Quality by Design meets combination drugs: simultaneous determination of captopril, hydrochlorothiazide and their impurities by capillary electrophoresis

A fast and selective capillary electrophoresis method was set up for the simultaneous quantitation of captopril, hydrochlorothiazide and related impurities in the combined dosage form. The method was developed following Quality by Design principles, according to ICH guideline Q8. Captopril is characterized by the lack of a strong chromophore and by the presence of a proline-similar moiety which causes in solution the presence of cis-trans isomers that interconvert around the amide bond. A large part of the experiments of the scouting phase was dedicated to the selection among different pseudostationary phases based on micelles or microemulsions, with or without additives, in order to overcome detection and isomerization issues. The best results among the evaluated operative modes were obtained by cholate-based micellar electrokinetic chromatography with the addition of n-butanol and γ-cyclodextrin. Risk assessment tools were employed to define critical process parameters: temperature and voltage, concentration and pH of borate buffer, concentration of sodium cholate, n-butanol and γ-cyclodextrin. A symmetric screening matrix was applied to investigate the effect of the change of level of the selected factors on critical quality attributes, represented by critical resolution values and analysis time. Response surface methodology and Monte-Carlo simulation led to identify the design space, defined as the multidimensional region where any combination of the variables has been demonstrated to provide assurance of quality of the analytical performances. The application of the selected working point settings allowed the baseline separation of analytes to be obtained in less than 3 minutes. The method was validated and finally applied to a real sample of tablets.