Submitted by Rodrigo Martins Cruz (rodrigo.cruz@ufvjm.edu.br) on 2016-01-08T13:04:54Z No. of bitstreams: 2 license_rdf: 22974 bytes, checksum: 99c771d9f0b9c46790009b9874d49253 (MD5) chrystiellen_ayana_aparecida_rodrigues.pdf: 1198860 bytes, checksum: 1562a3833c07d89b22a5def3ae97fe60 (MD5) / Approved for entry into archive by Rodrigo Martins Cruz (rodrigo.cruz@ufvjm.edu.br) on 2016-01-11T11:09:17Z (GMT) No. of bitstreams: 2 license_rdf: 22974 bytes, checksum: 99c771d9f0b9c46790009b9874d49253 (MD5) chrystiellen_ayana_aparecida_rodrigues.pdf: 1198860 bytes, checksum: 1562a3833c07d89b22a5def3ae97fe60 (MD5) / Made available in DSpace on 2016-01-11T11:09:17Z (GMT). No. of bitstreams: 2 license_rdf: 22974 bytes, checksum: 99c771d9f0b9c46790009b9874d49253 (MD5) chrystiellen_ayana_aparecida_rodrigues.pdf: 1198860 bytes, checksum: 1562a3833c07d89b22a5def3ae97fe60 (MD5) Previous issue date: 2014 / Este trabalho teve como finalidade desenvolver e caracaterizar formula??es de pat? de galinha com adi??o de concentrado proteico de soro de leite (WPC) como substituto parcial de gordura. Para tanto, foram realizados diversos testes para definir a formula??o padr?o do pat?, que foi estabelecida com 20% de gordura. A partir desta, foram preparadas tr?s outras formula??es com diferentes substitui??es de gordura por WPC, sendo denominada de G1 a formula??o contendo 3% de WPC (substitui??o de 15% de gordura), G2 contendo 5% (substitui??o de 25% de gordura) e G3 com 10% de WPC (substitui??o de 50% de gordura). Na massa crua das diferentes formula??es de pat? de galinha foi realizada a determina??o da composi??o qu?mica, segundo m?todos oficiais de an?lise e a avalia??o da qualidade, atrav?s das an?lises do pH, da estabilidade da massa crua (raw batter stability - RBS), dos teores de prote?nas sol?veis (salt-soluble protein - SSP) e nitrito de s?dio residual. Foram detectadas diferen?as significativas entre os teores de prote?nas e lip?deos entre as amostras analisadas, compat?veis com a substitui??o gradual destes ingredientes nas formula??es. Com rela??o ao teor de umidade, maior valor foi encontrado para formula??o G2. Verificou-se, ainda, que a substitui??o da gordura pelo WPC n?o promoveu altera??es significativas no teor de cinzas. Por?m, esta substitui??o elevou os valores de pH, da estabilidade da massa crua e do teor de prote?nas sal sol?veis das amostras. Em nenhuma das amostras foi detectado nitrito de s?dio residual. J? na massa cozida das formula??es de pat? de galinha, foram realizadas a determina??o da composi??o qu?mica e a avalia??o da estabilidade atrav?s das an?lises de pH, cor e oxida??o lip?dica, logo ap?s a esteriliza??o e tamb?m ap?s 7, 14, 21 e 28 dias de estocagem sob refrigera??o a 5?C. Houve diferen?as significativas entre os teores de prote?nas e lip?deos, compat?veis com a substitui??o de gordura efetuada, sendo poss?vel atribuir ?s formula??es G2 e G3 a denomina??o de produto light. Quanto ? avalia??o da estabilidade, todas as formula??es de pat? apresentaram boa estabilidade nos par?metro de cor e de pH, entretanto, a vida ?til foi limitada pela oxida??o lip?dica, sendo que as formula??es com substitui??o de gordura por WPC apresentaram maiores valores de subst?ncias reativas ao ?cido tiobarbit?rico (TBARS) quando comparadas ? formula??o controle. Concluiu?se, portanto, que foi poss?vel utilizar o WPC como substituto parcial de gordura e obter produtos com apelos mais saud?veis, entretanto os mesmos n?o devem ser armazenados por um per?odo maior que 21 dias. / Disserta??o (Mestrado Profissional) ? Programa de P?s-Gradua??o em Sa?de, Sociedade e Ambiente, Universidade Federal dos Vales do Jequitinhonha e Mucuri, 2014. / ABSTRACT This work is aimed to develop and caracaterizar formulations of whey protein concentrate (WPC) as a partial fat replacement to evaluate the physico-chemical characteristics. Several tests were performed to define the standard formula, which was established with 20% fat. From this, three other formulas were prepared with different fat replacements for WPC; G1, containing 3% WPC (15% replacement of fat), G2, containing 5% (substitution 25% fat), and G3, containing 10% WPC (substitution 50% fat). In the crood chicken paste, the determination of the chemical composition using the official methods of quality assessment; using the analysis of pH, stability of raw pasta (raw batter stability - RBS), ?the protein soluble (salt-soluble protein - SSP), and residual nitrite. Significant differences between the levels of proteins and lipids between the samples, consistent with the gradual replacement of these ingredients in the formulas, were detected. With respect to the moisture content, the higher value was found for the G2 formula. Additionally, it was found that the replacement of fat by the WPC did not cause significant changes in ash content. Evaluations of the quality of the uncooked paste show that replacement of fat by WPC increased the pH, affecting the stability of the batter and protein-soluble salt content of the samples. Residual nitrite was not detected in any of the samples. The chemical composition of the cooked chicken paste was determined using the analysis of pH, color, and oxidation. Those determinations were made after sterilization, and also after 7, 14, 21 and 28 days storage under refrigeration at 5 degrees C. As expected, there were significant differences between the levels of proteins and lipids, consistent with the replacement of fat. Due to these findings, it is possible to assign formulas G2 and G3 as a ?Light? version of the original formula. All formulas showed good stability in ?both color and pH , however, life was limited by lipid oxidation; which was affected by the reduction of fat, and the fat replacement. The formulas with WPC had higher Thiobarbituric acid reactive substances (TBARS) values when compared to the control. Therefore, it was concluded that it was possible to use WPC as a partial substitute for fat and create a healthier product. However, they should not be stored for longer than 21 days.

Submitted by Hiolanda Rêgo (hiolandar@gmail.com) on 2013-05-17T17:45:33Z No. of bitstreams: 1 Dissertação_Nut_ Maria Araújo.pdf: 811515 bytes, checksum: 1626279ca22c51803f9ab531c0858dcf (MD5) / Approved for entry into archive by Flávia Ferreira(flaviaccf@yahoo.com.br) on 2013-05-21T03:04:04Z (GMT) No. of bitstreams: 1 Dissertação_Nut_ Maria Araújo.pdf: 811515 bytes, checksum: 1626279ca22c51803f9ab531c0858dcf (MD5) / Made available in DSpace on 2013-05-21T03:04:04Z (GMT). No. of bitstreams: 1 Dissertação_Nut_ Maria Araújo.pdf: 811515 bytes, checksum: 1626279ca22c51803f9ab531c0858dcf (MD5) / Este estudo tem como objetivo principal avaliar o Programa de Alimentação do Trabalhador – PAT, contribuindo com reflexões que possam propiciar o entendimento de como a normatização deste programa pode significar o acesso do trabalhador ao direito à alimentação. Trata-se de um estudo descritivo baseado em dados secundários, que tem como ponto de partida uma dimensão mais global e qualitativa ao se analisar um conjunto de normas do PAT, entendidas como o próprio discurso do Estado à Política de Alimentação do Trabalhador. Em uma dimensão mais específica e quantitativa, fez-se o estudo de acesso dos trabalhadores e empresas ao programa no estado da Bahia. Como principais resultados pode-se perceber que o PAT instituído como um programa emergencial e transitório, continua sendo desenvolvido basicamente com os mesmos objetivos, embora tenha sofrido algumas modificações desde sua criação, os documentos normativos do programa não dão conta de mecanismos que possibilitem a viabilidade do alcance dos seus objetivos de forma mais efetiva, principalmente, os relacionados à saúde dos trabalhadores. Sendo o PAT uma política pública que vem se atualizando em termos de estratégia de distribuição do benefício, isso ainda não se faz acompanhar necessariamente de grandes avanços em sua cobertura, por outro lado, a tão buscada equidade, objetivo das políticas sociais, não se faz apresentar no estado da Bahia. Haja visto a importância do PAT enquanto um programa social que pode contribuir através de aspectos relacionados à alimentação para um melhor padrão de saúde da classe trabalhadora, esse estudo permite elucidar que até a década de 90 as mudanças implementadas podem ser caracterizadas como de controle jurídico-administrativo-financeiro. / Salvador

AN ABSTRACT OF THE DISSERTATION OF ASHLEY GREEN, for the Doctor of Philosophy degree in English, presented on November 5, 2012, at Southern Illinois University Carbondale. TITLE: TRAUMA INSCRIBED ON THE BODY IN PAT BARKER'S REGENERATION TRILOGY MAJOR PROFESSOR: Dr. Michael Molino In the nineties, British writer, Pat Barker, completed a sequence of novels entitled The Regeneration Trilogy in which she set to the task of understanding trauma in relation to our notions, or mis-notions rather, of WWI. In this trilogy, the author does not simply engage a discussion of the past through the integration of historical figures, personal recordings, and accurate accounts of society and the Western Front during 1917-1918; but through the complexity of her characters' personalities and lives a rather comprehensive evaluation of trauma and its effects on the subject emerges. In the initial book in her sequence, Regeneration, Barker is specifically interested in the ways in which the physical symptoms of war neurosis communicate the nature of an internal crisis, and how those very same manifestations enlighten our understanding of the obstacles of traumatic communication. Dr. Rivers's role as a therapist who endorses the "Talking Cure" establishes language as the key element to the process recovery, proposing, then, it is through a dialectical relationship that the wound[ed] can speak; language, for Barker, is the link reconnecting individuals to their trauma, subjects to their past and present selves, and, ultimately, the soul to its body. It is really through the process of integrating history and fiction that the author is able to evaluate the full breadth of Great Britain's traumatization during WWI. As Barker moves through her trilogy, her observations of trauma increase in scope as Dr. Rivers moves from Craiglockhart, Scotland, ultimately, to London working at the Empire Hospital with Dr. Henry Head. Initially, Dr. Rivers treats specifically shell-shocked soldiers but by The Eye in the Door, Rivers begins treating officers of a different branch, pilots of the Royal Flying Corps; and by the final book in the sequence, The Ghost Road, the doctor applies his clinical theories to both physically and emotionally damaged patients. In direct relation to Dr. Rivers's greater perspective, Barker also brings to light her observations of total traumatization by depicting her female characters as subverted elements of society and locales of crisis. In addition, Barker represents culture as one that also displays obvious clues of violence and traumatization. Ultimately, Barker does all this to make a comprehensive observation of trauma: the physical always reveals evidence of its experience. Through reading the material of -- and written on the body--we can only begin to understand fully the complex nature of trauma and the way in which it has entirely disrupted, yet composed our historical identities.

La façon dont l'industrie pharmaceutique développe et manufacture ses produits a évolué au cours de ces dernières années. L'environnement réglementaire auquel elle est contrainte a provoqué ce changement dans le but de doter de technologies de pointe dans ses différentes activités. L’encouragement pour utiliser les technologies d’analyse de procédé (PAT) afin d’implémenter le concept de « Quality By Design » (QbD) est l’exemple le plus significatif de ce nouveau paradigme. Lentement, les industries implémentent ces technologies pour de nouveaux produits, mais également pour certains produits déjà existants, bénéficiant ainsi de leurs avantages. Pour implémenter des PAT dans un procédé, plusieurs étapes doivent être franchies, de l’étude de faisabilité des instruments jusqu’à l’approbation règlementaire. Cette thèse décrit l’étude initiale (faisabilité et développement de modèles) avant toute demande d’autorisation d’utilisation d’outils PAT (proche infra-rouge (NIR), caméra RGB et fluorescence induite par laser (LIF)) pour suivre le procédé de compression d’un mélange commercial comprenant plusieurs ingrédients. Après avoir établi le potentiel de ces différents outils, des modèles quantitatifs calculés par régression par moindres carrés partiels (PLS) ont été développés pour suivre les composants ayant une concentration aussi faible que 0,1 w/w%, avec un coefficient de détermination (R2) de 0,95. Il a également été démontré que l’utilisation conjointe de données de plus d’un outil améliorait la précision du modèle. La spécificité de chacun des outils a également été évaluée à l’aide de plan d’expériences factoriels complets pour lesquels les modèles ont été construits en faisant varier simultanément la concentration de différents éléments. Même dans ces conditions, les modèles construits ont montré une précision acceptable, en considérant les critères d’acceptation utilisés pour les produits alimentaires comme les multivitamines. Le travail présenté dans cette thèse a contribué à la publication de trois articles et de trois présentations orales. En plus de l’établissement de la preuve de concept, ce qui augmente les opportunités pour tester d’autres sondes, la possibilité de suivre en ligne la composition quantitative dans la ligne d’alimentation de la presse a également été établi. Dans ce dernier cas, tous les outils sont suffisamment précis pour suivre au moins un des composants, même si celui-ci est présent en faible concentration et fait partie d’un mélange de plusieurs composants. Conséquemment, l’industrie peut utiliser ses connaissances pour suivre le procédé de compression de façon plus adéquate en augmentant l’éventail des outils utilisés à cet effet. Une recherche fondamentale pourrait également investiguer les phénomènes tels que la ségrégation afin mieux les comprendre. / Abstract : The way pharmaceutical industry develops and manufactures their products has been changing in recent years. The regulatory environment that they are obligated to comply has been pushing this change in order to endow this activity with state of art technology. The encouragement of the use of process analytical technology (PAT) to build the quality right from the design (QbD) is perhaps the most significant example of the new paradigm. The manufacturers are implementing this technology in new and existing products and benefiting from their advantages. To implement PAT in a process, many steps must be taken (from the study of feasibility of the instruments until regulatory approval). This thesis describes the initial study (feasibility and model developments), prior to any submission of authorization, of the use of PAT tools (Near-Infrared (NIR), Red Green Blue (RGB) camera and Light Induced Fluorescence (LIF)) to monitor the compression process of a commercial multi-component blend. After the potential of these tools was assessed, quantitative Partial Least Squares (PLS) models were able to be developed to monitor components with a concentration as low as 0.1 w/w % with a R2 of 0.95. It was also proved that combining data from more than one tool was benefit for the accuracy of the model. The tools were also evaluated to their specificity by using a full factorial design where the models were built with simultaneous variations of concentration of some of the components. Even in this challenging case, the models built remained with an acceptable accuracy, considering the acceptance criteria used for dietary products such as multi-vitamins. The work developed in this thesis contributed to the publication of 3 articles and 3 communications. Along with the proof of concept that it provided - which enlarged the opportunities for testing other probes - it also proved that is possible to monitor in-line the components in the feed frame. In this latter case, all the tools were accurate enough to monitor at least one component even if they are present in low concentration and part of multi-component blends. Therefore, the industry can use this knowledge to monitor the compression process more adequately, increasing the range of tools used for the effect. Fundamental research can also be investigated as phenomena like segregation can be more accurately identified.

This work presents a comprehensive study on the application of PAT tools to study, monitor and control polymorphism during batch cooling crystallization processes. For the first time, the same techniques were used to control and adjust polymorphic purity of the solid phase but also to investigate the relation between chemical equilibrium in solution and polymorphic outcome of cooling crystallization. Crystallization is an important unit operation used as separation and purification technique. It is widely employed in the pharmaceutical, chemical, agrochemical, food and cosmetics industries but also in the electronic, metallurgic and material industries. More than 90% of the APIs on the market are produced by crystallization, therefore, monitoring and control this process is fundamental to ensure the quality of the final product. The implementation of process analytical technology (PAT) tools during the development stage of APIs has largely helped in better understanding and optimizing both batch and, more recently, continuous crystallization. Polymorphism is the capacity of a compound to crystallize in more than one different crystalline structure, which can have different properties such as density, melting point, bioavailability and solubility. The choice of solvent, pH, kinetic conditions and presence of impurities has very strong effect on the polymorphic outcome of a cooling crystallization in solution. Understanding this phenomenon as well as being able to monitor and control it during industrial crystallization is one the biggest challenges for pharmaceutical industries.

A cefalexina é um dos antibióticos mais prescritos no Brasil e a sua disponibilidade nas instituições de saúde é de extrema importância para o tratamento adequado e seguro dos pacientes. Porém a distribuição dos medicamentos é prejudicada pela dificuldade de liberação pelos laboratórios de controle de qualidade que utilizam métodos convencionais como: o biológico (Difusão em Ágar) e o cromatográfico (Cromatografia Líquida de Alta Eficiência), que demandam tempo de análise e não permitem a obtenção de resultados em tempo real. O maior desafio dos centros produtivos é desenvolver métodos capazes de realizarem as análises dos produtos de forma rápida e eficaz durante as fases mais críticas da produção. As técnicas espectroscópicas por infravermelho são alternativas aos métodos convencionais, tendo como vantagens a rapidez, a capacidade de análise de amostras nas suas formas físico-químicas originais e a possibilidade de projetar a sua utilização na Tecnologia Analítica de Processos (PAT). Com esse propósito foi desenvolvido um método por espectroscopia no infravermelho médio (MID) por reflectância difusa (DRIFTS) combinado à técnica de regressão múltipla por mínimos quadrados parciais (PLS) para análise de cefalexina na forma pó para suspensão oral. A avaliação da eficácia do método desenvolvido foi feita mediante cálculo da precisão e exatidão do método e posteriormente os resultados experimentais foram submetidos à análise estatística. A verificação da equivalência dos métodos foi feita utilizando análise de variância (ANOVA) e, para finalizar o trabalho, foi determinado o intervalo de tolerância (δ) do método. O método espectroscópico apresentou significativa variabilidade de resultados, porém uma técnica padronizada de preparo das amostras de calibração capaz de produzir misturas homogêneas do fármaco com placebo, aliado à seleção criteriosa das regiões espectrais e tratamento espectral adequado, foi determinante para o desenvolvimento de um método equivalente aos convencionais, atendendo aos requisitos da PAT. Portanto, este trabalho pode servir de ferramenta para o avanço da PAT pelos produtores e agência regulatória no Brasil (ANVISA). / Cephalexin is the most prescribed antibiotics in Brazil and its availability in health institutions is of utmost importance for the proper and safe treatment of patients. But the distribution of drugs is hindered to difficulty of release by quality control laboratories using conventional methods such as biological (Agar Diffusion) and HPLC (High Performance Liquid Chromatography), which require analysis time and not allow to obtain results in real time. The biggest challenge of manufacturing centers is to develop analytical methods to perform quickly and effectively analyzes of the products during the most critical phases of production. The infrared spectroscopic technique is alternative to conventional methods, with the advantages of speed, the ability to analyze samples in their original physical-chemical forms and the possibility to use in designing the Process Analytical Technology (PAT). For this purpose, a method was developed in the mid-infrared spectroscopy (MID) by diffuse reflectance (DRIFTS) combined to technique of partial least squares (PLS) regression for cephalexin analysis in oral suspension product. Assessing the effectiveness of the method was done by calculation of precision and of the method and then the experimental results were subjected to statistical analysis. The equivalence of methods was verified using analysis of variance (ANOVA) and, to complete the work, the tolerance interval (δ) was determined. The spectroscopic method showed significant variability in results, but a standardized technique for preparation of calibration samples able to produce homogeneous mixtures of the drug with placebo, combined to careful selection of spectral regions and appropriate spectral treatment, was crucial for the development of an equivalent method to conventional, meeting the requirements of PAT. Therefore, this work can serve as a tool for advancing the PAT by manufacturers and regulatory agency in Brazil (ANVISA).

A zidovudina, conhecida como AZT, é um inibidor da transcriptase reversa, enquanto que a lamivudina é um fármaco antirretroviral que atua na inibição da síntese de ácidos nucléicos. Estes são dois dos 21 fármacos componentes dos medicamentos distribuídas pelo Ministério da Saúde Brasileiro em programas de combate a Síndrome da imunodeficiência Adquirida (Acquired Immunodeficiency Syndrome - AIDS), configurando-se assim uma grande demanda de produção de medicamentos com estes fármacos. Programas de Tecnologia Analítica em Processo (Process Analytical techology - PAT), embasadas por avanços nos guias internacionais da Conferência Internacional sobre a Harmonização dos Requerimentos Técnicos para o Registro de Produtos Farmacêuticos para o uso Humano (International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use - ICH) e pela agência norte-americana para a Administração de Alimentos e Medicamentos (Food and Drugs Administration - FDA), estão ganhando força como alternativas para aumentar a eficiência e a segurança na produção de medicamentos, tanto para aqueles já em processo produtivo como também para medicamentos em fase de desenvolvimento. Estes últimos são denominados desenvolvimento em programas de Qualidade por Design (QbD). Métodos de quantificação por espectroscopia (NIR, MID, RAMAM, entre outras) são reconhecidos como ferramentas para a PAT. Neste contexto propôs-se comparar objetivamente o método tradicional de quantificação destes dois fármacos frente a um método de quantificação desenvolvido utilizando-se a espectroscopia no infravermelho médio (MID). Prepararam-se assim 41 amostras de calibração e 23 amostras de validação, compostas por misturas de zidovudina, lamivudina e placebo (qs) em escala laboratorial, na faixa de 80 a 120% da concentração nominal de uma associação comercial dos dois fármacos. As concentrações de referência de todas as preparações foram determinadas empregando-se o método de referência por Cromatografia Líquida de Alta Eficiência (CLAE) da Farmacopeia Americana (United States Pharmacopeia - USP). Subsequentemente, obtiveram-se cinco espectros no infravermelho de cada uma das preparações, na faixa de 450 a 4000 cm-1. Os espectros foram então pré-processados e utilizados para a construção de um modelo de calibração multivariado por PLS (mínimo quadrados parciais), de acordo com a ASTM E1655-05. Adicionalmente, o método de CLAE foi transferido para um método de UPLC de acordo com o Capitulo Geral descrito no volume 37(3) do Fórum da USP (United States Pharmacopeia). O desempenho do método MID foi então comparado com o método tradicional, bem como com o novo método de quantificação por UPLC. Foram definidaLs assim regiões de confiança para embasar a utilização dos métodos desenvolvidos. O método de quantificação por MID apresentou uma grande variabilidade enquanto que o método por UPLC foi totalmente comparável com o método tradicional, reduzindo o tempo de corrida de 60 minutos para 12.55 minutos. / Zidovudine, also known as AZT is a reverse transcriptase inhibitor, whereas lamivudine is an antiretroviral drug that acts on the inhibition of nucleic acid synthesis. These are two of the 21 active ingredients components of medicines distributed by Brazilian Health Ministry in programs against the Acquired Immunodeficiency Syndrome (AIDS), becoming thus a great demand for production of these two drugs. Process Analytical Technology (PAT) programs, supported by advances in international guides from the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) and by the FDA (Food and Drugs Administration), are gaining momentum as alternatives to increase efficiency and safety in the production of medicines, both for those medicines already in the production process as well as to those medicines under development. The latter are called Quality by Design (QbD) programs. Spectroscopy quantification methodologies methodologies (NIR, MID, Ramam, among others) are recognized as PAT tools. In this context it was proposed to compare objectively the traditional method for quantification of these two drugs against a quantification method developed using the MID (middle infrared spectroscopy). Thus 41 calibration and 23 validation samples, comprising of laboratorial scale mixtures of lamivudine, zidovudine and placebo (qs), were prepared in the range equivalent to 80 to 120% of the nominal concentration of the commercial tablets product. The concentrations of all calibration and validation samples were determined using the HPLC reference method of USP (United States Pharmacopeia). Subsequently, there were obtained five infrared spectra of each of the preparations in the range 450-4000 cm-1. The spectra were then pre-processed and used to build a multivariate calibration model for PLS (Partial Least Squares) according to ASTM E1655-05. Additionally, the HPLC method was transferred to a UPLC method according to General Chapter described in volume 37 (3) Forum USP (United States Pharmacopeia). The performance of the method MID was then compared with the traditional method and with the new method of quantification by UPLC. Confidence regions were built to support the use of the methods developed. The MID quantification method presented considerable variability, while the method the UPLC method was fully comparable to the traditional method. Another advantage of the UPLC method was the reduction of running time from 60 minutes to 12:55 minutes.

A cefalexina é um dos antibióticos mais prescritos no Brasil e a sua disponibilidade nas instituições de saúde é de extrema importância para o tratamento adequado e seguro dos pacientes. Porém a distribuição dos medicamentos é prejudicada pela dificuldade de liberação pelos laboratórios de controle de qualidade que utilizam métodos convencionais como: o biológico (Difusão em Ágar) e o cromatográfico (Cromatografia Líquida de Alta Eficiência), que demandam tempo de análise e não permitem a obtenção de resultados em tempo real. O maior desafio dos centros produtivos é desenvolver métodos capazes de realizarem as análises dos produtos de forma rápida e eficaz durante as fases mais críticas da produção. As técnicas espectroscópicas por infravermelho são alternativas aos métodos convencionais, tendo como vantagens a rapidez, a capacidade de análise de amostras nas suas formas físico-químicas originais e a possibilidade de projetar a sua utilização na Tecnologia Analítica de Processos (PAT). Com esse propósito foi desenvolvido um método por espectroscopia no infravermelho médio (MID) por reflectância difusa (DRIFTS) combinado à técnica de regressão múltipla por mínimos quadrados parciais (PLS) para análise de cefalexina na forma pó para suspensão oral. A avaliação da eficácia do método desenvolvido foi feita mediante cálculo da precisão e exatidão do método e posteriormente os resultados experimentais foram submetidos à análise estatística. A verificação da equivalência dos métodos foi feita utilizando análise de variância (ANOVA) e, para finalizar o trabalho, foi determinado o intervalo de tolerância (δ) do método. O método espectroscópico apresentou significativa variabilidade de resultados, porém uma técnica padronizada de preparo das amostras de calibração capaz de produzir misturas homogêneas do fármaco com placebo, aliado à seleção criteriosa das regiões espectrais e tratamento espectral adequado, foi determinante para o desenvolvimento de um método equivalente aos convencionais, atendendo aos requisitos da PAT. Portanto, este trabalho pode servir de ferramenta para o avanço da PAT pelos produtores e agência regulatória no Brasil (ANVISA). / Cephalexin is the most prescribed antibiotics in Brazil and its availability in health institutions is of utmost importance for the proper and safe treatment of patients. But the distribution of drugs is hindered to difficulty of release by quality control laboratories using conventional methods such as biological (Agar Diffusion) and HPLC (High Performance Liquid Chromatography), which require analysis time and not allow to obtain results in real time. The biggest challenge of manufacturing centers is to develop analytical methods to perform quickly and effectively analyzes of the products during the most critical phases of production. The infrared spectroscopic technique is alternative to conventional methods, with the advantages of speed, the ability to analyze samples in their original physical-chemical forms and the possibility to use in designing the Process Analytical Technology (PAT). For this purpose, a method was developed in the mid-infrared spectroscopy (MID) by diffuse reflectance (DRIFTS) combined to technique of partial least squares (PLS) regression for cephalexin analysis in oral suspension product. Assessing the effectiveness of the method was done by calculation of precision and of the method and then the experimental results were subjected to statistical analysis. The equivalence of methods was verified using analysis of variance (ANOVA) and, to complete the work, the tolerance interval (δ) was determined. The spectroscopic method showed significant variability in results, but a standardized technique for preparation of calibration samples able to produce homogeneous mixtures of the drug with placebo, combined to careful selection of spectral regions and appropriate spectral treatment, was crucial for the development of an equivalent method to conventional, meeting the requirements of PAT. Therefore, this work can serve as a tool for advancing the PAT by manufacturers and regulatory agency in Brazil (ANVISA).

A zidovudina, conhecida como AZT, é um inibidor da transcriptase reversa, enquanto que a lamivudina é um fármaco antirretroviral que atua na inibição da síntese de ácidos nucléicos. Estes são dois dos 21 fármacos componentes dos medicamentos distribuídas pelo Ministério da Saúde Brasileiro em programas de combate a Síndrome da imunodeficiência Adquirida (Acquired Immunodeficiency Syndrome - AIDS), configurando-se assim uma grande demanda de produção de medicamentos com estes fármacos. Programas de Tecnologia Analítica em Processo (Process Analytical techology - PAT), embasadas por avanços nos guias internacionais da Conferência Internacional sobre a Harmonização dos Requerimentos Técnicos para o Registro de Produtos Farmacêuticos para o uso Humano (International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use - ICH) e pela agência norte-americana para a Administração de Alimentos e Medicamentos (Food and Drugs Administration - FDA), estão ganhando força como alternativas para aumentar a eficiência e a segurança na produção de medicamentos, tanto para aqueles já em processo produtivo como também para medicamentos em fase de desenvolvimento. Estes últimos são denominados desenvolvimento em programas de Qualidade por Design (QbD). Métodos de quantificação por espectroscopia (NIR, MID, RAMAM, entre outras) são reconhecidos como ferramentas para a PAT. Neste contexto propôs-se comparar objetivamente o método tradicional de quantificação destes dois fármacos frente a um método de quantificação desenvolvido utilizando-se a espectroscopia no infravermelho médio (MID). Prepararam-se assim 41 amostras de calibração e 23 amostras de validação, compostas por misturas de zidovudina, lamivudina e placebo (qs) em escala laboratorial, na faixa de 80 a 120% da concentração nominal de uma associação comercial dos dois fármacos. As concentrações de referência de todas as preparações foram determinadas empregando-se o método de referência por Cromatografia Líquida de Alta Eficiência (CLAE) da Farmacopeia Americana (United States Pharmacopeia - USP). Subsequentemente, obtiveram-se cinco espectros no infravermelho de cada uma das preparações, na faixa de 450 a 4000 cm-1. Os espectros foram então pré-processados e utilizados para a construção de um modelo de calibração multivariado por PLS (mínimo quadrados parciais), de acordo com a ASTM E1655-05. Adicionalmente, o método de CLAE foi transferido para um método de UPLC de acordo com o Capitulo Geral descrito no volume 37(3) do Fórum da USP (United States Pharmacopeia). O desempenho do método MID foi então comparado com o método tradicional, bem como com o novo método de quantificação por UPLC. Foram definidaLs assim regiões de confiança para embasar a utilização dos métodos desenvolvidos. O método de quantificação por MID apresentou uma grande variabilidade enquanto que o método por UPLC foi totalmente comparável com o método tradicional, reduzindo o tempo de corrida de 60 minutos para 12.55 minutos. / Zidovudine, also known as AZT is a reverse transcriptase inhibitor, whereas lamivudine is an antiretroviral drug that acts on the inhibition of nucleic acid synthesis. These are two of the 21 active ingredients components of medicines distributed by Brazilian Health Ministry in programs against the Acquired Immunodeficiency Syndrome (AIDS), becoming thus a great demand for production of these two drugs. Process Analytical Technology (PAT) programs, supported by advances in international guides from the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) and by the FDA (Food and Drugs Administration), are gaining momentum as alternatives to increase efficiency and safety in the production of medicines, both for those medicines already in the production process as well as to those medicines under development. The latter are called Quality by Design (QbD) programs. Spectroscopy quantification methodologies methodologies (NIR, MID, Ramam, among others) are recognized as PAT tools. In this context it was proposed to compare objectively the traditional method for quantification of these two drugs against a quantification method developed using the MID (middle infrared spectroscopy). Thus 41 calibration and 23 validation samples, comprising of laboratorial scale mixtures of lamivudine, zidovudine and placebo (qs), were prepared in the range equivalent to 80 to 120% of the nominal concentration of the commercial tablets product. The concentrations of all calibration and validation samples were determined using the HPLC reference method of USP (United States Pharmacopeia). Subsequently, there were obtained five infrared spectra of each of the preparations in the range 450-4000 cm-1. The spectra were then pre-processed and used to build a multivariate calibration model for PLS (Partial Least Squares) according to ASTM E1655-05. Additionally, the HPLC method was transferred to a UPLC method according to General Chapter described in volume 37 (3) Forum USP (United States Pharmacopeia). The performance of the method MID was then compared with the traditional method and with the new method of quantification by UPLC. Confidence regions were built to support the use of the methods developed. The MID quantification method presented considerable variability, while the method the UPLC method was fully comparable to the traditional method. Another advantage of the UPLC method was the reduction of running time from 60 minutes to 12:55 minutes.

Pat M. Neff served as governor of Texas from 1921 to 1925, a period marked by political conflict between rural conservatives and urban progressives. Neff, a progressive, found himself in the middle of this conflict. Neff supported prohibition, declared martial law in the oil boomtown of Mexia, and faced the rise of the Ku Klux Klan as a political force in Texas. Though often associated with the Klan, Neff did not approve of the organization and worked against it whenever possible. During the Railroad Shopmen's Strike of 1922, Neff stalled the federal government in its demand he send troops to Denison just long enough to win re-nomination. William Jennings Bryan mentioned Neff as a possible candidate for the presidency in 1924, but he pursued a back-door strategy that alienated his political base among Texas Democrats.