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2004vol. 3
RapidAnalysisofResidualSolvents
inPharmaceuticals
Using Static Headspace Sampling and Stop-FlowGC
The International Conference onHarmonization
(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-
uctsmust be analyzed for residual solvents,
regardless of thematrix, 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 aremajor hurdles in
drugmanufacture.
In February 2004,TeledyneTekmar 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 chemistswere develop-
ing an approach for resolving the Class I and
Class II solvents, using a new technology known
as Stop-FlowGC, but lacked a sample prepara-
tionmethod suitable for achieving the detection
limits required by the ICH.
3
By using aTeledyne
Tekmar 7000HT headspace autosampler unit in
conjunctionwith Stop-FlowGC 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-FlowGC
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 twoGC 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-FlowGC 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 separatedwhen 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 (whichwas not detected
at 200ppm), at 200ppm each in 5mL of 1,3-
dimethyl-2-imidazolidinone (DMI) solvent. By
resolving closely eluting component pairs, Stop-
FlowGC 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 tomonitor solvents in pharmaceuti-
cal products, wewelcome the opportunity to
discuss Stop-FlowGCwith you.
References
1.
ICHGuidance for Industry, Q3A Impurities: Residual
Solvents
USDept. of Health andHuman Services,
Food andDrug Administration, Center for Drug
Evaluation and Research, Center for Biologics
Evaluation and Research (CBER). International
Conference onHarmonization, Dec. 1997.
2.Wallace, B. and J. Kancler.
OneUniversal Method for
Residual Solvents in Pharmaceuticals Using aHigh
Temperature Static Headspace Sample Introduction
System
ApplicationNote 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 BrianWallace ofTeledyne
Tekmar for the use of the 7000HT headspace
autosampler.
by Christopher English, Environmental Innovations Chemist, RebeccaWittrig, Ph.D., HPLC Product
MarketingManager, and Frank Dorman, Ph.D., Director ofTechnical Development
•Resolve 35 residual solvents in 18minutes.
•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-FlowGC forAgilent6890GCs
Description
qty.
cat.#
price
Stop-Flow System for usewith Cool On-Column EPC
(includes: Stop-Flow enclosure, topmounting plate, 1-lineweldment,
and interface cable)
kit
21168
$3800
Stop-Flow System for usewith Split/Splitless EPC
(includes: Stop-Flow enclosure, topmounting plate, 2-lineweldment,
and interface cable)
kit
21169
$3800
We offermany referencemixes of residual
solvents for EP andUSPmethods.
For descriptions, please refer to our
chromatography supplies catalog, or visit
our website.
Did you
know
?
Rtx®-200Column
30-Meter, 0.25mm ID, 1.0µm df, cat.# 15053
,
$425
Kit is easilyattached toAgilent 6890GC!
