Rapid Analysis of Residual Solvents in Pharmaceuticals Innovation !
Using Static Headspace Sampling and Stop-Flow GC
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.
Kit is easily attached to Agilent 6890 GC!
The International Conference on Harmonization
second (Rtx®-200) column is interrupted briefly
(stop-flow pulses) to tune the separation at the
includes all ICH Class I and Class II solvents,
amounts of residual solvents considered safe in
except ethylene glycol (which was not detected
pharmaceutical finished goods. The ICH has
at 200ppm), at 200ppm each in 5mL of 1,3-
published guidelines and daily exposure limits
In an analysis on two GC columns in series
dimethyl-2-imidazolidinone (DMI) solvent. By
for 61 solvents, classified in three groups,
there are four possible outcomes for two sam-
resolving closely eluting component pairs, Stop-
according to their toxicity. Class I solvents are
Flow GC enables pharmaceutical laboratories to
known carcinogens or environmental hazards, to
resolved at the column junction and remain
monitor all ICH Class I and Class II solvents
be avoided if at all possible. Class II solvents
resolved at the end of the ensemble; 2) the two
with one pair of chromatography columns and a
are less toxic, but their use should be limited.
compounds coelute at the junction, but are
Class III solvents have low toxicity or no health-
resolved on the second column; 3) the two com-
related exposure limit.1 All pharmaceutical prod-
pounds are resolved at the junction, but coelute
This analysis for 35 residual Class I and Class II
ucts must be analyzed for residual solvents,
at the end of the column ensemble; 4) the two
solvents is rapid, sensitive, and reliable. If you
regardless of the matrix, and an enormous num-
compounds coelute at the column junction and
are required to monitor solvents in pharmaceuti-
ber of methods potentially can be required to
at the end of the ensemble. For 1) and 2) no
cal products, we welcome the opportunity to
address the total list of solvents. The complexity
adjustment is necessary. For 4) other stationary
and high cost of compliance are major hurdles in
phase combinations should be investigated to
ensure separation on at least one of the two
columns. For 3) Stop-Flow GC is appropriate.
1.ICH Guidance for Industry, Q3A Impurities: Residual
In February 2004, Teledyne Tekmar developed a
Carrier gas flow into the second column is inter-
Solvents US Dept. of Health and Human Services,Food and Drug Administration, Center for Drug
universal analytical method for extracting and
rupted briefly, immediately after one of the two
Evaluation and Research, Center for Biologics
determining 32 ICH Class II and Class III resid-
compounds has crossed the junction, but while
Evaluation and Research (CBER). International
ual solvents, using static headspace sampling.2
the other compound is still in the first column.
Conference on Harmonization, Dec. 1997.
Simultaneously, Restek chemists were develop-
The timing and duration of the stop-flow pulse
2.Wallace, B. and J. Kancler. One Universal Method for
ing an approach for resolving the Class I and
are set to ensure that the two components
Residual Solvents in Pharmaceuticals Using a High
Class II solvents, using a new technology known
remain separated when they reach the end of
Temperature Static Headspace Sample Introduction
as Stop-Flow GC, but lacked a sample prepara-
the column ensemble. The key to choosing a col-
System Application Note 7000-021b.doc, Teledyne
tion method suitable for achieving the detection
umn ensemble for a specific application is to
3.Wittrig, R.E.; F.L. Dorman, C.M. English, R.D. Sachs,
limits required by the ICH.3 By using a Teledyne
make separate analyses on each column, to
Tekmar 7000HT headspace autosampler unit in
ensure that no two compounds coelute on both
conjunction with Stop-Flow GC technology, it is
possible to achieve resolution, sensitivity, and
Special thanks to Brian Wallace of Teledyne
rapid sample turn-around times for the Class I
Figure 1 is the product of applying three stop-
Tekmar for the use of the 7000HT headspace
and Class II residual solvents. In Stop-Flow GC
flow pulses at the junction point of the column
the solvents are separated by passing the sam-
ple through a two-column ensemble consisting
trichloroethene, acetonitrile, and chloroform.
of a Stabilwax® column and an Rtx®-200 column
The other analytes are resolved by adjusting the
coupled in series. Carrier gas flow through the
carrier gas flow and temperature program, and
Stop-Flow GC for Agilent 6890 GCs
Stop-Flow System for use with Cool On-Column EPC(includes: Stop-Flow enclosure, top mounting plate, 1-line weldment,
We offer many reference mixes of residual
Stop-Flow System for use with Split/Splitless EPC
(includes: Stop-Flow enclosure, top mounting plate, 2-line weldment,
chromatography supplies catalog, or visit
Stabilwax® Column Rtx®-200 Column
15-Meter, 0.25mm, ID 0.5µm df, cat.# 10635,
30-Meter, 0.25mm ID, 1.0µm df, cat.# 15053,
2004 vol. 3 800-356-1688 • www.restek.com Figure 1 Stop-Flow GC provides a rapid, sensitive analysis for ICH Class I and Class II residual solvents. Headspace Conditions GC Conditions
Teledyne Tekmar 7000HT high temperature static
Stabilwax®, 15m x 0.25mm x 0.5µm (cat. # 10635)
Rtx®-200, 30m x 0.25mm x 1.0µm (cat. # 15053)
200ppm each component in 1,3-dimethyl-2-imidazolidinone (DMI)
40°C (hold 2 min.) to 55°C @ 4°C/min., to 110°C @ 25°C/min.
(hold 2 min.) to 250°C @ 25°C/min. (hold 5 min.)
FID #1 at column junction, FID #2 at sample outlet
1mL (standard size, Silcosteel® treated)
Stop-Flow Conditions
plumbed through injection port, 1:20 split
Restek Stop-Flow System for Agilent 6890 GC with cool on-column EPC (cat. #21168)
valve opened 3.00 - 3.15 min., 4.65 - 5.02 min., 5.10 - 5.40 min. 2004 vol. 3 800-356-1688 • www.restek.com
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