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Abstract(s)
Neste trabalho foi realizado um estudo de micronização com anti-solvente supercrítico do ácido fusídico, um antibiótico utilizado em formulações tópicas e oftálmicas. A micronização do ácido fusídico tem como objetivo o aumento da sua biodisponibilidade, bem como a alteração do seu tamanho de partícula de forma a ser utilizado nas diferentes formulações.
O processo foi realizado num aparelho de micronização supercrítica, onde o fluido supercrítico, CO2, é utilizado como anti-solvente e a acetona é utilizada como solvente. Neste processo foi estudado os efeitos das diferentes condições no tamanho médio de partícula utilizando o desenho experimental.
Numa primeira fase foi utilizado o Fractional Factorial Design com quatro fatores de estudo, a temperatura com valores entre 40 ºC e 60 ºC, a pressão entre 100 bar e 200 bar, a concentração entre 10 mg/mL e 40 mg/mL e o caudal de injeção de solvente entre 0,5 mL/min e 3 mL/min, e um fator de resposta, o tamanho médio de partícula. A análise estatística do FFD mostrou que a temperatura e o caudal são os fatores significativos deste processo.
Com os resultados do estudo estatístico é possível realizar a otimização do sistema utilizando o Central Composite Design onde a pressão foi estabelecida a 100bar e a concentração da solução foi mantida a 40 mg/mL, e fez-se variar a temperatura e o caudal de injeção entre 40 e 60 ºC e de 0,5 a 3 mL/min, respetivamente. Numa segunda, e última, fase a otimização do processo é efetuada de forma a obter a previsão das condições experimentais para minimizar o tamanho médio de partícula. A previsão obtida pela otimização estimou que o menor tamanho médio de partícula seria de 0,223 μm às condições de trabalho de 40 ºC, 100 bar, 40 mg/mL e 0,5 mL/min. Através desta otimização foi possível, também, obter a previsão das condições de trabalho para tamanhos médios de partícula entre 1 e 3 μm, valores necessários para produzir formulações oftálmicas, onde estas variam entre 40 e 45,08 ºC e de 0,560 a 2,552 mL/min, mantendo a pressão a 100 bar e a concentração a 40 mg/mL.
A micronization study with supercritical anti-solvent of fusidic acid, which is an antibiotic used in topical and ophthalmic formulations, was carried out in this work. The fusidic acid micronization aims at increasing its bioavailability, as well as the change of the particle size in order to be used in the various formulations. The process was carried out in a supercritical antisolvent micronization (SAS) apparatus where supercritical fluid, CO2, is used as antisolvent and acetone is used as the solvent. In this process the effect of different conditions on the mean particle size was studied, using the design of experiments. Initially a Fractional Factorial Design was used with four study factors, the temperature, with values between 40 °C and 60 °C, the pressure, varied between 100 bar and 200 bar, concentration ranging between 10 mg/ml and 40 mg/ml and the solvent injection flow rate with values between 0.5 mL/min and 3 mL/min, being the mean particle size the response factor. The statistical analysis of FFD showed that temperature and flow were the significant factors of this process. With the results of the statistical study and using the Central Composite Design it was possible to perform the optimisation of the system where the pressure was established at 100 bar and the concentration of the solution was maintained at 40 mg/mL and the temperature and the injection flow rate were varied between 40 to 60 °C and 0.5 to 3 mL/min, respectively. In a second and final stage a process optimisation was performed to obtain the prediction of the experimental conditions in order to minimize the mean particle size. The prediction obtained by the optimisation estimated that the smallest mean particle size would be 0.223 μm at the working conditions of 40ºC, 100 bar, 40 mg/mL and 0.5 mL/min. Through this optimisation was also possible to obtain the expected working conditions to obtain a mean particle size between 1 and 3 μm, values that are required to produce ophthalmic formulations, which were temperature ranging from 40 to 45.08 ºC and concentration from 0.560 to 2.552 mL/min, maintaining the pressure at 100 bar and the concentration at 40 mg/mL.
A micronization study with supercritical anti-solvent of fusidic acid, which is an antibiotic used in topical and ophthalmic formulations, was carried out in this work. The fusidic acid micronization aims at increasing its bioavailability, as well as the change of the particle size in order to be used in the various formulations. The process was carried out in a supercritical antisolvent micronization (SAS) apparatus where supercritical fluid, CO2, is used as antisolvent and acetone is used as the solvent. In this process the effect of different conditions on the mean particle size was studied, using the design of experiments. Initially a Fractional Factorial Design was used with four study factors, the temperature, with values between 40 °C and 60 °C, the pressure, varied between 100 bar and 200 bar, concentration ranging between 10 mg/ml and 40 mg/ml and the solvent injection flow rate with values between 0.5 mL/min and 3 mL/min, being the mean particle size the response factor. The statistical analysis of FFD showed that temperature and flow were the significant factors of this process. With the results of the statistical study and using the Central Composite Design it was possible to perform the optimisation of the system where the pressure was established at 100 bar and the concentration of the solution was maintained at 40 mg/mL and the temperature and the injection flow rate were varied between 40 to 60 °C and 0.5 to 3 mL/min, respectively. In a second and final stage a process optimisation was performed to obtain the prediction of the experimental conditions in order to minimize the mean particle size. The prediction obtained by the optimisation estimated that the smallest mean particle size would be 0.223 μm at the working conditions of 40ºC, 100 bar, 40 mg/mL and 0.5 mL/min. Through this optimisation was also possible to obtain the expected working conditions to obtain a mean particle size between 1 and 3 μm, values that are required to produce ophthalmic formulations, which were temperature ranging from 40 to 45.08 ºC and concentration from 0.560 to 2.552 mL/min, maintaining the pressure at 100 bar and the concentration at 40 mg/mL.
Description
Trabalho final de mestrado para obtenção do grau de Mestre em Engenharia Química e Biológica
Keywords
Ácido fusídico Fusidic acid Micronização Micronization Fluidos supercríticos Supercritical fluids Anti-solvente Anti-solvent Dióxido de carbono Carbon dioxide Desenho experimental Design of experiments
Citation
MATOS, Patrícia Alexandra Aniceto - Micronização de ácido fusídico. Lisboa: Instituto Superior de Engenharia de Lisboa, 2019. Dissertação de mestrado.
Publisher
Instituto Superior de Engenharia de Lisboa