Submitted by Automa??o e Estat?stica (sst@bczm.ufrn.br) on 2017-03-20T21:49:25Z No. of bitstreams: 1 EdilamarPereiraDaSilva_DISSERT.pdf: 3623493 bytes, checksum: a0b5d0f1284a116519496496c1ba17b3 (MD5) / Approved for entry into archive by Arlan Eloi Leite Silva (eloihistoriador@yahoo.com.br) on 2017-03-23T18:49:31Z (GMT) No. of bitstreams: 1 EdilamarPereiraDaSilva_DISSERT.pdf: 3623493 bytes, checksum: a0b5d0f1284a116519496496c1ba17b3 (MD5) / Made available in DSpace on 2017-03-23T18:49:31Z (GMT). No. of bitstreams: 1 EdilamarPereiraDaSilva_DISSERT.pdf: 3623493 bytes, checksum: a0b5d0f1284a116519496496c1ba17b3 (MD5) Previous issue date: 2016-07-29 / A atorvastatina ? um medicamento antilip?mico do grupo das estatinas, de grande import?ncia para a preven??o de doen?as cardiovasculares e normalmente usada como atorvastatina de c?lcio. O objetivo deste trabalho foi caracterizar a atorvastatina e estudar poss?veis intera??es desta com v?rios excipientes por DSC, TG e FT-IR. As curvas DSC foram obtidas usando o calor?metro SHIMADZU, modelo DSC-60, em cadinho de alum?nio sob raz?o de aquecimento de 20 ?C min-1, em uma temperatura de 25-400 ?C. As curvas foram analisadas usando o software TASYS da SHIMADZU. Os espectros das amostras foram obtidos em um espectrofot?metro ATR-FTIR modelo IRprestige-21 da Shimadzu, no comprimento de onda de 700 a 4000 cm-1 em uma m?dia de 20 varreduras. Avaliou-se a const?ncia espectral da atorvastatina e misturas bin?rias fazendo-se uma correla??o linear entre o espectro te?rico das amostras e o espectro real obtido em temperatura ambiente (25 ?C). O espectro te?rico foi obtido utilizando um algoritmo ad hoc. Por DSC avaliamos intera??es com manitol e laurilsulfato de s?dio, j? que houve desaparecimento do pico do f?rmaco e aparecimento apenas do pico do excipiente, caracterizando intera??o. A partir da avalia??o da correla??o de Pearson, n?o observamos intera??es f?sicas com os excipientes, glicolato de amido, amido pr? gelatinizado, croscarmelose, estearato de magn?sio e lactose, uma vez que o valor do r ficou entre 0,8 e 1,0, portanto boa correla??o. H? intera??es f?sicas com o laurilsulfato de s?dio. Assim, os resultados obtidos por DSC s?o confirmados por FTIR mostrando-se. Essas t?cnicas mostram-se extremamente efetivas no estudo de pr?-formula??o. / Atorvastatin is an antilipemic drug from the statins? group that has a great importance to prevent cardiovascular disease and it is usually used as atorvastatin calcium. The aim of this study was to characterize the atorvastatin and studying possible interactions with different excipients by DSC, TG and FTIR. DSC curves were obtained using a Shimadzu calorimeter, model DSC-60, aluminum pan, under heating rate of 20 ?C min-1 at temperature of 25-400 ?C. Consequently, curves were analyzed using TASYS software from Shimadzu. The spectra of the samples were obtained on a spectrophotometer ATR-FTIR (IRPrestige- 21 Shimadzu), between 700 and 4000 cm-1, on average of 20 scans. We evaluated the atorvastatin and binary mixtures? spectral steadiness by making a linear correlation between the theoretical spectra and the real ones obtained at room temperature (25 ?C). The theoretical spectra were obtained using an ad hoc algorithm. We evaluated by DSC that there are chemical interactions with mannitol and sodium lauryl sulfate because there was disappearance of the drug?s peak and appearance only of the excipients? peaks. With respect to the other excipients, there were only displacements of peaks suggesting physical interactions, it means no incompatibility. From the FTIR evaluation using Person?s correlation, it was not observed any physical interaction between atorvastatin and the following excipients: starch glycolate, pregelatinized starch, croscarmellose, magnesium stearate and lactose, since the value of r was between 0.8 and 1.0; in other words, it means a good correlation. Moreover, it was confirmed a physical interaction with the sodium lauryl sulfate. Finally, the results obtained by DSC were confirmed by FTIR data using the Person?s correlation, so both analytical techniques demonstrated to be extremelly important and effective tools for applying in a preformulation study.

Made available in DSpace on 2014-12-17T14:16:26Z (GMT). No. of bitstreams: 1 EdilenePL_DISSERT.pdf: 1151865 bytes, checksum: 7a412187753da50d4030404745c567f7 (MD5) Previous issue date: 2010-02-26 / According to the global framework regarding new cases of tuberculosis, Brazil appears at the 18th place. Thus, the Ministry of Health has defined this disease as a priority in the governmental policies. As a consequence, studies concerning treatment and prevention have increased. Fixed-dose combination formulations (FDC) are recognized as beneficial and are recommended by WHO, but they present instability and loss on rifampicin bioavailability. The main purpose of this work was to carry out a pre-formulation study with the schedule 1 tuberculosis treatment drugs: rifampicin, isoniazid, pyrazinamide and ethambutol and pharmaceutical excipients (lactose, cellulose, magnesium stearate and talc), in order to develop an FDC product (150 mg of rifampicin + 75 mg of isoniazid + 400 mg of pyrazinamide + 250 mg of ethambutol). The studies consisted of the determination of particle size and distribution (Ferret s diameter) and shape through optical microscopy, as well as rheological and technological properties (bulk and tapped densities, Hausner Factor, Carr s Index, repose angle and flux rate) and interactions among drugs and drug excipient through thermal analysis (DSC, DTA, TG and your derivate). The results showed that, except isoniazid, the other drugs presented poor rheological properties, determined by the physical characteristics of the particles: small size and rod like particles shape for rifampicin; rectangular shape for pyrazinamide and ethambutol, beyond its low density. The 4 drug mixture also not presented flowability, particularly that one containing drug quantity indicated for the formulation of FDC products. In this mixture, isoniazid, that has the best flowability, was added in a lower concentration. The addition of microcrystalline cellulose, magnesium stearate and talc to the drug mixtures improved flowability properties. In DSC analysis probable interactions among drugs were found, supporting the hypothesis of ethambutol and pyrazinamide catalysis of the rifampicin-isoniazid reaction resulting in 3- formylrifamycin isonicotinyl hydrazone (HYD) as a degradation product. In the mixtures containing lactose Supertab? DSC curves evidenced incompatibility among drugs and excipient. In the DSC curves of mixtures containing cellulose MC101?, magnesium stearate and talc, no alterations were observed comparing to the drug profiles. The TG/DTG of the binary and ternary mixtures curves showed different thermogravimetrics profiles relating that observed to the drug isolated, with the thermal decomposition early supporting the evidences of incompatibilities showed in the DSC and DTA curves / De acordo com o quadro mundial da tuberculose, o Brasil ocupa o 18? lugar em n?mero de casos novos, assim o Minist?rio da Sa?de definiu a doen?a como prioridade entre as Pol?ticas Governamentais de Sa?de. Desde ent?o se intensificaram os estudos relacionados ao tratamento e preven??o desta doen?a. As formula??es em dose fixa combinada (DFC) s?o reconhecidas como ben?ficas e apoiadas pela OMS, mas apresentam problemas de instabilidade e queda na biodisponibilidade da rifampicina. O objetivo principal desse trabalho foi realizar estudo de pr?-formula??o com os f?rmacos que integram o esquema 1 para o tratamento da tuberculose: rifampicina, isoniazida, pirazinamida e etambutol e excipientes farmac?uticos (lactose, celulose, estearato de magn?sio e talco), visando o desenvolvimento de um produto em dose fixa combinada (150 mg de rifampicina + 75 mg de isoniazida + 400 mg de pirazinamida + 250 mg de etambutol). Os estudos consistiram na determina??o do tamanho e distribui??o das part?culas (di?metro de Ferret) e forma por microscopia ?ptica, al?m das propriedades reol?gicas e tecnol?gicas (densidades aparente e de compacta??o, Fator de Hausner, ?ndice de Carr, ?ngulo de repouso e velocidade de escoamento) e das intera??es entre os f?rmacos e f?rmacos-excipientes por an?lise t?rmica (DSC, DTA, TG e sua derivada). Os resultados mostraram que ? exce??o da isoniazida, os demais f?rmacos apresentaram propriedades reol?gicas pobres, determinadas pelas caracter?sticas f?sicas das part?culas: tamanho reduzido e forma de agulhas da rifampicina; forma retangular da pirazinamida e etambutol, al?m da baixa densidade deste ?ltimo. A mistura dos quatro ativos tamb?m n?o apresentou fluxo, especialmente a prepara??o contendo a quantidade de f?rmacos preconizada para a formula??o de produtos em dose fixa combinada, uma vez que nessa mistura, a isoniazida, que possui o melhor fluxo, foi adicionada a uma concentra??o menor. A adi??o de celulose microcristalina, estearato de magn?sio e talco ?s misturas dos f?rmacos, melhorou as propriedades de fluxo. Nas an?lises por DSC foram encontradas prov?veis intera??es entre as subst?ncias ativas, refor?ando a hip?tese de cat?lise por etambutol e pirazinamida para a rea??o entre rifampicina e isoniazida que resulta no produto de degrada??o 3-(isonicotinoilhidrazinometil)rifamicina. Nas curvas de DSC das misturas contendo lactose Supertab? foi evidenciada a ocorr?ncia de incompatibilidade entre os f?rmacos e o excipiente. As curvas de DSC das misturas contendo celulose MC101?, estearato de magn?sio e talco n?o apresentaram altera??es em rela??o ao perfil dos f?rmacos. As curvas de TG/DTG das misturas bin?rias e tern?rias apresentaram perfis termogravim?tricos diferentes em rela??o ao observado para os f?rmacos isoladamente, com in?cio da decomposi??o t?rmica antecipada, dando suporte as evid?ncias de incompatibilidades encontradas nas curvas de DSC e DTA

Submitted by Automa??o e Estat?stica (sst@bczm.ufrn.br) on 2017-01-12T15:47:41Z No. of bitstreams: 1 JanainaDaSilvaGoes_DISSERT.pdf: 2421802 bytes, checksum: 8409f2ebc5498e05da2a012cbbab5963 (MD5) / Approved for entry into archive by Arlan Eloi Leite Silva (eloihistoriador@yahoo.com.br) on 2017-01-20T14:38:17Z (GMT) No. of bitstreams: 1 JanainaDaSilvaGoes_DISSERT.pdf: 2421802 bytes, checksum: 8409f2ebc5498e05da2a012cbbab5963 (MD5) / Made available in DSpace on 2017-01-20T14:38:17Z (GMT). No. of bitstreams: 1 JanainaDaSilvaGoes_DISSERT.pdf: 2421802 bytes, checksum: 8409f2ebc5498e05da2a012cbbab5963 (MD5) Previous issue date: 2013-08-29 / Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior (CAPES) / Atualmente, os medicamentos utilizados em crian?as s?o adaptados a partir de formas farmac?uticas s?lidas desenvolvidas para adultos. O captopril ? amplamente adaptado para formula??o l?quida em hospitais. Sua estabilidade em meio aquoso ? reduzida, pois sofre oxida??o gerando o dissulfeto de captopril. Com o intuito de garantir a estabilidade do f?rmaco e dosagem precisa, foi desenvolvido um estudo de pr?-formula??o para a obten??o de uma formula??o de captopril em p? para constitui??o de uma solu??o est?vel de uso pedi?trico. A compatibilidade entre o f?rmaco e os poss?veis excipientes foi avaliada atrav?s das an?lises de calorimetria de varredura diferencial (DSC) e o comportamento t?rmico do captopril atrav?s das an?lises termogravim?tica (TG) e t?rmica diferencial (DTA). Em seguida, foram realizados os ensaios de an?lise granulom?trica e das medidas indiretas de fluxo do captopril e dos excipientes. Para estudo em solu??o, foram obtidas diferentes formula??es a partir de planejamento fatorial, em que se variou a concentra??o de EDTA (0,005 e 0,1%) e pH (2,5; 4,0 e 5,5) em ?gua destilada e ?gua mineral, que foram armazenadas a 60?C e analisadas ao longo de doze dias por CLAE para avalia??o da estabilidade do captopril. Nas curvas DSC das misturas de captotpril com os conservantes, a sucralose e o ?cido c?trico, os eventos t?rmicos de cada subst?ncia isolada n?o foram mantidos. Nas demais curvas das misturas bin?rias os eventos correspondentes a cada componente foram preservados, indicando compatibilidade entre as subst?ncias. Foi observada uma grande diferen?a na distribui??o e di?metro m?dio das part?culas e densidade dos agentes tamponantes em compara??o ?s demais subst?ncias, o que pode ocasionar a segrega??o da mistura de p?s. A partir do estudo da estabilidade das solu??es, foi verificado que as vari?veis interferem significativamente (p = 0,05) no teor do captopril, sendo o pH o fator mais relevante. As intera??es entre as vari?veis foram significativas, com maior estabilidade observada em pH pr?ximo a 4,0, maior concentra??o de EDTA e uso de ?gua mineral. Com base nos resultados, pode-se concluir que o desenvolvimento de uma formula??o de captopril est?vel ? vi?vel desde que sejam adotadas medidas estrat?gicas a fim de se evitar a segrega??o dos p?s constituintes da formula??o. / Nowadays, drugs used in children are adapted from solid dosage forms developed for adults. Captopril in solid dosage form is widely adapted in hospitals into a liquid formulation. Its stability in aqueous solutions is reduced because it undergoes oxidation, forming captopril disulfide. In order to ensure a stable and accurate dosage form, a pre-formulation study was developed for obtaining a stable formulation of a powder for preparation of a captopril solution for pediatric use. The compatibility between drug and possible excipients were evaluated by differential scanning calorimetry (DSC) and the captopril thermic behavior, through thermogravimetric analysis (TG) and differential thermal analysis (DTA). Then, particle size and indirect flow measures of captopril and excipients were analyzed. For solution studies, different formulations were obtained through factorial design, varying the EDTA concentration (0.005 and 0.1%) and pH (2.5, 4.0 e 5.5) in distilled and mineral water, which were stored at 60?C and analyzed over twelve days by HPLC to evaluate the stability of captopril. In the DSC curves of captopril mixtures with preservatives, sucralose and citric acid, the isolated thermal events were not maintained. In the other binary mixtures, the events corresponding to each component were preserved in the curves, indicating compatibility between substances. There was a major difference in the distribution and average particles diameters and density of buffering agents in comparison to other substances, which can cause segregation of the powder mixture. From the study of the solutions stability it was found that the variables interfere significantly (p = 0.05) in the captopril content, the pH being the most important factor. The interactions between variables were significant, with greater stability around pH 4.0, higher EDTA concentrations and use of mineral water. Based on the results, it can be concluded that development of a stable captopril formulation is viable if strategic measures are adopted in order to avoid segregation of the powders constituents of the formulation.