Quality by Design Assisted Optimization of a Chiral Capillary Electrokinetic Chromatographic Method for the Separation of Amlodipine Enantiomers Using Maltodextrin as Chiral Selector

Abstract

Analytical-method development based on design of experiment has been applied for optimizing the enantioseparation of amlodipine by chiral capillary electrokinetic chromatography using maltodextrin as the chiral selector. The effect of different factors on the enantioresolution quality was screened. Three separation factors, namely maltodextrin concentration, pH of the background electrolyte and applied voltage were selected as independent variables. The number of experiments was reduced while maximizing the information content using design of experiment. Based on a full-quadratic design that included three variables on three levels, the total design space could be reduced to fifteen factor combinations using a D-optimal algorithm. The aim of the experiment was to find the optimal factor combinations with respect to resolution. The maltodextrin concentration (7.5-10% w/v) demonstrated the strongest effect on the resolution followed by pH (2-4) of the background electrolyte and the applied voltage (15-20 kV). An increase in the maltodextrin concentration was found to result in a greater stereoselectivity, represented by the higher resolution values (R_s ≥ 1.5). The separation conditions in the proposed method were feasible to be adjusted within the applied range with an acceptable resolution.

Keywords: D-optimal design; amlodipine; capillary electrophoresis; chiral capillary electrokinetic chromatography; design of experiment; enantioseparation; maltodextrin; quality by design.

Figure 1

Representative enantioseparation of AML at the shortest and longest analysis time.

Figure 2

The adjusted response graph of resolution (A) and Pareto chart of the effects of variables on resolution (B). MD: maltodextrin concentration (% w/v); U: voltage (kV).

Figure 3

Interaction graph for resolution at low, middle, and high levels. MD: maltodextrin concentration (% w/v); U: voltage (kV).

Figure 4

Contour plot of the predicted R_s at the respective combinations.

Figure 5

Enantioseparation profiles of amlodipine at the experimental condition MD 10% w/v (high), pH 2.0 (low), and voltage 15 kV (330 V/cm) for a 45.5 cm capillary (low). Peak identification shows that the migration order of amlodipine is the (S)-enantiomer followed by the (R)-enantiomer.

Figure 6

Enantioseparation profile of amlodipine in tablet matrices at the experimental condition MD 10% w/v (high), pH 2.0 (low), and voltage 15 kV (330 V/cm) for a 45.5 cm capillary (low).