Quality by Design for capillary electrophoresis method development: analysis of metformin and its impurities

Quality by Design (QbD) principles, recently outlined in ICH Q8 guidance for pharmaceutical development, have been increasingly embraced by drug analysis researchers. A QbD method development strategy leads to a deep comprehension of the analytical procedure, and finally to the definition of Design Space (DS), a multidimensional zone where any combination of the variables has been demonstrated to provide assurance of quality of the analytical data. Up to now, only a few examples have been provided concerning capillary electrophoresis (CE). In this study, a comprehensive QbD strategy was applied for developing a CE method for the simultaneous determination of metformin hydrochloride, a biguanide antidiabetic, and its main impurities. Method scouting was aimed to find an operative mode which could assure both a good selectivity and the separation of an impurity of very low basicity from the electroosmotic flow, and led to select capillary zone electrophoresis with the addition of carboxymethyl-β-cyclodextrin. The critical quality attributes (CQAs) were represented by critical resolution values and analysis time. The effects of selected critical process parameters were investigated by a screening asymmetric matrix spanning the knowledge space, and in a subsequent step by response surface methodology. The DS was computed by means of risk of failure maps describing the probability of meeting the specifications imposed on the CQAs. A control strategy was finally designed on the basis of system suitability tests.