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Problems of determination of selected Class 1 residual solvents (according to ICH*)) as process impurities of some Class 3 and 2 solvents in API by GC-HS method

Joanna M. Biernat ,  Magdalena M. Glice ,  Hanna M. Beczkowicz 

Pharmaceutical Research Institute (IF), Rydygiera 8, Warszawa 01-793, Poland


Class 1 (according to ICH*)) solvents should be determined in API: a) when they are used as starting materials, b) are formed as a by-product from a chemical reaction,  or c) arise from another solvent (ICH*). Class 2 or 3) used in the synthesis of pharmaceutical substances (API). It’s common knowledge that benzene is a known process impurity of acetone or toluene and some of chlorinated compounds may be process impurities of dichloromethane or chloroform.

The main problem of determination of residues of Class 1 solvents was to find the analysis method because of their very low content in API. On the one hand a task was to find solvent, which guarantee dissolution of tested API, and on the other, a task was to make possible quantity determination of Class 1 solvents in API on very low level.

According to the European Medicines Agency (EMEA) it is considered that amount of said solvents in pharmaceutical product must not exceed the following values: acetone (Class 3) - 5000 ppm, toluene (Class 2) - 890 ppm, dichloromethane (Class 2) - 600 ppm and chloroform (Class 2) 60 ppm. The Class 1 solvents have very low specification limit in API, for example, carbon tetrachloride - 4 ppm and benzene - 2 ppm.

The determination of residues of some Class 1 solvents in API by gas chromatography (GC) was elaborated. Following equipment were selected: headspace injection GC with flame-ionization detector (FID) and DB-624 (60 m long, 0,32 mm ID, 1,8 µm film thickness) column. Variety of conditions of gas chromatography and headspace injection parameters, also conditions of preparation of the sample of tested pharmaceutical substance were tested. The chosen method was validated. Validation included selectivity, specificity, system precision, method precision, intermediate precision, accuracy (recovery), linearity, limits of detection and quantitation and robustness.

As an example, the development and validation results of method determination of carbon tetrachloride as process impurity of dichloromethane and chloroform will be presented.

*) ICH - The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use


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Related papers

Presentation: Poster at VII Multidyscyplinarna Konferencja Nauki o Leku, by Joanna M. Biernat
See On-line Journal of VII Multidyscyplinarna Konferencja Nauki o Leku

Submitted: 2010-03-15 10:13
Revised:   2010-03-29 09:12