A capillary electrophoresis method for the simultaneous determination of the enantiomeric purity and of impurities of the chiral calcimimetic drug cinacalcet hydrochloride has been developed following Quality by Design principles. The scouting phase was aimed to select the separation operative mode and to identify a suitable chiral selector. Among the tested cyclodextrins, (2-carboxyethyl)-β-cyclodextrin and (2-hydroxypropyl)-γ-cyclodextrin (HPγCyD) showed good chiral resolving capabilities. The selected separation system was solvent-modified capillary zone electrophoresis with the addition of HPγCyD and methanol. Voltage, buffer pH, methanol concentration and HPγCyD concentration were investigated as critical method parameters by a multivariate strategy. Critical method attributes were represented by enantioresolution and analysis time. A Box-Behnken Design allowed the contour plots to be drawn and quadratic and interaction effects to be highlighted. The Method Operable Design Region (MODR) was identified by applying Monte-Carlo simulations and corresponded to the multidimensional zone where both the critical method attributes fulfilled the requirements with a desired probability π≥90%. The working conditions, with the MODR limits, corresponded to the following: capillary length, 48.5cm; temperature, 18°C; voltage, 26kV (26-27kV); background electrolyte, 150mM phosphate buffer pH 2.70 (2.60-2.80), 3.1mM (3.0-3.5mM) HPγCyD; 2.00% (0.00-8.40%) v/v methanol. Robustness testing was carried out by a Plackett-Burman matrix and finally a method control strategy was defined. The complete separation of the analytes was obtained in about 10min. The method was validated following the International Council for Harmonisation guidelines and was applied for the analysis of a real sample of cinacalcet hydrochloride tablets.

Department of Analytical Chemistry Faculty of Chemistry University of Seville 41012 Seville Spain

Department of Chemical Sciences University of Catania Viale A Doria 6 95125 Catania Italy

Department of Chemistry U Schiff University of Florence Via U Schiff 6 Via della Lastruccia 3 13 50019 Sesto Fiorentino Florence Italy

Department of Pharmacy and Biotechnology University of Bologna Via Belmeloro 6 40126 Bologna Italy

Zentiva K S Praha a Sanofi Company U Kabelovny 130 102 37 Praha 10 Czech Republic

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