title: Sensitive CE-MS analysis of potentially genotoxic alkylation compounds using derivatization and electrokinetic injection.
abstract: A CE-MS method has been developed to detect trace levels of potentially genotoxic alkyl halides. After derivatization of the target components with 4-dimethylaminopyridine (DMAP) or butyl 1-(pyridinyl-4yl) piperidine 4-carboxylate (BPPC), the natively positively charged derivatives are pre-concentrated by applying electrokinetic injection and separated by a highly efficient CZE method using a background electrolyte (BGE) consisting of 100mM of TRIS adjusted to pH 2.5 with phosphoric acid. Using a sheath liquid interface, subsequent MS detection allows highly specific and sensitive analysis of alkyl halides. Conditions for electrokinetic injection were optimized to allow selective and effective injection. Injection of samples with low water content at 10 kV for 150 s using a high concentration of buffer in the BGE resulted in optimum sample stacking during injection and a highly efficient CE separation. At the sample pH applied, neutral and negatively charged components are shown to be selectively discarded, resulting in injection of positively charged ions only. The sample matrix influences the efficiency of the injection, but when using an internal standard, reproducibilities better than 10% RSD are obtained. Relative recoveries of the derivatives spiked to different types of model API between 85 and 115% demonstrate that the method can be applied for quantitative analysis. Detection limits of lower than 1 mg kg(-1) for the tested alkyl halides obtained in CE-MS at least equal the sensitivity obtained in LC-MS. The CE-MS method is a valuable alternative for the LC-MS method used for analysis of alkylation compounds.
authors.affiliation: Abbott Healthcare Products BV, Manufacturing Science and Technology, Established Pharmaceuticals, C.J. van Houtenlaan 36, 1381 CP Weesp, The Netherlands.
authors.forename: A M
authors.initials: AM
authors.lastname: van Wijk
authors.affiliation: Niederländer Training and Consultancy, Workumstraat 23, 8244 EJ Lelystad, The Netherlands. Electronic address: info@niederlaender.nl.
authors.forename: H A G
authors.initials: HA
authors.lastname: Niederländer
authors.affiliation: Hogeschool Utrecht, F.C. Dondersstraat 65, 3572 JE, Utrecht, The Netherlands.
authors.forename: M D
authors.initials: MD
authors.lastname: van Ogten
authors.affiliation: University Utrecht, Department of Pharmaceutical Sciences, Biomolecular Analysis, Universiteitsweg 99, 3584 CG Utrecht, The Netherlands.
authors.forename: G J
authors.initials: GJ
authors.lastname: de Jong
mesh_terms: D015761:4-Aminopyridine / Q000031:analogs & derivatives / Q000737:chemistry; D000478:Alkylation; D002853:Chromatography, Liquid / Q000379:methods; D019075:Electrophoresis, Capillary / Q000379:methods*; D006842:Hydrocarbons, Brominated / Q000032:analysis*; D013058:Mass Spectrometry / Q000379:methods*; D009153:Mutagens / Q000032:analysis*
chemical_list: D006842:Hydrocarbons, Brominated; D009153:Mutagens; D015761:4-Aminopyridine; C003885:4-dimethylaminopyridine
keywords: Alkyl halides; Capillary electrophoresis; Derivatization; Electrokinetic injection; Genotoxic compounds; Impurity profiling; Mass spectrometry