Quality by Design and Mixture-Process Variable approach in the development of a cyclodextrin-MEEKC method for the assay of diclofenac and its impurities

The Quality by Design (QbD) concept is increasingly applied in pharmaceutical industries in order to improve the quality of products, as recently recommended by International Conference on Harmonization (ICH) guideline Q8(R2). The advantageous application of QbD in pharmaceutical analysis has been recently described by defining a systematic approach for the set up of analytical separation methods. The aim of this study was the development of a CE method for the analysis of diclofenac and its five impurities in pharmaceutical dosage forms, by applying QbD approach. In the scouting phase, several pseudostationary phases were tested and the selected operative mode was MEEKC with the addition of methyl-β-cyclodextrin. The critical quality attributes were defined as the critical resolution value between diclofenac and impurity ID and analysis time. When dealing with the optimization of MEEKC methods, the performance of the electrophoretic run depends both on the proportions of mixture components (MCs) of the microemulsion and on the value of process variables (PVs), and the number of potential critical process parameters (CPPs) is quite extensive. The CPPs were selected by an Ishikawa diagram and included PVs (voltage, buffer concentration, buffer pH, cyclodextrin concentration) and MCs (borate buffer, n-heptane, sodium dodecyl sulphate/n-butanol). A mixture-process variable (MPV) approach, which involved the simultaneous variation of MCs and PVs, was applied both in the screening phase and in response surface study. The contour plots allowed significant interaction effects between MCs and PVs to be found. The design space was defined by the combinations of MC proportions and PV settings which provided assurance of quality of the analytical data produced by the method, and was calculated by risk of failure maps based on Monte-Carlo simulations. Applying the working conditions, the complete separation of the analytes was obtained in less than 10 min. After the definition of a control strategy based on robustness and system suitability criteria, the CD-MEEKC method was validated and applied to a real sample of diclofenac tablets. The applied strategy, which integrated QbD and MPV approaches, demonstrated to be a really valuable tool for the set up of complex separation systems based on microemulsions.