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Degradação Forçada de um Medicamento para a Diabetes
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Resumo(s)
Para aprovar um medicamento, é necessário realizar a validação de métodos analíticos. Inserem-se nesses ensaios, o estudo de degradação forçada da substância ativa e do produto acabado.
Estudos de degradação forçada visam determinar a estabilidade intrínseca da molécula, estabelecer vias degradativas, prever potenciais impurezas e demonstrar a especificidade do método analítico como indicador de estabilidade.
A substância ativa e os comprimidos revestidos de 25 mg, foram expostos a 500 W/m2 de luz, temperatura de 70 ºC, 85% de humidade relativa, hidrólise ácida (5N HCl), hidrólise básica (5M NaOH) e oxidação (10% e 30% H2O2). Os ensaios foram realizados por cromatografia líquida de alta e ultra eficiência (HPLC e UPLC), no âmbito do método de doseamento, compostos relacionados e pureza enantiomérica.
Para a substância ativa, as vias degradativas predominantes são a hidrólise ácida com 5N HCl a 70 ºC (14 dias), hidrólise básica com 5M NaOH a 70 ºC (14 dias) e oxidação com 10% H2O2 a 70 ºC (1 dia). Por hidrólise ácida, as impurezas predominantes formadas foram a Impureza C com um teor de 0.05% e a impureza desconhecida com tempo de retenção relativo (RRT) de 0.36 com 1.5%. As impurezas com maior crescimento na condição de hidrólise básica foram a Impureza C com 0.08% e a impureza desconhecida com RRT de 1.13 com 1.0%. Por fim, a exposição à oxidação formou a Impureza A com um teor de 0.07% e a impureza desconhecida com RRT de 0.51 e um teor de 0.15%.
A via degradativa predominante para o produto acabado foi a oxidação com 30% H2O2 durante 7 dias. A exposição resultou no crescimento das impurezas A e B para 0.14% e 0.13%, respetivamente. Assim como o crescimento de duas impurezas desconhecidas com RRT de 0.66 e 0.70, ambas com um teor de 0.06%.
O perfil degradativo para a substância ativa e produto acabado foi semelhante, não tendo sido obtida uma degradação superior a 5%, o que comprova a estabilidade do composto X às condições de degradação propostas. Foi também demonstrada a adequabilidade dos métodos analíticos como indicadores de estabilidade.
The approval of a pharmaceutical drug includes the validation of analytical methods. The forced degradation study of the active ingredient and the finished product is included in the validation procedures. The purpose of forced degradation is to determine the intrinsic stability of the molecule, establish degradation pathways, predict potential impurities, and demonstrate the specificity of the analytical method as stability indicator. The drug substance and the 25 mg film coated tablets, were exposed to 500 W/m2 of light, 70 ºC temperature, 85% of relative humidity, acid hydrolysis (5N HCl), basic hydrolysis (5M NaOH), and oxidation (10% and 30% H2O2). The tests were carried out in high and ultra-performance liquid chromatography (HPLC and UPLC), according to the assay method, related substances, and enantiomeric purity. The results demonstrate that the predominant degradative routes for the active substance are acid hydrolysis with 5N HCl at 70°C (14 days), basic hydrolysis with 5M NaOH at 70°C (14 days) and oxidation with 10% H2O2 at 70°C (1 day). For acid hydrolysis, the predominant impurities formed were Impurity C with a content of 0.05%, and an unknow impurity with a relative retention time (RRT) of 0.36 with 1.5% content. The impurities with a predominant growth in alkaline conditions were Impurity C with 0.08%, and an unknown impurity with a RRT of 1.13 and 1% content. The exposure to oxidation formed Impurity A with a content of 0.07% and an unknown impurity with RRT of 0.51 having a 0.15% content. The predominant degradation pathway for the finished product was oxidation with 30% H2O2 for 7 days. The exposure resulted in an increase of Impurity A and B to 0.14% and 0.13%, respectively. As well as the increase of two unknown impurities with a RRT of 0.66 and 0.70, both with 0.06% content. The degradation profile for the drug substance and dug product was similar, as the decrease in assay was not greater that 5%, which demonstrates the stability of the active ingredient X when exposed to the selected degradation conditions. It was also demonstrated the suitability of the analytical methods as stability indicating.
The approval of a pharmaceutical drug includes the validation of analytical methods. The forced degradation study of the active ingredient and the finished product is included in the validation procedures. The purpose of forced degradation is to determine the intrinsic stability of the molecule, establish degradation pathways, predict potential impurities, and demonstrate the specificity of the analytical method as stability indicator. The drug substance and the 25 mg film coated tablets, were exposed to 500 W/m2 of light, 70 ºC temperature, 85% of relative humidity, acid hydrolysis (5N HCl), basic hydrolysis (5M NaOH), and oxidation (10% and 30% H2O2). The tests were carried out in high and ultra-performance liquid chromatography (HPLC and UPLC), according to the assay method, related substances, and enantiomeric purity. The results demonstrate that the predominant degradative routes for the active substance are acid hydrolysis with 5N HCl at 70°C (14 days), basic hydrolysis with 5M NaOH at 70°C (14 days) and oxidation with 10% H2O2 at 70°C (1 day). For acid hydrolysis, the predominant impurities formed were Impurity C with a content of 0.05%, and an unknow impurity with a relative retention time (RRT) of 0.36 with 1.5% content. The impurities with a predominant growth in alkaline conditions were Impurity C with 0.08%, and an unknown impurity with a RRT of 1.13 and 1% content. The exposure to oxidation formed Impurity A with a content of 0.07% and an unknown impurity with RRT of 0.51 having a 0.15% content. The predominant degradation pathway for the finished product was oxidation with 30% H2O2 for 7 days. The exposure resulted in an increase of Impurity A and B to 0.14% and 0.13%, respectively. As well as the increase of two unknown impurities with a RRT of 0.66 and 0.70, both with 0.06% content. The degradation profile for the drug substance and dug product was similar, as the decrease in assay was not greater that 5%, which demonstrates the stability of the active ingredient X when exposed to the selected degradation conditions. It was also demonstrated the suitability of the analytical methods as stability indicating.
Descrição
Palavras-chave
Cromatografia Líquida de Alta Eficiência (HPLC) Degradação Forçada Doseamento Compostos Relacionados Pureza Enantiomérica