Choosing the right solvent is critical for many industrial applications. A useful property for selection of solvents is their solubility parameters. This concept of solubility parameters is central to this thesis and has been used in two different case studies of material treatment applications. Silicone rubber (crosslinked poly(dimethyl siloxane), PDMS) has many favorable material properties making it useful in biomedical devices. However, a limiting aspect of its material properties is a hydrophobic surface. The aim of this work was to prepare a hydrophilic PDMS material while retaining the transparency of the material. To do this, PDMS was combined with a hydrophilic polymer, polyvinylpyrrolidone (PVP) in an interpenetrating polymer network (IPN). A two-step IPN synthesis method was developed and it was found that the solvent used for polymerization of PVP had a significant influence on the water-wettability and the transparency of the PVP/PDMS IPN. Several different analytical techniques were used for determining the degree of phase separation in the PVP/PDMS IPN. It was found, by using microscopy techniques, that the PVP phase domains varied between 200 nm up to a few micrometers, and the size of the phase domains was correlated to the solvent used for polymerization of the IPN. The second topic for which solvent effects were explored was for the use of mesoporous silica particles as potential drug delivery devices. In the present work a drug molecule, ibuprofen, was loaded into mesoporous silica particles using different solvents, and in addition adsorption isotherms were established in each solvent. The maximum loading of ibuprofen in the mesoporous material was achieved when using a nonpolar solvent, in particular liquid carbon dioxide was successfully used. One of the advantages of using liquid carbon dioxide is that no solvent residues are left in the final material, which is important for pharmaceutical applications. Furthermore, it was concluded that ibuprofen was stored in an X-ray amorphous form in the mesoporous particles. Release studies in water showed a rapid release of ibuprofen from the mesoporous silica particles, while the dissolution of samples with crystalline ibuprofen was slower. This was verified to be an effect of a larger exposed ibuprofen area in the ibuprofen-loaded mesoporous silica particles, and it was concluded that the intrinsic dissolution rate for the samples were identical.

Aujourd’hui, malgré la description des mécanismes à l’origine du développement de la dépression et de la MA, aucun traitement curatif n’existe pour ces pathologies suggérant l’implication d’un autre phénomène. L’un des processus retrouvé communément dans ces pathologies est la neuroinflammation. Or pour le moment, les essais cliniques entrepris dans la MA afin de réduire la neuroinflammation n’ont pas permis d’aboutir à une amélioration significative des symptômes. L’une des raisons de cet échec serait une mauvaise fenêtre thérapeutique qui aurait pour conséquence d’exacerber les effets délétères de la neuroinflammation. Ceci met en lumière la méconnaissance de la cinétique de la neuroinflammation dans la MA. Ainsi notre travail de thèse avait pour but, d’une part, d’étudier l’impact d’anti-inflammatoires comparativement à celui d’antidépresseur dans la dépression chez la souris, et d’autre part, d’étudier l’impact de l’utilisation d’antidépresseur et d’anti-inflammatoires dans un modèle murin de MA. / Today, despite the description of the mechanisms underlying the development of depression and AD (Alzheimer’s disease), no cure exists for these diseases suggesting the involvement of another phenomenon. One of the processes commonly found in these pathologies is neuroinflammation. However, clinical trials undertaken in the AD to reduce neuroinflammation have not led to a significant improvement of symptoms. One reason for this failure could be a bad therapeutic window which would result in the increase of deleterious effects of neuroinflammation. This highlights the lack of understanding of the kinetics of neuroinflammation in AD.

Alguns Agentes Farmacêuticos (AF) sólidos podem ser otimizados através de ajustes nas propriedades físicas, permitindo maior controle na solubilidade, estabilidade, biodisponibilidade e farmacocinética. Líquidos iônicos, sais que se apresentam líquidos à temperaturas inferiores a 100º C, representam uma classe de substâncias utilizadas como possível estratégia no planejamento e otimização de fármacos, através da escolha de íons ativos biologicamente. Neste trabalho foram investigadas interações entre pares iônicos formados pelos ânions acetilsalicilato (ASP) e ibuprofenato (IBU), em combinação com os cátions biologicamente ativos, benzil-decil-dimetil-amônio (BDDA) e didecil-dimetil-amônio (DDA) com a membrana biológica formada por palmitoil-oleil-fosfatidil-colina (POPC), pelo método de Dinâmica Molecular. A partir de otimizações geométricas e distribuições de cargas, estabeleceram-se topologias para os íons, definindo-se parâmetros ausentes no campo de força AMBER. Inicialmente simularam-se os pares iônicos solvatados e também sistemas contendo líquidos iônicos puros. Essas simulações indicaram adequada distribuição de cargas para os íons e forneceram informações a respeito da estrutura do líquido, formado por pares iônicos, como densidade e distâncias entre grupos de átomos. As simulações contendo sistemas completos (íons, POPC e água) indicaram que no sistema IBUDDA o par iônico é mantido, enquanto que nos outros sistemas ocorrem maiores variações nas distâncias entre os íons. O sistema ASPDDA apresenta indícios de fuga do ânion através da bicamada. Nos sistemas ASPBDDA e IBUBDDA, apesar da variação das distâncias mínimas, os íons mantêm-se no interior da membrana no tempo simulado. Nos sistemas IBUDDA, IBUBDA e ASPBDDA o grupo carboxilato dos ânions demonstra proximidade e preferência pelo grupo colina da POPC, enquanto que o grupo contendo o nitrogênio do cátion aproxima-se preferencialmente do grupo fosfato da POPC. / Some pharmaceutical agents (AF) solids may be optimized through adjustments in physical properties, allowing greater control on the solubility, stability, bioavailability and pharmacokinetics. Ionic Liquids, salts which are liquids at temperatures lower than 100 ° C, represent a class of substances used as a possible strategy in the design and optimization of drugs through the choice of biologically active ions. In this study were investigated interactions between ion pairs formed by the acetylsalicylate (ASP) and ibuprofenate (IBU) anions, in combination with the biologically active cations benzalkonium (BDDA) and didecyldimethylammonium (DDA) with the biological membrane palmitoyloleylphosphatidylcholine (POPC) by molecular dynamics method. From geometric optimizations and charge distributions, have established topologies for the ions, defining missing parameters in the AMBER force field. The ion pairs were simulated under vacuum and solvated as well as systems containing pure Ionic Liquids. These simulations showed suitable charge distribution for ions and provided information about the structure of the liquid formed by ion pairs, such as density and distances between groups of atoms. The simulations containing entire systems (ions, water and POPC) indicated that in the system IBUDDA the ion pair is maintained while in other systems transients distancing occur between ions. The system containing ASPDDA indicates leakage of the anion through the bilayer. In systems ASPBDDA, IBUDDA and IBUBDDA, despite the variation of minimum distances, the ions remain within the membrane in simulated time. In IBUDDA, IBUBDDA and ASPBDDA the carboxylate group of the anions demonstrate nearness and preference for POPC choline group, whereas the group containing the nitrogen cation preferentially approximates of the POPC phosphate group.

Alguns Agentes Farmacêuticos (AF) sólidos podem ser otimizados através de ajustes nas propriedades físicas, permitindo maior controle na solubilidade, estabilidade, biodisponibilidade e farmacocinética. Líquidos iônicos, sais que se apresentam líquidos à temperaturas inferiores a 100º C, representam uma classe de substâncias utilizadas como possível estratégia no planejamento e otimização de fármacos, através da escolha de íons ativos biologicamente. Neste trabalho foram investigadas interações entre pares iônicos formados pelos ânions acetilsalicilato (ASP) e ibuprofenato (IBU), em combinação com os cátions biologicamente ativos, benzil-decil-dimetil-amônio (BDDA) e didecil-dimetil-amônio (DDA) com a membrana biológica formada por palmitoil-oleil-fosfatidil-colina (POPC), pelo método de Dinâmica Molecular. A partir de otimizações geométricas e distribuições de cargas, estabeleceram-se topologias para os íons, definindo-se parâmetros ausentes no campo de força AMBER. Inicialmente simularam-se os pares iônicos solvatados e também sistemas contendo líquidos iônicos puros. Essas simulações indicaram adequada distribuição de cargas para os íons e forneceram informações a respeito da estrutura do líquido, formado por pares iônicos, como densidade e distâncias entre grupos de átomos. As simulações contendo sistemas completos (íons, POPC e água) indicaram que no sistema IBUDDA o par iônico é mantido, enquanto que nos outros sistemas ocorrem maiores variações nas distâncias entre os íons. O sistema ASPDDA apresenta indícios de fuga do ânion através da bicamada. Nos sistemas ASPBDDA e IBUBDDA, apesar da variação das distâncias mínimas, os íons mantêm-se no interior da membrana no tempo simulado. Nos sistemas IBUDDA, IBUBDA e ASPBDDA o grupo carboxilato dos ânions demonstra proximidade e preferência pelo grupo colina da POPC, enquanto que o grupo contendo o nitrogênio do cátion aproxima-se preferencialmente do grupo fosfato da POPC. / Some pharmaceutical agents (AF) solids may be optimized through adjustments in physical properties, allowing greater control on the solubility, stability, bioavailability and pharmacokinetics. Ionic Liquids, salts which are liquids at temperatures lower than 100 ° C, represent a class of substances used as a possible strategy in the design and optimization of drugs through the choice of biologically active ions. In this study were investigated interactions between ion pairs formed by the acetylsalicylate (ASP) and ibuprofenate (IBU) anions, in combination with the biologically active cations benzalkonium (BDDA) and didecyldimethylammonium (DDA) with the biological membrane palmitoyloleylphosphatidylcholine (POPC) by molecular dynamics method. From geometric optimizations and charge distributions, have established topologies for the ions, defining missing parameters in the AMBER force field. The ion pairs were simulated under vacuum and solvated as well as systems containing pure Ionic Liquids. These simulations showed suitable charge distribution for ions and provided information about the structure of the liquid formed by ion pairs, such as density and distances between groups of atoms. The simulations containing entire systems (ions, water and POPC) indicated that in the system IBUDDA the ion pair is maintained while in other systems transients distancing occur between ions. The system containing ASPDDA indicates leakage of the anion through the bilayer. In systems ASPBDDA, IBUDDA and IBUBDDA, despite the variation of minimum distances, the ions remain within the membrane in simulated time. In IBUDDA, IBUBDDA and ASPBDDA the carboxylate group of the anions demonstrate nearness and preference for POPC choline group, whereas the group containing the nitrogen cation preferentially approximates of the POPC phosphate group.

Alguns Agentes Farmacêuticos (AF) sólidos podem ser otimizados através de ajustes nas propriedades físicas, permitindo maior controle na solubilidade, estabilidade, biodisponibilidade e farmacocinética. Líquidos iônicos, sais que se apresentam líquidos à temperaturas inferiores a 100º C, representam uma classe de substâncias utilizadas como possível estratégia no planejamento e otimização de fármacos, através da escolha de íons ativos biologicamente. Neste trabalho foram investigadas interações entre pares iônicos formados pelos ânions acetilsalicilato (ASP) e ibuprofenato (IBU), em combinação com os cátions biologicamente ativos, benzil-decil-dimetil-amônio (BDDA) e didecil-dimetil-amônio (DDA) com a membrana biológica formada por palmitoil-oleil-fosfatidil-colina (POPC), pelo método de Dinâmica Molecular. A partir de otimizações geométricas e distribuições de cargas, estabeleceram-se topologias para os íons, definindo-se parâmetros ausentes no campo de força AMBER. Inicialmente simularam-se os pares iônicos solvatados e também sistemas contendo líquidos iônicos puros. Essas simulações indicaram adequada distribuição de cargas para os íons e forneceram informações a respeito da estrutura do líquido, formado por pares iônicos, como densidade e distâncias entre grupos de átomos. As simulações contendo sistemas completos (íons, POPC e água) indicaram que no sistema IBUDDA o par iônico é mantido, enquanto que nos outros sistemas ocorrem maiores variações nas distâncias entre os íons. O sistema ASPDDA apresenta indícios de fuga do ânion através da bicamada. Nos sistemas ASPBDDA e IBUBDDA, apesar da variação das distâncias mínimas, os íons mantêm-se no interior da membrana no tempo simulado. Nos sistemas IBUDDA, IBUBDA e ASPBDDA o grupo carboxilato dos ânions demonstra proximidade e preferência pelo grupo colina da POPC, enquanto que o grupo contendo o nitrogênio do cátion aproxima-se preferencialmente do grupo fosfato da POPC. / Some pharmaceutical agents (AF) solids may be optimized through adjustments in physical properties, allowing greater control on the solubility, stability, bioavailability and pharmacokinetics. Ionic Liquids, salts which are liquids at temperatures lower than 100 ° C, represent a class of substances used as a possible strategy in the design and optimization of drugs through the choice of biologically active ions. In this study were investigated interactions between ion pairs formed by the acetylsalicylate (ASP) and ibuprofenate (IBU) anions, in combination with the biologically active cations benzalkonium (BDDA) and didecyldimethylammonium (DDA) with the biological membrane palmitoyloleylphosphatidylcholine (POPC) by molecular dynamics method. From geometric optimizations and charge distributions, have established topologies for the ions, defining missing parameters in the AMBER force field. The ion pairs were simulated under vacuum and solvated as well as systems containing pure Ionic Liquids. These simulations showed suitable charge distribution for ions and provided information about the structure of the liquid formed by ion pairs, such as density and distances between groups of atoms. The simulations containing entire systems (ions, water and POPC) indicated that in the system IBUDDA the ion pair is maintained while in other systems transients distancing occur between ions. The system containing ASPDDA indicates leakage of the anion through the bilayer. In systems ASPBDDA, IBUDDA and IBUBDDA, despite the variation of minimum distances, the ions remain within the membrane in simulated time. In IBUDDA, IBUBDDA and ASPBDDA the carboxylate group of the anions demonstrate nearness and preference for POPC choline group, whereas the group containing the nitrogen cation preferentially approximates of the POPC phosphate group.

Este trabalho teve por finalidade o desenvolvimento e validação de métodos para análise estereosseletiva de alguns fármacos e metabólitos, bem como a aplicação desses métodos na avaliação do potencial de fungos, principalmente endofíticos, em processos de biotransformação. Os seguintes fármacos foram selecionados para esse estudo: fluoxetina, propranolol, omeprazol, oxibutinina e ibuprofeno. Para determinação simultânea dos enantiômeros da fluoxetina (FLX) e norfluoxetina (NFLX) em meios de cultura de fungos endofíticos, empregou-se a cromatografia líquida de alta eficiência com detecção por absorção no ultravioleta, em um sistema com duas colunas em série, sendo uma de fase reversa (C18) e outra com fase estacionária quiral (Chirobiotic® V). A fase móvel foi composta por etanol: tampão acetato de amônio 15 mmol L-1, pH 5,90: acetonitrila (77,5: 17,5: 5, v/v/v) e a detecção foi realizada em 227 nm. A extração líquido-líquido foi empregada na preparação das amostras. As curvas analíticas foram lineares no intervalo de concentração de 12,5 a 3750 ng mL-1 (r 0,996) para todos os enantiômeros analisados. Os coeficientes de variação e erros relativos obtidos nos estudos de precisão e exatidão foram inferiores a 10%. Nas condições empregadas, os cinco fungos endofíticos estudados não foram capazes de promover a biotransformação da FLX (reação de demetilação). A eletroforese capilar foi empregada para análise enantiosseletiva do propranolol (PROP) e 4-hidroxipropranolol (4-OHPROP). A melhor condição de resolução dos enantiômeros foi encontrada com a aplicação de um planejamento experimental de Box-Behnken: solução de eletrólitos composta por tampão trietilamina / ácido fosfórico (TEA/H3PO4), 25 mmol L-1, pH 9,00, carboximetil--ciclodextrina 4% (m/v) como seletor quiral e análise realizada na voltagem de 17 kV. O método de extração líquido-líquido também foi empregado para preparação das amostras. As curvas analíticas foram lineares no intervalo de concentração de 0,25 a 10,0 g mL-1 para 4-OHPROP e de 0,10 a 10,0 g mL-1 para PROP, apresentando coeficientes de correlação (r) 0,995 para todos os enantiômeros analisados. Os coeficientes de variação e erros relativos obtidos nos estudos de precisão e exatidão foram inferiores a 15%. Os cinco fungos endofíticos em estudo se mostraram eficientes na biotransformação estereosseletiva do PROP, com maior formação do metabólito (-)-(S)-4-OHPROP. O fungo Glomerella cingulata (VA1), em especial, apresentou uma concentração de 1,745 g mL-1 do enantiômero (-)-(S)-4-OHPROP depois de 72 horas de incubação, ao passo que a formação do enantiômero (+)-(R)-4-OHPROP não foi observada. A utilização deste fungo em escalas ampliadas pode ser uma fonte promissora de obtenção do metabólito 4-OHPROP na forma enantiomericamente pura. A determinação simultânea de omeprazol (OMZ), 5-hidroxiomeprazol (5-HOMZ) e omeprazol sulfona (OMZ SUL) em meio de cultura Czapek Dox modificado ii tamponado foi realizada empregando um método rápido de análise por cromatografia líquida de ultra eficiência com detector por arranjo de diodos (UPLC / DAD), usando coluna monolítica de fase reversa e eluição por gradiente. OMZ, 5-HOMZ e OMZ SUL foram extraídos das amostras utilizando uma mistura de acetato de etila: t-butil metil éter (9: 1, v/v). A separação foi obtida empregando uma coluna RP 18 Chromolith Fast Gradient endcapped e fase móvel constituída por 0,15% (v/v) de ácido trifluoroacético (TFA) em água (solvente A) e 0,15% (v/v) de TFA em acetonitrila (solvente B). Os tempos de retenção foram de 0,70 min para 5-HOMZ, 0,74 min para OMZ, 0,77 min para OMZ SUL e 0,91 min para o padrão interno (bupropiona, BUP). O método foi linear no intervalo de 0,2 a 10,0 g mL-1 (r 0,995) para todos os analitos. O processo de biotransformação foi realizado durante apenas 24 horas de incubação, por causa de problemas de estabilidade do OMZ. Por esse mesmo motivo, a biotransformação estereosseletiva não foi avaliada. Apenas três fungos apresentaram formação do metabólito 5-HOMZ, e dentre estes, apenas o fungo Botritis cinerea (BC) produziu esse metabólito em concentração superior ao limite de quantificação do método. A formação do metabólito OMZ SUL foi observada para todos os fungos, exceto para Glomerella cingulata (VA1) e Guignardia mangiferae (VA15). Esses fungos podem ser úteis para a obtenção dos metabólitos do OMZ, mas estudos detalhados do comportamento do fármaco nas condições de cultivo são necessários, uma vez que este substrato pode sofrer degradação em meio ácido e na presença de luz. A análise simultânea dos enantiômeros da oxibutinina (OXY) e da N-desetiloxibutinina (DEOB) em meio de cultura Czapek foi obtida empregando a cromatografia líquida de alta eficiência com detector UV (HPLC/UV). Os analitos foram separados usando coluna quiral Chiralpak AD e fase móvel constituída por hexano: isopropanol: etanol: dietilamina (94: 4: 2: 0,05, v/v/v/v) e detectados em 210 nm. Um estudo piloto de biotransformação empregando os mesmos fungos e as condições de biotransformação utilizadas para os demais fármacos mostrou que não houve a formação do metabólito de interesse. Além disso, não houve uma diminuição significativa da concentração de OXY durante o período de incubação, o que poderia ser um indicativo da formação de outros metabólitos não monitorados nas condições de análise. Como a reação de desetilação da OXY para formar a DEOB não foi observada nos experimentos, não foi necessário realizar a validação do método analítico. A separação simultânea do ibuprofeno (IBP), dos enantiômeros do 2-hidroxi-ibuprofeno (2-OH-IBP) e dos estereoisômeros do carboxi-ibuprofeno (COOH-IBP) foi realizada empregando-se uma coluna Chiralpak AS-H e fase móvel constituída por hexano: isopropanol: TFA (95: 5: 0,1, v/v/v). O solvente extrator usado na extração líquido-líquido foi uma mistura de hexano: acetato de etila (1: 1, v/v). A detecção foi feita por espectrometria de massas (MS/MS), com a fonte de ionização por eletronebulização operada no modo positivo (ESI+). O método foi linear nos intervalos de 0,1 a 20,0 g mL-1 para IBP, de 0,05 a 7,5 g mL-1 para o cada enantiômero do 2-OH-IBP e de 0,025 a 5,0 g mL-1 para cada estereoisômero do COOH-IBP. Os demais parâmetros de validação obtidos para o método apresentaram-se dentro dos limites recomendados pela literatura. Os sete fungos endofíticos estudados se mostraram eficientes na biotransformação do IBP em seu principal metabólito 2-OH-IBP, mas apenas os fungos Nigrospora sphaerica (SS67) e Chaetomium globosum (VR10) iii biotransformaram o IBP de forma enantiosseletiva mais acentuada, observando-se maior formação do metabólito ativo (+)-(S)-2-OH-IBP. A não estereosseletividade observada para os demais fungos pode ser indício de uma possível conversão quiral do fármaco, similar a que ocorre em humanos. A formação dos estereoisômeros do COOH-IBP não foi observada, provavelmente, porque sua rota de formação envolve uma seqüência de reações. Os resultados apresentados nesse trabalho mostram que fungos, particularmente os endofíticos, podem ser uma fonte promissora para obtenção de metabólitos de fármacos, inclusive de forma enantiomericamente pura. / This work aimed the development and validation of suitable methods for the stereoselective analysis of some drugs and metabolites, as well as, the application of these methods to assess the potential of fungi, mainly the endophytic ones, in biotransformation processes. The following drugs were selected for this study: fluoxetine, propranolol, omeprazole, oxybutynin and ibuprofen. The simultaneous determination of fluoxetine (FLX) and norfluoxetine (NFLX) enantiomers in culture media of endophytic fungi was carried out by high-performance liquid chromatography with UV-detection, in a system of two columns coupled in series, in which one of them was a reversed phase (C18) column and the another one was a chiral stationary phase column (Chirobiotic ® V). The mobile phase consisted of ethanol: ammonium acetate buffer, 15 mol L-1, pH 5.90: acetonitrile (77.5: 17.5: 5, v/v/v) and the detection was performed at 227 nm. Liquid-liquid extraction was employed for sample preparation. The analytical curves were linear over the concentration range of 12.5 to 3750 ng mL-1 (r 0.996) for all enantiomers evaluated. The coefficients of variation and relative errors obtained in the evaluation of method precision and accuracy were lower than 10%. In the studied conditions, the five endophytic fungi used were not able to perform the biotransformation of FLX (demethylation reaction). Capillary electrophoresis was employed for the enantioselective analysis of propranolol (PROP) and 4-hydroxypropranolol (4-OHPROP). The best condition for enantiomer resolution was obtained by applying an experimental design of Box-Behnken: electrolyte solution composed of triethylamine / phosphoric acid (TEA/H3PO4) buffer, 25 mmol L-1, pH 9.00, with 4% (w/v) carboxymethyl--cyclodextrin as the chiral selector and analysis performed at 17 kV. Liquid-liquid extraction was also used for sample preparation. The analytical curves were linear over the concentration range of 0.25 to 10.0 g mL-1 for 4-OHPROP and 0.10 to 10.0 g mL-1 for PROP, presenting correlation coefficients (r) 0.995 for all enantiomers evaluated. The coefficients of variation and relative errors obtained in the evaluation of precision and accuracy were lower than 15%. All the five endophytic fungi (Phomopsis sp. (TD2), Glomerella cingulata (VA1), Penicillium crustosum (VR4), Chaetomium globosum (VR10) and Aspergillus fumigatus (VR12)) showed effectiveness in the stereoselective biotransformation of PROP, with higher formation of (-)-(S)-4-OH-PROP. The fungus Glomerella cingulata (VA1), in particular, showed a concentration of 1.745 g mL-1 for the enantiomer (-)-(S)-4-OHPROP after 72 hours of incubation, whereas there was no formation of the enantiomer (+)-(R)-4-OHPROP. Therefore, the use of this fungus in large scale may be a promising source to obtain 4-OHPROP in the enantiomerically pure form. A fast analytical method based on ultra-performance liquid chromatography / diode array detector (UPLC/DAD) using a monolithic reversed phase column and gradient elution was developed for the simultaneous determination of omeprazole (OMZ), 5-hydroxyomeprazole (5-HOMZ) and omeprazole sulfone (OMZ SUL) in modified and buffered Czapek-Dox culture medium. OMZ, 5-HOMZ and OMZ SUL were extracted using a mixture of ethyl acetate: methyl t-butyl ether (9: 1, v/v). The separation was achieved using a Chromolith Fast Gradient RP 18 endcapped column with the mobile phase consisting of 0.15% (v/v) trifluoroacetic acid (TFA) in water (solvent A) and 0.15% (v/v) TFA in acetonitrile (solvent B). Retention times were 0.70 min for 5-HOMZ, 0.74 min for OMZ, 0.77 min for OMZ SUL and 0.91 min for internal standard (bupropion, BUP). The method was linear over the concentration range of 0.2 to 10.0 g mL-1 (r 0.995) for all analytes. The biotransformation process was carried out only within 24 hours of incubation, due to OMZ instability. For the same reason, the stereoselectivity in this process was not evaluated. The formation of the metabolite 5-HOMZ was observed only for three fungi, and among them, only the fungus Botrytis cinerea (BC) produced this metabolite in concentrations higher than the limit of quantification. The formation of OMZ SUL was observed for all fungi, except for Guignardia mangiferae (VA1) and Glomerella cingulata (VA15). The fungi evaluated in this study can be useful to obtain the metabolites of OMZ, but detailed study of the drug stability in culture conditions is required, since this substrate can undergo degradation in acidic conditions and in the presence of light. The simultaneous analysis of oxybutinin (OXY) and N-desethyloxybutinin (DEOB) enantiomers in Czapek culture medium was carried out by liquid chromatography with UV detection (HPLC/UV). The analytes were separated using a Chiralpak AD column employing as mobile phase hexane: isopropanol: ethanol: diethylamine (94: 4: 2: 0.05, v/v/v/v) and detection at 210 nm. A pilot study of biotransformation using the same fungi and conditions employed for the biotransformation of the other drugs showed that the metabolite of interest was not formed. Moreover, the decrease in the concentration of OXY, which could be indicative of the formation of other metabolites not monitored under the conditions of analysis, was not observed. Since the reaction of OXY desethylation to form DEOB was not observed in the experiments, the validation of the analytical method was not required. The method for the simultaneous analysis of ibuprofen (IBP), 2-hydroxyibuprofen (2-OH-IBP) enantiomers and carboxyibuprofen (IBP-COOH) stereoisomers was developed using a Chiralpak AS-H column and a mobile phase consisting of hexane: isopropanol: TFA (95: 5: 0.1, v/v/v). A mixture of hexane: ethyl acetate (1: 1, v/v) was used as solvent extractor for sample preparation. The detection was performed by tanden mass spectrometry (MS/MS) with the electrospray interface operated in the positive mode (ESI+). The method was linear over the concentration range of 0.1 to 20.0 g mL-1 for IBP, 0.05 to 7.5 g mL-1 for each 2-OH-IBP enantiomer and 0.025 to 5.0 g mL-1 for each COOH-IBP stereoisomer. The other validation parameters studied were within the limits established in the literature. The seven studied endophytic fungi showed to be efficient in the biotransformation of IBP to its main metabolite 2-OH-IBP, however, only the fungi Nigrospora sphaerica (SS67) and Chaetomium globosum (VR10) biotransformed IBP enantioselectively, with greater formation of the active metabolite (+)-(S)-2-OH-IBP. The lack of stereoselectivity observed for the other fungi could be caused by a possible chiral inversion process occurring for IBP, in a similar way that happens in humans. The formation of COOH-IBP stereoisomers was not observed probably because the route of formation of this metabolite requires a sequence of reactions. The results presented here show that fungi, particularly the endophytic ones, may be a promising source to obtain the metabolites of drugs, including in their enantiomerically pure form.

Orientador: Pedro Luiz Onófrio Volpe / Tese (doutorado) - Universidade Estadual de Campinas, Instituto de Química / Made available in DSpace on 2018-08-25T19:42:54Z (GMT). No. of bitstreams: 1 Fozia_D.pdf: 5148812 bytes, checksum: 468649b9d5c06383a0fcd0b39c0fc098 (MD5) Previous issue date: 2014 / Resumo: Híbridos polisilsesquioxanos arranjados em pontos, foram sintetizados e caracterizados por análise elementar, espectroscopia de absorção na região do infravermelho, ressonância magnética nuclear no estado sólido, difração de raios X, microscopia eletrônica de varredura e transmissão eletrônica. Os dados de sorção/dessorção de nitrogênio para sílica pura, SBA-15 e os híbridos funcionalizados resultaram na isoterma do tipo IV com histerese do tipo H1. A estrutura da sílica mesoporosa ficou preservada após a pós-funcionalização com cadeias orgânicas. Pos-funcionalização da superfície com amina e outros grupos orgânicos contendo estrutura hidrofóbica, resultou numa diminuição da área da superfície 802,4-63,0 m2g-1 e volume de poros de 0,09 nm e aumento capacidade de carga de ibuprofeno a partir de 18,0 até 29% e um muito lento taxa de liberação ao longo do período de 72,5 h. Para investigar a taxa de liberação e o mecanismo a partir desses materiais híbridos sintetizados, zero-ordem, primeira ordem, Higuchi, Hixson-Crowell, Peppas e Korsmeyer-Peppas modelos cinéticos foram aplicados. Os materiais foram utilizados para a liberação controlada do fármaco ibuprofeno. Estes também foram avaliados quanto à capacidade de remover o corante aniônico azul reativo-15 e o corante catiônico verde brilhante de soluções aquosas. As sílicas modificadas apresentaram alta capacidade de carregamento do fármaco ibuprofeno e de sorção seletiva para o corante azul reativo 15. A sílica não modificada, SBA-15, apresentou alta capacidade de remover o corante verde brilhante. As isotermas de equilíbrio obtidas foram ajustadas aos modelos de Langmuir, Freundlich e Sips e os dados cinéticos foram ajustados aos modelos de pseudo-primeira-ordem e pseudo-segunda-ordem. Os resultados sugerem que os compostos organofuncionalizados de sílica podem ser um método simples, eficiente, barato e conveniente para a liberação controlada de fármacos e também para a remoção eficaz e seletiva de poluentes orgânicos tais como, corantes em soluções aquosas / Abstract: Bridged polysilsesquioxane silica hybrids, synthesized by the combination of SBA-15 type silica with new synthesized silylating agents containing bridged chains, were characterized by elemental analysis, absorption spectroscopy in the infrared region, nuclear magnetic resonance in the solid state, X-ray diffraction, scanning/transmission electron microscopy and thermogravimetry. The sorption/desorption of nitrogen to pure silica, SBA-15 and functionalized hybrids resulted in the isotherms of type IV with type H1 hysteresis. The structure of the precursor mesoporous silica was preserved after post-functionalization with bridged organic bridged chains. The precursor and its derivative silicas were ibuprofen-loaded for controlled delivery in simulated biological fluids. Surface functionalization with amine and other organic groups containing bridged hydrophobic structure resulted in significantly decreased surface area from 802.4 to 63.0 m2g-1 and pore volume to 0.09 nm, which ultimately increased the drug-loading capacity from 18.0 up to 29 % and a very slow release rate of ibuprofen over the period of 72.5 h. To investigate the release rate and mechanism from these synthesized hybrid materials, Zero-order, first-order, Higuchi, Hixson-Crowell and Peppas and Korsmeyer-Peppas kinetic models were applied. The synthesized materials were also evaluated for their ability to remove the anionic dye reactive blue-15 and cationic dye brilliant green from aqueous solutions. The hybrid silica showed selective sorption capacity for the anionic dye, reactive blue 15. The unmodified silica, SBA -15 showed high ability to remove the cationic dye, brilliant green from the aqueous medium. The obtained equilibrium isotherms were fitted to Langmuir, Freundlich and Sips models and the kinetic data were used to fit pseudo-first-order and pseudo-second-order. The results suggest that the organo-functionalized hybrid silicates could be a simple, efficient, inexpensive and convenient for the controlled release of drugs and for effective and selective removal of organic pollutants such as dyes from the aqueous solutions / Doutorado / Quimica Inorganica / Doutora em Ciências

Contexte : Il y a très peu de données sur l’utilisation et la sécurité CV du paracétamol et des AINS à faible dose en l’automédication. Objectifs : établir les caractéristiques des utilisateurs, évaluer et comparer le risque de syndrome coronarien aigu (SCA), associé au paracétamol (P) et à l'ibuprofène à dose antalgique (IDA). Méthodes : Études d'utilisation, études de cohorte auto-contrôlées (self-controlled cohort - SCC), étude de cohorte appariée sur le score de propension et étude cas-témoin nichée (CTN) ont été réalisé dans l’Echantillon Généraliste Bénéficiaires (EGB) en incluant les épisodes de traitement d’IDA et de P chez les adultes entre 2009 et 2014. Des risques de SCA ont été estimés par les rapports de taux d'événement (RTE) ou les hazard ratios (HRs) avec l’IC à 95%. Résultats : L’utilisation d’OSI et de P concerne surtout des jeunes pour des courtes durées de traitement. Les études SCC ont inclu 316265 et 1025877 épisodes d’IDA et P respectivement chez 168407 et 342494 utilisateurs. Chez les utilisateurs d'aspirine à faible dose (AFD) (3,5% et 5,3% des épisodes d’IDA et de P), le risque de SCA a augmenté après la dispensation d’IDA (RTE 1,52 [1.07 à 2.16]) mais diminué après la dispensation de P (HR 0,39 [0,32 à 0,47]). Chez les non-utilisateurs d’AFD (96,5% d’IDA et 94,7% de P), le risque de SCA n’a augmenté qu’après P (1,32 [1,16 à 1,49]). Dans l'étude de cohorte appariée (age moyen 45 ans), il n'y avait pas de différence entre le P et l’IDA sur la durée totale du suivi (HR 0,97 [0,71 à 1,32]), en dépit d'une augmentation plus élevée avec l’IDA dans les 2 premières semaines (1,75 [1,08 à 2,82]). Dans l'étude CTN (age moyen 67), le risque n’a augmenté qu’avec P, pas avec l’IDA (P : 1,36 [1,23 à 1,50]; IDA : 1,16 [0,78 à 1,72]). 11. Conclusion : Le risque de SCA associé à l’IDA ou au P varie en fonction du statut d’utilisation d’AFD et de l'âge. Pour l’IDA, le risque n'a augmenté que chez les utilisateurs d’AFD. Au contraire, pour P, le risque a augmenté seulement chez les non-utilisateurs d’AFD. Chez les jeunes non-utilisateurs d’AFD, il n'y avait pas de différence entre l’IDA et le P (étude de cohorte apparié). Chez les patients âgés (étude CTN), P semble être associé à un risque plus élevé. / Background : There is little data about the CV safety of Paracetamol (P) and OTC NSAIDs. Objectives : Describe usage patterns, to evaluate and compare the risk of acute coronary syndrome (ACS) associated with P and OTC-Strength ibuprofen (OSI). Methods : Drug utilisation, self-controlled cohort (SCC), propensity score- (PS) matched cohort, nested case-control (NCC) studies were conducted in the Echantillon Généraliste Bénéficiaires (EGB). Studies included P and OSI treatment episodes in adults in 2009-2014. Risks were quantified by event rate ratios (ERRs) or hazard ratio (HRs) with 95% CI. Results : Use of OSI and P concerning mostly young persons for short durations. The SCC studies included 316265 OSI and 1025877 P episodes in 168407 and 342494 users. In low-dose aspirin (LDA) users (3.5% OSI and 5% P episodes), ACS risk increased after OSI dispensing (ERR 1.52 [1.07-2.16]) but decreased after P (HR 0.39 [0.32-0.47]). In LDA nonusers, ACS risk increased after P (1.32 [1.16-1.49]), but not after OSI (1.22 [0.63-2.36]). In the PS-matched study (mean age 45), there was no difference between P and OSI over the total follow-up (HR 0.97 [0.71-1.32]), despite a higher increase with OSI in the first 2 weeks (1.75 [1.08-2.82]). In the NCC study (mean age 67), the risk increased with P but not with OSI (P: 1.36 [1.23-1.50]; OSI: 1.16 [0.78-1.72]). Conclusion : ACS risk associated with OSI or P vary according to LDA use and age. For OSI, ACS risk increased only in LDA users. Conversely, for P, ACS risk increased only in LDA nonusers. In young LDA 9 nonusers, there was no difference between OSI and P (PS-matched study). In older patients (NCC study), P appeared to be associated with a higher risk.

Experimental mole fraction solubilities of several carboxylic acids (2-methoxybenzoic acid, 4-methoxybenzoic acid, 4-nitrobenzoic acid, 4-chloro-3-nitrobenzoic acid, 2-chloro-5-nitrobenzoic acid,2-methylbenzoic acid and ibuprofen) and 9-fluorenone, thianthrene and xanthene were measured in a wide range of solvents of varying polarity and hydrogen-bonding characteristics. Results of these measurements were used to calculate gas-to-organic solvent and water-to-organic solvent solubility ratios, which were then substituted into known Abraham process partitioning correlations. The molecular solute descriptors that were obtained as the result of these computations described the measured solubility data to within an average absolute deviation of 0.2 log units. The calculated solute descriptors also enable one to estimate many chemically, biologically and pharmaceutically important properties for the ten solutes studied using published mathematical correlations.

Nowadays, huge amounts of drugs get into watercourses and soil due to wrong disposal in sewage treatment plants. In this work, the sorption and desorption behavior of Ibuprofen in the soil system was studied, especially in relation to humic acids. The degree of sorption and desorption was defined from the change in ibuprofen concentration analyzed by UV-VIS spectrometry, changes in conductivity and pH were also observed. Ibuprofen shows good sorption properties, desorption was really minimal. It can be assumed that there is a strong bond between ibuprofen and both soil and lignite humic acids and therefore there is no risk of leaching back into solutions. Therefore, if ibuprofen entered the environment, it would be sorbed into the humic acids contained in lignite or soil, which means that it should not be harmful in any way.