title: Determination of trace level genotoxic impurities in small molecule drug substances using conventional headspace gas chromatography with contemporary ionic liquid diluents and electron capture detection.
abstract: Ionic liquids (ILs) were used as a new class of diluents for the analysis of two classes of genotoxic impurities (GTIs), namely, alkyl/aryl halides and nitro-aromatics, in small molecule drug substances by headspace gas chromatography (HS-GC) coupled with electron capture detection (ECD). This novel approach using ILs as contemporary diluents greatly broadens the applicability of HS-GC for the determination of high boiling (≥ 130°C) analytes including GTIs with limits of detection (LOD) ranging from 5 to 500 parts-per-billion (ppb) of analytes in a drug substance. This represents up to tens of thousands-fold improvement compared to traditional HS-GC diluents such as dimethyl sulfoxide (DMSO) and dimethylacetamide (DMAC). Various ILs were screened to determine their suitability as diluents for the HS-GC/ECD analysis. Increasing the HS oven temperatures resulted in varying responses for alkyl/aryl halides and a significant increase in response for all nitroaromatic GTIs. Linear ranges of up to five orders of magnitude were found for a number of analytes. The technique was validated on two active pharmaceutical ingredients with excellent recovery. This simple and robust methodology offers a key advantage in the ease of method transfer from development laboratories to quality control environments since conventional validated chromatographic data systems and GC instruments can be used. For many analytes, it is a cost effective alternative to more complex trace analytical methodologies like LC/MS and GC/MS, and significantly reduces the training needed for operation.
authors.affiliation: Genentech Small Molecule Pharmaceutical Sciences, 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Tien D
authors.initials: TD
authors.lastname: Ho
authors.affiliation: Genentech Small Molecule Pharmaceutical Sciences, 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Yehl
authors.affiliation: Genentech Small Molecule Pharmaceutical Sciences, 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Nik P
authors.initials: NP
authors.lastname: Chetwyn
authors.affiliation: Genentech Small Molecule Pharmaceutical Sciences, 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Jin
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Chemistry and Biochemistry, The University of Toledo, Toledo, OH 43606, USA.
authors.forename: Jared L
authors.initials: JL
authors.lastname: Anderson
authors.affiliation: Genentech Small Molecule Pharmaceutical Sciences, 1 DNA Way, South San Francisco, CA 94080, USA. Electronic address: zhong.qiqing@gene.com.
authors.forename: Qiqing
authors.initials: Q
authors.lastname: Zhong
mesh_terms: D002849:Chromatography, Gas / Q000295:instrumentation / Q000379:methods*; D004583:Electrons; D052578:Ionic Liquids / Q000737:chemistry*; D057230:Limit of Detection; D009153:Mutagens / Q000032:analysis*; D054852:Small Molecule Libraries / Q000737:chemistry*; D013696:Temperature
chemical_list: D052578:Ionic Liquids; D009153:Mutagens; D054852:Small Molecule Libraries
keywords: Alkyl/aryl halide; Electron capture detector; Genotoxic impurity; Headspace gas chromatography; Ionic liquid; Nitro-aromatic compound