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

作者：Ho Tien D; Yehl Peter M; Chetwyn Nik P; Wang Jin; Anderson Jared L; Zhong Qiqing^*

来源：Journal of Chromatography A, 2014, 1361: 217-228.

DOI：10.1016/j.chroma.2014.07.099

• Genotoxic impurity
• Ionic liquid
• Alkyl/aryl halide
• Nitro-aromatic compound
• Headspace gas chromatography
• Electron capture detector

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 (%26gt;= 130 degrees 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 dei/elopment 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.

• 出版日期2014-9-26