Quality by Design-Based Development of a Chiral Capillary Electrophoresis Method for the Determination of Dextrodropropizine and 1-Phenylpiperazine as Impurities of Levodropropizine

Abstract

Based on a quality by design approach, a capillary electrophoresis method for the simultaneous determination of dextrodropropizine and the achiral precursor 1-phenylpiperazine in levodropropizine was developed. The analytical target profile was defined as a method allowing the simultaneous determination below the 0.5% level within a maximum analysis time of 20 min with an acceptable precision and accuracy. Based on scouting experiments, sulfated β-cyclodextrin in a 25 mM potassium phosphate buffer, pH 7.0, was selected. Subsequently, cyclodextrin concentration, propan-2-ol concentration, capillary temperature and applied voltage were identified as critical process parameters using a full factorial design followed by a central composite face-centered design for the final optimization of cyclodextrin concentration and temperature. The design space was obtained by Monte Carlo simulations. The final method comprised a 40/50.2 cm effective/total length, 75 µm inner diameter fused-silica-capillary, 25 mM potassium phosphate buffer, pH 7.0, containing 23.5 mg mL−1 sulfated β-cyclodextrin and 10% (v/v) propan-2-ol as background electrolyte, 16.3 °C capillary temperature and an applied voltage of 16.5 kV. The robustness was assessed using a Plackett–Burman design followed by method validation. Finally, the method was applied to the analysis levodropropizine reference substance of the European Pharmacopoeia and a liquid dosage form.