was developed combining the design of experiments and response surface methodologies (DoE-RSM) with computer simulations, aimed at providing good operating conditions with low complexity and reduced computational effort. This optimization technique was applied to the separation of trans-stilbene oxide (TSO) enantiomers using data from the literature and compared with other existing procedures for the determination of the best operation conditions. It allowed purities above 99.5 % for both TSO enantiomers while requiring a small number of simulations. The separation of triterpenic acids was initially studied at analytical scale, through a series of chromatographic assays under different conditions, to select appropriate mobile and stationary phases. Best results were obtained using an Apollo C18 column and methanol/water 95/5 (%, v/v), and equilibrium and mass transport parameters were determined through breakthrough experiments with pure compounds. This information was then successfully applied in the simulation of a ternary mixture separation, whose results were validated with ternary breakthrough measurements. The SMB separation of a representative natural extract containing betulinic, oleanolic and ursolic acids was designed using a two-step process: firstly, betulinic acid was isolated from oleanolic and ursolic acids, and secondly, oleanolic and ursolic acids were fractionated. This separation approach was optimized using DoE-RSM combined with rigorous simulations, and it was demonstrated that it is possible to produce betulinic, oleanolic and ursolic acids with purities of at least 99.4 %, 99.1 %, and 99.4 %. Molecularly imprinted polymers (MIPs) are synthesized to possess binding sites highly selective to specific molecules, making them very promising adsorbents. Several MIPs were synthetized by precipitation polymerization using different formulations. After preparation, these polymers were characterized by scanning electron microscopy and the most successful ones, in terms of morphological features, were directly tested carrying out batch adsorption experiments. The results disclosed that “MIP1b” material exhibits infinite selectivity for oleanolic acid, the template molecule used in its synthesis. Together with its adsorption capacity – even higher than that of the previously studied C18 phase – these results demonstrate the high potential of “MIP1b” polymer for application on the separation of triterpenic acids. Additional research is required in this topic, where distinct separation approaches may be anticipated. This PhD work culminated in the design and assembling of a laboratory simulated moving bed unit based on a recently patented system using a one- ST valve per column valve scheme, thus allowing the SMB to run under several operation strategies and configurations.

Adsorption separation processes are extremely important to the chemical industry, especially in the manufacturing of food, pharmaceutical, and fine chemical products. This work addresses three main topics: first, systematic decision-making between rival gas phase adsorption processes for the same separation problem; second, process development for liquid phase simulated moving bed chromatography (SMB); third, accelerated startup for SMB units. All of the work in this thesis uses model-based optimization to answer complicated questions about process selection, process development, and control of transient operation. It is shown in this thesis that there is a trade-off between productivity and product recovery in the gaseous separation of enantiomers using SMB and pressure swing adsorption (PSA). These processes are considered as rivals for the same separation problem and it is found that each process has a particular advantage that may be exploited depending on the production goals and economics. The processes are compared on a fair basis of equal capitol investment and the same multi-objective optimization problem is solved with equal constraints on the operating parameters. Secondly, this thesis demonstrates by experiment a systematic algorithm for SMB process development that utilizes dynamic optimization, transient experimental data, and parameter estimation to arrive at optimal operating conditions for a new separation problem in a matter of hours. Comparatively, the conventional process development for SMB relies on careful system characterization using single-column experiments, and manual tuning of operating parameters, that may take days and weeks. The optimal operating conditions that are found by this new method ensure both high purity constraints and optimal productivity are satisfied. The proposed algorithm proceeds until the SMB process is optimized without manual tuning. In some case studies, it is shown with both linear and nonlinear isotherm systems that the optimal performance can be reached in only two changes of operating conditions following the proposed algorithm. Finally, it is shown experimentally that the startup time for a real SMB unit is significantly reduced by solving model-based startup optimization problems using the SMB model developed from the proposed algorithm. The startup acceleration with purity constraints is shown to be successful at reducing the startup time by about 44%, and it is confirmed that the product purities are maintained during the operation. Significant cost savings in terms of decreased processing time and increased average product concentration can be attained using a relatively simple startup acceleration strategy.

This dissertation describes the simulation and optimization of adsorptive and chromatographic separation processes. The first part focus on the simulation and comparison of operational modes in simulated moving bed (SMB) chromatography for separation and purification in bioprocesses. The second part includes the simulation of gas-phase adsorptive processes by pressure swing adsorption and temperature swing adsorption technologies. The applications of SMB chromatography are popular in separating and purifying enantiomers, petrochemicals, pharmaceuticals and biochemicals with higher yield and lower solvent consumption. We simulate and compare several operational modes of simulated moving bed (SMB) for a binary and a ternary bioprocess using Aspen Chromatography. These operational modes are able to improve the separation efficiency of the basic SMB process by our simulation and optimization. We compare their separation performances and identify heuristics that will guide the selection of operational modes across a variety of systems. Pressure swing adsorption (PSA) and temperature swing adsorption (TSA) are two of the main technologies for gas-phase adsorption separation processes. We simulate and demonstrate a PSA model for air separation system and a TSA model for CO2 capture system in Aspen Adsorption. We present their separation performance plots to provide the physical insights of these two systems.
Ph. D.

This dissertation presents an analysis of two aspects of the chromatographic separation process known as Simulated Moving Bed (SMB) chromatography. The first aspect is system design, and the second is improving computer simulations to generate heuristics for choosing operational modes. For the past 15-20 years, there has been a surge of interest in the use of Simulated Moving Bed systems for the chromatographic separation of chemicals¹. A wide variety of methods, nomenclatures, and conventions have been adopted over the years²⁻⁴, as teams from different backgrounds adopt and improve on the SMB technology. This work presents a unifying discussion of the two major design methods, Triangle Theory and Standing Wave Design, used in the SMB field. We provide the complete computer code required to execute both design methods. A sample problem is worked, which demonstrates the novelty and ease of use that such tools provide. Mathematica was chosen for the implementation of these design methods, because of its strong symbolic analysis capabilities, and simplicity of creating interfaces for new users. We present derivations of the classic Langmuir results in Mathematica, and proceed to extend those implementations. When analytic solutions are impossible, we use Mathematica's numerical methods. This work also develops a distributed computing tool known as ChromRunner which allows large numbers of detailed numerical simulations to be run simultaneously. The motivations and benefits of this approach are discussed alongside implementation details. We apply the distributed computing system to two separate SMB separations in order to optimize them, as well as determine heuristics governing their operational modes. We wrote ChromRunner in C#, and took advantage of Visual Studio's Entity Framework to create the database backend. The user interface for this software was created using Microsoft's "Windows Presentation Foundation" (WPF) technologies.
Ph. D.

Simulated Moving Bed (SMB) chromatography is a separation process where the components are separated due to their varying affinity towards the stationary phase. Over the past decade, many modifications have been proposed in SMB chromatography in order to effectively separate a binary mixture. However, the separation of multi-component mixtures using SMB is still one of the major challenges. Although many different strategies have been proposed, previous studies have rarely performed comprehensive investigations for finding the best ternary separation strategy from various possible alternatives. Furthermore, the concept of combining reaction with SMB has been proposed in the past for driving the equilibrium limited reactions to completion by separating the products from the reaction zone. However, the design of such systems is still challenging due to the complex dynamics of simultaneous reaction and adsorption. The first objective of the study is to find the best ternary separation strategy among various alternatives design of SMB. The performance of several ternary SMB operating schemes, that are proposed in the literature, are compared in terms of the optimal productivity obtained and the amount of solvent consumed. A multi- objective optimization problem is formulated which maximizes the SMB productivity and purity of intermediate eluting component at the same time. Furthermore, the concept of optimizing a superstructure formulation is proposed, where numerous SMB operating schemes can be incorporated into a single formulation. This superstructure approach has a potential to find more advantageous operating scheme compared to existing operating schemes in the literature. The second objective of the study is to demonstrate the Generalized Full Cycle (GFC) operation experimentally for the first time, and compare its performance to the JO process. A Semba OctaveTM chromatography system is used as an experimental SMB unit to implement the optimal operating schemes. In addition, a simultaneous optimization and model correction (SOMC) scheme is used to resolve the model mismatch in a systematic way. We also show a systematic comparison of both JO and GFC operations by presenting a Pareto plot of the productivity achieved against the desired purity of the intermediate eluting component experimentally. The third objective of the study is to develop an simulated moving bed reactor (SMBR) process for an industrial-scale application, and demonstrate the potential of the ModiCon operation for improving the performance of the SMBR compared to the conventional operating strategy. A novel industrial application involving the esterification of acetic acid and 1-methoxy-2-propanol is considered to produce propylene glycol methyl ether (PMA) as the product. A multi-objective optimization study is presented to find the best reactive separation strategy for the production of the PMA product. We also present a Pareto plot that compares the ModiCon operation, which allows periodical change of the feed composition and the conventional operating strategy for the optimal production rate of PMA that can be achieved against the desired conversion of acetic acid.

The cost of pretreatment process for saccharification from biomass and the cost of dilute ethanol purification are significant components of the overall cost for fuel grade ethanol production through fermentation or other biological routes. This work focuses on developing optimal designs of dilute ethanol purification process and the new acid hydrolysis technology for the production of fermentable sugars from biomass where the overarching goal is to reduce the cost of ethanol production from biomass. In this thesis, the ethanol separation process with the reverse osmosis membrane pretreatment is developed to reduce separation cost and energy consumption especially when the feed is dilute. In addition, the new solid phase reactive separation system for biomass saccharification via acid hydrolysis is proposed. This new process is applied for both dilute and concentrated acid hydrolysis where the goal is to increase sugar yield and to reduce byproduct formation. The reaction kinetics of the concentrated acid hydrolysis is investigated through batch experiment. All of these use optimization approaches for seeking the best process designs and for parameter estimations.

Modèle monodimensionnel de type Piston-Dispersion. Le terme de dispersion axiale englobe alors toutes les imperfections de l'écoulement : injection des fluides non homogène dans l’espace et étalée dans le temps, effet de parois, et enfin volumes morts derrière les obstacles noyés dans le tamis (poutres, conduites...) dans le cas des Lits Mobiles Simulés. Cette représentation, quoique très simpliste, s'avère généralement suffisante tant que l’étalement des fronts de concentration est d'abord induit par les limitations au transfert externe, interne (macro/microporeux) et par la thermodynamique du système. Par contre, lorsque l’adsorbant employé présente d’excellentes performances de transfert, une approche aussi simple s'avère extrêmement risquée. En effet, les phénomènes dispersifs associés à l’adsorbant (transfert et thermodynamique) et à l’hydrodynamique ont des contributions de même ordre de grandeur sur la dispersion des fronts de concentration. Dans ce cas, une description plus réaliste de l'écoulement est requise afin de mieux appréhender son effet sur les performances de séparation.Dans ce contexte, l’objectif de ce projet de thèse est de mettre en place une méthodologie pour prendre en compte ces phénomènes hydrodynamiques lors de l’extrapolation d’un procédé de séparation par adsorption. Pour cela, nous proposons une étude du couplage entre les phénomènes hydrodynamiques et le phénomène d’adsorption
Hydrodynamics inside industrial Simulated Moving Bed (SMB) adsorption columns can be complex due to the presence of internal distribution devices, free flow chambers and heterogeneous injections. These have to be taken into account in SMB numerical models to scale-up purposes. In the present thesis, a CFD approach is adopted as an intermediate step to develop a 1D model simple enough to be used for cyclic SMB simulations while being able to represent realistic hydrodynamics. This model results from the interpretation of the moments of the fluid age distribution, transported by CFD according to the method developed by Liu and Tilton (2010) that allows to estimate the degree of mixing (Liu, 2011) of the adsorption columns. The resulting 1D model consists in the two examples provided by Zwietering (1959) of a completely segregated system and a maximum mixedness system. This model is able to reproduce the residence time distribution of the CFD model of an adsorption column, while being representative of the internal flow patterns. This results in a good representation of the coupling of adsorption and hydrodynamics by the 1D model. When integrated in a SMB simulator and compared to the traditionally used dispersed plug flow model, the new 1D model demonstrates that for most of the adsorption column geometries considered a detailed hydrodynamic description is mandatory. Such detailed hydrodynamic description is even more important when employing adsorbents with better mass transfer performances than those currently used for the p-xylene purification, which is expected in the upcoming years

Orientador: Cesar Costapinto Santana
Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Engenharia Quimica
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Resumo: O mitotano (o,p?-diclorodifenildicloroetano) é um fármaco utilizado no tratamento de carcinoma adrenocortical. Ele é comercializado na forma racêmica, ou seja, na proporção 1:1 dos seus enantiômeros R e S. A influência da quiralidade da molécula sobre seu efeito farmacológico ainda não foi estudada. Portanto, a separação dos enantiômeros é importante para testes biológicos comparativos de efeitos colaterais. Este trabalho foi desenvolvido com o intuito de estudar a separação deste fármaco pela técnica de cromatografia líquida de alta eficiência utilizando coluna recheada com a fase estacionária quiral O,O?-bis[4-tercbutilbenzoil]-N,N?-dialil-L-tartardiamida. Diferentes combinações de fase móvel foram testadas e os melhores resultados foram obtidos com hexano/acetato de etila na proporção 95/5 (v/v). Experimentos de pulsos com soluções diluídas do traçador e dos enantiômeros do mitotano foram realizados variando a vazão de fase móvel e a temperatura do sistema. Foram determinados as porosidades do sistema, os parâmetros cromatográficos, os dados de equilíbrio, coeficientes de dispersão axial e parâmetros de transferência de massa. Os resultados mostraram separação satisfatória, com número de pratos superando 9000 e fatores de separação na ordem de 1,13. Os valores dos coeficientes de Henry foram maiores que a unidade para ambos os enantiômeros, sendo que o enantiômero mais retido R-(+)-mitotano, apresentou maior afinidade pela coluna quiral. Valores de km superiores a 300 min-1 revelaram baixo efeito dos fenômenos de transferência de massa e consequentemente predomínio dos efeitos termodinâmicos (energia entálpica superior -10 kJ/mol para os enantiômeros). Experimentos a altas concentrações foram realizados com a finalidade de se determinar às isotermas pelo método da análise frontal e também os cromatogramas sob estas condições. Para a concentração da mistura até 16 g/L as isotermas mostraram um bom ajuste ao modelo de Langmuir. A partir da separação em batelada determinaram-se as regiões de separação dos enantiômeros para um sistema cromatográfico contínuo do tipo leito móvel simulado para diferentes concentrações de alimentação da mistura racêmica. Avaliaram-se as variáveis desempenho (consumo de solvente e produtividade) no sistema contínuo e compararam-se com as obtidas em separações em batelada. Melhores resultados foram obtidos para um sistema contínuo do tipo leito móvel simulado
Abstract: Mitotane (o, p'-dichlorodiphenyldichloroethane) is a drug used in the treatment of adrenocortical carcinoma. It is marketed in the racemic form, proportion 1:1 of their R and S enantiomers. The influence of the molecule quirality on its pharmacology effect was not studied yet. For this reason, this separation is important for comparative biological tests of collateral effects. This work was developed with intention to study the separation of this drug via liquid chromatography using columns packed with the chiral stationary phase, O,O?-bis[4-terc-butylbenzoyl] - N, N' - diallyl-L-tartardiamide. Different combinations of mobile phase was tested and better results were achieved with hexane/ethyl acetate in ratio 95/5 (v/v). Pulses experiments with diluted solutions of the inert and the enantiomers were accomplished at different flow rates and temperature. The system porosities, chromatographic parameters, equilibrium constants, axial dispersion and mass transference parameters were obtained. The results showed satisfactory separation, with number of plates overcoming 9000 and separation factors in the order of 1,13. The values of Henry coefficients were greater than one for both enantiomers, the most retained was R (+) -mitotane, and it presented greater affinity for the chiral column. The overall mass transfer coefficient achieved values higher than 300 min-1, demonstrating low mass transfer effect rates and consequently a prevalence of the thermodynamic effects (enthalpy energy greater than -10 kJ/mol for the enantiomers). Experiments in overload conditions were realized in order to determining the isotherms using the method of the frontal analysis as well the chromatograms under these conditions. For the concentration of the mixture smaller than 16 g/L the isotherms showed a good adjusted to the Langmuir model. The separation regions for a chromatographic continuous system like simulated moving bed were determined with different feed concentrations. This permits the comparison of the performance parameters using the continuous system and batch ones
Mestrado
Desenvolvimento de Processos Biotecnologicos
Mestre em Engenharia Química

Les procédés chromatographiques multicolonnes continus se sont imposés comme technique séparative dans l’industrie pharmaceutique en raison de leur productivité élevée et de leur développement rapide. De nos jours, la modélisation, le dimensionnement et l’optimisation des procédés LMS et Varicol sont considérés comme établis. Le fonctionnement automatique optimisé et robuste de ces procédés reste cependant un sujet de recherche. Le plus souvent, les paramètres opératoires sont choisis en deçà du réglage optimal afin d’inclure une marge de robustesse. Ils sont ajustés manuellement par un opérateur expérimenté pour maintenir les produits à leurs spécifications de pureté. Le nombre élevé de séparations chromatographiques rend crucial le développement d’une application d’un contrôle avancé de ces procédés. Récemment, plusieurs méthodes de contrôle des procédés LMS ont été proposées. Ce travail de thèse présente une nouvelle approche de contrôle avancé. Cette commande ajuste les paramètres opératoires d’une séparation grâce à deux types de mesure : une mesure en ligne et une mesure hors ligne. Une validation expérimentale du schéma de contrôle a été effectuée sur un procédé Varicol. Les résultats présentés démontrent que la commande permet d’amener la pureté des produits à leurs spécifications, d’optimiser les performances du procédé et de répondre aux perturbations, tout en sécurisant la pureté du produit cible
Multicolumn continuous chromatographic processes became a key separation technology in the areas of pharmaceutical industry thanks to high productivity and short process development times. Today, modeling, design, and optimization of SMB and Varicol, are well established. However a robust and optimized operation of processes is still an open issue. The common practice is to operate processes under suboptimal operating conditions in order to gain the necessary robustness. The operating parameters are tuned manually by experienced operators in order to maintain the product specifications. Therefore, as chromatographic applications spread, process control problem becomes increasingly important. Recently, several control methodologies of SMB process have been proposed. This thesis work introduces a new advanced control system approach. This system adjusts operating parameters thanks to two kinds of measurements : an in-line measurement and an at-line measurement. The performance of this control scheme is demonstrated through several experiments on Varicol. The reported results aim to demonstrate that the controller is able to deliver the products within the specifications, to optimize the process performance and to answer to disturbances while protecting the key product

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior
O Leito Móvel Simulado (LMS) é um processo de separação de compostos por adsorção muito eficiente, por trabalhar em um regime contínuo e também possuir fluxo contracorrente da fase sólida. Dentre as diversas aplicações, este processo tem se destacado na resolução de petroquímicos e principalmente na atualidade na separação de misturas racêmicas que são separações de um grau elevado de dificuldade. Neste trabalho foram propostas duas novas abordagens na modelagem do LMS, a abordagem Stepwise e a abordagem Front Velocity. Na modelagem Stepwise as colunas cromatográficas do LMS foram modeladas com uma abordagem discreta, onde cada uma delas teve seu domínio dividido em N células de mistura interligadas em série, e as concentrações dos compostos nas fases líquida e sólida foram simuladas usando duas cinéticas de transferência de massa distintas. Essa abordagem pressupõe que as interações decorrentes da transferência de massa entre as moléculas do composto nas suas fases líquida e sólida ocorram somente na superfície, de forma que com essa suposição pode-se admitir que o volume ocupado por cada molécula nas fases sólida e líquida é o mesmo, o que implica que o fator de residência pode ser considerado igual a constante de equilíbrio. Para descrever a transferência de massa que ocorre no processo cromatográfico a abordagem Front Velocity estabelece que a convecção é a fase dominante no transporte de soluto ao longo da coluna cromatográfica. O Front Velocity é um modelo discreto (etapas) em que a vazão determina o avanço da fase líquida ao longo da coluna. As etapas são: avanço da fase líquida e posterior transporte de massa entre as fases líquida e sólida, este último no mesmo intervalo de tempo. Desta forma, o fluxo volumétrico experimental é utilizado para a discretização dos volumes de controle que se deslocam ao longo da coluna porosa com a mesma velocidade da fase líquida. A transferência de massa foi representada por dois mecanismos cinéticos distintos, sem (tipo linear) e com capacidade máxima de adsorção (tipo Langmuir). Ambas as abordagens propostas foram estudadas e avaliadas mediante a comparação com dados experimentais de separação em LMS do anestésico cetamina e, posteriormente, com o fármaco Verapamil. Também foram comparados com as simulações do modelo de equilíbrio dispersivo para o caso da Cetamina, usado por Santos (2004), e para o caso do Verapamil (Perna 2013). Na etapa de caracterização da coluna cromatográfica as novas abordagens foram associadas à ferramenta inversa R2W de forma a determinar os parâmetros globais de transferência de massa apenas usando os tempos experimentais de residência de cada enantiômero na coluna de cromatografia líquida de alta eficiência (CLAE). Na segunda etapa os modelos cinéticos desenvolvidos nas abordagens foram aplicados nas colunas do LMS com os valores determinados na caracterização da coluna cromatográfica, para a simulação do processo de separação contínua. Os resultados das simulações mostram boa concordância entre as duas abordagens propostas e os experimentos de pulso para a caracterização da coluna na separação enantiomérica da cetamina ao longo do tempo. As simulações da separação em LMS, tanto do Verapamil quando da Cetamina apresentam uma discrepância com os dados experimentais nos primeiros ciclos, entretanto após esses ciclos iniciais a correlação entre os dados experimentais e as simulações. Para o caso da separação da cetamina (Santos, 2004), a qual a concentração da alimentação era relativamente baixa, os modelos foram capazes de predizer o processo de separação com as cinéticas Linear e Langmuir. No caso da separação do Verapamil (Perna, 2013), onde a concentração da alimentação é relativamente alta, somente a cinética de Langmuir representou o processo, devido a cinética Linear não representar a saturação das colunas cromatográficas. De acordo como o estudo conduzido ambas as abordagens propostas mostraram-se ferramentas com potencial na predição do comportamento cromatográfico de uma amostra em um experimento de pulso, assim como na simulação da separação de um composto no LMS, apesar das pequenas discrepâncias apresentadas nos primeiros ciclos de trabalho do LMS. Além disso, podem ser facilmente implementadas e aplicadas na análise do processo, pois requer um baixo número de parâmetros e são constituídas de equações diferenciais ordinárias.
Simulated Moving Bed (SMB) is a very efficient process in the compounds separation by adsorption, because works in a continuous regime, and with countercurrent flow of the solid phase. Among different applications, SMB has stood out in the petrochemical products separation and mainly in the separation of racemic compounds, which are separations of a high degree of difficulty. In this work, two new approaches to modeling the LMS process have been proposed, stepwise approach and Front Velocity approach. In the Stepwise approach, each chromatographic column of the SMB, is divided in to N cells connected in series, and the concentrations of compounds in liquid and solid phases were simulated using two different kinetics of mass transfer. This approach assumes that the interactions resulting from the mass transfer between the molecules of the compound in its liquid and solid phases occur only on the surface. So that with this assumption the volume occupied by each molecule in the solid and liquid phases is the same, implying that the factor of residence is equal to the equilibrium constant. To describe the mass transfer that occurs in the Chromatographic process, the Front Velocity approach considers that the convection is the dominant phase in the solute transport along the chromatographic column. The "Front Velocity" is a discrete model (steps) where the flow rate determines the liquid phase advance along the column. The steps are: advancing liquid phase and subsequent mass transfer between the liquid and solid phases, the latter in the same time interval. Thus, the experimental volumetric flow is used for the discretization of the control volume moving along the porous column with the same velocity of the liquid phase. The mass transfer was represented by two distinct kinetic mechanisms without (linear type) and with maximum adsorption capacity (Langmuir type). Both proposed approaches were studied and evaluated by comparison with experimental data separation LMS of the anesthetic ketamine and subsequently with the drug Verapamil. Were also compared with the simulations of dispersive equilibrium model for the case of ketamine used by Santos (2004) and the simulations of the software Help for the case of Verapamil (Perna 2013). In the chromatographic column characterization step, the new approaches have been associated with inverse R2W tool to determine the global mass transfer parameters using only the experimental residence times of each enantiomer in the high performance liquid chromatography (HPLC) column. In the second step, the kinetic models developed in both approaches were applied to the columns of the LMS with the values determined in the characterization of the chromatographic column step, for the simulation of continuous separation process. The simulation results show good agreement between the two proposed approaches and pulse experiments to characterize the column in the enantiomeric separation of ketamine over time. In the simulation of the SMB process, when the approaches admit one kinetic mechanism of the Langmuir type showed good agreement with the results obtained from the dispersive equilibrium model, it is a classical tool for the simulation of this process. While using a kinetic linear mechanism the results is more similar to the experimental data. According to the study conducted, both the proposed approaches were shown to be potential tools to predict the chromatographic behavior of a sample in a test pulse, as well as the simulation of separation of a compound in SMB process despite minor discrepancies presented in the first work cycles of the SMB. Moreover, the approaches can be easily programed and applied in the analysis of the process, because it requires a low number of parameters and consist of ordinary differential equations.

Orientador: Cesar Costapinto Santana
Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Engenharia Quimica
Made available in DSpace on 2018-08-30T12:54:54Z (GMT). No. of bitstreams: 1 Veredas, Vinicius de_D.pdf: 13205142 bytes, checksum: 97c5009c255088bef6fcdc1fd92294c3 (MD5) Previous issue date: 2005
Doutorado
Desenvolvimento de Processos Biotecnologicos
Mestre em Engenharia Química

Diversas aplicações industriais relevantes envolvem os processos de adsorção, citando como exemplos a purificação de produtos, separação de substâncias, controle de poluição e umidade entre outros. O interesse crescente pelos processos de purificação de biomoléculas deve-se principalmente ao desenvolvimento da biotecnologia e à demanda das indústrias farmacêutica e química por produtos com alto grau de pureza. O leito móvel simulado (LMS) é um processo cromatográfico contínuo que tem sido aplicado para simular o movimento do leito de adsorvente, de forma contracorrente ao movimento do líquido, através da troca periódica das posições das correntes de entrada e saída, sendo operado de forma contínua, sem prejuízo da pureza das correntes de saída. Esta consiste no extrato, rico no componente mais fortemente adsorvido, e no rafinado, rico no componente mais fracamente adsorvido, sendo o processo particularmente adequado a separações binárias. O objetivo desta tese é estudar e avaliar diferentes abordagens utilizando métodos estocásticos de otimização para o problema inverso dos fenômenos envolvidos no processo de separação em LMS. Foram utilizados modelos discretos com diferentes abordagens de transferência de massa, com a vantagem da utilização de um grande número de pratos teóricos em uma coluna de comprimento moderado, neste processo a separação cresce à medida que os solutos fluem através do leito, isto é, ao maior número de vezes que as moléculas interagem entre a fase móvel e a fase estacionária alcançando assim o equilíbrio. A modelagem e a simulação verificadas nestas abordagens permitiram a avaliação e a identificação das principais características de uma unidade de separação do LMS. A aplicação em estudo refere-se à simulação de processos de separação do Baclofen e da Cetamina. Estes compostos foram escolhidos por estarem bem caracterizados na literatura, estando disponíveis em estudos de cinética e de equilíbrio de adsorção nos resultados experimentais. De posse de resultados experimentais avaliou-se o comportamento do problema direto e inverso de uma unidade de separação LMS visando comparar os resultados obtidos com os experimentais, sempre se baseando em critérios de eficiência de separação entre as fases móvel e estacionária. Os métodos estudados foram o GA (Genetic Algorithm) e o PCA (Particle Collision Algorithm) e também foi feita uma hibridização entre o GA e o PCA. Como resultado desta tese analisouse e comparou-se os métodos de otimização em diferentes aspectos relacionados com o mecanismo cinético de transferência de massa por adsorção e dessorção entre as fases sólidas do adsorvente.
Several important industrial applications involving adsorption processes, citing as an example the product purification, separation of substances, pollution control and moisture among others. The growing interest in processes of purification of biomolecules is mainly due to the development of biotechnology and the demand of pharmaceutical and chemical products with high purity. The simulated moving bed (SMB) chromatography is a continuous process that has been applied to simulate the movement of the adsorbent bed, in a countercurrent to the movement of liquid through the periodic exchange of the positions of input and output currents, being operated so continuous, notwithstanding the purity of the outlet streams. This is the extract, rich in the more strongly adsorbed component, and the raffinate, rich in the more weakly adsorbed component, the method being particularly suited to binary separations. The aim of this thesis is to study and evaluate different approaches using stochastic optimization methods for the inverse problem of the phenomena involved in the separation process in LMS. We used discrete models with different approaches to mass transfer. With the benefit of using a large number of theoretical plates in a column of moderate length, in this process the separation increases as the solute flowing through the bed, i.e. as many times as molecules interact between the mobile phase and stationary phase thus achieving the equilibrium. The modeling and simulation verified in these approaches allowed the assessment and identification of the main characteristics of a separation unit LMS. The application under consideration refers to the simulation of the separation of Ketamine and Baclofen. These compounds were chosen because they are well characterized in the literature and are available in kinetic studies and equilibrium adsorption on experimental results. With the results of experiments evaluated the behavior of the direct and inverse problem of a separation unit LMS in order to compare these results, always based on the criteria of separation efficiency between the mobile and stationary phases. The methods studied were the GA (Genetic Algorithm) and PCA (Particle Collision Algorithm) and we also made a hybridization between the GA and PCA. This thesis, we analyzed and compared the optimization methods in different aspects of the kinetic mechanism for mass transfer between the adsorption and desorption of the adsorbent solid phases.

The main objective of this work is to study the chiral separation of stereoisomers of nadolol by preparative liquid chromatography. In this report it is presented the state of the art and experimental results obtained for optimizing the methodology for preparative scale separation of nadolol stereoisomers using an immobilized chiral stationary phase (Chiralpak® IA). The screening of the solvent composition is based on the best solvent or solvents mixture to perform the pseudo-binary separation (1+2+3/4) of the more retained stereoisomer using the simulated moving bed technology. The three least retained components (1, 2 and 3) co-elute in the raffinate outlet stream and the more retained component (4) will elute in the extract outlet stream. After the solvent composition optimization, 100%methanol:0.1%diethylamine solvent composition was selected to perform the experimental SMB separation. Experimental results also include adsorption equilibrium isotherm and breakthroughs measurements followed by SMB experimental operation. Using a 2 g/L total feed concentration, the more retained stereoisomer was totally recovered at the extract outlet stream with 100% purity, obtaining a system productivity of 0.31 gtarget product/(Lbed.hr) and requiring a solvent consumption of 27.71 Lsolvent/gtarget product. Another SMB run was performed using a considerable higher feed concentration of 10 g/L and an improvement in the performance parameters were observed. For the more retained stereoisomer in the extract outlet stream, a purity of 99.5%, and a recovery of 97.6% was obtained, with a productivity of 1.98 gtarget product/(Lbed.hr) and a solvent consumption of 3.13 Lsolvent/gtarget product. The extract and raffinate SMB outlet streams were collected and used to perform additional adsorption equilibrium isotherm and breakthroughs experiments. These results were used to evaluate the differences in the adsorption equilibrium dynamics for pure and racemic nadolol feed mixtures. This work introduced new alternative results for the separation of nadolol stereoisomers and contributed for a future objective of the complete separation of the four nadolol stereoisomers by SMB technology using different modes of SMB operation, adsorbents and solvent compositions.
O principal objetivo deste trabalho consiste no estudo da separação quiral dos estereoisómeros do nadolol por cromatografia líquida preparativa. Neste relatório apresenta-se o estado da arte assim como alguns resultados obtidos da otimização da composição do solvente para a separação à escala preparativa utilizando uma fase estacionária quiral (Chiralpak® IA). O estudo da composição do solvente é baseado na seleção do solvente ou mistura de solventes mais apropriada para realizar a separação pseudo-binária (1+2+3/4) dos estereoisómeros do nadolol utilizando a tecnologia de leito móvel simulado. Os três componentes menos retidos (1, 2 e 3) co-eluem na corrente de refinado e o componente mais retido é recuperado na corrente de extrato. Na fase inicial, realiza-se uma comparação dos resultados experimentais obtidos com a fase estacionária Chiralpak® IA com os resultados obtidos com a fase estacionária Chiralpak® AD. Para este estudo, empacotaram-se duas colunas com dimensões preparativas, com estas fases estacionárias e repetiram-se algumas análises cromatográficas com a fase estacionária Chiralpak®AD. Após a otimização da composição do solvente, foi selecionada a mistura 100%methanol:0.1%diethylamine para realizar a separação preparativa utilizando a tecnologia de leito móvel simulado. Os resultados experimentais incluem a determinação experimental de dados de equilíbrio através da medição e modelização de isotérmicas de equilíbrio de adsorção assim como medições experimentais e a modelização de experiências de cromatografia frontal (breakthroughs). Finalmente, apersentam.se os resultados experimentais obtidos das experiências de separação pseudo-binária dos estereoisómeros de nadolol utilizando um sistema de leito móvel simulado (SMB). Utilizando uma concentração da solução de alimentação de 2 g/L, o estereoisómero mais retido foi totalmente recuperado na corrente de extrato com uma pureza de 100%, obtendo-se uma produtividade de 0.31 gtarget product/(Lbed.hr) sendo necessário um consumo de solvente de 27.71 Lsolvent/gtarget product. Uma outra experiência de SMB foi realizada utilizando uma concentração da corrente de alimentação de 10 g/L, tendo-se obtido um aumento da produtividade e uma diminuição do consumo de solvente. Para o estereoisómero mais retido, obteve-se na corrente de extrato, uma pureza de 99.5% e uma recuperação de 97.6%, uma produtividade de 1.98 gtarget product/(Lbed.hr) e um consumo de solvente de 3.13 Lsolvent/gtarget product. As correntes de extrato e de refinado das operações de SMB foram recolhidas e utilizadas para realizar experiências adicionais de medidas de isotérmicas de equilíbrio de adsorção e experiências de breakthrough de forma a avaliar a diferença do comportamento de adsorção dos estereoisómeros quando presentes na mistura ou na forma “pura” (1+2+3 e 4). Este trabalho introduz novas alternativas para a separação dos estereoisómeros do nadolol, contribuindo para o objetivo futuro que será a separação completa dos quatro estereoisómeros do nadolol, utilizando diferentes modos de operação SMB, adsorventes e composições de solvente.
إن الهدف الرئيسي من هذا العمل هو دراسة عملية الفصل الكيرالي للنظائر الفراغية لمركب النادولول بواسطة الكرومتغرافيا السائلة التحضيرية. نتطرق في هذا التقرير إلى بعض الدراسات السابقة إضافة لعرض النتائج ال م ح ص لة بهدف التوصل إلى افضل منهجية لفصل النظائر الفراغية للنادولول ضمن النطاق التحضيري بإستخدام الطور الكيرالي الثابت ) IA ®Chiralpak ) . يستند فحص تركيب المذيب على أفضل مذيب أو خليط من المذيبات التي تسمح بإجراء عملية الفصل الثنائية ( 1 + 2 + 3 / 4 ( للنظير الذي يمتلك زمن البقاء الأكبر وذلك بإستخدام تقنية محاكاة السرير المتحرك ( SMB (. المركبات الثلاثة التي تمتلك زمن بقاء أقل ) 1 , 2 و 3 ( تمتزج مع المذيب لتخرج مع التيار الثانوي, أما المركب الأكثر بقا ء ) 4( يخرج مع تيار الإستخلاص. بعد الإنتهاء مع عملية تحسين تركيب المذيب, 100% ميثانول: % 0.1 داي إيثيل أمين هو المذيب الذي تم إختياره لإجراء عملية الفصل بتقنية SMB . النتائج التجريبية تتضمن الإمتزاز التوازني عند درجة حرارة ثابتة إضافة إلى تجارب الإختراقات أو ما يعرف بالكروموتغرافية الأمامية (breakthrough) , في النهاية نعرض النتائج التجريبية لمحاكي السرير المتحرك SMB . بإستخدام 2 g/L كتركيز كلي للمحلول المغذي, تم الإسترجاع وبشكل كامل للنظير الفراغي الأكثر إحتفاظا من تيار الإستخلاص وبنفاوة وصلت إلى % 100 , بإنتاجية بلغت .hr)bed/(Ltarget productg 0.31 إضافة إلى إستهلاكية المذيب target product/gsolventL.27.71 بإستخدام تركيز أعلى للمحلول المغذي 10 g/L , تمت عملية الفصل مرة آخرى بواسطة تقنية SMB حيث لوحظ تحسن في معايير الأداء. نقاوة النظير الأكثر بقا ء الخارج مع تيار الإستخلاص وصلت إلى 99.5% , وإسترجع بنسبة 97.6% , الإنتاجية وصلت إلى .hr)bed/(Ltarget productg1.98 إضافة إلى إستهلاكية المذيب target product/gsolventL3.13 . ت م جمع عينات من تيارات الإستخلاص والرشاحة الخارجة من SMB لغرض القيام بدراسات إضافية حول الإمتزاز عند درجة حرارة ثابتة وكذلك تجارب الغروماتوغرافيا الأمامية. لتقييم الفروقات في ديناميكية الإمتزاز التوازني لكلا الحالتين للنادولول سواء إن كان نفيا أو إن كان كمركب عنقودي. هذا العمل قدم نتائج إضافية لفصل النظائر الفراغية لمركب النادولول وساهمت هذه النتائج في وضع الخطة المستقبلية لفصل نظائر النادولول بشكل كامل بإستخدام تقنية SMB بمتواليات مختلفة من طرق التشغيل, كذلك الممتزات وأخيرا تراكيب المذيب.

The general objective of this work is the study of the behaviour of the Simulated Moving Bed (SMB) processes, with applications to chiral separations. Briefly, SMB chromatography allows the continuous injection and separation of binary mixtures. The simulated countercurrent contact between the solid and liquid phases maximizes the mass transfer driving force, leading lo a significant reduction in mobile and stationary phases consumption when cornpared with elution chromatography. The problem of modeling a SMB separation process is analyzed by two different strategies: one, by simulating the system directly, taking into account its intermittent behaviour (the SMB model); other by representing its operation in terms of a true countercurrent system (TMB model). From the comparative study, we conclude that the prediction of the performance of a SMB operation, and so its flow-rate optimization, can be safely done by using the TMB approach. The effect of the model parameters and operating variables on the SMB performance is analyzed in terms of four parameters: purity, recovery, solvent consumption, and adsorbent productivity. This work shows the influence of the switch time interval, recycling flow-rate, and inlet and outlet flow-rates. Also studied is the influence of axial dispersion and mass transfer resistance on the 8MB performance. We conclude that the mass transfer resistance can reduce significantly the possible set of operating conditions that lead to the desired separation. Moreover, mass transfer resistance can affect the SMB operating conditions, being this influence emphasized when a higher purity requirement is desired. The experimental operation of a Simulated Moving Bed unit was implemented in a Licosep 12-26 SMB pilot unit (Novasep, France), available at the LSRE. Two chiral systems were considered: the bi-naphlhol and the chiral epoxide enantiomers. For the bi-naphthol system purities and recoveries higher than 95% were obtained for both extract and raffinate with an adsorbent productivity of 68 grams of racemic mixture processed per day and per liter of bed. The solvent consumption was 1.2 liter per gram ofracemie mixture processed. For the chiral epoxide system, a first set of experimental runs Ied to purities and recoveries higher than 90%. A productivity of 52 grams of racemic mixture per day and per liter of bed was achieved, with a solvent consumption of 0.4 liter of mobile phase per gram of racemic mixture processed. In a second seI of experimental runs, we obtained 98% pure extract and raffinate, with a productivity of 34 grams per day and per liter of bed, and a solvent consumption of 1.3 liter per gram. The experimental results obtained in the Licosep 12-2 6 SMB pilot unil are reported in terms of process performance, steady-state internal concentration profiles, and transient evolution of the concentration of both species in the extract and raffinate streams. The simulation packages developed in this work are used lo predict the SMB behaviour in reasonable agreement with the experimental results.
O objectivo deste trabalho consistiu no estudo do processo de leito móvel simulado (Simulated Moving Bed, 8MB) com aplicações a separações quirais. Resumidamente, a cromatografia de SMB permite a injecção e separação contínua de misturas binárias. A simulação do contacto em contracorrente entre as fases sólida e líquida maximiza a força motriz de transferência de massa, permitindo uma diminuição significativa do consumo das fases móvel e estacionária comparativamente com a cromatografia de eluição. O problema da modelização de um processo de separação por SMB foi analisado recorrendo a duas estratégias alternativas: uma, por simulação directa do sistema, levando em consideração o seu comportamento intermitente (o modelo 8MB); a outro por representação da sua operação em termos de um sistema equivalente em contracorrente (o modelo TMB, True Moving Bed). Por estudo comparativo destas duas estratégias concluiu-se que o desempenho da operação do 8MB, e assim a optimização das suas condições de operação, pode ser avaliada de forma segura por utilização do modelo TMI3. A influência dos parâmetros do modelo e das variáveis de operação no desempenho do 8MB foi analisada recorrendo a quatro parâmetros: pureza, recuperação, consumo de solvente e produtividade do adsorvente. Este trabalho mostra o efeito do período de rotação, caudal de reciclo e caudais de entrada e saída. Foi também estudada a influência da dispersão axial e resistência à transferência de massa no desempenho do 8MB. Concluiu-se que a resistência à transferência de massa pode reduzir significativamente o domínio de condições de operação que permitem uma desejada separação. Mais, a resistência à transferência de massa pode alterar as condições óptimas de operação do 8MB, sendo esta influência particularmente importante quando se pretendem purezas elevadas. A operação experimental de um leito móvel simulado foi efectuada na unidade piloto de 8MB Licosep 12-26 (Novasep. França), disponível no LSRE. Foram estudados dois sistemas: a separação de enantiómeros do bi-naftol e de um epóxido quiral. Para o sistema bi-naftol, foram obtidas purezas e recuperações superiores a 95% no extrato e refinado. A produtividade do adsorvente foi de 68 gramas de mistura racémica processada por dia e por litro de leito, sendo o consumo de solvente de 1,2 litros por grama de mistura racémica processada. Para o sistema do epóxido quiral, um primeiro conjunto de experiências conduziu a recuperações e purezas superiores a 90%. A produtividade do adsorvente foi de 52 gramas de mistura racémica processada por dia e por litro de leito, com um consumo de solvente de 0,4 litros por grama de mistura racémica processada. Num segundo conjuntas de experiências foram obtidas purezas de 98% para extracto e refinado, com uma produtividade de 34 gramas por dia e litro de leito e um consumo de solvente de 1,3 litros por grama. Os resultados experimentais obtidos na unidade piloto de 8MB Licosep 12-26 foram representados em termos do desempenho do processo, perfis internos de concentração e evolução transiente da concentração de ambos os componentes nas correntes de extrato e refinado. O simulador desenvolvido neste trabalho foi utilizado na previsão da operação do 8MB, em concordância razoável com os resultados experimentais obtidos.
Le but générique de ce travail est l’étude des procédés à Lit Mobile Simulé (Simulated Moving Bed, 8MB), avec des applications à la séparation de composés chiraux. En bref, la chromatographie à 8MB permet l’injection continue et la séparation de mélanges binaires. Le contact à contre-courant simulé entre les phases solide et liquide rend maximale la force directrice de transfert de masse, conduisant à une réduction appréciable de la consummation des phases liquide et solide en comparaison avec la chromatographie d’élution. Le problème de la modélisation d’un procédé de séparation à 8MB est attaqué selon deux stratégies différentes: l’une, fondée sur la simulation directe du système, en tenant compte de son comportement intermitant (le modèle 8MB); l’autre, partant de la représentation de son opération en tentes d’un vrai système à contre-courant (le modèle TMB, True Moving Bed). D’après une étude comparative, nous sommes arrivés à conclure que la prévision de la performance d’une opération SMB, et donc son optimisation par rapport au débit, peut être faite en sécurité avec l’approche TMB. L’effet des paramètres du modèle et des variables opératoires sur la performance du 8MB est discutée selon quatre paramètres la pureté, le taux de récupération, la consommation de solvant et la productivité de l’adsorbant. Ce travail montre l’influence de la période de rotation, des débits de recyclage, d’alimentation et de soutirage. L’influence de la dispersion axiale et de la résistance au transfert de masse sur la performance du 8MB sont également étudiées. Nous concluons que la résistance au transfert de matière peut réduire significativement le domaine de conditions opératoires ou l’on obtient la séparation souhaitée. En plus, la résistance au transfert de matière peut changer les meilleures conditions d’opération à 8MB, et cet effet est particulièrement important lorsqu’on exige une plus grande pureté. L’opération expérimentale d’une unit6 à 8MB a été menée à bien avec un système pilote Licosep 12-26 (Novasep. France), installé au LSRE. Deux systèmes chiraux ont été choisis: le binaphtol et les énantiomères d’un epoxide chiral. Pour le binaphtol, des puretés et des taux de récupération au dessus de 95% ont été obtenus tant pour l’extrait que pour le raffiné, avec une productivité de l’adsorbant de 68 grammes de mélange racémique par jour et par litre de lit. La consoinfl1atioht de solvant a été de 1,2 litres par gramme de mélange racémique processé. Pour l’epoxide chiral, un premier ensemble d’essais a conduit à des puretés et des taux de récupération au dessus de 90%. La productivité de 52 grammes de mélange racémique par jour et par litre de lit a été atteinte, avec une consommation de solvant de 0,4 litre de phase mobile par gramme de mélange racémique traité. Sur un deuxième groupe d’essais, nous avons réussi à atteindre des extraits et raffinés purs à 98%, avec une productivité de l’adsorbant de 34 grammes par jour et par litre de Itt, et une consommation de solvant de 1,3 litres par gramme. Les résultats expérimentaux obtenus sur le 8MB LicoseP 12-26 ont eté rapportés en tentes de la performance du procédé, des profils de concentrations internes dans l’état stationnaire et de l’évolution transitoire de la concentration de toutes les deux espèces aux courants d’extrait et de raffiné. Les paquets de simulation développés pendant cc travail ont été utilisés pour la prévision du comportement du 8MB avec un accord raisonnable avec les données expérimentales.

博士
義守大學
化學工程學系暨生物技術與化學工程研究所
107
Separation and purification is the basic technology for industry. It works for the pretreatment of raw materials and the purification of final products for petrochemicals, specialities, biotechnologies, pharmaceuticals. Compared to distillation and membrane separation, chromatography is more widely apply in biotechnology and pharmaceutical industries because of low-temperature operation and high selectivity of adsorbent. SMB(Simulated Moving Bed), one of the continuous chromatographic technique, can greatly increase the productivity of solid adsorbent and reduce the solvent consumption. SMB gains its importance in the last two decade in pharmaceutical industry. This study is divided into two major parts. The first part aims to combine the use of supercritical fluid and the simulated moving bed, and the second part aims to use a 6 zones SMB with an additional CIP section for the ternary separation with very strong retention components in the feedstock. SF-SMB is a continuous chromatography with supercritical fluid as the desorbent, which can avoid the problem of high energy consumption for the down stream concentration and solvent recovery. By using the SF-SMB, which was designed and manufactured in our laboratory, sesamin and sesamolin can be separated, and the Triterpenoids can also be separated from the crude extract of Taiwanofugus camphorata. The results show that the purity of sesamin is 99.4% and the recovery is 98.1%. In the study of separating Triterpenoids from other impurities, the results reveal that the design of grad-SF-SMB with silica has the highest effectiveness on removing the impurities. It is also found that an iso-SF-SMB with silica also can successfully remove the impurities, and an iso-SF-SMB with RP-18 can also be used for removing the impurities with little lost of the triterpenoids. However, a traditional SMB with RP-18 is not suitable for removing the impurities. Both studies demonstrate that SF-SMB would be a useful technology for developing botanical drugs and provides greener alternative for industries. The second part of this thesis aims to use a SMB cascade for the multi-component separation. This study presents two three-step procedures for the SMB cascade to separate the intermediate retention component from a feedstock with very strong retention component. The feedstock is classified into two categories: (A) KA＜KB＜＜KC; and (B) KA＜＜KB＜KC. Based on the procedures, this study can successfully separate the intermediate retention component from two crude extracts. The experimental results for both crude extracts shows that the separation of the intermediate retention component with near 90% purity and recovery can be achieved without knowing the adsorption isotherms foe each impurity. This study provides a quick and simple method to operate a SMB cascade for the ternary separation.

The pharmaceutical industry is developing a growing interest in natural compounds with biological and nutritional properties. Betulinic and oleanolic acids are two naturally occurring triterpenic acids, which possess such characteristics. These two compounds can be extracted from natural resources, i.e., from the bark of Eucalyptus globulus. However, their separation is difficult because these compounds present similar structures (they are constitutional isomers). In this work, the chromatographic separation of betulinic and oleanolic acids from representative extracts of E. globulus was studied. High performance liquid chromatography (HPLC) assays were initially performed using an Acclaim C30 column as stationary phase. Through these tests it was found that the mobile phase methanol/acetonitrile 50/50 (%, v/v) is the most suitable for the separation of both triterpenic acids. In order to determine the equilibrium constants (𝐻𝑖) and the global linear driving force mass transfer coefficients (𝐾𝐿𝐷𝐹), several breakthrough experiments of pure acids (unary solutions) were carried out. The two parameters were correlated using experimental data and then validated by simulating the breakthrough curve of a binary mixture containing the same proportion of betulinic and oleanolic acids found in E. globulus extracts. The outcomes of all experiments were modeled using Carta’s analytical solution. In parallel, the method of moments was also used to obtain the transport parameters. The results were consistent. Lastly, the separation of betulinic and oleanolic acids by simulating moving bed (SMB) has been studied, carrying out simulations using the transport parameters obtained before from the breakthrough assays. Two different column configurations (1-1-1-1 and 2-2-2-2) and column lengths (from 10 to 25 cm) were adopted. It was concluded that using an SMB unit is able to separate betulinic and oleanolic acids with purity higher than 99 % both in extract and raffinate for all the scenarios presented. Posteriorly, the recovery of both triterpenic acids from the extract and raffinate streams of a future process was also investigated, taking advantage of their low solubility in water. Accordingly, the solubility of each triterpenic acid in solvent mixtures of increasing water concentration was experimentally measured and discussed.
A indústria farmacêutica tem manifestado um crescente interesse em compostos naturais com propriedades biológicas e nutricionais. Os ácidos betulínico e oleanólico são dois ácidos triterpénicos que ocorrem naturalmente na natureza e que possuem tais características. Estes dois compostos podem ser extraídos de recursos naturais, tais como da casca do Eucalyptus globulus. No entanto, a sua separação é difícil, pois os compostos apresentam estruturas muito semelhantes (são isómeros constitucionais). Neste trabalho estudou-se a separação cromatográfica de uma amostra representativa dos extratos de E. globulus dos ácidos betulínico e oleanólico. Inicialmente foram realizados testes cromatográficos em cromatografia líquida de alta eficiência, recorrendo à fase estacionária Acclaim C30. Através destes ensaios determinou-se que a fase móvel metanol/acetonitrilo 50/50 (%, v/v) é a mais adequada para a separação destes ácidos triterpénicos. De modo a averiguar as constantes de equilíbrio (𝐻𝑖) e os coeficientes globais de transferência de massa (𝐾𝐿𝐷𝐹), foram determinadas as curvas de rutura dos ácidos puros (soluções unárias). Estes parâmetros foram correlacionados recorrendo a dados experimentais e posteriormente validados pela simulação da curva de rutura de uma mistura binária contendo a mesma proporção de ácido betulínico e oleanólico encontrada no E. globulus. Os dados advindos deste ensaio foram modelados pela solução analítica de Carta. Paralelamente, foi também usado o método dos momentos para obter os parâmetros de transporte. Os resultados obtidos foram consistentes. Por fim, estudou-se a separação dos ácidos betulínico e oleanólico por leito móvel simulado (SMB), realizando simulações utilizando os parâmetros de transporte obtidos anteriormente pela modelação das curvas de rutura. Foram adotadas duas configurações diferentes (1-1-1-1 e 2-2-2-2) e diferentes comprimentos de coluna (variando dos 10 aos 25 cm), usando os parâmetros de transporte obtidos. Foi concluído que usando uma unidade SMB é possível separar os ácidos betulínico e oleanólico com purezas superiores a 99 % tanto no extrato como no rafinado para todos os cenários apresentados. Posteriormente, foi analisada a recuperação dos ácidos triterpénicos das correntes de extrato e rafinado de um futuro processo, tirando vantagem da sua baixa solubilidade em água. Por conseguinte, a solubilidade de cada ácido triterpénico em misturas de solventes com o aumento da concentração de água foi medida e discutida.
Mestrado em Engenharia Química

Natural products have been progressively forgotten by major pharmaceutical research companies as sources for new drugs in the last half century. Currently one observes a change of strategy, which is promoting a renewed interest on the integration of natural products into pharmaceuticals. Triterpenic acids are a promising group of plant secondary metabolites occurring in cuticular waxes covering fruits, owers, and leaves, providing a wide variety of bene cial biological activities. In this dissertation it was studied the oleanolic and ursolic acids isolation by chromatographic tecnique of simulated moving bed (SMB). The seperation of triterpenic acids is complex due their similar structure. EgiChem laboratory (CICECO, UA) has a SMB unit, but it is necessary to carry out preliminary experiments in order to select the best mobile phase and optimal operating conditions for separation of both acids. For that, it was analyzed the infuence of the solvent/mixture of solvents on the chromatographic separation by measuring selectivity, retention factor and resolution. It was tested a triacontyl column (Acclaim C30), and the best results were obtained with a mobile phase of methanol/ water 95/5 (%, v/v). Then, breakthrough curves have been measured in order to determine process parameters like the equilibrium isotherms (constants Hi) of both oleanolic and ursolic acids, and the global linear driving force (LDF) coe cients of mass transfer (KLDF,i). Data modeling was accomplished using Klinkenberg equation, which is specifcially applicable to linear systems. The equilibrium constants of oleanolic and ursolic acdis were HOA= 2.06 and HUA= 2.16, respectively, and global LDF coe cients were KLDF,OA= 30.48 min-1 and KLDF,UA= 101.45 min-1 with average deviaions of AADROA=18.29 % and AADRUA=26.88 %. Finally the simulation of a SMB unit for a oleanolic/ursolic acids mixture separation was accomplished, with a 2-2-2-2 con guration, using the packing of Acclaim C30 column and methanol/water 95/5 (%, v/v) as mobile phase and the equilibrium and kinetic parameters previously optimized. The obtained results for con guration showed that the separation of oleanolic and ursolic acids is viable, being possible to produce puri ed streams of each acid with concentrations above 99%.
No último meio século, os produtos naturais tem sido gradualmente esquecidos pelas maiores companhias de investigação farmacêuticas como fontes de novos medicamentos. Porém atualmente observou-se uma mudança de estratégia que promoveu um novo interesse na integração dos produtos naturais nestes. Os ácidos triterpénicos fazem parte de um grupo promissor de metabolitos secundários que podem ser encontrados em plantas, flores, folhas com grande variedade de benficios. Nesta dissertação estudou-se o isolamento dos ácidos oleanólico e ursólico por técnicas cromatográficas, recorrendo à tecnologia de leito móvel simulado (SMB). A separação dos ácidos triterpénicos é complexa dada à sua semelhança estrutural. No laboratório do grupo EgiChem (CICECO, UA) está a ser instalada uma unidade de SMB, porém é necessário realizar ensaios preliminares para selecionar a fase móvel mais adequada, bem como a otimização das condições de operação de ambos os ácidos. Posto isto, analisou-se a influência do solvente/mistura de solventes na separação cromatográfica recorrendo à medição de seletividades, factores de retenção e resolução. Foi testada uma coluna triacontyl (Acclaim C30), sendo que os melhores resultados foram obtidos com a fase móvel metanol/água 95/5 (%, v/v). Seguiu-se à medição das curvas de rutura de modo a determinar os parametros de processo como as isotérmicas de equilibrio (constantes Hi) do ácido oleanólico e do ácido ursólico, e os coeficientes globais de transferência de massa do modelo da força motriz linear (KLDF,i). Os dados obtidos foram modelados através da equação de Klinkenberg, que é aplicado especificamente para sistemas lineares. As constantes de equilíbrio linear dos ácidos oleanólico e ursólico foram HOA= 2.06 e HUA= 2.16, respetivamente, e os coeficientes globais de transferência de massa LDF de KLDF,OA= 30.48 min-1 e KLDF,UA= 101.45 min-1 com desvios médios de AADROA=18.29 % e AADRUA=26.88 %. Por fim foi realizada uma simulação de uma unidade SMB para a separação de uma mistura de ácidos oleanólico e ursólico, com uma configuração 2-2-2-2, usando o enchimento da coluna Acclaim C30 e a fase móvel metanol/água 95/5 (%, v/v) e os parâmetros de equilibrio e cinética otimizados anteriormente. Os resultados obtidos para esta configuração mostraram que é possível produzir correntes purificadas de cada ácido com concentrações acima dos 99%.
Mestrado em Engenharia Química

碩士
義守大學
生物技術與化學工程研究所碩士班
98
SMB (simulated moving bed) is a continuous chromatographic separation technology. Compared with batch-type preparative chromatography, the advantages of SMB include high yield, high purity, and high efficiency per unit weight of the adsorbent. In addition, SMB can be readily scaled-up for higher volume purification and can be conducted relatively quickly to meet the demand of tightened schedule in new product development. This work report the separations of sesamin and sesamolin, respectively, by two SMBs. The two SMBs have different piping design and configuration. The 1st SMB has four sections and 2nd SMB has three sections. Both sections has two subsections so the 1st SMB is marked as 2-2-2-2 and the 2nd is 2-2-2-0. Effect of ingredient of desorbent, flow rate of desorbent, temperature, concentration of mixture, and impurities are reviewed by the triangle theory to explain the periodical change of concentration of effluents.

碩士
國立雲林科技大學
工業化學與災害防治研究所碩士班
89
The simulated moving-bed (SMB) technology developed by UOP has been used in chemical industry for several bulk large-scale separations known as SORBEX processes. This technology has been recently applied in new areas such as biotechnology, pharmaceutical, and fine chemistry. Especially in the pharmaceutical industry, SMB is considered to be the best technology for continuous large-scale production of enantiomers. The concept of the SMB is base on the true moving bed (TMB) process, where the liquid goes up and solid goes down in each zone, and then the countercurrent contact between solid and liquid occurs, leading to a high mass transfer driving force. The design of a SMB mainly relies on the appropriate choice of different operating parameter, i.e., liquid (recycle, feed, eluent, extract, raffinate) and solid (equivalent to the switching time) flow rates. ²Triangle theory², based on the TMB concept, provides explicit criteria for the choice of the proper operating conditions for both linear and non-linear system. The SMB laboratory unit for the continuous separation of enantiomers of 1- 1¢-bi-2-naphthol on Pirkle D-phenylglycine was built, operated and considered as a model system in this study. A quick and straightforward strategy presented determines the set of operating conditions that yield desired product purities for the SMB unit. This is based on the “triangle theory” and the good separation regions that take non-linear equilibrium and mass-transfer effects into consideration were found based on experimental results of a small number of SMB experiments. The effects of operating parameter (switch time, feed flow rate, and feed concentration) and design parameter (column length and column number) on the system performance where also investigated. Good separation ( purity and recovery of each isomer higher than 95 %) was achieved for the model system. This method is shown to provide a convenient and reliable tool to find both optimal and robust operating conditions of SMB units.

碩士
國立臺北科技大學
化學工程與生物科技系化學工程碩士班
107
The objective of this study is to purify hydroxymethylfurfural (HMF) from dime-thylacetamide (DMAC) by designing a simulated moving bed (SMB) process. HMF is a heat-sensitive compound therefore is suitable for purification by liquid chromatography. After obtaining the isotherm parameters of the two materials from the pulse and frontal ex-periments. Aspen, a process design software, was used to find the optimized separation process. In order to evaluate the effects of mass transfer on SMB, two adsorbents, C18 and polystyrene, were chose to study. The C18 adsorbent particles are small, ca.5µm, and the effect of the mass transfer is negligible, but the polystyrene adsorbent has a larger particle size, 50-100 µm, and the effect of the mass transfer must be considered in the simulation. To ensure the effectiveness of the SMB study, two different design theories, the standing wave design (SWD) and triangle method, were used for comparison and obtaining the de-sign parameters. For SWD, the method required initial guess of HMF concentration in the column for estimating other relevant parameters. Moreover, the effects of competitive ad-sorption were also taken into account for the SMB design. The triangle method was used to search for the operating parameters, and these parameters were verified by the Aspen simulations. The triangle theory specifies a triangular region, which encloses all feasible operating conditions that guarantee 100 % purity and yield for an ideal system, in which mass-transfer effects are negligible. However, our results showed that the boundary of the region defined by the triangle theory did not exactly correspond to the region of successful separation, but to the certain shape of HMF concentration wave. With the effects of the mass transfer, HMF and DMAC could not be competely separated. In addition, triangle method was used to optimize conditions. It was found that the use of the optimized design parameters inferred from the triangle method lead to higher concentration products and lower production cost.

Simulated Moving Bed Chromatography is a well-established separation method. Its conventional system has proved its utility for the separation of binary mixtures. Since in industry one of the main challenges is to separate complex mixtures, several studies were conducted and novel structures have been proposed to address this problem, including the 8-zone Simulated Moving Bed. This works’ aim is to experimentally demonstrate the isolation of an intermediary eluting molecule out of a pseudo ternary mixture using 8-zone SMB. This was performed through adsorption isotherm characterization, using multicomponent single column experiments, and subsequent model and design of the 8-zone SMB process for raffinate recycle configuration. This study was carried out for a mixture of food colorants: Tartrazine, Sunset Yellow, Crystal Ponceau (0,04g/L) and Fast Green (0,012g/L) .The respective solvent had a composition of 20% Ethanol and 80% Acetic Acid 70mmolar. The analysis of the separation performance is achieved using spectroscopy and Lambert Beer Law to calculate each molecule’s concentration at each outlet port.

Simulated moving bed (SMB) chromatography is attracting more and more attention since it is a powerful technique for complex separation tasks. Nowadays, more than 60% of preparative SMB units are installed in the pharmaceutical and in the food in- dustry [SDI, Preparative and Process Liquid Chromatography: The Future of Process Separations, International Strategic Directions, Los Angeles, USA, 2002. http://www. strategicdirections.com]. Chromatography is the method of choice in these ¯elds, be- cause often pharmaceuticals and ¯ne-chemicals have physico-chemical properties which di®er little from those of the by-products, and they may be thermally instable. In these cases, standard separation techniques as distillation and extraction are not applicable. The noteworthiness of preparative chromatography, particulary SMB process, as a sep- aration and puri¯cation process in the above mentioned industries has been increasing, due to its °exibility, energy e±ciency and higher product purity performance. Consequently, a new SMB paradigm is requested by the large number of potential small- scale applications of the SMB technology, which exploits the °exibility and versatility of the technology. In this new SMB paradigm, a number of possibilities for improving SMB performance through variation of parameters during a switching interval, are pushing the trend toward the use of units with smaller number of columns because less stationary phase is used and the setup is more economical. This is especially important for the phar- maceutical industry, where SMBs are seen as multipurpose units that can be applied to di®erent separations in all stages of the drug-development cycle. In order to reduce the experimental e®ort and accordingly the coast associated with the development of separation processes, simulation models are intensively used. One impor- tant aspect in this context refers to the determination of the adsorption isotherms in SMB chromatography, where separations are usually carried out under strongly nonlinear conditions in order to achieve higher productivities. The accurate determination of the competitive adsorption equilibrium of the enantiomeric species is thus of fundamental importance to allow computer-assisted optimization or process scale-up. Two major SMB operating problems are apparent at production scale: the assessment of product quality and the maintenance of long-term stable and controlled operation. Constraints regarding product purity, dictated by pharmaceutical and food regulatory organizations, have drastically increased the demand for product quality control. The strict imposed regulations are increasing the need for developing optically pure drugs.(...)

The chromatography steps dominate the Downstream Processing (DSP) costs of a new biopharmaceutical, which has propelled the biopharmaceutical industry to invest a lot of effort on their improvement in order to reduce the costs of the biopharmaceutical production. Liquid chromatography (LC) is currently the core technique within the DSP strategy for the purification of biopharmaceuticals. Although single-column batch chromatography is simpler to operate than continuous (multicolumn) chromatography, the latter has many advantages over the former, including improved purity, yield, and productivity. The main objective of this thesis is the development of a new chromatographic platform based on a novel single-column device that mimics the operation of multicolumn chromatography through ingenious management and recycling of the mixed fractions exiting the chromatographic column. The platform shares the benefits of the Simulated- Moving-Bed (SMB) technology. However, the newly developed process uses only a single chromatographic column. The conceptual design of the set-up and its mathematical model were successfully established. The laboratory prototype was built focusing on a simple, compact, and versatile design with small footprint. The binary separation of nucleosides by reversedphase chromatography was experimentally realized as proof of concept of the new system. An effort was made in 3D manufacturing of flow distributors and internals to ensure the proper operation of the recycle device and the improvement of its efficiency. A second case study—the capture step of monoclonal antibodies by affinity chromatography on protein A—was successfully used as a demonstration of the applicability of the newly developed process. The new system offers a more compact, less expensive, and simpler-to-operate alternative to multicolumn SMB chromatography. Depending on the efficiency of the recycle device, the single-column process can achieve the same purities as the analogous SMB unit while keeping the specific productivity constant. Moreover, the single-column chromatograph can be easily integrated into the existing downstream processing platforms of complex biopharmaceuticals.

With the advancements in technology, the development of tools for the control and testing of the progress in different fields, such as chromatography, has become essential in concerns to lab work and prototyping. As such, many programming languages have been adapted and developed with the objective to make the development of such tools easier. As our group built the Single-Column Analog Simulated Moving Bed chromatography process, the need for a versatile program to ease and simplify the procedure of tests and adjustments was met with the development of a tool written in the Julia and Python programming languages. The use of the aforementioned languages enabled us to speed up the processes of testing and modifying the system built, helping us to get more accurate results and meet deadlines for reports and presentations. With this it can be summarized that the development of easy-to-use programs aided by effective programming languages for the purpose of technological and scientific research is of the interest of various different fields as it allows them to hasten the development of the processes in study.