title: An integrated quality by design and mixture-process variable approach in the development of a capillary electrophoresis method for the analysis of almotriptan and its impurities.
abstract: The development of a capillary electrophoresis (CE) method for the assay of almotriptan (ALM) and its main impurities using an integrated Quality by Design and mixture-process variable (MPV) approach is described. A scouting phase was initially carried out by evaluating different CE operative modes, including the addition of pseudostationary phases and additives to the background electrolyte, in order to approach the analytical target profile. This step made it possible to select normal polarity microemulsion electrokinetic chromatography (MEEKC) as operative mode, which allowed a good selectivity to be achieved in a low analysis time. On the basis of a general Ishikawa diagram for MEEKC methods, a screening asymmetric matrix was applied in order to screen the effects of the process variables (PVs) voltage, temperature, buffer concentration and buffer pH, on critical quality attributes (CQAs), represented by critical separation values and analysis time. A response surface study was then carried out considering all the critical process parameters, including both the PVs and the mixture components (MCs) of the microemulsion (borate buffer, n-heptane as oil, sodium dodecyl sulphate/n-butanol as surfactant/cosurfactant). The values of PVs and MCs were simultaneously changed in a MPV study, making it possible to find significant interaction effects. The design space (DS) was defined as the multidimensional combination of PVs and MCs where the probability for the different considered CQAs to be acceptable was higher than a quality level π=90%. DS was identified by risk of failure maps, which were drawn on the basis of Monte-Carlo simulations, and verification points spanning the design space were tested. Robustness testing of the method, performed by a D-optimal design, and system suitability criteria allowed a control strategy to be designed. The optimized method was validated following ICH Guideline Q2(R1) and was applied to a real sample of ALM coated tablets.
authors.affiliation: Department of Chemistry "U. Schiff", University of Florence, Via U. Schiff 6, 50019 Sesto Fiorentino, Florence, Italy. Electronic address: serena.orlandini@unifi.it.
authors.forename: S
authors.initials: S
authors.lastname: Orlandini
authors.affiliation: Department of Chemistry "U. Schiff", University of Florence, Via U. Schiff 6, 50019 Sesto Fiorentino, Florence, Italy.
authors.forename: B
authors.initials: B
authors.lastname: Pasquini
authors.affiliation: S-IN Soluzioni Informatiche, Via G. Ferrari 14, 36100 Vicenza, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Stocchero
authors.affiliation: Department of Chemistry "U. Schiff", University of Florence, Via U. Schiff 6, 50019 Sesto Fiorentino, Florence, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Pinzauti
authors.affiliation: Department of Chemistry "U. Schiff", University of Florence, Via U. Schiff 6, 50019 Sesto Fiorentino, Florence, Italy. Electronic address: furlanetto@unifi.it.
authors.forename: S
authors.initials: S
authors.lastname: Furlanetto
mesh_terms: D020001:1-Butanol; D020374:Chromatography, Micellar Electrokinetic Capillary / Q000379:methods; D004340:Drug Contamination; D019075:Electrophoresis, Capillary / Q000379:methods; D004655:Emulsions; D006536:Heptanes; D009010:Monte Carlo Method; D012044:Regression Analysis; D058825:Serotonin 5-HT1 Receptor Agonists / Q000032:analysis*; D012967:Sodium Dodecyl Sulfate; D013501:Surface-Active Agents; D013607:Tablets; D014363:Tryptamines / Q000032:analysis*
chemical_list: D004655:Emulsions; D006536:Heptanes; D058825:Serotonin 5-HT1 Receptor Agonists; D013501:Surface-Active Agents; D013607:Tablets; D014363:Tryptamines; C409045:almotriptan; D012967:Sodium Dodecyl Sulfate; C028618:n-heptane; D020001:1-Butanol
keywords: Almotriptan; Capillary electrophoresis; Experimental design; Impurities; Mixture-process variable approach; Quality by Design