Qualidade por Design Analítico (AQbD) aplicado ao desenvolvimento de métodos por cromatografia gasosa na matéria-prima de Cloridrato de Duloxetina

Abstract

This work aimed to apply Quality by Analytical Design (AQbD) in the development and validation of an analytical method of residual solvents by gas chromatography with Headspace transferline injection of the raw material of Duloxetine Hydrochloride. Multivariate optimization of the analytical method was performed to control residual solvents methanol, acetone, 2-propanol, dichloromethane, tert-butanol, Ethyl acetate, Chloroform, Triethylamine, Dimethylsulfoxide, Cyclohexane and Toluene with the application of experimental designs aimed at meeting the objectives, characteristics and quality criteria. The execution was carried out in stages that can be summarized as screening, optimization, data evaluation, validation and strategic control. In screening, the Plackett-Burman experimental design was applied in order to define the best conditions for the use of Headspace transferline, allowing signal maximization and recovery close to 100% of the analytes. However, there was a division of the analytes to be controlled, and thus opted to present validation of residual solvents Methanol, Acetone, 2-Propanol, Dichloromethane and Tert-butanol. In the optimization stage, the identification of the Performance Characteristics of the Analytical Method (AMPC), Critical Quality Attributes (CQA) and Risk Analysis (QRM) were carried out and finalized with the application of the central composite design (CCD) for the definition of the method operable design region (MODR). The results were evaluated, in which the data were processed and evaluated, allowing the necessary adjustments to be made to the method. The analytical validation step was performed according to RDC 166/2017, obtaining a precise, linear, selective, robust method and limit of quantification. The MODR was defined after varying the kiln initial temperature and carrier gas flow factors, obtaining design regions ranging from 29.3 to 31.1 oC and 0.9 to 1.03 mL.min-1, respectively. Finally, the results are maximized analytical response and recovery close to 100%, ensuring operationality and regulatory flexibility allowing immediate adjustments to the analytical method. The determination of the sensitivity/Limit of analytical quantification at the 40% level for the analytes Methanol, Acetone, Tert-butanol, 2-propanol and Dichloromethane at a content of 1197.50, 1995.58, 398.16, 1997.84 and 239 .26 μg.g-1, respectively. The application of AQbD enabled the paradigm shift through a multivariable approach with the use of quality tools, which demonstrate important points in the development and validation of an analytical method to identify and mitigate weak points.