Introdução: a analgesia multimodal é amplamente usada para o controle da dor perioperatória em um esforço para reduzir o uso de opioides. A duloxetina é um inibidor seletivo da recaptação da serotonina e noradrenalina com eficácia para estados de dor crônica. O objetivo principal deste estudo foi avaliar a eficácia de duas doses orais de 60 mg de duloxetina em termos de consumo de fentanil durante o período pós-operatório em pacientes submetidos à cirurgia eletiva de artrodese de coluna lombar. Método: este estudo foi um ensaio clínico prospectivo, duplo encoberto, aleatório e controlado com placebo. Os pacientes receberam 60 mg de duloxetina ou placebo idêntico uma hora antes da cirurgia e 24 horas depois. Os sujeitos do estudo foram divididos em dois grupos: grupo C (controle) de indivíduos que receberam o placebo; e grupo D (duloxetina) de indivíduos que receberam 60 mg de duloxetina. O consumo total de fentanil administrado pelo próprio paciente em 24 e 48 horas após a cirurgia foi mensurado. Os desfechos secundários foram os escores de dor e a presença ou ausência de efeitos adversos, tais como cefaleia, náuseas, vômitos, prurido, tonturas e sonolência. Resultados: as características demográficas não diferiram entre os grupos. Houve uma diferença significativa no consumo de fentanil nas primeiras 24 horas entre os grupos C e D (diferença média, 223,11 ± 39,32 ?g; p < 0,001). O consumo de fentanil também diferiu entre os grupos C e D após 48 horas (diferença média, 179,35 ± 32,55 ug; p < 0,00). Os escores de dor em mais de 48 horas não diferiram significativamente entre os grupos. A incidência de efeitos colaterais foi semelhante nos dois grupos. Conclusão: a duloxetina foi associada à redução do consumo de fentanil no pós-operatório de cirurgias sobre a coluna lombar, portanto, sendo eficaz como adjuvante para a analgesia pós-operatória e redução do consumo de opioides / Background: Multimodal analgesia is widely advocated for the control of perioperative pain in an effort to reduce the use of opioids. Duloxetine is a selective serotonin and noradrenaline reuptake inhibitor with efficacy for chronic pain states. The main objective of this study was to evaluate the efficacy of two oral doses of 60 mg duloxetine in terms of fentanyl submitted to elective lumbar spine arthrodesis surgery. Method: This study was prospective, double blind, randomized, and placebo controlled clinical trial. Patients received duloxetine 60 mg or identical placebo one hour before surgery and 24 hours later. The study subjects were divided into two groups: group C (control) of subjects who received placebo; and group D (duloxetine) from subjects received 60 mg. The total fentanyl consumption by the patient himself at 24 and 48 hours after surgery was measured. Secondary outcomes were pain scores and the presence or absence of adverse effects such as headache, nausea, vomiting, pruritus, dizziness and drowsiness. Results: Demographic characteristics did not differ between groups. There was a significant difference in fentanyl consumption in the first 24 hours between groups C and D (mean difference, 223.11 ± 39.32 ?g; p < 0.001). Fentanyl consumption also differed between groups C and D after 48 hours (mean difference, 179.35 ± 32.55 ?g; p < 0.00). Pain scores in more than 48 hours did not differ significantly between groups. The incidence of side effects was similar in both groups. Conclusion: Duloxetine was associated with reduction of fentanyl consumption in the postoperative period of surgeries on the lumbar spine, therefore, it was effective as adjuvant for postoperative analgesia and reduction of opioid consumption

O cloridrato de milnaciprana (MNC) é um inibidor da recaptação da serotonina e noradrenalina (IRSN), produzido na forma farmacêutica cápsula, Ixel, Dalcipran e Toledomin, para o tratamento da depressão, e como comprimido, sob o nome comercial Savella, indicado no manejo da fibromialgia. Levando-se em consideração que não existem métodos oficiais para o doseamento do MNC em produto acabado, faz-se necessário o desenvolvimento e validação de métodos para assegurar a qualidade da forma farmacêutica. Deste modo, o objetivo deste trabalho foi a validação de métodos analíticos para o controle de qualidade do MNC cápsulas e a realização de estudo da degradação forçada do fármaco. A identificação e caracterização do fármaco foram realizadas através da análise do ponto de fusão, DSC, rotação específica e IV. Para a quantificação foram validados, segundo normas da ICH, os métodos UV-D2, CLAE e EC. A análise estatística demonstrou equivalência entre os métodos UV-D2 e CLAE, assim como entre CLAE e EC, para doseamento do MNC cápsulas. O teste de dissolução foi desenvolvido e validado utilizando cestas (50 rpm) em HCl 0,01M como meio de dissolução. A porcentagem de fármaco dissolvido foi determinada por ambos os métodos, CLAE e UV-D2. Os parâmetros cinéticos (ED% e t80%) da dissolução foram determinados e o modelo de Hixson-Crowell é o que melhor descreve a cinética de dissolução das cápsulas. A influência das condições de armazenamento da formulação farmacêutica no perfil de dissolução também foi avaliada. No estudo de degradação forçada, o MNC foi submetido à radiação UV (254 nm) e à oxidação com peróxido de hidrogênio. A CLAE foi o método empregado na análise do teor e pureza das amostras submetidas às degradações. Os resultados demonstraram a sensibilidade do fármaco nas condições testadas, havendo redução significativa de seu teor e a formação de produtos de degradação. A fotodegradação do MNC demonstrou cinética de 1ª ordem para o fármaco no estado sólido e para a solução das cápsulas, enquanto para o fármaco em solução demonstrou cinética de ordem zero. / Milnacipran hydrochloride (MNC) is a serotonin and noradrenaline reuptake inhibitor (SNRI), produced as capsules, Ixel, Dalcipran and Toledomin, for the treatment of depression, and as tablets, under the trade name Savella, indicated in the management of fibromyalgia. Considering that there are no official methods for the determination of the MNC capsules, it is necessary to develop and validate methods to ensure the quality of pharmaceutical formulation. Thus, the objective of this study was the validation of analytical methods for quality control of the MNC capsules and the forced degradation studies of the drug. The identification and characterization of the drug were performed by analyzing the melting point, DSC, specific rotation and IR. For the quantification were validated a second-derivative UV spectrophotometric (UV-D2), HPLC and a CE methods, according to ICH guide. Statistical analysis showed that the methods UV-D2 / HPLC, and HPLC / CE were equivalent to assay MNC capsules. The dissolution test was developed and validated using baskets (50 rpm) in 0.01N HCl as dissolution medium. The percentage of dissolved drug was determined by both methods (HPLC and UV-D2). The kinetic parameters (dissolution efficiency% and t80%) of drug release were determined and the Hixson-Crowell model is which best describes the dissolution kinetics of the capsules. The influence of storage conditions of the pharmaceutical formulation in the dissolution rate was also evaluated. In forced degradation study, the MNC was subjected to UV (254nm) and oxidation with hydrogen peroxide. The HPLC method was employed to analyze the assay and purity of samples subjected to degradation. The results showed levels of the drug decreased significantly and the presence of its degradation products. The photodegradation of MNC showed first order kinetics of reaction to the drug at solid state and to capsules solution, but the drug solution presented zero order kinetics.

Submitted by Erika Demachki (erikademachki@gmail.com) on 2017-02-14T16:45:23Z No. of bitstreams: 2 Dissertação - João Hélio Venâncio Gomes - 2015.pdf: 2182325 bytes, checksum: 05a2adca44bd1d62895d3e1db48e449c (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) / Approved for entry into archive by Luciana Ferreira (lucgeral@gmail.com) on 2017-02-15T09:31:12Z (GMT) No. of bitstreams: 2 Dissertação - João Hélio Venâncio Gomes - 2015.pdf: 2182325 bytes, checksum: 05a2adca44bd1d62895d3e1db48e449c (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) / Made available in DSpace on 2017-02-15T09:31:12Z (GMT). No. of bitstreams: 2 Dissertação - João Hélio Venâncio Gomes - 2015.pdf: 2182325 bytes, checksum: 05a2adca44bd1d62895d3e1db48e449c (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Previous issue date: 2015-09-30 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES / Topotecan (TPT) is a potent cytotoxic agent used in the treatment of various tumors, and studies have reported its effectiveness in the treatment of melanoma. Local treatment of melanoma with TPT appears to be a viable alternative since conventional treatments result in scarring, pain, inflammation and possible recurrence. However, the permeation of hydrophilic drugs such as TPT, is quite difficult. The encapsulation of the drug into nanostructured lipid carriers (NLC) may facilitate TPT permeation to deeper skin layers. Therefore, the final formulation shall provide appropriate viscosity for easy application and remain in the desired location. Thus, the objective was to incorporate the CLN-TPT in hydrogels hydroxyethyl cellulose (NLC-TPT-HEC) and chitosan (NLC-TPT-QUIT) and evaluate the skin permeation of the merged formulations or not in gels. NLC were incorporated into the hydrogels and were characterized as mean diameter, polydispersity index (PdI), zeta potential, drug recovery (REC%) and encapsulation efficiency (EE%). The release profiles and in vitro permeation studies were carried out in Franz-type diffusion cells using synthetic membrane and porcine ear skin, respectively. To quantify the TPT, high-performance liquid chromatography (HPLC) was used and a method for its extraction and quantitation in different skin layers was developed. The NLC-TPT-HEC and NLC-TPT-QUIT obtained respectively mean diameters of 117.8 nm and 183.2 nm; PdI of 0.32 and 0.33 and zeta potential -12,0mV and 75,0mV. Approximately 60% of TPT was recovered at the end of the preparation of formulations and EE% remained higher than 85% after the incorporation of the particles in the gels. The NLCTPT-HEC and NLC-TPT-QUIT demonstrated a significantly lower drug release (p <0.05) than the drug incorporated in the hydrogel and in NLC aqueous dispersion, demonstrating a potentiation in controlling the release of TPT. The NLC-TPT formulations CLN-TPT-HEC and CLN-TPT-QUIT increased respectively 1.93, 2.37 and 2.06 times the permeation of the drug into the deeper layers of the skin, compared to unloaded drug in same formulations. The NLCTPT-HEC / QUIT showed a lower permeation of the drug into the deeper skin layers when compared with the CLN-TPT dispersed in water. The controlled release resulted in a lower amount of drug available for permeation. Thus, the formulations allow control of permeation through the control of the drug release, which can meet different needs. The gel QUIT, for example, decreased the amount of drug retained in the EC and increases the amount of TPT permeated to the deeper layers. The developed formulations have potential use for topical treatment of melanoma. / O topotecano (TPT) é um potente agente citotóxico utilizado no tratamento de diversos tumores, e estudos têm relatado a sua eficácia no tratamento de melanoma. O tratamento local de melanoma com TPT parece ser uma alternativa viável, visto que os tratamentos convencionais resultam em cicatrizes desagradáveis, dor, inflamação e possíveis recidivas. Entretanto, a permeação de fármacos hidrofílicos, como o TPT, é bastante difícil. A encapsulação deste fármaco em carreadores lipídicos nanoestruturados (CLN) poderá facilitar a permeação do TPT para as camadas mais profundas da pele. Para tanto, a formulação final deve apresentar viscosidade adequada para facilitar a aplicação e manter-se no local desejado. Desta forma, o objetivo do trabalho foi incorporar os CLN-TPT em hidrogéis de hidroxietilcelulose (CLN-TPT-HEC) e quitosana (CLN-TPT-QUIT) e avaliar a permeação cutânea do TPT a partir das diferentes formulações. Os CLN incorporados nos hidrogéis foram caracterizados quanto ao diâmetro médio, índice de polidispersividade (PdI), potencial zeta, recuperação (REC%) e eficiência de encapsulação (EE%). Os perfis de liberação e permeação in vitro foram determinados utilizando células de difusão tipo Franz, utilizando membrana sintética e pele de orelha suína, respectivamente. Para a quantificação do TPT utilizou-se metodologia desenvolvida e validada por cromatografia líquida de alta eficiência (CLAE), e um método para a sua extração das camadas da pele foi desenvolvido. Os CLN-TPT-HEC e CLNTPT-QUIT apresentaram, respectivamente, diâmetros médios de 117,8 nm e 183,2 nm; PdI de 0,32 e 0,33 e potencial zeta -12,0mV e 75,9mV. Aproximadamente 60% do TPT foi recuperado ao final do preparo das formulações e a EE% manteve-se maior que 85% após a incorporação das partículas nos géis. Os CLN-TPT-HEC e CLN-TPT-QUIT demonstraram uma liberação significativamente menor (p<0,05) do que do fármaco incorporado nos hidrogéis e nos CLN em dispersão aquosa, demonstrando uma potencialização no controle da liberação do TPT, quando os CLN estão dispersos nos hidrogéis. As formulações CLN-TPT, CLN-TPT-HEC e CLN-TPT-QUIT aumentaram respectivamente 1,93, 2,37 e 2,06 vezes a permeação do fármaco para as camadas mais profundas da pele, em relação ao fármaco não encapsulado (nas mesmas formulações). Os CLN-TPT-HEC/QUT demonstraram menor permeação do fármaco para as camadas mais profundas da pele quando comparado com o CLN-TPT disperso em água. O controle da liberação resultou em uma quantidade menor de fármaco disponível para permeação. Desta forma, as formulações permitiram o controle da permeação através do controle da liberação do fármaco, podendo atender a diferentes necessidades. O gel de QUIT, por exemplo, diminuiu a quantidade de fármaco retido no EC e aumentou a quantidade de TPT permeado para as camadas mais profundas. As formulações desenvolvidas têm potencial de utilização para tratamento tópico do melanoma.

Submitted by Biblioteca da Faculdade de Farmácia (bff@ndc.uff.br) on 2017-03-23T19:00:13Z No. of bitstreams: 1 Peçanha, Bruna Rachel de Britto [Dissertação, 2012].pdf: 3907379 bytes, checksum: f2acabc3c1c39363b86f0d651d6b5936 (MD5) / Made available in DSpace on 2017-03-23T19:00:13Z (GMT). No. of bitstreams: 1 Peçanha, Bruna Rachel de Britto [Dissertação, 2012].pdf: 3907379 bytes, checksum: f2acabc3c1c39363b86f0d651d6b5936 (MD5) / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / Polímeros de impressão molecular (MIPs) foram sintetizados e aplicados como adsorventes na técnica de extração em fase sólida (EFS). O método de polimerização por precipitação foi utilizado para a síntese dos polímeros, devido à simplicidade de preparo, altos rendimentos e obtenção de partículas mais uniformes, devido a não trituração do polímero. O MIP foi sintetizado com ácido metacrílico (MAA) como monômero funcional, trimetacrilato de trimetilolpropano (TRIM) e dimetacrilato de etilenoglicol (EDMA) como agentes de reticulação e o cloridrato de amilorida (AMI) foi escolhido como molécula-molde. Diferentes proporções de MAA, TRIM, EDMA, volume e tipo de solvente foram utilizadas para ajuste das condições ideais de síntese. Os MIP foram avaliados quanto à capacidade de adsorção comparando-se a polímeros sintetizados na ausência da molécula-molde (NIP, polímeros não impressos). O solvente de elevada polaridade empregado na síntese (THF:MeOH:H2O) permitiu o emprego da técnica para moléculas polares como AMI. O controle no volume de solvente permitiu a obtenção de partículas maiores, de modo que a EFS foi realizada em condições usuais, o que confere um potencial para aplicação dessa técnica de polimerização na preparação de adsorventes para EFS. O polímero que apresentou maior capacidade adsortiva no ensaio realizado em tampão citrato-acetato pH 6,5 foi o MIP/NIP 12 (AMI:MAA:TRIM 1:8:10), com uma taxa média de adsorção de 83 e 88% para NIP e MIP, respectivamente. A adsorção foi elevada devido a interação iônica entre MAA e AMI promovida pelo controle de pH, porém foi não específica. O polímero MIP/NIP 12 foi aplicado como adsorvente na EFS, onde a recuperação de AMI foi avaliada nos resíduos de carregamento e eluição com solventes. O carregamento com tampão citrato-acetato pH 6,5 foi o ideal, favorecendo a interação iônica do polímero com o analito. A eluição total de AMI do cartucho somente ocorre após lavagem com o solvente na presença de ácido, que protona os grupos carboxila do polímero, rompendo assim a interação iônica com o analito / Molecularly imprinted polymers (MIPs) were synthesized and applied as adsorbents in solid-phase extraction technique (SPE). The polymers have been synthesized by precipitation polymerization method because of its simplicity, high yields and good control of final size and shape of particles. MIP was synthesized using methacrylic acid (MAA) as functional monomer, trimethylolpropane trimethacrylate (TRIM) and ethyleneglycol dimethacrylate (EDMA) as cross-linker and amiloride hydrochloride (AMI) was chosen as template. Different ratios of MAA, TRIM and EDMA, volume and type of solvent were used to adjust the optimal synthesis conditions. The MIP were tested for adsorption capacity compared to the polymers synthesized in the absence of template molecule (NIP, non-imprinted polymers). The polar solvent mixture used (THF:MeOH:H2O) allowed the synthesis of MIP of polar molecules as AMI. The solvent volume control afforded the larger particles so the SPE was performed in the usual conditions, giving a potential application for this polymerization technique in the preparation of adsorbents for SPE. The polymers with higher adsorption capacity at the test performed in citrateacetate buffer pH 6,5 was MIP/NIP 12 (AMI:MAA:TRIM 1:8:10) with adsorption rate of 83 and 88% for NIP and MIP, respectively. The recognition of MIP was due to ionic interaction between MAA and AMI promoted by pH control, but was not specific. The polymer MIP/NIP 12 was used as a solid-phase extraction sorbent and the recoveries of AMI was evaluated using different loading and elution conditions. The loading with buffer citrate-acetate pH 6,5 was optimal, due to ionic interaction of the polymer with the analyte. Total elution of AMI bound to the polymers only occurs after washing with a acid-containing solvent, because of protonation of the carboxyl groups of the polymer and disrupting the ionic interaction with the analyte

This diploma thesis deals with the preparation and characterization of negatively charged catanionic vesicular systems and their combination with selected polycations. The catanionic vesicular system was prepared by mixing of two oppositely charged surfactants SDS and CTAB. The negative charge as well as the stability of the vesicular system was provided by the incorporation of phosphatidic acid. Polycations, DEAE and TMC, have been selected for use in a pharmaceutical applications. Characterization of the prepared systems was performed by measuring DLS and ELS. The results indicate that we were able to prepare stable negatively charged vesicles that were eligible to non-covalently interact with selected polycations.

The master´s thesis deals with the study of the interaction between the polysaccharide hyaluronan of diffrerent molecular weights with the amino acids arginine, lysine, arginine hydrochloride and 6-aminocaproic acid. They are expected interaction between carboxyl groups of hyaluronan and amino groups of amino acids. These interactions were investigated by using ultrasonic spectroscopy, DLS, measuring pH and conductivity. Obtained results were compared with sodium polystyrene sulfonate. With ultrasonic spectroscopy was observed a change of concentration inkrement for titration of amino acid to water or polymers solutions especially for high molecular weight hyaluronan and for NaPSS in combination with 6AKK in concentration range of added amino acid 0–30 mM. The size of this change could mean a degree of interaction between polymers and amino acids. This theory has not been confirmed by other methods. By pH and conductivity measurements interations between arginine and low molecular weight hyaluronan and NaPSS were only confirmed. There was no possibility to make unequivocal conclusions from determination of particle size and zeta potential by DLS. Overall, the issue of the interaction of amino acids with polyanions was proved above expectations complex and will be appropriate to further expand the observations made in this thesis.

Le manque de produits pharmaceutiques destinés à la population pédiatrique est un problème auquel sont confrontés les professionnels de la santé. Les pharmaciens doivent fréquemment se tourner vers les médicaments destinés aux adultes afin de fournir aux jeunes patients les traitements adéquats. L’utilisation de préparations magistrales pour adapter les médicaments homologués aux besoins de la population pédiatrique reste, encore à ce jour, l’option la plus souvent utilisée. Dans ce mémoire, nous proposons le développement et l’évaluation de nouvelles formulations pharmaceutiques destinées à la population pédiatrique afin de bonifier les options thérapeutiques mises à la disposition des professionnels de la santé. De plus, nous avons exploré l’utilisation de nouvelles techniques spécialisées pour surmonter des défis analytiques rencontrés, ultimement dans le but de déterminer en toute confiance la stabilité et la sécurité de ces nouvelles formulations. La première étude visait à évaluer la stabilité de préparations magistrales de chlorhydrate de clonidine (20 µg/mL) préparées avec des comprimés dans le véhicule commercial Ora-Blend. Les formulations embouteillées ont été conservées à 25°C/60% RH pendant 90 jours. Les défis analytiques rencontrés lors de l’analyse de la stabilité chimique ont été surmontés par l’implémentation d'une nouvelle méthode d'extraction en phase solide, ayant permis d’optimiser la quantification du chlorhydrate de clonidine, se retrouvant qu’en très faible quantité dans les formulations orales. L'absence d'instabilités physiques, évaluée par des mesures qualitatives et quantitatives, et l’absence d'instabilités chimiques, mise en évidence par une méthode HPLC-UV indicatrice de stabilité, confirment qu’accorder une date de péremption de 90 jours à ces préparations magistrales serait approprié. La deuxième étude portait sur l’évaluation de la stabilité de préparations magistrales d’hydroxyurée (100 mg/mL) dans l’Ora-Blend. Dans le cadre de cette étude, différentes méthodes de préparation (mortier, mélangeur, QuartetRx) et différentes sources de principe actifs (poudre, contenu des capsules, capsules entières) ont été étudiées. Toutes les formulations ont été conservées à 25°C pendant 90 jours dans des bouteilles et 14 jours dans des seringues orales. Le développement d'une méthode HPLC indicatrice de stabilité impliquant la dérivation de l’hydroxyurée par le xanthydrol aura permis la rétention l’hydroxyurée sur une colonne à phase inverse de type C18. Plus de 90.0 % de la concentration initiale d’hydroxyurée a été conservé tout au long de l’étude, et ce, pour toutes les conditions testées. L’évaluation visuelle des préparations n’a révélé aucun changement au cours de l’étude de stabilité. Des changements de pH allant jusqu'à 1.6 unités ont toutefois été observés après 90 jours d’entreposage et ont mis en lumière une voie de dégradation de l’hydroxyurée, générant ultimement l’ion ammonium. Ce dernier a été quantifié et les concentrations mesurées, définies comme acceptables. Les résultats ont montré que toutes les formulations d’hydroxyurée étudiées sont demeurées stables jusqu’à 90 jours à 25°C. Pour terminer, une étude exploratoire ayant pour but d’évaluer des comprimés à croquer à saveur d’érable a été réalisée. Le sucre d’érable et un arôme naturel d’érable ont été ajoutés à la composition des comprimés afin d’obtenir une saveur suffisamment prononcée pour masquer le goût amer de l’acétaminophène. Une étude de stabilité préliminaire, impliquant une période de 30 jours d’entreposage dans des conditions de stabilité accélérées (40°C/75%RH), aura permis d’explorer les propriétés physico-chimiques de cette nouvelle formulation, de soulever les défis potentiels et de générer des hypothèses en lien avec l’augmentation de dureté observée après seulement 14 jours d’entreposage. Les résultats de cette étude préliminaire serviront de point de départ pour le futur développement de produits pharmaceutiques à la saveur du Québec. Les techniques utilisées et les études réalisées dans le cadre de ce projet de maîtrise auront permis de générer des résultats robustes qui pourront être utilisés par les professionnels de la santé. Ces informations seront pertinentes à la pratique pharmaceutique et permettront d’offrir à la population pédiatrique des nouvelles options de traitement sécuritaires et efficaces. / The lack of pharmaceuticals intended to the pediatric population is an issue facing healthcare professionals. Pharmacists must frequently resort to adult treatments to provide adequate treatment to young patients. The use of compounding to adapt commercial drugs to the needs of the pediatric population is still, to this day, the most considered option. In this master’s thesis, we propose the development and evaluation of new medicinal preparations for pediatrics in order to improve and diversify the therapeutic options available to healthcare professionals. In addition, we have explored the use of new specialized techniques to overcome analytical challenges encountered, with the goal of confidently determining the stability and safety of these new formulations. The first study aimed to assess the stability of compound preparations of clonidine hydrochloride (20 µg / mL) prepared with tablets in the commercial vehicle Ora-Blend. Bottled formulations were stored at 25°C/60% RH for 90 days. The analytical challenges encountered during the analysis of chemical stability were overcome by the implementation of a new method of solid phase extraction, which allowed to optimize the quantification of clonidine hydrochloride, present in very small amount in oral formulations. The absence of physical instabilities, assessed by qualitative and quantitative measurements, and the absence of chemical instabilities, as demonstrated by a stability indicating HPLC-UV method, confirm that it would be appropriate to grant a 90-day expiration date to these compounded oral liquids. The second study evaluated the stability of compound preparations of hydroxyurea (100 mg / mL) in Ora-Blend. In this study, different preparation methods (mortar, mixer, QuartetRx) and different sources of hydroxyurea (powder, content of capsules, whole capsules) were studied. All formulations were stored at 25°C for 90 days in bottles and 14 days in oral syringes. The development of a stability indicating HPLC method involving the derivatization of hydroxyurea by xanthydrol will have enabled hydroxyurea retention on a C18 type reverse phase column. Over 90.0% of the initial hydroxyurea concentration was recovered throughout the study under all conditions tested. Visual evaluation of the preparations did not reveal any changes during the stability study. Changes in pH of up to 1.6 units were observed after 90 days of storage and revealed a degradation pathway for hydroxyurea, ultimately generating ammonium ion. The latter was quantified, and the measured concentrations defined as acceptable. The results showed that all hydroxyurea formulations studied were stable for up to 90 days at 25°C. Finally, an exploratory study to evaluate maple flavored chewable tablets was carried out. Maple sugar and a natural maple flavor have been added to the composition of the tablets to achieve a flavor strong enough to mask the bitter taste of acetaminophen. The pre-stability study, involving a period of 30 days of storage under accelerated stability conditions (40°C/75% RH), will have made it possible to explore the physicochemical properties of this new formulation, to raise the potential challenges and generate hypotheses related to the increase in hardness observed after only 14 days of storage. The results of this preliminary study will serve as a starting point for the future development of pharmaceutical products with a Quebec flavor. The techniques used and the studies performed will have generated robust results that could help healthcare professionals in their practice.

This diploma thesis is focused to the determination of procaine using flow injection and sequential injection analysis coupled with spectrophotometric detection. This determination is based on the reaction of procaine with a colouring agent, 1,2-naphthoquinone-4-sulfonic acid. An orange coloured product is formed, which is determined spectrophotometrically at the wavelength 484 nm. The high of the absorption signal of the product is directly proportional to the concentration of procaine. The aim of this work was to optimize the parameters of both methods of flow analysis so that the limit concentration of procaine can be as low as possible and at the same time, high sensibility is achieved. The next step was to apply these methods on the determination of procaine in real samples. It was found that in flow injection analysis, the absorbance of procaine hydrochloride obeys Beer's law for concentrations from 2.5 to 120 µg/ml. The linear regression equation of calibration graph was y = 0.0059x - 0.0051, with a linear regression correlation coefficient 0.9993. Limit of detection was 0.72 µg/ml. Effects of standing time (stopped-flow), flow rate, concentration of colouring agent, pH and the volume of the sample loop have been examined and optimized. It was also found that in sequential injection...

Submitted by Rosivalda Pereira (mrs.pereira@ufma.br) on 2017-05-05T19:45:04Z No. of bitstreams: 1 RicardoSousaFerreira.pdf: 2802747 bytes, checksum: 0d4bf284379fe32714f3b112e464cf64 (MD5) / Made available in DSpace on 2017-05-05T19:45:04Z (GMT). No. of bitstreams: 1 RicardoSousaFerreira.pdf: 2802747 bytes, checksum: 0d4bf284379fe32714f3b112e464cf64 (MD5) Previous issue date: 2016-03-24 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / Fundação de Amparo à Pesquisa e ao Desenvolvimento Científico e Tecnológico do Maranhão (FAPEMA) / Currently, the amino acid salt crystals are extensively studied, primarily because of their possible application in opto-electronic devices. Many amino acids complexed with chlorine crystals were synthesized and characterized, and suggested as promising materials in frequency conversion. However, the characterization of L-isoleucine hydrochloride monohydrate crystals (L-Ile.H2O.HCl) is poor because to date, one article has been published and only the authors determined the crystal structure of the synthesized material. Thus, the objective of this study was to synthesize crystals of L-Ile.HCl.H2O by the method of slow evaporation and characterize them by X-Ray Fluorescence (XRF), Differential Thermal Analysis (DTA), Differential Scanning Calorimetry (DSC), Thermogravimetric Analysis (TG), X-Ray diffraction (XRD) as a function of temperature and time, Raman scattering as a function of temperature and heat treating the material in a sealed glass tube with argon atmosphere for 24h at 170 °C. The XRF confirms the presence of chlorine. The XRD at 25 oC shows that the crystal belongs to orthorhombic system with lattice parameters a = 5.873 (3) Å, b = 24.814 (4) Å, c = 6.873 (5) Å. The TG, DTA and DSC indicated that the material loses water of solvation and crystallization at approximately 55 °C and 132 °C, respectively .The DRX a function of temperature, the material shows phase transformation starts at 60 oC and 155 oC extends to. The XRD at 140 oC shows that after 32h, the crystal loses water and chlorine. Raman spectra as a function of temperature, confirm the phase transformation at 60 °C and 100 °C. The material when subjected to 170 °C, for a period of 24 sealed in a glass tube with an inert atmosphere (Ar) and undergoes vaporization sublimate the same orthorhombic phase, when it has its temperature reduced to 25 °C. Therefore, the L-Ile.HCl.H2O crystal is not a material suitable for use in optical devices due to their low thermal stability. / Atualmente, os cristais de sais de aminoácidos são amplamente estudados, principalmente devido à sua possível aplicação em dispositivos opto eletrônicos. Muitos cristais de aminoácidos complexados com cloro foram sintetizados, caracterizados e sugeridos como materiais promissores na conversão de frequência. No entanto, a caracterização de cristais de L-isoleucina hidroclorídrica monohidratada (L-Ile.H2O.HCl) é deficiente, pois até o momento, um único artigo foi publicado e os autores apenas determinaram a estrutura cristalina do material sintetizado. Dessa forma, o objetivo do presente trabalho foi sintetizar cristais de L-Ile.HCl.H2O pelo método de evaporação lenta e caracterizá-los por Fluorescência de Raios-X (FRX), Análise Térmica Diferencial (DTA), Calorimetria Exploratória Diferencial (DSC), Análise Termogravimétrica (TG), Difração de Raios-X (DRX) em função da temperatura e do tempo, espalhamento Raman em função da temperatura e tratar termicamente o material em um tubo de vidro selado com atmosfera de argônio por 24h a 170 oC. A FRX confirmou a presença de cloro. O DRX a 25 oC mostrou que o cristal pertence ao sistema ortorrômbico, com parâmetros de rede a = 5,873(3) Å, b = 24,814(4) Å, c = 6,873(5) Å. O TG, DTA e DSC indicaram que o material perde água de solvatação e cristalização em aproximadamente 55 oC e 132 oC, respectivamente. O DRX em função da temperatura, revelou que o material inicia transformação de fase em 60 oC e se estende até 155 oC. O DRX a 140 oC mostrou que após 32h, o cristal perdeu água e cloro. Os espectros Raman em função da temperatura, confirmaram as transformações de fase em 60 oC e 100 oC. O material quando submetido a 170 oC, por um período de 24h selado em um tubo de vidro com atmosfera inerte (Ar), sofreu vaporização e ressublimou na mesma fase ortorrômbica, quando teve sua temperatura reduzida a 25 oC. Portanto, o cristal de L-Ile.HCl.H2O não é um material indicado para ser utilizado em dispositivos ópticos devido a sua baixa estabilidade térmica.

O cloridrato de tramadol, analgésico sintético de ação central, possui dois centros quirais: o isômero cis é ativo e o isômero trans é uma impureza de processo. Ambos os enantiômeros do cloridrato de cis-tramadol contribuem para o efeito analgésico, mas através de mecanismos diferentes, complementares e interativos farmacologicamente. Os dois isômeros do cis-tramadol apresentam efeitos terapêuticos, e a presença de impurezas, incluindo os isômeros trans - decorrentes do processo de síntese ou devido à decomposição - podem comprometer a qualidade do produto comercializado. Assim, este trabalho teve como objetivo desenvolver e validar metodologia estereosseletiva para análise do cloridrato de cis-tramadol e das possíveis impurezas quirais ou não na matéria-prima e formulações farmacêuticas. Para a separação e quantificação dos enantiômeros do cloridrato de cis-tramadol e das impurezas trans-tramadol, 1,2-olefina e 1,6-olefina, foi utilizada a coluna Chiralcel® OD-H, fase móvel constituída por hexano (60% e 100% de n-hexano, 1:1, v/v):isopropanol:dietilamina:ácido trifluoracético (99,5:0,5:0,3:0,1, v/v/v/v), na vazão de 0,7 mL min-1 e detecção em 274 nm. A coluna Chiralpak® AD fase móvel constituída por hexano (60% de n-hexano):etanol absoluto:dietilamina (95:5:0,1, v/v/v), na vazão de 1,0 mL min-1 e o comprimento de onda para detecção dos compostos foi de 228 nm foi utilizada para a separação e quantificação das impurezas O-desmetiltramadol, N-desmetiltramadol e tramadol N-óxido. Os métodos desenvolvidos foram devidamente validados através dos parâmetros seletividade, linearidade, precisão, exatidão, intervalo, limite de detecção e limite de quantificação. Os resultados obtidos na validação mostraram que os métodos são adequados para a determinação do cis-tramadol e de suas impurezas na matéria prima e na formulação farmacêutica. / Tramadol hydrochloride is a centrally acting analgesic with two chiral centers; the cis isomer is the active drug and the trans isomer is a process impurity. Both enantiomers of cis-tramadol hydrochloride contribute to the analgesic effect through different, but complementary and interactive pharmacological mechanisms. Although both isomers of cis-tramadol hydrochloride show therapeutic effects, the presence of impurities, originated from the synthesis process or due to degradation, can compromise the quality of the marketed product. The aim of this present work was the development and validation of a stereosselective methodology for the analysis of the drug cis-tramadol hydrochloride and the possible chiral or non-chiral impurities in raw materials and pharmaceutical formulations. The separation and quantitation of cis-tramadol enantiomers and the impurities trans-tramadol, 1,2-olefin and 1,6-olefin were carried out using a Chiralcel® OD-H column, mobile phase of hexane (60% and 100% of n-hexane, 1:1, v/v):2-propanol:diethylamine:trifluoroacetic acid (99,5:0,5:0,3:0,1, v/v/v/v) at a flow rate of 0,7 mL min-1 and detection at 274 nm. For the separation and quantitation of the impurities O-desmethyltramadol, N-desmethyltramadol and tramadol N-oxide, a Chiralpak® AD column was used with a mobile phase of hexane (60% of n-hexane):ethanol absolute: diethylamine (95:5:0,1, v/v/v) at a flow rate of 1,0 mL min-1 and detection at 228 nm. The methods were validated using the parameters selectivity, linearity, precision, accuracy, range, detection limit and quantitation limit. The results obtained show that the methods are suitable for the analysis of cis-tramadol and its impurities in raw material and pharmaceutical formulation.