title: Cyclodextrin- and solvent-modified micellar electrokinetic chromatography for the determination of captopril, hydrochlorothiazide and their impurities: A Quality by Design approach.
abstract: A fast and selective capillary electrophoresis method has been developed for the simultaneous determination 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 workflow, 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 isomerization issues. The best performances were obtained with sodium cholate-based micellar electrokinetic 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 defined 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 significant 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 validated and applied to the analysis of a real sample of coformulation tablets.
authors: Department of Chemistry "U. Schiff", University of Florence, Via U. Schiff 6, Sesto Fiorentino, Florence, 50019 Italy. Electronic address: benedetta.pasquini@unifi.it.
authors: Benedetta
authors: B
authors: Pasquini
authors: Department of Chemistry "U. Schiff", University of Florence, Via U. Schiff 6, Sesto Fiorentino, Florence, 50019 Italy. Electronic address: serena.orlandini@unifi.it.
authors: Serena
authors: S
authors: Orlandini
authors: Department of Chemistry "U. Schiff", University of Florence, Via U. Schiff 6, Sesto Fiorentino, Florence, 50019 Italy. Electronic address: claudia.caprini@unifi.it.
authors: Claudia
authors: C
authors: Caprini
authors: Department of Chemistry "U. Schiff", University of Florence, Via della Lastruccia 3-13, Sesto Fiorentino, Florence, 50019 Italy. Electronic address: massimo.delbubba@unifi.it.
authors: Massimo
authors: M
authors: Del Bubba
authors: Department of Chemistry "U. Schiff", University of Florence, Via della Lastruccia 3-13, Sesto Fiorentino, Florence, 50019 Italy. Electronic address: m.innocenti@unifi.it.
authors: Massimo
authors: M
authors: Innocenti
authors: Department of Drug Sciences, University of Pavia, Viale Taramelli 12, Pavia, 27100 Italy. Electronic address: gloria.brusotti@unipv.it.
authors: Gloria
authors: G
authors: Brusotti
authors: Department of Chemistry "U. Schiff", University of Florence, Via U. Schiff 6, Sesto Fiorentino, Florence, 50019 Italy. Electronic address: sandra.furlanetto@unifi.it.
authors: Sandra
authors: S
authors: Furlanetto
mesh_terms: D020001:1-Butanol / Q000737:chemistry; D002216:Captopril / Q000032:analysis*; D020374:Chromatography, Micellar Electrokinetic Capillary; D004338:Drug Combinations; D004340:Drug Contamination; D019075:Electrophoresis, Capillary; D006852:Hydrochlorothiazide / Q000032:analysis*; D008823:Micelles; D012997:Solvents / Q000737:chemistry; D013607:Tablets; D047408:gamma-Cyclodextrins / Q000737:chemistry
chemical_list: D004338:Drug Combinations; D008823:Micelles; D012997:Solvents; D013607:Tablets; D047408:gamma-Cyclodextrins; D006852:Hydrochlorothiazide; D020001:1-Butanol; D002216:Captopril; C023792:gamma-cyclodextrin
keywords: Capillary electrophoresis; Cis-trans isomerization; Combined dosage form; Experimental design; Impurities; Quality by Design