<p>Professionals and researchers have developed a number of strategies aimed at improving the quality and safety of medication use. However, studies continue to demonstrate persistent problems. For instance, the first paper in this thesis reveals the prevalence of potentially harmful drug combinations among elderly people in Europe. The following four papers focus on two professional groups and how they have approached safety and quality issues related to medication use: 1) the Swedish drug and therapeutics committees (DTCs) and 2) pharmacist involved in pharmaceutical care, an international movement. Qualitative research approaches were applied.</p><p>Papers II and III focus on the DTCs: analyses indicate a development of the perception of the DTC role over time. The focus of the activities was broadened – from targeting prescribing physicians to incorporating decision-makers and patients. However, a clear patient-centered perspective was generally lacking. Moreover, the findings indicate a shift in focus from cost aspects of medication use to an increased focus on quality and safety aspects. </p><p>In the studies addressing pharmaceutical care (Papers IV and V), the findings propose that different classification systems for drug-related problems had different characteristics which reflected differences in goals in the pharmaceutical care process. It was also found that the concept of pharmaceutical care was understood in different ways and that the perceptions were based on at least two different understandings of health and illness. First, a patient-centered perspective characterized by a <i>holistic</i> understanding of health and illness, and, second, an “EBM perspective” primarily based on a <i>biomedical</i> understanding of health and illness. </p><p>This thesis has disclosed new aspects of how two groups of professionals perceive their work towards improved quality and safety of medication use. A patient-centered perspective among healthcare collectives is not obvious; therefore, efforts and comprehensive strategies supporting change are necessary. Strategies should focus on challenging the traditional thought patterns and care approaches among professionals and students. </p>

Professionals and researchers have developed a number of strategies aimed at improving the quality and safety of medication use. However, studies continue to demonstrate persistent problems. For instance, the first paper in this thesis reveals the prevalence of potentially harmful drug combinations among elderly people in Europe. The following four papers focus on two professional groups and how they have approached safety and quality issues related to medication use: 1) the Swedish drug and therapeutics committees (DTCs) and 2) pharmacist involved in pharmaceutical care, an international movement. Qualitative research approaches were applied. Papers II and III focus on the DTCs: analyses indicate a development of the perception of the DTC role over time. The focus of the activities was broadened – from targeting prescribing physicians to incorporating decision-makers and patients. However, a clear patient-centered perspective was generally lacking. Moreover, the findings indicate a shift in focus from cost aspects of medication use to an increased focus on quality and safety aspects. In the studies addressing pharmaceutical care (Papers IV and V), the findings propose that different classification systems for drug-related problems had different characteristics which reflected differences in goals in the pharmaceutical care process. It was also found that the concept of pharmaceutical care was understood in different ways and that the perceptions were based on at least two different understandings of health and illness. First, a patient-centered perspective characterized by a holistic understanding of health and illness, and, second, an “EBM perspective” primarily based on a biomedical understanding of health and illness. This thesis has disclosed new aspects of how two groups of professionals perceive their work towards improved quality and safety of medication use. A patient-centered perspective among healthcare collectives is not obvious; therefore, efforts and comprehensive strategies supporting change are necessary. Strategies should focus on challenging the traditional thought patterns and care approaches among professionals and students.

En Afrique subsaharienne, l'épilepsie reste un problème de santé publique majeur. En plus d'un manque de ressources en soins de santé, le déficit thérapeutique dans la prise en charge de l'épilepsie est très élevé. Seuls quelques antiépileptiques de première ligne sont disponibles et leur qualité pose question. Actuellement, quelques données sont disponibles sur la question de la qualité des antiépileptiques dans les pays en développement. Deux études ont montré une proportion de mauvaise qualité allant de 13,7% pour le phénobarbital en Mauritanie à 65,0% pour la phénytoïne, la carbamazépine et le valproate de sodium au Vietnam. L'objectif de cette étude était d'évaluer les déterminants du déficit thérapeutique des personnes vivant avec l'épilepsie dans les pays en développement. Les objectifs de recherche étaient d'identifier et de décrire les programmes d'intervention visant à améliorer la prise en charge médicamenteuse, d'identifier les déterminants sociaux du déficit thérapeutique, d'évaluer la qualité des antiépileptiques disponibles en Afrique subsaharienne et d’en mesurer la disponibilité, le coût et l’accessibilité financière. Le schéma d'étude pour l'évaluation des interventions et des déterminants sociaux était une revue systématique de la littérature. Pour les questions de qualité, de disponibilité, de coût et d'accessibilité, une étude transversale multicentrique a été réalisée dans 9 pays d’Afrique ubsaharienne. Dans chaque pays, les zones urbaines et rurales ont été systématiquement étudiées de la même manière, en explorant la chaîne d'approvisionnement officielle et le secteur illicite. Les soins communautaires et le personnel paramédical ont été des facteurs de succès dans ces pays où les ressources médicales sont limitées. L'adhésion thérapeutique était l’une des pierres angulaires dans la prise en charge médicamenteuse des personnes vivant avec l'épilepsie, souvent mal ou peu maitrisée. L'éducation thérapeutique était une dimension prometteuse à développer. Au total, 32,3 % des antiépileptiques étaient de mauvaise qualité. La carbamazépine (38,7 % [intervalle de confiance à 95 % (IC 95 %)] : 21,8 - 57,8) et la phénytoïne 83,3 % (IC 95 % : 35,8 - 99,5) présentaient la proportion la plus élevée de substandards, principalement en raison d’une mauvaise dissolution. Le valproate de sodium était l’antiépileptique avec la qualité la plus mauvaise (32,1 % ; IC à 95 %, 15,8 - 42,3). Le phénobarbital (94,1 % ; IC à 95 %, 80,3 - 99,2) possédait la meilleure qualité. La prévalence d’antiépileptiques de mauvaise qualité augmentait pour les échantillons distribués par une structure publique (Odds Ratio OR, 9,9 ; IC à 95 %, 1,2-84,1 ; p<0,04) ainsi que ceux fabriqués en Chine (OR, 119,8 ; IC 95 %, 8,7-1651,9 ; p<0,001). De même cette prévalence augmentait lorsqu'ils étaient stockés dans de mauvaises conditions (OR, 5,4 ; IC à 95 %, 1,2-24,1 ; p<0,03). Aucune contrefaçon n'a été observée dans cette étude. Le phénobarbital et les formes génériques étaient les plus accessibles mais les moins disponibles, principalement dans le secteur privé, chaîne d'approvisionnement ayant le plus grand réseau de distribution dans ces pays.Le rôle du pharmacien et du personnel paramédical devrait être renforcé. Des conditions de stockage inadéquates, comprenant le manque de contrôle de la température et de l'humidité, sont susceptibles de conduire à des médicaments inefficaces voire dangereux. Le déconditionnement, pratique courante et potentiellement dangereuse, doit être supervisée et sécurisée. La production locale d’antiépileptiques a plusieurs aspects positifs pour diminuer le déficit thérapeutique en agissant sur l'accessibilité géographique, financière et sur la qualité. Le programme de pré-qualification de l'OMS a permis d'améliorer considérablement la qualité des médicaments dans les pays en développement. L'inclusion des antiépileptiques dans ce programme constituerait une amélioration certaine pour le traitement de l'épilepsie. / In sub-Saharan Africa, epilepsy remains a neglected public health issue. In addition to a lack of trained healthcare resources, including staff and infrastructure, the high epilepsy treatment gap has been a source of concern. Only a few major first-line antiepileptic drugs are readily available and the quality of these drugs could pose further issues. Currently, there are a few data available to address the question of the quality of antiepileptic drugs in low- and middle-income countries. Two studies have shown the proportion of poor-quality drugs to range from 13.7% for phenobarbital in Mauritania to 65,0% for phenytoin, carbamazepine, and sodium valproate in Vietnam. The aim of this study was to assess the determinants of the treatment gap of people living with epilepsy in low- and middle-income countries. Research objectives were to identify and describe intervention programmes aimed at improving drug management, to extract social determinants of the treatment gap, to evaluate the quality of antiepileptic drugs available in sub-Saharan Africa and to measure the availability, cost and affordability of antiepileptic drugs in sub-Saharan Africa.The study design for intervention and social determinants assessment was a systematic literature review. For quality, availability, cost and affordability issues a multicentre cross-sectional study has been carried out in 9 sub-Saharan Africa countries with an identical data and sample collection protocol. In each country, urban and rural areas have been systematically investigated in the same manner, exploring both the official supply chain and the illicit system in each setting. All the structures where a patient could buy or obtain antiepileptic drugs have been investigated. Community-based care and allied health staff were success factors in resource limited settings. Adherence to treatment has been pointed out to be a corner stone of people living with epilepsy drug management, poorly and slightly controlled. Therapeutic patient education was a promising dimension to be developed. Overall 32.3% of the tablets were of poor quality, but no statistical difference was observed across the sites. Carbamazepine (38.7% [95% Confidence Interval (95%CI)]: 21.8 – 57.8) and phenytoin 83.3% (95% CI 35.8 – 99.5) had the highest proportion of substandard quality, mainly due to dissolution failure. Sodium valproate was the antiepileptic drug with the poorest quality (32.1%; 95% CI 15.8 – 42.3). Phenobarbital (94.1%; 95% CI 80.3 – 99.2) had better quality. Prevalence of substandard quality increased in samples supplied from a public structure (Odds Ratio (OR), 9.9; 95% CI 1.2-84.1; p<.04) as well as those manufactured in China (OR, 119.8; CI 8.7-1651.9; p<.001). The prevalence of antiepileptic drugs with bad quality increased when improperly stored (OR, 5.4; 95% CI 1.2-24.1; p<.03). Phenobarbital and generic formulations remained the most affordable antiepileptic drugs but the least available mainly in the private sector, the supply chain with the largest distribution network in countries.The role of pharmacist and other allied staffs should be enhanced. No counterfeiting has been observed for antiepileptic drugs in this study. However, inadequate storage conditions, including the lack of temperature and humidity control, are likely to lead to ineffective and maybe dangerous antiepileptic drugs, even when good quality antiepileptic drugs are initially imported. Unpacking practice, common and potentially dangerous, must be supervised and secured. Local production of antiepileptic drugs has several positive aspects for decreasing treatment gap by enhancing geographical, financial accessibility and quality of drugs. WHO prequalification program has produced great improvement in diseases management in developing countries. Inclusion of antiepileptic drugs in this program may be highly profitable for people living with epilepsy.

Durante muito tempo, os fármacos quirais de origem sintética foram comercializados predominantemente como racematos. Atualmente, sabe-se que os enantiômeros de um fármaco quiral podem apresentar propriedades farmacocinéticas, farmacodinâmicas e toxicológicas bastante distintas. Assim sendo, técnicas analíticas enantiosseletivas são fundamentais para a pesquisa e para o controle da qualidade desses fármacos. O cetoprofeno e o fenoprofeno são dois fármacos quirais, pertencentes à classe dos agentes antiinflamatórios não-esteróides derivados do ácido propiônico. Seus enantiômeros apresentam significativas diferenças farmacodinâmicas. Por essa razão, pretendeu-se desenvolver, no presente trabalho, métodos de separação enantiomérica para ambos os fármacos. Para tanto, utilizou-se a técnica de cromatografia a líquido de alta eficiência em fase estacionária quiral (coluna Whelk-O 1), nos modos normal e reverso. Abordagens uni- e multivariadas foram utilizadas para desenvolver e otimizar os métodos de separação. Pôde-se observar que a enantiosseletividade exibida pela coluna Whelk-O 1 em fase normal é superior àquela exibida em fase reversa. Empregando a CLAE em fase normal, foi possível desenvolver métodos de separação apropriados para os enantiômeros de ambos os fármacos. Em fase reversa, no entanto, apenas os enantiômeros do fenoprofeno puderam ser separados satisfatoriamente. / For a long time, the synthetic chiral drugs were marketed mainly as racemates. Currently, it is known that enantiomers of chiral drugs may exhibit quite different pharmacokinetic, pharmacodynamic and toxicological properties. Therefore, enantioselective analytical techniques are critical to the research and quality control of these drugs. Ketoprofen and fenoprofen are two chiral drugs, belonging to the class of propionic acid-derived nonsteroidal anti-inflammatory agents. Their enantiomers show significant pharmacodynamic differences. For that reason, we aimed to develop, in this work, separation methods for the enantiomers of both drugs. In order to do so, it was used the high-performance liquid chromatography technique and the Whelk-O 1 column as the chiral stationary phase, under normal- and reversed-phase modes. Uni- and multivariate approaches were used to develop and optimize the separation methods. It was noted that the enantioselectivity exhibited by the Whelk-O 1 column under normal-phase mode is higher than that exhibited under reversed-phase mode. Under normal-phase mode, it was possible to achieve an appropriate separation for the enantiomers of both drugs. Under reversed-phase mode, however, only the enantiomers of fenoprofen could be successfully separated.

Durante muito tempo, os fármacos quirais de origem sintética foram comercializados predominantemente como racematos. Atualmente, sabe-se que os enantiômeros de um fármaco quiral podem apresentar propriedades farmacocinéticas, farmacodinâmicas e toxicológicas bastante distintas. Assim sendo, técnicas analíticas enantiosseletivas são fundamentais para a pesquisa e para o controle da qualidade desses fármacos. O cetoprofeno e o fenoprofeno são dois fármacos quirais, pertencentes à classe dos agentes antiinflamatórios não-esteróides derivados do ácido propiônico. Seus enantiômeros apresentam significativas diferenças farmacodinâmicas. Por essa razão, pretendeu-se desenvolver, no presente trabalho, métodos de separação enantiomérica para ambos os fármacos. Para tanto, utilizou-se a técnica de cromatografia a líquido de alta eficiência em fase estacionária quiral (coluna Whelk-O 1), nos modos normal e reverso. Abordagens uni- e multivariadas foram utilizadas para desenvolver e otimizar os métodos de separação. Pôde-se observar que a enantiosseletividade exibida pela coluna Whelk-O 1 em fase normal é superior àquela exibida em fase reversa. Empregando a CLAE em fase normal, foi possível desenvolver métodos de separação apropriados para os enantiômeros de ambos os fármacos. Em fase reversa, no entanto, apenas os enantiômeros do fenoprofeno puderam ser separados satisfatoriamente. / For a long time, the synthetic chiral drugs were marketed mainly as racemates. Currently, it is known that enantiomers of chiral drugs may exhibit quite different pharmacokinetic, pharmacodynamic and toxicological properties. Therefore, enantioselective analytical techniques are critical to the research and quality control of these drugs. Ketoprofen and fenoprofen are two chiral drugs, belonging to the class of propionic acid-derived nonsteroidal anti-inflammatory agents. Their enantiomers show significant pharmacodynamic differences. For that reason, we aimed to develop, in this work, separation methods for the enantiomers of both drugs. In order to do so, it was used the high-performance liquid chromatography technique and the Whelk-O 1 column as the chiral stationary phase, under normal- and reversed-phase modes. Uni- and multivariate approaches were used to develop and optimize the separation methods. It was noted that the enantioselectivity exhibited by the Whelk-O 1 column under normal-phase mode is higher than that exhibited under reversed-phase mode. Under normal-phase mode, it was possible to achieve an appropriate separation for the enantiomers of both drugs. Under reversed-phase mode, however, only the enantiomers of fenoprofen could be successfully separated.

Estudos envolvendo o emprego de novas técnicas de esterilização têm apresentado nítido crescimento nos últimos anos como alternativa aos processos convencionais. A grande possibilidade consiste no emprego do plasma como agente de esterilização. Essa tecnologia tem considerável potencial para desenvolver o meio mais eficiente e seguro de esterilização de artigos termossensíveis com ênfase para a indústria farmacêutica e médica e até mesmo em outras áreas industriais. O objetivo deste trabalho foi investigar a influência de alguns parâmetros de processos por plasma e correlacionar sua eficácia com processos por óxido de etileno. Neste trabalho, estudos foram realizados empregando tecnologia de esterilização por plasma usando reator Reactive Ion Etching (RIE). Os valores aplicados de potências de rádio-frequência, a 13,56 MHz foram 25 W, 50 W, 100 W e 150 W. Os gases testados foram oxigênio puro e misturas de oxigênio e peróxido de hidrogênio (190/10, 180/20 e 160/40 sccm) e fluxo constante de 200 sccm, pressão de 0,100 torr e temperatura abaixo de 60°C. Esterilizador por óxido de etileno foi empregado a 450 mg/L (Oxyfume 2002&#174;), 55°C, 60% de umidade e -0,65 e 0,60 kgf/cm2 de pressão. Os indicadores biológicos empregados foram constituídos de esporos de Bacillus subtilis var. niger ATCC 9372, inoculados em lamínulas de vidro de 18 x 18 mm e discos de papel de 13 mm de diâmetro em uma carga de 2,0 x 107 UFC/suporte. Os tempos de exposição aos processos por plasma foram de 3 a 120 minutos. Reduções progressivas da contagem inicial de microrganismos foram observadas nos valores D: 215,91,55,55,9,19 e 2,91 minutos para processos por plasma com oxigênio puro, a 25 W, 50 W, 100 W e 150 W, respectivamente. Misturas de oxigênio e peróxido de hidrogênio apresentaram os seguintes valores D: 190/10 sccm (6,41 min), 180/20 sccm (6,47 min) e 160/40 sccm (4,02 min), a 100 W e 190/10 sccm (1,47 min), 180/20 sccm (3,11 min) e 160/40 sccm (1,94 min), a 150 W. Processos empregando óxido de etileno apresentaram valor D de 2,86 minutos. Análises por Microscopia Eletrônica de Varredura demonstraram danos causados ao córtex dos esporos. Sistema empregando plasma como principal agente de esterilização apresentou-se efetivo em desafios com indicadores biológicos. Os processos por plasma provaram ser a mais apropriada tecnologia de esterilização de materias termossensíveis e com grande potencial para substituir os métodos convencionais de esterilização em futuro próximo. / Studies involving new sterilization techniques have increased in the past few years as alternatives to conventional processes. The great possibility consists in the use of plasma as sterilization agent. This technology has the enormous potential to develop a more efficient and safer means of sterilization at thermo-sensitive matters, focusing the pharmaceutical and medical industry - even though it can be applied to other industrial areas. The aim of the present study was to investigate the influence at some parameters of plasma processes and correlate the effectiveness plasma with ethylene oxide sterilizer. In this work, studies were performed taking into account a plasma sterilization technology using a Reactive Ion Etching (RIE) reactor. Power was applied at 13.56 MHz using a 6 inch diameter electrode. The gases tested were pure oxygen and oxygen-hydrogen peroxide mixtures (190/10, 180/20, and 160/40 sccm), and gas flow held constant 200 sccm, pressure at 0.100 torr and radio-frequency power at 25 W, 50 W, 100 W, and 150 W and temperature below 60°C. Ethylene oxide sterilizer were performed using 450 mg/L (Oxyfume 2002&#174;) at 55°C, 60% humidity and -0.65 and 0.60 kgf/cm2 pressure. The biological indicator used was Bacillus subtilis var. niger ATCC 9372, witch was inoculated in glass carries (18 x 18 mm) and paper discs (13 mm diameter) in a load of 2.0 x 107 CFU/support. The exposition times were 3 to 120 minutes. Progressive reductions of the initial microbial count could be observed in the D values witch were 215.91, 55.55, 9.19, and 2.91 minutes for pure oxygen plasma at 25 W, 50 W, 100 W and 150 W, respectively. Oxygen-hydrogen peroxide mixtures plasma showed D values: 190/10 sccm (6.41 min), 180/20 sccm (6.47 min) and 160/40 sccm (4.02 min) at 100 W and 190/10 sccm (1.47 min), 180/20 sccm (3.11 min) and 160/40 sccm (1.94 min) at 150 W. Ethylene oxide processes showed D value to 2.86 minutes. Scanning Electron Microscopy analyses showed some damage on the spore cortex. Processes using plasma as main sterilization agent are presented effective in challenge with biological indicators. The plasma proved to be the most appropriate sterilization technology in thermosensitive matters and to have a great potential to replace conventional sterilization methods in the near future.

Neste trabalho realizaram-se provas de identificação qualitativa e quantitativa do nitrato de econazol (matéria-prima); ensaios de caracterização térmica do nitrato de econazol, excipientes e formulação farmacêutica (creme), assim como desenvolvimento de metodologia analítica específica e seletiva para a quantificação do nitrato de econazol na formulação farmacêutica de creme. A caracterização térmica dos excipientes foi realizada usando-se a Termogravimetria (TG). Para a caracterização térmica do nitrato de econazol e da formulação foram empregadas a Termogravimetria, a Termogravimetria Derivada (TG/DTG) e a Calorimetria Exploratória Diferencial (DSC). Na caracterização térmica da formulação foram identificados e quantificados dois tipos de água com interações diferentes com a matriz. No desenvolvimento da metodologia específica utilizou-se a eletroforese capilar em zona, método linear com concentrações entre 80 e 120 &#181;g mL-1, com coeficiente de correlação de 0,9995; precisão calculada como desvio padrão relativo (DPR) menor de 2%; exatidão do método comprovada mediante teste de recuperação, obtendo-se valores de 100&#177;2,5%; limites de detecção e quantificação 1,853 &#181;g.mL-1 e 5,617 &#181;g.mL-1, respectivamente, comprovando-se também que o método é robusto. No desenvolvimento da metodologia seletiva foram usadas a cromatografia líquida de alta eficiência com eluição em gradiente (CLAE) e a eletroforese capilar pelo método da cromatografia eletrocinética micelar (MEKC). Nestes métodos foram separados o nitrato de econazol, as impurezas relatadas na literatura do nitrato de econazol (4-álcool clorobenzílico, alfa-2,4-diclorofenil-1 H¬imidazol-1-etanol) e os conservantes presentes na formulação (metilparabeno e propilparabeno). O método seletivo desenvolvido por CLAE foi linear para todas as moléculas, com coeficientes de correlação maiores de 0,99. A precisão calculada para o nitrato de econazol como DPR foi menor de 2%; a exatidão para o nitrato de econazol foi comprovada mediante teste de recuperação, obtendo-se valores de 100&#177;2%; comprovou-se também que o método é robusto e que poderia ser aplicado para a quantificação de cada um destes cinco compostos. No método seletivo desenvolvido por MEKC se obteve tempo menor em comparação ao método por CLAE. / In this work, were performed qualitative and quantitative identitication econazole nitrate (raw material); thermal characterization of econazole nitrate, excipients and formulation (cream). There also were developed and validated specific and selective analytical methodology for quantitative determination of econazole nitrate in creams. The thermal characterization of drug product excipients was performed using the Thermogravimetry (TG). For the thermal characterization of econazole nitrate drug and their formulation were used the Thermogravimetry, Derivative Thermogravimetry (TG/DTG) and Differential Scanning Calorimetry (DSC). From cream formulation were identified and quantified two kinds of water which have different interactions with matrix. As regards lo developing of specific methodology was used the capillary zone electrophoresis (CZE). The method was linear, with a correlation coefficient of 0.9995 in the concentration range of 80 to 120 &#181;g.mL-1 of econazole nitrate, precision calculated as relative standard deviation (RSD) was less than 2%, accuracy calculated percentage of recovery for commercial sample was of 100 &#177; 2.5%, detection and quantitation limits were 1.853 &#181;g.mL-1 and 5.617 &#181;g.mL-1, respectively. The CZE method showed to be robust. For developing of selective methodology were used high performance liquid chromatography (HPLC) with gradient elution, and micellar electrokinetic chromatography (MEKC) methods. Econazole nitrate, related impurities the drug (4-Chlorobenzyl alcohol, alpha-2,4-dichlorophenyl-1H - imidazole-1-ethanol) and preservatives (methylparaben, propylparaben) present in the drug product were separated. The HPLC method was linear for all analytes, the correlation coefficients were higher than 0.99. The precision for nitrate econazol in terms of RSD was less than 2%, the percentage of recovery for commercial sample of econazole nitrate was 100&#177;2%, the method is robust and could be applied for the quantitation of the five substances cited above. With the MEKC method developed the five substances were separated less time comparated with HPLC method.

Neste trabalho realizaram-se provas de identificação qualitativa e quantitativa do nitrato de econazol (matéria-prima); ensaios de caracterização térmica do nitrato de econazol, excipientes e formulação farmacêutica (creme), assim como desenvolvimento de metodologia analítica específica e seletiva para a quantificação do nitrato de econazol na formulação farmacêutica de creme. A caracterização térmica dos excipientes foi realizada usando-se a Termogravimetria (TG). Para a caracterização térmica do nitrato de econazol e da formulação foram empregadas a Termogravimetria, a Termogravimetria Derivada (TG/DTG) e a Calorimetria Exploratória Diferencial (DSC). Na caracterização térmica da formulação foram identificados e quantificados dois tipos de água com interações diferentes com a matriz. No desenvolvimento da metodologia específica utilizou-se a eletroforese capilar em zona, método linear com concentrações entre 80 e 120 &#181;g mL-1, com coeficiente de correlação de 0,9995; precisão calculada como desvio padrão relativo (DPR) menor de 2%; exatidão do método comprovada mediante teste de recuperação, obtendo-se valores de 100&#177;2,5%; limites de detecção e quantificação 1,853 &#181;g.mL-1 e 5,617 &#181;g.mL-1, respectivamente, comprovando-se também que o método é robusto. No desenvolvimento da metodologia seletiva foram usadas a cromatografia líquida de alta eficiência com eluição em gradiente (CLAE) e a eletroforese capilar pelo método da cromatografia eletrocinética micelar (MEKC). Nestes métodos foram separados o nitrato de econazol, as impurezas relatadas na literatura do nitrato de econazol (4-álcool clorobenzílico, alfa-2,4-diclorofenil-1 H¬imidazol-1-etanol) e os conservantes presentes na formulação (metilparabeno e propilparabeno). O método seletivo desenvolvido por CLAE foi linear para todas as moléculas, com coeficientes de correlação maiores de 0,99. A precisão calculada para o nitrato de econazol como DPR foi menor de 2%; a exatidão para o nitrato de econazol foi comprovada mediante teste de recuperação, obtendo-se valores de 100&#177;2%; comprovou-se também que o método é robusto e que poderia ser aplicado para a quantificação de cada um destes cinco compostos. No método seletivo desenvolvido por MEKC se obteve tempo menor em comparação ao método por CLAE. / In this work, were performed qualitative and quantitative identitication econazole nitrate (raw material); thermal characterization of econazole nitrate, excipients and formulation (cream). There also were developed and validated specific and selective analytical methodology for quantitative determination of econazole nitrate in creams. The thermal characterization of drug product excipients was performed using the Thermogravimetry (TG). For the thermal characterization of econazole nitrate drug and their formulation were used the Thermogravimetry, Derivative Thermogravimetry (TG/DTG) and Differential Scanning Calorimetry (DSC). From cream formulation were identified and quantified two kinds of water which have different interactions with matrix. As regards lo developing of specific methodology was used the capillary zone electrophoresis (CZE). The method was linear, with a correlation coefficient of 0.9995 in the concentration range of 80 to 120 &#181;g.mL-1 of econazole nitrate, precision calculated as relative standard deviation (RSD) was less than 2%, accuracy calculated percentage of recovery for commercial sample was of 100 &#177; 2.5%, detection and quantitation limits were 1.853 &#181;g.mL-1 and 5.617 &#181;g.mL-1, respectively. The CZE method showed to be robust. For developing of selective methodology were used high performance liquid chromatography (HPLC) with gradient elution, and micellar electrokinetic chromatography (MEKC) methods. Econazole nitrate, related impurities the drug (4-Chlorobenzyl alcohol, alpha-2,4-dichlorophenyl-1H - imidazole-1-ethanol) and preservatives (methylparaben, propylparaben) present in the drug product were separated. The HPLC method was linear for all analytes, the correlation coefficients were higher than 0.99. The precision for nitrate econazol in terms of RSD was less than 2%, the percentage of recovery for commercial sample of econazole nitrate was 100&#177;2%, the method is robust and could be applied for the quantitation of the five substances cited above. With the MEKC method developed the five substances were separated less time comparated with HPLC method.

Estudos envolvendo o emprego de novas técnicas de esterilização têm apresentado nítido crescimento nos últimos anos como alternativa aos processos convencionais. A grande possibilidade consiste no emprego do plasma como agente de esterilização. Essa tecnologia tem considerável potencial para desenvolver o meio mais eficiente e seguro de esterilização de artigos termossensíveis com ênfase para a indústria farmacêutica e médica e até mesmo em outras áreas industriais. O objetivo deste trabalho foi investigar a influência de alguns parâmetros de processos por plasma e correlacionar sua eficácia com processos por óxido de etileno. Neste trabalho, estudos foram realizados empregando tecnologia de esterilização por plasma usando reator Reactive Ion Etching (RIE). Os valores aplicados de potências de rádio-frequência, a 13,56 MHz foram 25 W, 50 W, 100 W e 150 W. Os gases testados foram oxigênio puro e misturas de oxigênio e peróxido de hidrogênio (190/10, 180/20 e 160/40 sccm) e fluxo constante de 200 sccm, pressão de 0,100 torr e temperatura abaixo de 60°C. Esterilizador por óxido de etileno foi empregado a 450 mg/L (Oxyfume 2002&#174;), 55°C, 60% de umidade e -0,65 e 0,60 kgf/cm2 de pressão. Os indicadores biológicos empregados foram constituídos de esporos de Bacillus subtilis var. niger ATCC 9372, inoculados em lamínulas de vidro de 18 x 18 mm e discos de papel de 13 mm de diâmetro em uma carga de 2,0 x 107 UFC/suporte. Os tempos de exposição aos processos por plasma foram de 3 a 120 minutos. Reduções progressivas da contagem inicial de microrganismos foram observadas nos valores D: 215,91,55,55,9,19 e 2,91 minutos para processos por plasma com oxigênio puro, a 25 W, 50 W, 100 W e 150 W, respectivamente. Misturas de oxigênio e peróxido de hidrogênio apresentaram os seguintes valores D: 190/10 sccm (6,41 min), 180/20 sccm (6,47 min) e 160/40 sccm (4,02 min), a 100 W e 190/10 sccm (1,47 min), 180/20 sccm (3,11 min) e 160/40 sccm (1,94 min), a 150 W. Processos empregando óxido de etileno apresentaram valor D de 2,86 minutos. Análises por Microscopia Eletrônica de Varredura demonstraram danos causados ao córtex dos esporos. Sistema empregando plasma como principal agente de esterilização apresentou-se efetivo em desafios com indicadores biológicos. Os processos por plasma provaram ser a mais apropriada tecnologia de esterilização de materias termossensíveis e com grande potencial para substituir os métodos convencionais de esterilização em futuro próximo. / Studies involving new sterilization techniques have increased in the past few years as alternatives to conventional processes. The great possibility consists in the use of plasma as sterilization agent. This technology has the enormous potential to develop a more efficient and safer means of sterilization at thermo-sensitive matters, focusing the pharmaceutical and medical industry - even though it can be applied to other industrial areas. The aim of the present study was to investigate the influence at some parameters of plasma processes and correlate the effectiveness plasma with ethylene oxide sterilizer. In this work, studies were performed taking into account a plasma sterilization technology using a Reactive Ion Etching (RIE) reactor. Power was applied at 13.56 MHz using a 6 inch diameter electrode. The gases tested were pure oxygen and oxygen-hydrogen peroxide mixtures (190/10, 180/20, and 160/40 sccm), and gas flow held constant 200 sccm, pressure at 0.100 torr and radio-frequency power at 25 W, 50 W, 100 W, and 150 W and temperature below 60°C. Ethylene oxide sterilizer were performed using 450 mg/L (Oxyfume 2002&#174;) at 55°C, 60% humidity and -0.65 and 0.60 kgf/cm2 pressure. The biological indicator used was Bacillus subtilis var. niger ATCC 9372, witch was inoculated in glass carries (18 x 18 mm) and paper discs (13 mm diameter) in a load of 2.0 x 107 CFU/support. The exposition times were 3 to 120 minutes. Progressive reductions of the initial microbial count could be observed in the D values witch were 215.91, 55.55, 9.19, and 2.91 minutes for pure oxygen plasma at 25 W, 50 W, 100 W and 150 W, respectively. Oxygen-hydrogen peroxide mixtures plasma showed D values: 190/10 sccm (6.41 min), 180/20 sccm (6.47 min) and 160/40 sccm (4.02 min) at 100 W and 190/10 sccm (1.47 min), 180/20 sccm (3.11 min) and 160/40 sccm (1.94 min) at 150 W. Ethylene oxide processes showed D value to 2.86 minutes. Scanning Electron Microscopy analyses showed some damage on the spore cortex. Processes using plasma as main sterilization agent are presented effective in challenge with biological indicators. The plasma proved to be the most appropriate sterilization technology in thermosensitive matters and to have a great potential to replace conventional sterilization methods in the near future.

O objetivo desta pesquisa foi desenvolver e validar métodos analíticos para o fármaco besilato de anlodipino (ABC) em comprimidos. O método espectrofotométrico no ultra violeta e o método por cromatografia líquida de alta eficiência (CLAE) desenvolvidos foram considerados simples, exatos e precisos. Foram analisadas amostras contendo 5 mg,10 mg e uma amostra formulada de 5mg de ABC/comprimido. Para o método espectrofotométrico, a primeira diluição das amostras foi feita em metanol e as subseqüentes em água. A leitura foi efetuada a 364,4 nm. A linearidade para ABC foi estabelecida na faixa de 41,0-61,0 mg/mL e o coeficiente de correlação foi R= 0,9996. O limite de detecção e o de quantificação foram respectivamente 0,54 e 1,8 mcg/mL. A exatidão e a precisão foram 98,99% e 0,37%, respectivamente. Nas análises por cromatografia líquida de alta eficiência (CLAE), foram utilizadas as seguintes condições: coluna LiChrospher &#174; 100 RP-18 Merck &#174; (250 mm x 4,6 mm, 5&#181;m), fase móvel constituída por metanol: água: (35:65) com 1% de TEA e pH ajustado para 5.0 com ácido fosfórico; fluxo de 1,0 mL/min; detecção UV a 238 nm e temperatura de 22 &#177;1°C.Tempo de retenção (RT) ABC foi de 3,7 min. Foi obtida linearidade no intervalo de 50 a 350 mcg/mL e coeficiente de correlação = 0,9999. O limite de detecção e o de quantificação foram respectivamente de 2,26 mcg/mL e 7,52 mcg/mL. A exatidão foi de 100,18% e a precisão foi de 0,37% para a CLAE. Ambos os métodos podem ser usados na rotina de análise para o controle de qualidade de comprimidos contendo ABC. / The objective of this research was to develop and validate analytical methods for the amlodipine besylate (ABC) determination in tablets. Simple, accurate and precise spectrophotometric and HPLC methods were validate for ABC determination in samples containing 5.0 and 10.0 mg of ABC / tablet. For the spectrophotometric method, the first dilutions of samples were made in methanol and the consecutive in distilled water. Determination was made at 364.4 nm. Linearity was in the range of 41.0-61.0 &#181;g/mL and r= 0.9996. The detection and quantitation limits were respectively, 0.54 &#181;g/mL and 1.80 &#181;g/mL. Accuracy and precision were respectively, 98.99% and 0.37%. For HPLC analysis, the following conditions were used: a LiChrospher &#174; 100 RP-18 Merck&#174; (250 mm x 4,6 mm, 5&#181;m) column; methanol: water with 1% of triethylamine adjusted to pH 5.0 with phosphoric acid (35:65), as mobile phase; a flow rate of 1.0 mL /min; UV detection at 238 nm and temperature of 22 &#177;1 °C . Retention time was 3.7 min. Linearity was in the range of 50.0 - 350.0 &#181;g/mL and r = 0.9999. The detection and quantitation limits were respectively, 2.26 &#181;g/mL and 7.52 &#181;g/mL. Accuracy and precision were respectively, 100.18% and 0.37%. Both methods can be used in routine analysis for quality control of tablets containing ABC.