Cyclodextrin- and solvent-modified micellar electrokinetic chromatography for the determination of captopril, hydrochlorothiazide and their impurities: A Quality by Design approach

A fast and selective capillary electrophoresis method has been developed for the simultaneous de-
termination of the antihypertensive drugs captopril and hydrochlorothiazide and their related impurities
in a combined dosage form. Method development was carried out implementing each step of Quality by
Design work
fl
ow, the new paradigm of quality outlined in International Conference on Harmonisation
Guidelines. Captopril is characterized by the lack of a strong chromophore and contains a proline-similar
moiety, which gives rise to the presence of interconverting cis-trans isomers and leads to the possible
interference between electrophoretic migration and reaction of isomerization. The scouting phase was
dedicated to the investigation of several operative modes in order to overcome detection and iso-
merization issues. The best performances were obtained with sodium cholate-based micellar electro-
kinetic chromatography with the addition of
n
-butanol and
γ
-cyclodextrin. Critical quality attributes
were represented by the critical resolution values and by analysis time. Critical process parameters were
de
fi
ned as temperature, voltage, concentration and pH of borate buffer, concentration of sodium cholate,
n
-butanol and
γ
-cyclodextrin. Screening experimental design was applied for investigating knowledge
space. Response surface methodology pointed out several signi
fi
cant interaction effects, and with Monte-
Carlo simulations led to map out the design space at a selected probability level. Robustness testing was
carried out and a control strategy based on system suitability tests was defined. The selected working
conditions gave a complete separation of the analytes in less than three minutes. The method was va-
lidated and applied to the analysis of a real sample of coformulation tablets