Abstract
The influence of the matrix medium used for the determination of residual solvents in pharmaceuticals by static headspace gas chromatography was investigated. The purpose of this paper is to propose a guide for the choice of a matrix medium suitable for the determination of residual solvents of interest. Dimethylsulfoxide (DMSO), N, N-dimethyformamide (DMF), N, N-dimethylacetamide (DMA), benzyl alcohol (BA), 1,3-dimethyl-2-imidazolidinone (DMI) and water were studied as matrix media, and seventeen solvents used for the synthesis and purification of drug substances were used as target analytes. The peak shape of each analyte was not affected by the matrix medium, whereas the peak intensities for all solvents were strongly affected by the matrix medium; for example, the peak intensity of methanol in a BA matrix was more than four times that in a DMSO matrix. With a few exceptions, the peak intensities are approximately doubled for every 20 °C rise in equilibrium temperature between 80 and 140 °C, and there is no difference in this behavior among the matrix media. In addition, the formation of artifacts from the matrix media, upon heating in a headspace sampling apparatus, was investigated. Artifacts were also formed following ultrasonication of sample solutions used to increase dissolution of the sample into the matrix medium selected. These artifacts included benzene and toluene which were restricted as Class 1 and 2 toxic solvents in the ICH guideline.
Published Version
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