Journal of Chromatography A, 1141 (2007) 123–130

Analysis of class 1 residual solvents in pharmaceuticals using

headspace-programmed temperature vaporization-fast gas
chromatography–mass spectrometry
José Luis Pérez Pavón ∗ , Miguel del Nogal Sánchez, Ma Esther Fernández Laespada,
Carmelo Garcı́a Pinto, Bernardo Moreno Cordero
Departamento de Quı́mica Analı́tica, Nutrición y Bromatologı́a, Facultad de Ciencias Quı́micas, Universidad de Salamanca, 37008 Salamanca, Spain
Received 17 July 2006; received in revised form 28 November 2006; accepted 1 December 2006
Available online 19 December 2006

Abstract
A sensitive method is presented for the fast screening and determination of residual class 1 solvents (1,1-dichloroethene, 1,2-dichloroethane, 1,1,1-
trichloroethane, carbon tetrachloride and benzene) in pharmaceutical products. The applicability of a headspace (HS) autosampler in combination
with GC equipped with a programmed temperature vaporizer (PTV) and a MS detector is explored. Different injection techniques were compared.
The benefits of using solvent vent injection instead of split or splitless-hot injection for the measurement of volatile compounds are shown: better
peak shapes, better signal-to-noise ratios, and hence better detection limits. The proposed method is extremely sensitive. The limits of detection
ranged from 4.9 ppt (benzene) to 7.9 ppt (1,2-dichloroethane) and precision (measured as the relative standard deviation) was equal to or lower
than 12% in all cases. The method was applied to the determination of residual solvents in nine different pharmaceutical products. The analytical
performance of the method shows that it is appropriate for the determination of residual class 1 solvents and has much lower detection limits
than the concentration limits proposed by the International Conference on Harmonization (ICH) of Technical Requirements for the Registration
of Pharmaceuticals for Human Use. The proposed method achieves a clear improvement in sensitivity with respect to conventional headspace
methods due to the use of the PTV.
© 2006 Elsevier B.V. All rights reserved.

Keywords: Headspace analysis; Programmed temperature vaporizers; Residual solvents; Contour plots

1. Introduction in the production of pharmaceutical products. These chem-

The volatile organic solvents used in the manufacture of phar-
maceutical formulations need to be removed from the finished
product because of their possible health risks and toxicity. The
acceptable maximum levels of residual solvents that can be left
behind according to worldwide regulatory standards [1–3] were
originally derived for patient safety considerations.
Guideline Q3C [1] was adopted by the International Con-
ference on Harmonisation (ICH) of Technical Requirements
for Registration of Pharmaceuticals for Human Use in 1997.
It classified residual solvents into three categories according
to their toxic potential. Class 1 includes the solvents consid-
ered to be the most toxic, such that their use should be avoided
∗ Corresponding author. Tel.: +34 923 29 4483; fax: +34 923 29 4483.
E-mail address: jlpp@usal.es (J.L. Pérez Pavón).
icals are: benzene, carbon tetrachloride, 1,2-dichloroethane,
1,1-dichloroethene and 1,1,1-trichloroethane (the latter owing to
its environmental impact). Class 2 and class 3 residual solvents
are considered a lesser risk.
The most frequently used technique for the determination
of residual solvents in pharmaceutical quality assurance/quality
control (QA/QC) is static headspace-gas chromatography
[4–11]. Even though the sensitivity provided by headspace meth-
ods is in many cases sufficient to achieve the maximum permitted
levels, it can be enhanced through the use of dynamic headspace,
i.e. purge and trap (P&T) [11,12], although more complex instru-
mentation is required. Headspace-solid phase microextraction
(HS-SPME) [12,13] has also been proposed.
Another alternative to explore in order to improve sensitivity,
maintaining the simple headspace instrumentation, is the use
of a programmed temperature vaporizer inlet (PTV) to inject
the samples into the chromatographic column [14–16]. The

0021-9673/$ – see front matter © 2006 Elsevier B.V. All rights reserved.
doi:10.1016/j.chroma.2006.12.046
124 J.L. Pérez Pavón et al. / J. Chromatogr. A 1141 (2007) 123–130
conditions are chosen such that the components are retained
in the liner by cold trapping, while the solvent is eliminated
through the split line. The PTV injector is equipped with an
efficient heating and cooling system, in which cooling is carried
out by means of air, liquid nitrogen, carbon dioxide, or by
electrical systems. By using liners [17] packed with a selective
adsorption material, such as Tenax TA, the range of components
that can be trapped in the liner can be significantly extended
towards the more volatile components. Tenax TA is a porous
polymer designed to trap organics without retaining water.
In a previous work [18], we reported the use of headspace
generation and fast gas chromatography–mass spectrometry to
generate an initial low-resolution chromatogram and contour
plots with time and mass/charge ratio axes that would allow
the rapid identification of residual solvents present in drugs.
In the present work, we propose the use of this strategy for
the identification of toxic ICH class 1 solvents and their deter-
mination in pharmaceutical products with a highly sensitive
method, using a programmed temperature vaporizer inlet fol-
lowed by fast capillary gas chromatography coupled to mass
spectrometry in the selected ion-monitoring mode acquisition
(PTV-fastGC/MS(SIM)).
2. Experimental
2.1. Chemicals
The solvents used were purchased from the following
sources: methanol was from Merck (Darmstadt, Germany);
1,1-dichloroethene from Supelco (Bellefonte, USA); 1,2-
dichloroethane and 1,1,1-trichloroethane from Sigma–Aldrich
(Sleinheim, Germany); carbon tetrachloride from Panreac
(Barcelona, Spain) and benzene from Acros Organics (Geel,
Belgium).
2.2. Standard solutions and samples
In order to optimize the chromatographic parameters for
the identification of the solvents, solutions of the five analytes
indicated in Section 2.1 were prepared in ultra-pure water. Like-
wise, aqueous solutions of these compounds were employed to
obtain the calibration curves and detection and quantification
limits.
To perform the measurements, 5 mL of sample was placed in
10 mL vials sealed with silicone septum caps. Each sample was
analyzed in triplicate.
One liquid (L1) and eight solid (S1–S8) pharmaceutical for-
mulations were analyzed. The liquid sample was prepared by
adding 1.5 mL of the formulation plus 3.5 mL of ultra-pure water
to the vials. In the case of the solid samples, 5 mL of ultra-pure
water was added directly to the samples. Each sample, after
homogenization, was analyzed in triplicate.
Once the residual solvents had been identified, they were
determined with the standard additions method, using 3.5 mL
(liquid samples) or 5 mL (solid samples) of aqueous solutions
of the residual solvents corresponding to the different drugs. All
samples were prepared in a cold chamber at 5 ◦ C.
2.3. HS-PTV-fast GC–MS measurements
2.3.1. Headspace sampling
HS sampling was performed with a model 7694 headspace
sampler from Agilent Technologies. This sampler is equipped
with a tray for 44 consecutive samples and an oven with posi-
tions for 6 sample vials. The oven temperature was kept at
90 ◦ C for 30 min. The sampling system consisted of a stainless
steel needle, a 316-SS six-port valve with a 3 mL nickel loop
(heated to 100 ◦ C), and two solenoid valves (for pressurization
and venting). The headspace sampler was coupled to a PTV
injector through a thermostatted transfer line heated to 100 ◦ C.
The carrier gas was helium N50 (99.995% pure; Air Liquide).
2.3.2. Programmed-temperature vaporization
Different injection techniques were compared (classical split-
hot injection, classical splitless-hot injection and solvent vent
injection). All experiments were carried out in a PTV inlet (CIS-
4; Gerstel, Baltimore, MD, USA). The CIS-4 inlet was equipped
with a 71 mm × 2.0 mm Tenax-TA packed liner. Cooling was
carried out by means of CO2 .
2.3.2.1. Split/splitless-hot injection. The injector temperature
was kept at 250 ◦ C throughout the analysis time. The split ratio
was 1:10. The splitless time was 2.25 min.
2.3.2.2. Solvent vent injection. The injector starting tempera-
ture was 5 ◦ C. The vent flow was adjusted to 50.0 mL/min and
the vent pressure to 5.00 psi. After 1.70 min, the split valve was
closed and the liner was flash-heated at 12 ◦ C/s to 250 ◦ C. The
analytes were transferred from the liner to the capillary col-
umn (0.60 min). The split valve was then opened and the liner
temperature was held at 250 ◦ C for 8.00 min. The experimental
conditions are shown schematically in Fig. 1.
2.3.3. Gas chromatography
To perform the gas chromatographic measurements, an Agi-
lent 6890 GC device equipped with a DB-VRX capillary column
(20 m × 0.18 mm × 1 ␮m) was used. The column oven tem-
perature program involved an initial temperature of 35 ◦ C for
4.50 min; this was increased at a rate of 20 ◦ C/min to 70 ◦ C, then
increased at 70 ◦ C/min to 175 ◦ C, and then further increased at
45 ◦ C/min to 240 ◦ C and held for 1.0 min. The latter two temper-
ature ramps are the maximum ones permitted by the instrumental
configuration employed. The total chromatographic run time
was 10.19 min. The experimental conditions are schematized
in Fig. 1.
2.3.4. Mass spectrometry
The detector was a quadrupole mass spectrometer (HP
5973 N). It was operated in the electron impact mode using 70 eV
ionization voltage. The ion source temperature was 230 ◦ C and
the quadrupole was set to 150 ◦ C. The analyses were performed
in the scan and SIM modes.
2.3.4.1. Scan detection mode. The m/z range was 25–125 amu,
and the abundance threshold value was set to 0. The different
 J.L. Pérez Pavón et al. / J. Chromatogr. A 1141 (2007) 123–130
Fig. 1. Sequence of events for solvent vent injection.
compounds were identified by comparison of the experimental

spectra with those of the NIST 98 database (NIST/EPA/NIH
Mass Spectral Library, version 1.6).
2.3.4.2. SIM detection mode. Three SIM groups were used. The
first (3.25–5.40 min) contained the two most abundant ions of
1,1-dichloroethene (61, 96). The second (5.40–5.84 min) was
formed by two characteristic ions of 1,2-dichloroethane (27,
62) and two of 1,1,1-trichloroethane (97, 99). The last group
(5.84–10.19 min) contained four m/z variables, two characteris-
tic ions of carbon tetrachloride (117, 121) and two of benzene
(51, 78). The ions were acquired with a dwell time of 100 ms
for group 1 and 50 ms for groups 2 and 3, respectively.
2.4. Data analysis
Data collection was performed with Enhanced ChemStation,
G1701CA Ver. C 00.00 software [19] from Agilent Technolo-
gies. This software was used to calculate S/N ratios.
The plotting of the information contained in the chro-
matograms with contour plots was accomplished using Matlab
v 6.5 [20].
3. Results and discussion
3.1. Preliminary study of HS-PTV-fast GC–MS data
3.1.1. Comparison of the different injection modes
In the present work, we studied all the class 1 solvents
included in the ICH [1]. The boiling points and maximum per-
mitted limits [1] for each are shown in Table 1.
Initially, we carried out a comparative study of the signal
obtained when using different injection techniques: split-hot
injection, splitless-hot injection and solvent vent injection. To
125
Table 1
Maximum permitted concentrations, boiling points, retention times and m/z
ratios selected for the 5 solvents studied
Compound ICH Limit Boiling tR (min) m/z
(ppm) point (◦ C)
1,1-Dichloroethene 8 32 3.69 61, 96
1,2-Dichloroethane 5 83 5.69 27, 62
1,1,1-Trichloroethane 1500 72 5.73 97, 99
Carbon tetrachloride 4 77 6.00 117, 121
Benzene 2 80 6.06 51, 78
do so, we employed a solution of the five compounds studied
in ultra-pure water at concentrations of 24.2, 12.0, 12.0, 12.0
and 3.12 ppb for 1,1-dichloroethene, 1,2-dichloroethane, 1,1,1-
trichloroethane, carbon tetrachloride and benzene, respectively.
The sequence of steps involved when solvent vent injection
was used is shown in Fig. 1. In the first step, the sample coming
from the headspace reaches 100 ◦ C through the transfer line and
is injected into the PTV injector, which is at 5 ◦ C, such that
the analytes are retained in the liner. The split valve is opened,
allowing solvent elimination. The boiling point of the analytes
should be higher than that of the solvent. However, even when
dealing with compounds with low boiling points, as is the case
of the analytes studied here, they can be trapped using liners
packed with adequate adsorbents, such as Tenax TA.
In the second step, involving transfer of the sample to the
column (PTV transfer time), the split valve is closed and the
PTV is rapidly heated (12 ◦ C/s) until it reaches 250 ◦ C, the same
temperature used in the split and splitless injections. Thus, the
analytes are desorbed and transferred onto the column.
Finally, the split valve is opened again, and chromatographic
separation is accomplished, with the temperature program also
shown in Fig. 1.
Fig. 2 shows the window of the chromatograms (scan mode)
of the most abundant extracted ion for three of the residual sol-
vents with the three injection modes described above: the one
with the shortest retention time (1,1-dichloroethene, Fig. 2a),
an intermediate one (1,1,1-trichloroethane, Fig. 2b) and the one
with the longest retention time (benzene, Fig. 2c). In all three
cases, the area under the curve was greater when solvent vent
injection was used. The analytical signal increased 6.1, 6.3 and
7.5 times, respectively, with respect to that obtained with split-
hot injection. On comparing solvent vent injection with splitless
injection, the most important observation was an improvement
in peak shapes, which were much narrower owing to the fact
that the splitless injection of a large volume of headspace is too
slow to give sharp peaks (splitless time: 2.25 min). However, in
solvent vent injection, there is previously a preconcentration in
the liner at low temperature and transfer to the column takes
place in a much shorter time (0.6 min).
The S/N ratios in the case of the first compound (Fig. 2a)
were 267, 98 and 61 when solvent vent injection, splitless-hot
injection and split-hot injection was used, respectively. In the
case of 1,1,1-trichloroethane (Fig. 2b), these ratios were 514,
259 and 114. The last compound, (Fig. 2c) had S/N ratios of 504,
124 and 47 when the above injection modes were employed.
126 J.L. Pérez Pavón et al. / J. Chromatogr. A 1141 (2007) 123–130

roethane (Fig. 3a) and 44-fold higher for carbon tetrachloride

(Fig. 3b) when the SIM mode was used in data acquisition as
compared with the scan mode. Similar results were obtained for
the other analytes. Accordingly, it was decided to perform the
identification and determination of the five residual solvents in
SIM mode.

3.1.3. Generation of contour plots for rapid identification

of the analytes
Fig. 4 shows the chromatogram obtained on analyzing the
solution containing all five solvents. The retention times are
shown in Table 1. 1,1-Dichloroethene appears completely sepa-
rated from the others and the other four are seen in two partially
overlapping groups (b and c).
The partial overlapping of some of the compounds seen
in Fig. 4a does not prevent their individual chromatographic
determination. The determination of all the solvents is possible
using the chromatograms extracted from specific ions, as may
be seen for the pairs of compounds 1,2-dichloroethane/1,1,1-
trichloroethane (Fig. 4b) or carbon tetrachloride/benzene
(Fig. 4c).
The information contained in these chromatograms can be
visualized by using contour plots with time and mass/charge
ratio axes. Fig. 5a corresponds to a plot of the information con-
tained in the chromatogram shown in Fig. 4a. Thus, it is possible
to visualize all the information in a single figure: signal inten-
sity, retention time, and the mass spectrum. Fig. 5a shows the
plot corresponding to a data matrix where each row represents
the analysis time and each column contains the intensities for
the m/z ratios.

Fig. 2. Extracted ion chromatograms for m/z 61 (a), 97 (b) and 78 (c) when the
three different injection modes studied were used: classical split-hot injection,
classical splitless-hot injection and solvent vent injection. A solution of the five
compounds studied in ultra-pure water at concentrations of 24.2, 12.0, 12.0, 12.0
and 3.1 ppb for 1,1-dichoroethene, 1,2-dichloroethane, 1,1,1-trichloroethane,
carbon tetrachloride and benzene, respectively was used.

The improved peak shape and higher peak response of mea-

surements with the solvent vent injection mode resulted in higher
signal-to-noise ratios and hence lower detection limits.
The shift in the retention times for each compound when all
three injection modes were used is mainly due to the short delay
in liner heating (12 ◦ C/s) on using the solvent vent-based system.
In the other two cases, the temperature of the injection port was
maintained constant at 250 ◦ C.
In light of the results obtained, we decided to use the solvent
vent injection technique.

3.1.2. Comparison of the scan and SIM data acquisition

modes
Fig. 3 shows the window of the chromatograms obtained for
the previous sample when the m/z 62 (Fig. 3a) and m/z 117
Fig. 3. Extracted ion chromatograms for m/z 62 (a) and 117 (b) when SIM
(Fig. 3b) ratios characteristic of 1,2-dichloroethane and carbon
and scan mode were used. A solution of the five compounds studied in
tetrachloride, respectively, were used. In both cases, the analyt- ultra-pure water at concentrations of 24.2, 12.0, 12.0, 12.0 and 3.1 ppb for 1,1-
ical signal obtained in SIM mode and in scan mode was com- dichoroethene, 1,2-dichloroethane, 1,1,1-trichloroethane, carbon tetrachloride
pared. The S/N ratio was 35-fold higher in the case 1,2-dichlo- and benzene, respectively was used.
 J.L. Pérez Pavón et al. / J. Chromatogr. A 1141 (2007) 123–130 127

Analytical Procedures: Methodology) [21]:

3.3σ
DL =
S
where σ is the standard deviation of peak response correspond-
ing to an S/N ratio of approximately 3, and S is the slope of the
calibration curve. DLs as low as 4.9 ppt for benzene and 5.1 ppt
for carbon tetrachloride were obtained. The DLs for the other
analytes were similar.

Fig. 4. (a) Total ion current chromatogram for a laboratory-prepared solution

containing the five solvents studied in ultra-pure water. (b) Extracted ion chro-
matograms corresponding to m/z 62 and 97. (c) Extracted ion chromatograms
corresponding to m/z 117 and 78. A solution of the five compounds studied in
ultra-pure water at concentrations of 24.2, 12.0, 12.0, 12.0 and 3.1 ppb for 1,1-
dichoroethene, 1,2-dichloroethane, 1,1,1-trichloroethane, carbon tetrachloride
and benzene, respectively was used.

In this plot, it is also possible to establish specific zones for

each of the solvents studied. In Fig. 5b, the zones used to identify
the solvents are marked with black symbols.
Finally, it is possible to compile a template that has the
columns tR (column 4) and m/z (column 5) from Table 1 as
coordinates. Use of this template allows rapid identification of
the residual solvents present in the samples. Fig. 5c shows the
template generated.

3.2. HS-PTV-fast GC–MS method evaluation

The linearity of the method was evaluated from triplicate

injections of a series of standard solutions prepared for each
analyte over the concentration range studied. The variables
used in the calibrations were the area under the curve of
1,1-dichloroethene, 1,2-dichloroethane, 1,1,1-trichloroethane,
carbon tetrachloride, and benzene in the extracted ion chro-
matogram for m/z 61, 62, 97, 117 and 78, respectively. All the
calibrations showed good linear behavior, with coefficient of
determination (R2 ) values above 0.99. The intercept included
zero in all cases.
For the set of five solvents, repeatability (n = 10) was evalu-
ated at a level corresponding to an S/N ratio of approximately
3. The repeatability was satisfactory, with an RSD equal to
or less than 12%. In many cases, the RSD was lower than
Fig. 5. (a) Contour plots with time and mass/charge ratio axes for a laboratory-
10%. prepared solution containing the five solvents studied in ultra-pure water. (b)
The detection limits (DLs) were estimated using the fol- Zones selected for each solvent studied. (c) Template generated for the identifi-
lowing equation based on ICH guideline Q2B (Validation of cation of solvents in pharmaceutical products.
128 J.L. Pérez Pavón et al. / J. Chromatogr. A 1141 (2007) 123–130

The quantitation limits (QLs) were estimated using the fol-

lowing equation based on ICH guideline Q2B (Validation of
Analytical Procedures: Methodology) [21]:
10σ
QL =
S
where σ is the standard deviation of peak response correspond-
ing to an S/N ratio of approximately 3, and S is the slope of the
calibration curve. For all the solvents, the QLs are well below
the ICH limits.
The results for linearity, precision, and detection and quanti-
tation limits are summarized in Table 2.
When compared with related methods, the results obtained
in this study are highly satisfactory, particularly in terms of
simplification of the sample preparation step. According to
the literature, the use of HS-GC-FID [8] for determination of
benzene provided a detection limit of 100 ppb, with 2.7% of
precision (RSD %). HS-GC–MS, without a programmed tem-
perature vaporizer [18] achieved limits of detection equal to
8 ppb and 42 ppb for benzene and carbon tetrachloride, respec-
tively, with RSD values of 7.2% and 13%.
If preconcentration steps are added to the method, better
detection limits are accordingly achieved, but they are in the
same order of magnitude that the ones achieved in the present
work. Thus, solid phase microextraction coupled to GC–MS [13]
provided limits of detection of 10 ppt for 1,2-dichloroethane and
benzene, with RSD values of 2% (at a 100 ppb concentration
level).

3.3. Analysis of pharmaceutical products

The detection of residual solvents by using low-resolution

chromatograms and visual inspection of the contour plots was
carried out in nine drugs. In six of them (S3–S8), none of the
compounds studied was detected. The characteristic zones of
these compounds in the template used did not show any signal.
In the liquid formulation (L1), from the contour plot of the
chromatogram only one residual solvent was detected: benzene.
Fig. 6a shows the signal obtained on analyzing this drug, on
which the previously generated template had been superim-
posed. Visualization of the template favors the rapid detection
of any of the solvents studied. Only the zone of benzene showed
a signal. Even though it is also possible to observe a signal in Fig. 6. Superimposition of the template on the contour plots for the L1 (a) liquid
formulation and S1 (b) and S2 (c) solid pharmaceuticals.
the zone of 1,2-dichloroethane, this corresponds to only one of
its characteristics m/z ratios, such that it cannot be attributed to
that analyte.

Table 2
Figures of merit for the HS-PTV-fast GC–MS method
Solvent Linearity Precision RSD (%) Detection limit (ppt) Quantitation limit (ppt)

Concentrations (ppb) R2

1,1-Dichloroethene 0–24.2–48.4–72.6–96.8–121 0.9914 12 6.1 19

1,2-Dichloroethane 0–12.0–24.0–36.0–48.0–60.0 0.9913 10 7.9 24
1,1,1-Trichloroethane 0–12.0–24.0–36.0–48.0–60.0 0.9926 7.7 6.3 19
Carbon tetrachloride 0–12.0–24.0–36.0–48.0–60.0 0.9909 4.5 5.1 15
Benzene 0–3.12–6.24–9.36–12.5–15.6 0.9908 5.7 4.9 15
 J.L. Pérez Pavón et al. / J. Chromatogr. A 1141 (2007) 123–130 129

Table 3
Analytes found in the pharmaceutical products containing residual solvents
Pharmaceuticals Residual solvents (ppb)

1,1-Dichloroethene 1,2-Dichloroethane 1,1,1-Trichloroethane Carbon tetrachloride Benzene

L1 ND ND ND ND 4.0 ± 0.3
S1 ND 1.1 ± 0.1 ND ND ND
S2 ND 1.0 ± 0.3 ND ND ND

ND: not detected.

The benzene content was determined with HS-PTV-fast the injection interval between samples could be considerably
GC–MS. To overcome matrix effects, standard additions quan- reduced (5 min).
titation was used. The benzene contents and the confidence The methodology required about 10 min for the tempera-
interval for 95% probability was 4.0 ± 0.3 ppb (Table 3). This ture program to be completed and to ensure complete elution
concentration is well below the maximum permitted for benzene of the compounds present in the sample injected. Additionally,
(2 ppm). about 10 min were necessary to measure the next sample since
In S1 and S2, only 1,2-dichloroethane was found. The corre- the column had to be cooled down from the final temperature
sponding contour plots are shown in Fig. 6b and c, respectively. attained (240 ◦ C) to initial conditions of 35 ◦ C. Considering the
The 1,2-dichloroethane contents and the confidence interval for time invested in re-establishing the initial conditions, the anal-
95% probability were 1.1 ± 0.1 ppb and 1.0 ± 0.3 ppb for S1 and ysis time per sample (after the first 30 min) was therefore in the
S2, respectively (Table 3). Both pharmaceutical products had region of 20 min.
1,2-dichloroethane concentrations much lower than the maxi- After the first 30 min, it is possible to analyse three samples
mum permitted (5 ppm). per hour.
To check the possibilities of the methodology for those com-
pounds that were not detected, two of the formulations studied 4. Conclusions
(one liquid and the other solid) were spiked with them. In L1, 1,1-
dichloroethene, 1,2-dichoroethane, 1,1,1-trichloroethane and The proposed methodology has been successfully applied in
carbon tetrachloride were added. S2 was spiked with 1,1- different types of pharmaceutical products.
dichloroethene, 1,1,1-trichloroethane carbon tetrachloride and The advantage of this approach over others described
benzene. Again, standard additions quantitation was used. previously [18] is that in the present case, a PTV inlet was
The predicted versus added concentrations are shown in used. Important benefits of using solvent vent injection instead
Table 4. These results confirm the applicability of the proposed of classical-hot injection, such as better peak shapes and better
methodology for the quantification of all five class 1 residual signal-to-noise ratios, were found. Using solvent vent injection,
solvents. it was possible to carry out screening and quantitative analysis
for residual class 1 solvents at the low ppt level. It should
3.4. Time of analysis be emphasized that the method showed good precision and
accuracy.
The volatile generation time used in the present work was The use of headspace generation for introducing the sample
30 min. However, since the instrumental configuration employed and standard additions procedure as a quantification technique
had an oven with six positions for heating samples simulta- provided satisfactory results and minimized the matrix effect.
neously, this headspace generation could be overlapped and An important advantage of the methodology used here is that no
prior treatment of the sample is required, thus minimizing the
creation of analytical artifacts and the errors associated with this
Table 4 step of the analytical process.
Predicted concentrations and confidence intervals (95% probability) for the The importance of using automatic configurations for cryo-
solvents added in the different pharmaceutical products genic focusing coupled to static headspace sampling has been
Pharmaceutical Compound Added Predicted recently pointed out by Kolb and Ettre in their monography on
products concentration concentration headspace-gas chromatography [22]. Only a few reports on this
(ppb) (ppb) coupling have been published, mainly as application notes, by
1,1-Dichloroethene 4.1 5 ± 1 instrumentation companies [17].
1,2-Dichloroethane 4.1 5 ± 1
L1
1,1,1-Trichloroethane 4.1 5 ± 1 Acknowledgments
Carbon tetrachloride 4.1 4 ± 1
1,1-Dichloroethene 4.1 4 ± 1 We acknowledge the financial support of the DGI (Project
1,1,1-Trichloroethane 2.6 2.5 ± 0.8 CTQ2004-01379/BQU) and the Consejerı́a de Educación y Cul-
S2
Carbon tetrachloride 1.0 1.1 ± 0.3
tura of the Junta de Castilla y León (Project SA057A05) for this
Benzene 1.0 1.1 ± 0.3
research.
130 J.L. Pérez Pavón et al. / J. Chromatogr. A 1141 (2007) 123–130
References
[1] International Conference on Harmonization (ICH) of Technical Require-
ments for the Registration of Pharmaceuticals for Human Use, Q3C:
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