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Analysis of potential genotoxic impurities in pharmaceuticals by two-dimensional gas chromatography with Deans switching and independent column temperature control using a low-thermal-mass oven module

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Abstract

The analysis of potential genotoxic impurities (PGIs) in active pharmaceutical ingredients (APIs) is a challenging task. The target limit of detection for a PGI in an API is typically 1 ppm (1 µg/g API). This is about 500 times lower than for classical impurity analysis. Consequently, analytical methods for trace analysis, mostly in combination with MS detection, need to be applied for the qualitative and quantitative determination of these impurities. A two-dimensional capillary GC method is presented that can be used for the determination of some target PGIs. A concentrated solution of the API sample is directly introduced in the GC-MS system, using an apolar column for first-dimension separation. The fraction (heart-cut) containing the PGIs is transferred to a second capillary column, installed in a low-thermal-mass oven (LTM). The LTM focuses the heart-cut(s) and allows independent temperature-programmed analysis with a polar second-dimension column. The API, solvent, and derivatization agents are not introduced in the second column or in the MS detector, avoiding contamination, column degradation, and target analyte peak detection/integration issues. The performance of this set-up is illustrated by the analysis of some Michael-reactive acceptor PGIs and haloalcohols in carbamazepine as test matrix. Excellent reproducibility (<10% RSD) at the low parts per million level and low detection limits (<1 ppm) were obtained.

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Authors and Affiliations

  1. Research Institute for Chromatography, Pres. Kennedypark 26, 8500, Kortrijk, Belgium

    Frank David, Karine Jacq & Pat Sandra

  2. AstraZeneca R&D Charnwood, Bakewell Road, Loughborough, Leicestershire, LE11 5RH, England

    Andrew Baker

  3. Agilent Technologies, Wilmington, DE, 19808, USA

    Matthew S. Klee

Authors
  1. Frank David
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  2. Karine Jacq
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  3. Pat Sandra
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  4. Andrew Baker
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  5. Matthew S. Klee
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Correspondence to Frank David.

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David, F., Jacq, K., Sandra, P. et al. Analysis of potential genotoxic impurities in pharmaceuticals by two-dimensional gas chromatography with Deans switching and independent column temperature control using a low-thermal-mass oven module. Anal Bioanal Chem 396, 1291–1300 (2010). https://doi.org/10.1007/s00216-009-3304-9

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  • DOI: https://doi.org/10.1007/s00216-009-3304-9

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