Robust Optimization of Chaotropic Chromatography Assay for Lamotrigine and its Two Impurities in Tablets

Abstract

In this study robust optimization was applied for the development of a reliable analytical assay for lamotrigine, its impurity A, and impurity G in tablets by chaotropic chromatography. The influence of the critical method parameters (acetonitrile content, concentration of chaotropic agent, and pH of the water phase) on the set of selected critical method attributes (retention factor of impurity A, separation factor between lamotrigine and impurity G, and retention factor of impurity G) is studied by Box-Behnken design. Monte Carlo simulations were applied to propagate the errors originating from the model coefficients' calculation to the selected responses and obtain their predictive distribution. Design space was defined (95%) and a working point selected: 23% of acetonitrile in the mobile phase, 77% of water phase containing 140mM of perchloric acid, and pH of the water phase adjusted to 2.50. Further robustness testing was performed by Plackett-Burman design to evaluate the quantitative performance of the developed method. The obtained models included not only active main effects but also interactions that were identified as active with the aid of an alias matrix approach and examination of resulting alias plots. The method was validated and its reliability for routine pharmaceutical analysis confirmed. [GRAPHICS] .