Desenvolvimento e otimização de método analítico indicativo de estabilidade utilizando a abordagem Quality by Design (QBD) na determinação de succinato de solifenacina em medicamentos comercializados em território nacional
Data
2023-05-29
Autores
Cabral, Raphael Cyriaco 
Orientadores
Calixto, Leandro Augusto
Tipo
Dissertação de mestrado
Título da Revista
ISSN da Revista
Título de Volume
Resumo
Solifenacina é um antagonista competitivo dos receptores muscarínicos, sendo este indicado para o alívio dos sintomas de frequência urinária, incontinência urinária ou urgência associados com uma bexiga hiperativa. A estabilidade de produtos farmacêuticos depende de diversos fatores intrínsecos e extrínsecos e deve ser avaliada através de estudos de estabilidade. Para isso, são necessários métodos indicativos de estabilidade, uma abordagem de fundamental papel nas exigências regulatórias no que diz respeito à obtenção de registro ou alteração de pós-registro de medicamentos. Desta forma, o presente trabalho teve como objetivo o desenvolvimento, otimização e validação de um método analítico indicativo de estabilidade (MIE) para a quantificação de succinato de solifenacina e seus produtos de degradação e então aplicá-la em formulações farmacêuticas sólidas de uso oral. O método analítico foi desenvolvido em cromatógrafo líquido de alta performance com detector de arranjo de diodos (HPLC-DAD), utilizando-se a abordagem Quality by Design (QbD), baseada na análise de risco e com ênfase na compreensão do processo e variáveis envolvidas, mitigando assim, o risco de falhas e possibilitando o desenvolvimento de um método simples e rápido. O método analítico desenvolvido apresentou seletividade adequada sendo capaz de quantificar com exatidão o succinato de solifenacina e respectivos produtos de degradação, o que foi comprovado através das figuras de mérito da validação analítica. Foi realizado um estudo de degradação forçada, onde, foram levantadas evidências de que o método é indicativo de estabilidade e obteve-se o perfil de degradação potencial do insumo farmacêutico ativo (IFA). O IFA mostrou-se susceptível à degradação principalmente quando submetido à condição oxidativa, sendo identificado um produto de degradação majoritário proveniente da N-oxidação de amina terciária do anel quinicludina presente na molécula. Foi realizado um estudo para a otimização do preparo de amostra, onde, foi obtida a condição ótima para a recuperação do IFA e impureza N-óxido utilizando-se a proporção de água ultrapurificada e acetonitrila 7,7:92,3 (v/v) com 30 minutos de extração assistida por ultrassom. Foram analisadas diferentes formulações sólidas orais obtidas comercialmente contendo 10 mg de succinato de solifenacina, estas então foram submetidas às condições de estabilidade acelerada por 6 meses e então foi possível, fazer uma avaliação comparativa destes medicamentos. Observou-se que mesmo apresentando formulações qualitativamente semelhantes, estas apresentaram perfis de impurezas diferentes o que pode ser associado principalmente a qualidade dos excipientes utilizados nestas formulações, tendo impacto direto na qualidade, segurança e eficácia destas formulações.
Solifenacin is a competitive muscarinic receptor antagonist and is indicated for the relief of symptoms of urinary frequency, urinary incontinence or urgency associated with an overactive bladder. The stability of pharmaceutical products depends on several intrinsic and extrinsic factors and must be evaluated through stability studies. For this, stability-indicating methods (SIM) are needed, an approach that plays a fundamental role in regulatory requirements with regard to obtaining registration or post-registration alteration of drugs. In this way, the present work had as objective the development, optimization and validation of an analytical stability-indicating methods for the quantification of solifenacin succinate and its degradation products and then to apply it in solid pharmaceutical formulations for oral use. The analytical method was developed in a high performance liquid chromatography with a diode array detector (HPLC-DAD), using the Quality by Design (QbD) approach, based on risk analysis and with emphasis on understanding the process and variables involved, thus mitigating the risk of failures and enabling the development of a simple and fast method. The SIM showed adequate selectivity being able to accurately quantify the active solifenacin succinate and degradation products which was proven through the figures of merit of the analytical validation A forced degradation study was carried out, where evidence was raised that the method is indicative of stability and the potential degradation profile of the active pharmaceutical ingredient (API) was obtained. The API showed to be susceptible to degradation mainly when subjected to oxidative conditions, being identified a major degradation product from the N-oxidation of tertiary amine of the quinicludine ring present in the molecule. A study was carried out for the optimization of the sample preparation, where the optimal condition for the recovery of the API and N-oxide impurity was received using the proportion of ultrapure water and acetonitrile 7.7:92.3 (v/v) using 30 minutes of ultrasound-assisted extraction. Different oral solid formulations obtained commercially containing 10 mg of solifenacin succinate were analyzed, these were then subjected to conditions of accelerated stability for 6 months and then it was possible to make a comparative evaluation of these drugs. It was observed that even presenting qualitatively similar formulations, they presented different impurity profiles, which can be mainly associated with the quality of the excipients used in these formulations, having a direct impact on the quality, safety and efficacy of these formulations.
Solifenacin is a competitive muscarinic receptor antagonist and is indicated for the relief of symptoms of urinary frequency, urinary incontinence or urgency associated with an overactive bladder. The stability of pharmaceutical products depends on several intrinsic and extrinsic factors and must be evaluated through stability studies. For this, stability-indicating methods (SIM) are needed, an approach that plays a fundamental role in regulatory requirements with regard to obtaining registration or post-registration alteration of drugs. In this way, the present work had as objective the development, optimization and validation of an analytical stability-indicating methods for the quantification of solifenacin succinate and its degradation products and then to apply it in solid pharmaceutical formulations for oral use. The analytical method was developed in a high performance liquid chromatography with a diode array detector (HPLC-DAD), using the Quality by Design (QbD) approach, based on risk analysis and with emphasis on understanding the process and variables involved, thus mitigating the risk of failures and enabling the development of a simple and fast method. The SIM showed adequate selectivity being able to accurately quantify the active solifenacin succinate and degradation products which was proven through the figures of merit of the analytical validation A forced degradation study was carried out, where evidence was raised that the method is indicative of stability and the potential degradation profile of the active pharmaceutical ingredient (API) was obtained. The API showed to be susceptible to degradation mainly when subjected to oxidative conditions, being identified a major degradation product from the N-oxidation of tertiary amine of the quinicludine ring present in the molecule. A study was carried out for the optimization of the sample preparation, where the optimal condition for the recovery of the API and N-oxide impurity was received using the proportion of ultrapure water and acetonitrile 7.7:92.3 (v/v) using 30 minutes of ultrasound-assisted extraction. Different oral solid formulations obtained commercially containing 10 mg of solifenacin succinate were analyzed, these were then subjected to conditions of accelerated stability for 6 months and then it was possible to make a comparative evaluation of these drugs. It was observed that even presenting qualitatively similar formulations, they presented different impurity profiles, which can be mainly associated with the quality of the excipients used in these formulations, having a direct impact on the quality, safety and efficacy of these formulations.