Um sistema diferencial foi desenvolvido para resolver as principais dificuldades na medida do aumento da condução protônica na interface filme de Langmuir-água, a saber: a) pequeno aumento da condução devido ao filme comparado com a condução da água; b) diminuição da área imersa dos eletrodos para tensões superficiais diferentes da tensão da água; c) obtenção de uma subfase isenta de impurezas. Com o novo sistema mediu-se a condutância de filmes de Langmuir tradicionais (moléculas anfipáticas com cadeias de hidrocarbonos longas), de filmes mistos de fosfolipídio-fármacos e de um polímero condutor. Realizaram-se, também, medidas de pressão de superfície e potencial de superfície. Os resultados da condutância lateral e do potencial de superfície obtidos com os filmes tradicionais indicam que a área crítica (área em que a condutância do filme aparece e o potencial de superfície aumenta abruptamente) é área em que se forma uma rede de pontes de hidrogênio. Cálculos de área crítica realizados para os ácidos graxos, utilizando um modelo unidimensional para a transferência de prótons, reproduzem os resultados experimentais. Resultados obtidos com o polímero condutor mostram que é possível medir a contribuição eletrônica para a condutância com o novo sistema diferencial. Um estudo de filmes mistos de fosfolípídios-anestésicos locais (tetracaína e dibucaína) foi realizado utilizando a técnica de coespalhamento. Está técnica tem a vantagem, sobre as de adsorção de Langmuir usada tradicionalmente, de se ter certeza de que todas as mudanças nas propriedades do filme sejam causadas pelos compostos adicionados na monocamada. Ambos os anestésicos expandiram a matriz de fosfolípidios. Os resultados mostraram que a tetracaína possui ligações hidrofóbicas mais fortes que a dibucaína, fazendo com que a tetracaína penetrasse mais profundamente na matriz de fosfolipídio / A different system has been developed for overcoming the main difficulties associated with the measurement of an enhanced protonic conductance at the Langmuir film/water interface. These difficulties are: a) small increase in conductance due to the film as compared to the bulk water conductance; b) decrease in the electrode immersed area for surface tensions lower than that of the subphase water; c) obtaining an impurity-free subphase. With the new system the lateral conductance of traditional Langmuir films (possessing amphiphilic molecules with long hydrocarbon tails), of mixed films madeup of phospholipid and pharmaceutical drugs and of a conducting polymer. Measurements were also performed of monolayer surface pressure and surface potential. The conductance and surface potential results obtained with the traditional compounds have indicated that the critical area (at which the conductance appears and the surface potential increase abruptly) is the area for which a H-bonded network is formed. The critical area for fatty acids was calculated , employing a unidimensional proton transfer model, which is consistent with the measured value. Results obtained using the differential system with a conducting polymer also show that it is a possible to detect an electronic contribution to the lateral conductance. A study of mixed films from phospholipid and local anesthetics (tetracaine and dibucaine) was conducted using the co-spreading technique. This method offers the advantage, compared to the traditionally employed Langmuir adsorption method, of making sure that all changes in the film properties are caused by incorporation of the drugs added to the phospholipid monolayer. Both anesthetics caused the phospholipid matrix to expand. The results showed that tetracaine has stronger hydrophobic interaction than dibucaine, and therefore tetracaine penetrates deeper into the phospholipid matrix

Pharmaceutical drugs are one of the most socially important heath care products. They are part of many individuals' everyday lives, from the eradicating of diseases at birth to treating patients at the end of life. However, for many patients access is prevented due to expensive cost. This study explored cost-related non-adherence (CRN) and researched if reimportation of pharmaceutical drugs from other countries could increase patient drug adherence. The perceptions of 10 patients and 10 providers in Maine were assessed. Maine is the only state that allowed its citizens to purchase prescription drugs from abroad. The research questions addressed (a) how reimportation drugs could contribute to drug adherence, (b) the perceptions of patients, and (c) the perceptions of key providers of reimportation. This study was guided by a theoretical framework utilizing Kurt Lewin's theory of organizational change. Participants answered 15 open-ended questions. The study utilized a qualitative grounded theory approach; data were analyzed inductively. The research demonstrated that patients and healthcare providers had positive perceptions for a reimportation policy. Future research of other regions for this topic should prevail. Member checking was used to validate the emerging theories of increased long term drug adherence incentivized by affordable drug cost, which contributes to perception of competence, better management of current disease, and decreased safety concerns. Positive social change implications can be achieved through savings to the health-care industry by creating a pathway to affordable drugs that will bring more drugs to market and create a competitive structure that can drive down pricing.

Um sistema diferencial foi desenvolvido para resolver as principais dificuldades na medida do aumento da condução protônica na interface filme de Langmuir-água, a saber: a) pequeno aumento da condução devido ao filme comparado com a condução da água; b) diminuição da área imersa dos eletrodos para tensões superficiais diferentes da tensão da água; c) obtenção de uma subfase isenta de impurezas. Com o novo sistema mediu-se a condutância de filmes de Langmuir tradicionais (moléculas anfipáticas com cadeias de hidrocarbonos longas), de filmes mistos de fosfolipídio-fármacos e de um polímero condutor. Realizaram-se, também, medidas de pressão de superfície e potencial de superfície. Os resultados da condutância lateral e do potencial de superfície obtidos com os filmes tradicionais indicam que a área crítica (área em que a condutância do filme aparece e o potencial de superfície aumenta abruptamente) é área em que se forma uma rede de pontes de hidrogênio. Cálculos de área crítica realizados para os ácidos graxos, utilizando um modelo unidimensional para a transferência de prótons, reproduzem os resultados experimentais. Resultados obtidos com o polímero condutor mostram que é possível medir a contribuição eletrônica para a condutância com o novo sistema diferencial. Um estudo de filmes mistos de fosfolípídios-anestésicos locais (tetracaína e dibucaína) foi realizado utilizando a técnica de coespalhamento. Está técnica tem a vantagem, sobre as de adsorção de Langmuir usada tradicionalmente, de se ter certeza de que todas as mudanças nas propriedades do filme sejam causadas pelos compostos adicionados na monocamada. Ambos os anestésicos expandiram a matriz de fosfolípidios. Os resultados mostraram que a tetracaína possui ligações hidrofóbicas mais fortes que a dibucaína, fazendo com que a tetracaína penetrasse mais profundamente na matriz de fosfolipídio / A different system has been developed for overcoming the main difficulties associated with the measurement of an enhanced protonic conductance at the Langmuir film/water interface. These difficulties are: a) small increase in conductance due to the film as compared to the bulk water conductance; b) decrease in the electrode immersed area for surface tensions lower than that of the subphase water; c) obtaining an impurity-free subphase. With the new system the lateral conductance of traditional Langmuir films (possessing amphiphilic molecules with long hydrocarbon tails), of mixed films madeup of phospholipid and pharmaceutical drugs and of a conducting polymer. Measurements were also performed of monolayer surface pressure and surface potential. The conductance and surface potential results obtained with the traditional compounds have indicated that the critical area (at which the conductance appears and the surface potential increase abruptly) is the area for which a H-bonded network is formed. The critical area for fatty acids was calculated , employing a unidimensional proton transfer model, which is consistent with the measured value. Results obtained using the differential system with a conducting polymer also show that it is a possible to detect an electronic contribution to the lateral conductance. A study of mixed films from phospholipid and local anesthetics (tetracaine and dibucaine) was conducted using the co-spreading technique. This method offers the advantage, compared to the traditionally employed Langmuir adsorption method, of making sure that all changes in the film properties are caused by incorporation of the drugs added to the phospholipid monolayer. Both anesthetics caused the phospholipid matrix to expand. The results showed that tetracaine has stronger hydrophobic interaction than dibucaine, and therefore tetracaine penetrates deeper into the phospholipid matrix

The objective of this research is to explore the use of ionic liquds in crystal engineering and drug delivery. Ionic liquids have a wide range of applications in pharmaceutical field due to their unique physicochemical propertie ssuch as chemical, thermal stability, low melting point, nonvolatility, nonflamability, low toxicity and recyclability which offer unique and interesting potential for pharmaceuitcal applications. Currently, many research groups are working on the development of ionic liquids to use in this field but there is need to develop systematic understanding about new techniques for synthesis and applications of ionic liquids to obtain new crystal form and potential of drug ionic salts. The synthesis of fifteen phosphonium ionic liquids under microwave irradiation and their physicochemical properties was investigated. The reaction time was significantly reduced compared to conventional methods, and higher yields were reported. The crystallisation of pharmaceutical drugs such as sulfathiazole, chlorpropamide, phenobarbital and nifedipine were investigated using imidazolium ionic liquids. The supramolecular complex of sulfathiazole and phenobarbital with imidazolium ionic liquids and polymorphic change in chlorpropamide was achieved. The ionic liquids provides unique environment for the crystallisation. The imidazolium salts of ibuprofen and diclofenac were synthesised and evaluated for physicochemical properties and their pharmaceutical performances especially transdermal absorption. The investigation of physicochemcal properties and pharmaceutical performance of imidazolium drug salts indicated opportunity to optimise lipophilicity and other physicochemical properties such as molecular size, osmolality, viscosity to achieve desired skin deposition and permeation. This study will provide a new approach to design of new drug salts develop using the interdisciplinary knowledge of chemical synthesis and drug delivery.

Fossils fuels are highly demanded in everyday life domestically or industrially. Fossil fuels are finite resources and they are rapidly depleting, as such alternative renewable feedstocks are sought to replace fossil fuels. Tall oil from paper processing and cashew nut shell liquid from the cashew nut industry are the two major renewable sources we studied, they are both waste byproducts, and have the potential to be converted into value-added materials. Tall oil from the paper industry mainly contained tall oil fatty acid, and under isomerising methoxycarbonylation with palladium catalyst, dimethyl 1,19-dimethyl nonadecanedioate can be obtained. This difunctional ester, dimethyl 1,19-dimethyl nonadecanedioate, is converted to diols, secondary and primary diamines by a hydrogenation reaction with ruthenium complexes of 1,1,1-tris(diphenylphosphinometyl)ethane (triphos) as catalysts in the presence of water, amine or aqueous ammonia respectively. In the case of aqueous ammonia it is necessary to use a two step reaction via diol to obtain 1,19-diaminononadecane. Diesters, diols and diamines are useful precursors for the synthesis of polyesters and polyamides. Difunctional substrates with 8-19 carbon chains are all tolerated under the reaction conditions and are successfully converted to the corresponding diols and diamines in high yields. Under similar hydrogenation conditions with the same ruthenium catalyst, cyclic products were predominantly produced with decreased chain length. N-heterocycles, which are important building blocks for the synthesis of drug molecules, were formed from the hydrogenation of diesters with 4-7 carbon chains in the presence of an amine. Another polymer precursor, ε-caprolactam, which is the precursor for Nylon 6, is obtained in a reasonable yield from both adipic acid and adipate esters together with aqueous ammonia in the presence of ruthenium catalyst. Cashew nut shell liquid was also converted into useful medical drugs, such as norfenefrine, rac-phenylephrine, etilefrine and fenoprofene in reasonable yields. Most of these drug molecules have been formed from 3-vinylphenol by catalytic hydroxyamination followed by methylation or ethylation. 3-Vinylphenol was synthesised from cardanol by ethenolysis to 3-non-8-enylphenol followed by isomerising ethenolysis, whilst the N-alkylation reactions used methyl or ethyl triflate to avoid dialkylation. Fenoprofene was formed by firstly O-phenylating cardanol then ethenolysis followed by isomerising ethenolysis to form 1-phenoxy-3-vinylbenzene. Methoxycarbonyation followed by hydrolysis formed the final product in good yield. Our methods start from renewable waste materials and avoid unpleasant reagents in the original stoichiometric synthesis of those drugs, for example, cyanide is no longer essential for the synthesis of fenoprofene.

The objective of this research is to explore the use of ionic liquds in crystal engineering and drug delivery. Ionic liquids have a wide range of applications in pharmaceutical field due to their unique physicochemical propertie ssuch as chemical, thermal stability, low melting point, nonvolatility, nonflamability, low toxicity and recyclability which offer unique and interesting potential for pharmaceuitcal applications. Currently, many research groups are working on the development of ionic liquids to use in this field but there is need to develop systematic understanding about new techniques for synthesis and applications of ionic liquids to obtain new crystal form and potential of drug ionic salts. The synthesis of fifteen phosphonium ionic liquids under microwave irradiation and their physicochemical properties was investigated. The reaction time was significantly reduced compared to conventional methods, and higher yields were reported. The crystallisation of pharmaceutical drugs such as sulfathiazole, chlorpropamide, phenobarbital and nifedipine were investigated using imidazolium ionic liquids. The supramolecular complex of sulfathiazole and phenobarbital with imidazolium ionic liquids and polymorphic change in chlorpropamide was achieved. The ionic liquids provides unique environment for the crystallisation. The imidazolium salts of ibuprofen and diclofenac were synthesised and evaluated for physicochemical properties and their pharmaceutical performances especially transdermal absorption. The investigation of physicochemcal properties and pharmaceutical performance of imidazolium drug salts indicated opportunity to optimise lipophilicity and other physicochemical properties such as molecular size, osmolality, viscosity to achieve desired skin deposition and permeation. This study will provide a new approach to design of new drug salts develop using the interdisciplinary knowledge of chemical synthesis and drug delivery. / Social Justice Department, Government of Maharashtra, India.

O crescimento da população mundial e a expansão industrial são fatores que atualmente desencadeiam um aumento no consumo de produtos e geração de resíduos. Frequentemente utilizados na medicina tradicional e veterinária, os antibióticos são classificados como uma classe emergente de poluentes, pois, devido à sua baixa taxa de degradação e à ineficácia dos sistemas de tratamentos de água, encontram-se disseminados no meio ambiente e nos alimentos. Em consequência desse fato, estudos para o desenvolvimento de novos materiais e métodos que removam estes contaminantes utilizando menor quantidade de consumíveis químicos e a baixo custo, têm sido um campo em desenvolvimento na química analítica. Inserido nesse contexto encontra-se o grafeno, que devido à sua estrutura de anéis aromáticos com elétrons π deslocalizados e elevada área superficial (3600 m2/g), pode favorecer fenômenos de sorção, elevando a eficiência na extração de contaminantes presentes em matrizes complexas. O objetivo do projeto foi sintetizar e caracterizar novas fases sorventes à base de grafeno para atuar no preparo da amostra avaliando a eficácia destas na remoção de tetraciclinas presentes em leite. Para isso, utilizou-se da microextração por sorvente empacotado MEPS como método de preparo de amostra com posterior análise por cromatografia líquida acoplada a espectrometria de massas HPLC-MS/MS. A caracterização dos materiais foi feita através de microscopia eletrônica de varredura MEV e espectroscopia vibracional na região do infravermelho IV revelando eficácia na síntese das folhas de óxido de grafeno, assim como, no recobrimento das partículas de sílica com os novos materiais. Foram avaliadas as fases extratoras: G, GO-SIL, G-Sil e C18-G-Sil com relação a eficiência na extração das tetraciclinas. A fase G-Sil mostrou-se a mais apropriada para continuidade do estudo, pois apresentou os melhores resultados. Com o objetivo de otimizar a etapa de preparo de amostra, foi feito um planejamento fatorial fracionário 24-1 avaliando as variáveis químicas: solvente de eluição, força iônica, pH da solução de lavagem e inclusão de EDTA na solução tampão de Mcllvaine (pH 4.2). Posteriormente foi feito um planejamento fatorial completo 23 visando a otimização dos ciclos de extração da MEPS, possibilitando determinar a condição ótima de extração do método. Baseando-se no documento: ICH - Q2 (R1) guideline, a metodologia foi submetida a testes para avaliar as figuras de mérito referentes a validação analítica. O método apresentou faixa linear de 15 - 110 µg/L, LQ entre 0,05 e 0,9 µg/L e boa seletividade. A precisão foi avaliada intra e inter-dia apresentando desvio padrão relativo - RSD abaixo de 18%. Ao final do desenvolvimento do estudo foram analisadas onze amostras reais incluindo leite bovino, caprino, ovino e leite em pó. A aplicação em amostras de diferentes espécies reforça a versatilidade do método desenvolvido, além de evidenciar o elevado potencial dos novos materiais de grafeno para atuar como sorvente no preparo da amostra. / Nowadays, the rise of world population and industrial expansion are leading to an increase in consumption and consequently waste generation. Large quantities of chemical residues are released into the environment affecting humans and wildlife. Among these residues, antibiotics used in medicine and veterinary are classified as an emerging contaminant due to their low degradation rate, ineffectiveness of wastewater treatment and consequently water and food contamination. An effort has been made to develop microextraction techniques to remove these drugs using reduce volume of solvent and chemical consumable and researches of new sorbent phases are increasing due the high potential to improve these microextraction techniques. Recent studies pinpoint graphene (G) as an effectively sorbent phase to act in sample preparation. G has a structure composed by carbon nanosheets arranged in a honeycomb pattern with large surface area (3600 m2 /g) and delocalized π-electrons system that suggests good interaction between them and contaminants compounds such as veterinary drugs, pesticides, personal care products etc. This study focuses to evaluate sorbent phases based upon graphene particle supported on silica to analyze Tetracycline residues present in milk. For this purpose, was used microextraction by packed sorbent - MEPS as sample preparation method with analysis by liquid chromatography and mass spectrometry. The characterization of synthesized materials was performed by scanning electron microscopy - SEM and vibrational spectroscopy in infrared region - FTIR. The results suggest that synthesis of graphene\'s particles as well as the coating of silica surface with these materials were both performed. To evaluate extraction efficiency each sorbent material: GO-Sil, G-Sil, G, C18-GO-Sil were tested in MEPS and confronted to commercial phases: C8 and C18. By the results, G-Sil was choose to application as sorbent phase. MEPS extractions were optimized and the effect of some factors was investigated by application of experimental design. Firstly, a factorial experimental design 2(4-1) was executed to evaluate chemistry variables such as elution solvent, washing solution, media ionic strength and inclusion of EDTA salt in Mcllvaine solution. After, an experimental design 23 was made in order to estimate the cycles of MEPS extraction like sampling, washing and elution steps. By the results, an optimized extraction conditional was achieved and evaluation of validation parameters was carried out on sequence based on the ICH - Q2 (R1) guide. The method showed linearity ranging from 15 - 110 µg/L, LOQ values from 0,05 to 0,9 µg/L and good selectivity. Precision showed relative standard deviation RSD less than 18% to intra and inter-day analysis. The developed method was applied in analysis of eleven milk samples including bovine, caprine and ovine milk and milk powder. Application in samples from different species enhances the versatility of this analytical method and show the great potential for graphene\'s particles to act as sorbent phase in sample preparation.

O crescimento da população mundial e a expansão industrial são fatores que atualmente desencadeiam um aumento no consumo de produtos e geração de resíduos. Frequentemente utilizados na medicina tradicional e veterinária, os antibióticos são classificados como uma classe emergente de poluentes, pois, devido à sua baixa taxa de degradação e à ineficácia dos sistemas de tratamentos de água, encontram-se disseminados no meio ambiente e nos alimentos. Em consequência desse fato, estudos para o desenvolvimento de novos materiais e métodos que removam estes contaminantes utilizando menor quantidade de consumíveis químicos e a baixo custo, têm sido um campo em desenvolvimento na química analítica. Inserido nesse contexto encontra-se o grafeno, que devido à sua estrutura de anéis aromáticos com elétrons π deslocalizados e elevada área superficial (3600 m2/g), pode favorecer fenômenos de sorção, elevando a eficiência na extração de contaminantes presentes em matrizes complexas. O objetivo do projeto foi sintetizar e caracterizar novas fases sorventes à base de grafeno para atuar no preparo da amostra avaliando a eficácia destas na remoção de tetraciclinas presentes em leite. Para isso, utilizou-se da microextração por sorvente empacotado MEPS como método de preparo de amostra com posterior análise por cromatografia líquida acoplada a espectrometria de massas HPLC-MS/MS. A caracterização dos materiais foi feita através de microscopia eletrônica de varredura MEV e espectroscopia vibracional na região do infravermelho IV revelando eficácia na síntese das folhas de óxido de grafeno, assim como, no recobrimento das partículas de sílica com os novos materiais. Foram avaliadas as fases extratoras: G, GO-SIL, G-Sil e C18-G-Sil com relação a eficiência na extração das tetraciclinas. A fase G-Sil mostrou-se a mais apropriada para continuidade do estudo, pois apresentou os melhores resultados. Com o objetivo de otimizar a etapa de preparo de amostra, foi feito um planejamento fatorial fracionário 24-1 avaliando as variáveis químicas: solvente de eluição, força iônica, pH da solução de lavagem e inclusão de EDTA na solução tampão de Mcllvaine (pH 4.2). Posteriormente foi feito um planejamento fatorial completo 23 visando a otimização dos ciclos de extração da MEPS, possibilitando determinar a condição ótima de extração do método. Baseando-se no documento: ICH - Q2 (R1) guideline, a metodologia foi submetida a testes para avaliar as figuras de mérito referentes a validação analítica. O método apresentou faixa linear de 15 - 110 µg/L, LQ entre 0,05 e 0,9 µg/L e boa seletividade. A precisão foi avaliada intra e inter-dia apresentando desvio padrão relativo - RSD abaixo de 18%. Ao final do desenvolvimento do estudo foram analisadas onze amostras reais incluindo leite bovino, caprino, ovino e leite em pó. A aplicação em amostras de diferentes espécies reforça a versatilidade do método desenvolvido, além de evidenciar o elevado potencial dos novos materiais de grafeno para atuar como sorvente no preparo da amostra. / Nowadays, the rise of world population and industrial expansion are leading to an increase in consumption and consequently waste generation. Large quantities of chemical residues are released into the environment affecting humans and wildlife. Among these residues, antibiotics used in medicine and veterinary are classified as an emerging contaminant due to their low degradation rate, ineffectiveness of wastewater treatment and consequently water and food contamination. An effort has been made to develop microextraction techniques to remove these drugs using reduce volume of solvent and chemical consumable and researches of new sorbent phases are increasing due the high potential to improve these microextraction techniques. Recent studies pinpoint graphene (G) as an effectively sorbent phase to act in sample preparation. G has a structure composed by carbon nanosheets arranged in a honeycomb pattern with large surface area (3600 m2 /g) and delocalized π-electrons system that suggests good interaction between them and contaminants compounds such as veterinary drugs, pesticides, personal care products etc. This study focuses to evaluate sorbent phases based upon graphene particle supported on silica to analyze Tetracycline residues present in milk. For this purpose, was used microextraction by packed sorbent - MEPS as sample preparation method with analysis by liquid chromatography and mass spectrometry. The characterization of synthesized materials was performed by scanning electron microscopy - SEM and vibrational spectroscopy in infrared region - FTIR. The results suggest that synthesis of graphene\'s particles as well as the coating of silica surface with these materials were both performed. To evaluate extraction efficiency each sorbent material: GO-Sil, G-Sil, G, C18-GO-Sil were tested in MEPS and confronted to commercial phases: C8 and C18. By the results, G-Sil was choose to application as sorbent phase. MEPS extractions were optimized and the effect of some factors was investigated by application of experimental design. Firstly, a factorial experimental design 2(4-1) was executed to evaluate chemistry variables such as elution solvent, washing solution, media ionic strength and inclusion of EDTA salt in Mcllvaine solution. After, an experimental design 23 was made in order to estimate the cycles of MEPS extraction like sampling, washing and elution steps. By the results, an optimized extraction conditional was achieved and evaluation of validation parameters was carried out on sequence based on the ICH - Q2 (R1) guide. The method showed linearity ranging from 15 - 110 µg/L, LOQ values from 0,05 to 0,9 µg/L and good selectivity. Precision showed relative standard deviation RSD less than 18% to intra and inter-day analysis. The developed method was applied in analysis of eleven milk samples including bovine, caprine and ovine milk and milk powder. Application in samples from different species enhances the versatility of this analytical method and show the great potential for graphene\'s particles to act as sorbent phase in sample preparation.