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• 6 • 800-356-1688 • 2004 vol. 3
Rapid Analysis of Residual Solvents
in Pharmaceuticals
Using Static Headspace Sampling and Stop-Flow GC
The International Conference on Harmonization
(ICH) makes recommendations concerning
amounts of residual solvents considered safe in
pharmaceutical finished goods. The ICH has
published guidelines and daily exposure limits
for 61 solvents, classified in three groups,
according to their toxicity. Class I solvents are
known carcinogens or environmental hazards, to
be avoided if at all possible. Class II solvents
are less toxic, but their use should be limited.
Class III solvents have low toxicity or no health-
related exposure limit.1 All pharmaceutical prod-
ucts must be analyzed for residual solvents,
regardless of the matrix, and an enormous num-
ber of methods potentially can be required to
address the total list of solvents. The complexity
and high cost of compliance are major hurdles in
drug manufacture.
In February 2004, Teledyne Tekmar developed a
universal analytical method for extracting and
determining 32 ICH Class II and Class III resid-
ual solvents, using static headspace sampling.2
Simultaneously, Restek chemists were develop-
ing an approach for resolving the Class I and
Class II solvents, using a new technology known
as Stop-Flow GC, but lacked a sample prepara-
tion method suitable for achieving the detection
limits required by the ICH.3 By using a Teledyne
Tekmar 7000HT headspace autosampler unit in
conjunction with Stop-Flow GC technology, it is
possible to achieve resolution, sensitivity, and
rapid sample turn-around times for the Class I
and Class II residual solvents. In Stop-Flow GC
the solvents are separated by passing the sam-
ple through a two-column ensemble consisting
of a Stabilwax® column and an Rtx®-200 column
coupled in series. Carrier gas flow through the
second (Rtx ®-200) column is interrupted briefly
(stop-flow pulses) to tune the separation at the
outlet of the column ensemble.
In an analysis on two GC columns in series
there are four possible outcomes for two sam-
ple components: 1) the two compounds are
resolved at the column junction and remain
resolved at the end of the ensemble; 2) the two
compounds coelute at the junction, but are
resolved on the second column; 3) the two com-
pounds are resolved at the junction, but coelute
at the end of the column ensemble; 4) the two
compounds coelute at the column junction and
at the end of the ensemble. For 1) and 2) no
adjustment is necessary. For 4) other stationary
phase combinations should be investigated to
ensure separation on at least one of the two
columns. For 3) Stop-Flow GC is appropriate.
Carrier gas flow into the second column is inter-
rupted briefly, immediately after one of the two
compounds has crossed the junction, but while
the other compound is still in the first column.
The timing and duration of the stop-flow pulse
are set to ensure that the two components
remain separated when they reach the end of
the column ensemble. The key to choosing a col-
umn ensemble for a specific application is to
make separate analyses on each column, to
ensure that no two compounds coelute on both
stationary phases.
Figure 1 is the product of applying three stop-
flow pulses at the junction point of the column
ensemble, to pull apart three analytes:
trichloroethene, acetonitrile, and chloroform.
The other analytes are resolved by adjusting the
carrier gas flow and temperature program, and
do not require pulses. The chromatogram
includes all ICH Class I and Class II solvents,
except ethylene glycol (which was not detected
at 200ppm), at 200ppm each in 5mL of 1,3-
dimethyl-2-imidazolidinone (DMI) solvent. By
resolving closely eluting component pairs, Stop-
Flow GC enables pharmaceutical laboratories to
monitor all ICH Class I and Class II solvents
with one pair of chromatography columns and a
single set of conditions.
This analysis for 35 residual Class I and Class II
solvents is rapid, sensitive, and reliable. If you
are required to monitor solvents in pharmaceuti-
cal products, we welcome the opportunity to
discuss Stop-Flow GC with you.
References
1. ICH Guidance for Industry, Q3A Impurities: Residual
SolventsUS Dept. of Health and Human Services,
Food and Drug Administration, Center for Drug
Evaluation and Research, Center for Biologics
Evaluation and Research (CBER). International
Conference on Harmonization, Dec. 1997.
2.Wallace, B. and J. Kancler. One Universal Method for
Residual Solvents in Pharmaceuticals Using a High
Temperature Static Headspace Sample Introduction
SystemApplication Note 7000-021b.doc, Teledyne
Tekmar Instruments, Feb. 2004.
3.Wittrig, R.E.; F.L. Dorman, C.M. English, R.D. Sachs,
J.Chromatogr. A 1027: 75-82 (2004).
Acknowledgement
Special thanks to Brian Wallace of Teledyne
Tekmar for the use of the 7000HT headspace
autosampler.
by Christopher English, Environmental Innovations Chemist, Rebecca Wittrig, Ph.D., HPLC Product
Marketing Manager, and Frank Dorman, Ph.D., Director of Technical Development
•Resolve 35 residual solvents in 18 minutes.
•Simplify inventory—use one pair of chromatography columns and one set of conditions for
all ICH Class I and Class II solvents.
•Complete, easy to install system.
Stabilwax® Column
15-Meter, 0.25mm, ID 0.5µm df, cat.# 10635,
$240
Restek
Innovation !
Stop-Flow GC for Agilent 6890 GCs
Description qty. cat.# price
Stop-Flow System for use with Cool On-Column EPC
(includes: Stop-Flow enclosure, top mounting plate, 1-line weldment,
and interface cable) kit 21168 $3800
Stop-Flow System for use with Split/Splitless EPC
(includes: Stop-Flow enclosure, top mounting plate, 2-line weldment,
and interface cable) kit 21169 $3800
We offer many reference mixes of residual
solvents for EP and USP methods.
For descriptions, please refer to our
chromatography supplies catalog, or visit
our website.
Did you
know ?
Rtx®-200 Column
30-Meter, 0.25mm ID, 1.0µm df, cat.# 15053,
$425
Kit is easily attached to Agilent 6890 GC!