Design of Experiments-Design Space Approach for Development of Chaotropic Chromatography Method for Determination of Trimetazidine Dihydrochloride and Two Impurities

摘要

The quality by design approach has been applied to develop a chaotropic chromatography method for determination of trimetazidine dihydrochloride (TMZ) and two impurities (Y-145, Y-234). Baseline separation and accurate determination of the investigated analytes was set as the target analytical profile, with k (Y-145), k (TMZ), and alpha (Y-145/TMZ) selected as critical quality attributes. The critical process parameters studied in this research were pH of water phase, acetonitrile content in mobile phase, and concentration of perchloric acid in water phase. To compute a design space as a region of the knowledge space having satisfactory values of all critical quality attributes at the desired quality level, Monte Carlo simulations were performed to propagate the error originating from the calculated model coefficients to the predicted responses. At each of 4851 defined grid points, 5000 iterations were performed and the region having probability pi ae 95% of achieving all defined critical quality attributes was computed. A working point situated in the center of the design space was chosen, corresponding to 27% acetonitrile in mobile phase, 63% 170 mM perchloric acid in water phase, and pH of water phase adjusted to 3.60. The method was validated to confirm its reliability for use in routine pharmaceutical analysis.