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Aplicação da abordagem Quality-by-Design no desenvolvimento de um método analítico preditivo de estabilidade de uma formulação semi-sólida
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O desenvolvimento de um método analítico preditivo de estabilidade é um processo trabalhoso e demorado. Deste modo, para melhorar estas limitações recorreu-se à abordagem de Quality-by-Design (QbD). Esta metodologia equaciona diferentes parâmetros numa mesma análise, permitindo o estudo das suas interações, e consequentemente a sua influência nas respostas. Assim, o desenvolvimento de métodos analíticos é realizado de forma mais célere. De modo atingir o objetivo de desenvolver e otimizar o método cromatográfico para quantificação de maleato de fluvoxamina (doravante designado por fluvoxamina) numa formulação semi-sólida, implementou-se um planeamento experimental, o Full Factorial Design (FFD) com 12 experiências e três níveis por fator. Este permitiu estimar a influência dos fatores críticos do método (proporção de acetonitrilo (ACN) na fase móvel e volume de injeção (μL) na variação das respostas.
A estabilidade intrínseca da fluvoxamina foi analisada através de ensaios de degradação forçada. As condições hidrolíticas resultam da exposição ao meio ácido e básico, que promoveram a formação de dois produtos de degradação cada. A condição térmica, por exposição a 55ºC, e a fotolítica, por exposição à luz UV, também originaram a formação de dois produtos de degradação cada. A condição oxidativa não promoveu a formação de nenhum produto de degradação.
O método de doseamento da fluvoxamina foi validado, de acordo com as normas em vigor. Os parâmetros estudados incluem seletividade, a gama de trabalho, a linearidade, a precisão (repetibilidade e reprodutibilidade), a exatidão e a robustez. Todos os parâmetros obtidos apresentam valores, que estão de acordo com os critérios de aceitação específicos.
O método de impurezas foi desenvolvido, contudo apenas as impurezas conhecidas A, B, C, F e G foram analisadas. No entanto, esta análise demonstrou que este método apresentava seletividade entre os picos das impurezas e os picos correspondentes aos conservantes e à substância ativa.
O DoE e análise multivariada no desenvolvimento de métodos são vantajosos, uma vez que permitem uma diminuição do tempo e dos meios despendidos comparativamente à abordagem univariada.
The development of a predictive analytical method of stability is a labored and time-consuming process. Thus, to improve these limitations, the Quality-by-Design (QbD) approach was used. This methodology equates different parameters in the same analysis, allowing the study of their interactions, and consequently their influence on responses. Thus, the development of analytical methods is carried out more quickly. In order to achieve the point of developing and optimizing chromatographic method for the quantification of fluvoxamine maleate (hereinafter referred to as fluvoxamine) in a semi-solid formulation, an experimental design Full Factorial Design (FFD) per factor was implemented with (12) twelve experiments and three levels. This allowed estimating the influence of the critical factors of the method (proportion of acetonitrile (ACN) in the mobile phase and injection volume (μL) on the variation of responses. The intrinsic stability of fluvoxamine was analyzed by forced degradation tests. Hydrolytic conditions result from exposure to acid and basic medium, which promoted the formation of two degradation products each. The thermal condition, by exposure to 55ºC, and the photolytic, by exposure to UV light, also resulted in the formation of two degradation products each. The oxidative condition did not promote the formation of any degradation product. The fluvoxamine dosing method was validated according to the current standards. The parameters studied include selectivity, working range, linearity, accuracy (repeatability and reproducibility), accuracy and robustness. All parameters obtained present standard values. The impurities method was developed, however only known impurities A, B, C, F and G were analyzed. However, this analysis demonstrated that this method presented selectivity between the peaks of impurities and the peaks corresponding to preservatives and the active substance. DoE and multivariate analysis in the development of methods are advantageous, since it allows a reduction in the time and means spent compared to the univariate approach.
The development of a predictive analytical method of stability is a labored and time-consuming process. Thus, to improve these limitations, the Quality-by-Design (QbD) approach was used. This methodology equates different parameters in the same analysis, allowing the study of their interactions, and consequently their influence on responses. Thus, the development of analytical methods is carried out more quickly. In order to achieve the point of developing and optimizing chromatographic method for the quantification of fluvoxamine maleate (hereinafter referred to as fluvoxamine) in a semi-solid formulation, an experimental design Full Factorial Design (FFD) per factor was implemented with (12) twelve experiments and three levels. This allowed estimating the influence of the critical factors of the method (proportion of acetonitrile (ACN) in the mobile phase and injection volume (μL) on the variation of responses. The intrinsic stability of fluvoxamine was analyzed by forced degradation tests. Hydrolytic conditions result from exposure to acid and basic medium, which promoted the formation of two degradation products each. The thermal condition, by exposure to 55ºC, and the photolytic, by exposure to UV light, also resulted in the formation of two degradation products each. The oxidative condition did not promote the formation of any degradation product. The fluvoxamine dosing method was validated according to the current standards. The parameters studied include selectivity, working range, linearity, accuracy (repeatability and reproducibility), accuracy and robustness. All parameters obtained present standard values. The impurities method was developed, however only known impurities A, B, C, F and G were analyzed. However, this analysis demonstrated that this method presented selectivity between the peaks of impurities and the peaks corresponding to preservatives and the active substance. DoE and multivariate analysis in the development of methods are advantageous, since it allows a reduction in the time and means spent compared to the univariate approach.
Descrição
Tese de mestrado, Engenharia Farmacêutica, 2020, Universidade de Lisboa, Faculdade de Farmácia
Palavras-chave
Métodos analíticos Experimental design Ensaios de degradação Fluvoxamina Validação de métodos analíticos Teses de mestrado - 2020