Analytical quality by design in the development of a cyclodextrin‐modified capillary electrophoresis method for the assay of metformin and its related substances

Abstract

Quality by Design (QbD) is a new paradigm of quality to be applied to pharmaceutical products and processes, recently encouraged by International Conference on Harmonisation guidelines. In this paper QbD approach was applied to the development of a CE method for the simultaneous assay of metformin hydrochloride (MET) and its main impurities. QbD strategy was focused on electrophoretic process understanding, and the analytical method was thoroughly evaluated by applying risk assessment and chemometric tools. Method scouting allowed CD-CZE based on the addition of carboxymethyl-β-CD to Britton-Robinson acidic buffer to be chosen as operative mode. Seven critical process parameters (CPPs) were selected, related to capillary, injection, BGE and instrumental settings. The effect of the different levels of the CPPs on critical quality attributes (CQAs), e.g. critical resolution values and analysis time, was evaluated in a screening study. Response surface methodology led to draw contour plots and sweet spot plots. The definition of design space was accomplished by applying Monte-Carlo simulations, thus identifying by risk of failure maps a multivariate zone where the CQAs fulfilled the requirements with a selected probability. Finally, a control strategy was designed and the method was applied to a real sample of MET tablets.

Recent advances in capillary electrophoretic migration techniques for pharmaceutical analysis (2013–2015)

“…Most publications are in the form of lectures and posters at industrial scientific meeting series like “CE in the Pharmaceutical and Biotech Industry” and “Analytical Technologies Europe” . The research papers that appeared since the previous review are all by the same group . These papers give excellent explanations on the DoE procedures used.…”

“…LODs were in the low microgram per milliliter to sub microgram per milliliter or 0.1% range allowing the sensitive detection of the respective impurities. Furthermore, AQbD approaches have been applied in order to develop robust and precise methods for drug purity control . The topic has also been reviewed .…”

“…Recent publications on the analysis of related substances in pharmaceutical drugs have been compiled in Table 1 [39,40,42,43,45,[62][63][64][65][66][67][68][69][70][71][72]. Most separations were carried out in the CZE mode, while four methods applied MEKC [42,65,69,70] and one MEEKC conditions [40].…”

Analytical Quality by Design in pharmaceutical quality assurance: Development of a capillary electrophoresis method for the analysis of zolmitriptan and its impurities

“…Amiloride hydrochloride (AMI), boric acid, 86.1% phosphoric acid, acetic acid, triethanolamine, methanol, n-butanol, n-heptane, SDS, all the CDs tested with the corresponding degree of substitution in parentheses, i.e. ␣-CD, ␤-CD, ␥ -CD, (2-hydroxypropyl)-␣-CD (0.6), (2-hydroxypropyl)-␤-CD (0.6), (2-hydroxypropyl)-␥ -CD (0.6), methyl-␤-CD (1.5-2.1), heptakis(2,3,6-tri-O-methyl)-␤-CD, sulfated-␤-CD sodium salt (12)(13)(14)(15), carboxymethyl-␤-CD sodium salt (ß3), and all the other chemicals used were from Sigma-Aldrich.…”

“…Nevertheless, up to now there is a negligible experience within the analytical QbD approach, and more discussions on QbD implementation are needed. The majority of methods which employ a QbD development regard chromatographic techniques , while a few papers have been dedicated to QbD development of CE methods .…”