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Solvent residues by GCMS, an alternative to USP<467>

An alternative to USP <467> OVI

For established pharmaceuticals and raw materials, residual solvents are usually determined using USP <467>, Organic Volatile Impurities. This determines four solvents: methylene chloride, chloroform, trichloroethylene and 1,4-dioxane. However, during the drug development process, many other potential solvents may be used in the synthesis and purification of drug substances. 

Measuring these other solvents can be accomplished using GCMS. GCMS has advantages over other GC techniques, in that solvents may be positively identified, non-target solvents can be identified and estimated, and complete chromatographic resolution usually isn’t necessary for identification or quantitation.

We have developed a method that routinely determines more than 20 different solvents by GCMS. 

Other compounds may be added, but these cover most commonly used solvents, including the four required by USP<467>. The analysis can also screen for unknown volatiles. This method, although based on <467> Method I, does not replace it. It is intended to be used in the drug development process for characterization of impurities. 

The sample is dissolved in DMSO and analyzed by direct injection onto a capillary column.  Using a 100 mg sample in 2 mL of DMSO, the detection limits for most compounds are about 20 ppm. Sample and solvent amounts can be reduced to 5 mg in 150 uL if necessary.  DMF is an optional solvent using 1,3-dimethyl-2-imidazolidinone (DMI) instead of DMSO.

If you have any questions about this method, please give us a call.

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The current target list includes:

  1. Methanol-d3 (IS) 
  2. Methanol
  3. Ethanol
  4. Acetonitrile
  5. Acetone
  6. Isopropanol
  7. Ethyl ether
  8. Freon-113
  9. Methylene Chloride
  10. n-Propanol
  11. Methyl t-butyl ether
  12. Methyl ethyl ketone
  13. Hexane
  14. Ethyl acetate
  15. Chloroform
  16. Tetrahydrofuran
  17. Benzene-d6 (IS)
  18. Benzene
  19. n-Heptane
  20. Trichloroethylene
  21. 1,4-Dioxane
  22. Methyl isobutyl ketone
  23. Pyridine
  24. Toluene
  25. Dimethylformamide (optional)

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