title: Implementation of a design space approach for enantiomeric separations in polar organic solvent chromatography.
abstract: This paper focuses on implementing a design space approach and on the critical process parameters (CPPs) to consider when applying the Quality by Design (QbD) concepts outlined in ICH Q8(R2), Q9 and Q10 to analytical method development and optimization for three chiral compounds developed as modulators of small conductance calcium-activated potassium (SK) channels. In this sense, an HPLC method using a polysaccharide-based stationary phase containing a cellulose tris (4-chloro-3-methylphenylcarbamate) chiral selector in polar organic solvent chromatography mode was considered. The effects of trifluoroacetic acid (TFA) and n-hexane concentration in an acetonitrile (MeCN) mobile phase were investigated under a wide range of column temperatures. Good correlations were found between the observed data obtained after using a central composite design and the expected chromatographic behaviours predicted by applying the design of experiments-design space (DoE-DS) methodology. The critical quality attribute represented here by the separation criterion (S(crit)) allowed assessing the quality of the enantioseparation. Baseline separation for the compounds of interest in an analysis time of less than 20 min was possible due to the original and powerful tools applied which facilitated an enhanced method comprehension. Finally, the advantage of the DoE-DS approach resides in granting the possibility to concurrently assess robustness and identify the optimal conditions which are compound dependent.
authors.affiliation: Laboratory of Analytical Chemistry and CIRM, University of Liège, B 36, B-4000 Liège, Belgium.
authors.forename: Iolanda
authors.initials: I
authors.lastname: Nistor
authors.forename: Pierre
authors.initials: P
authors.lastname: Lebrun
authors.forename: Attilio
authors.initials: A
authors.lastname: Ceccato
authors.forename: Frédéric
authors.initials: F
authors.lastname: Lecomte
authors.forename: Ines
authors.initials: I
authors.lastname: Slama
authors.forename: Radu
authors.initials: R
authors.lastname: Oprean
authors.forename: Eduard
authors.initials: E
authors.lastname: Badarau
authors.forename: Fabien
authors.initials: F
authors.lastname: Dufour
authors.forename: Katina Sourou Sylvestre
authors.initials: KS
authors.lastname: Dossou
authors.forename: Marianne
authors.initials: M
authors.lastname: Fillet
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Liégeois
authors.forename: Philippe
authors.initials: P
authors.lastname: Hubert
authors.forename: Eric
authors.initials: E
authors.lastname: Rozet
mesh_terms: D000097:Acetonitriles / Q000032:analysis / Q000737:chemistry; D002851:Chromatography, High Pressure Liquid / Q000379:methods / Q000592:standards; D004048:Diethylamines / Q000032:analysis / Q000737:chemistry; D004867:Equipment Design / Q000379:methods* / Q000592:standards; D012997:Solvents / Q000032:analysis* / Q000737:chemistry*; D013237:Stereoisomerism; D014269:Trifluoroacetic Acid / Q000032:analysis / Q000737:chemistry
chemical_list: D000097:Acetonitriles; D004048:Diethylamines; D012997:Solvents; C034281:diethylamine; D014269:Trifluoroacetic Acid; C032159:acetonitrile