Three aspects of headspace method development were examined for a set of small basic amines. This compound class was chosen
because these compounds are being used more frequently in the pharmaceutical industry in place of more traditional bases and
because they often present problems in GC analyses because of their low sensitivity. It was shown that increasing the sample
volume in the headspace vial does not always yield the desired increase in signal and that smaller amounts in the sammple
vial can give the desired sensitivity. Specifically, the USP calls for solution volumes of 5 mL to be used, whereas these data show that 1 or 2 mL volumes can give equivalent signals
using less material.
Equilibration time is another aspect of headspace method development that was examined. One must ensure that the sample has
incubated long enough for all the solvents in the vial to achieve equilibrium with solvent in the liquid in the vial. If the
sample does not reach equilibrium, the injection precision will vary from sample to sample. If the solution is in equilibrium
with the gas phase, the injections will be consistent and precise. If the sample incubates too long, there is a risk of matrix
degradation, which could add complexity to the residual-solvent analysis. The data showed that 15 min and often only 5 min
were required for the residual amines to reach equilibrium. This finding is supported by the fact that upon longer incubation,
there was no increase in signal. These data are in contrast to USP <467>, which sets a vial equilibrium time of 60 min. The data show that such an extended incubation is unnecessary; the time
of analyses could be increased as much as 4–30 times and demonstrate the same sensitivity.
The final aspect of method development studied was multicomponent diluents. In some cases, it was possible to increase sensitivity
by adding a small percentage of water or aqueous base to the sample diluents, as the water or aqueous base can aid in partitioning
the solvents into the gas phase. In the case of triethylamine, the signal increased by 60% by using a diluent 80:20 ratio
of DMSO:water instead of just DMSO. For allylamine, however, no combination of solvents yielded a signal higher than that
with just using DMSO.
Many laboratories have generic residual-solvent methods that use a particular high-boiling solvent (i.e., DMSO, DMF, dimethlyacetamine,
or n-methylpyrolidone) and a standard set of headspace conditions. These may work for many solvents/matrices; however, there are
solvents that are more difficult to analyze, for example, the small organic amines that were studied in this work. This work
has shown that by adjusting two of the GC headspace parameters (i.e., vial volume and equilibriation time), the consumption
of sample and analysis time can be reduced. Finally, by trying different diluents (i.e., DMF versus DMSO for allylamine) and
multicomponent diluents, containing a small amount of aqueous, the analysis of difficult analytes may be improved by enhanced
Laila Kott* is a senior scientist in analytical development, small molecules at Millennium Pharmaceuticals, 40 Landsdowne St., Cambridge,
MA 02139, firstname.lastname@example.org
and Hong Ming Chen is a quality control chemist at Ash Stevens Inc., 18655 Krause St., Riverview, MI 48193.
*To whom all correspondence should be addressed.
Submitted: May 19, 2009; Accepted Sept. 18, 2009
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2. ICH, Q3(R4) Impurities: Guideline for Residual Solvents (July 2007).
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