GC HS-20 NX/Nexis™ GC-2030 /GCMS-QP 2020 NX

Qualitative Analysis Using HS-GC-FID/MS when

Application Testing for Residual Solvents in Pharmaceuticals
News — JP18, USP467: Water-Soluble Samples —
Y. Nagao, A. Hashimoto, A. Miyamoto

User Benefits
 Good separation was achieved for tert-butyl alcohol (t-BuOH) and cyclopentyl methyl ether (CPME), both recently
recommended for classification as class 2 solvents in ICH Q3C (R8).
 HS-GC/MS can obtain qualitative information about unknown components that are difficult to distinguish by flame ionization
detection (FID) analysis.
 LabSolutionsTM DB/CS can be used to support data integrity and prevent data falsification and other similar problems.
 Introduction Table 1 Water-Soluble Sample Analysis Conditions

The Japanese Pharmacopoeia 18th Edition (JP18) and United GC-MS Analysis Conditions (Procedure A)
States Pharmacopeia General Chapter <467> Residual Solvents Model : GCMS-QP2020 NX
Column : SH-I-624 Sil MS
describe tests for residual solvents in pharmaceuticals that are (0.32 mm I.D. × 30 m, d.f.= 1.8 µm)
mainly performed by headspace gas chromatography coupled Column Temp. : 40 °C (20 min) – 10 °C/min – 240 °C (20 min)
with flame ionization detection (HS-GC-FID). Residual solvents Total 60 min
in pharmaceuticals are strictly controlled based on an Injection Mode : Split 1 : 5
evaluation of the risk they pose to human health and classified Carrier Gas Controller : Constant linear velocity mode (He)
Linear Velocity : 40 cm/sec
as Class 1, 2, or 3 solvents. Testing for these residual solvents in
pharmaceuticals requires highly sensitive analytical methods. [FID-2030]
Qualitative analysis by GC-FID normally requires the use of Detector Temp. : 250 °C
standard reference solvents, and accurate solvent identification FID H2 Flowrate : 32 mL/min
can be difficult when peaks overlap. However, gas FID Make-up Flowrate : 24 mL/min (He)
FID Air Flowrate : 200 mL/min
chromatography-mass spectrometry (GC-MS) can also provide
qualitative information about sample components based on
[MS]
mass spectra. Unknown peaks or peaks that are difficult to Ion Source Temp. : 200 °C
distinguish due to their proximity to other analyte peaks can be Interface Temp. : 250 °C
identified using mass spectrometry, or mass spectrometry can SCAN Range : m/z 30 to 250
be used to investigate causes of contamination and other Event Time : 0.3 sec
issues. HS Analysis Conditions (Procedure A)
Oven Temperature : 80 °C
This article presents results from using an HS-20 NX headspace Equilibration Time : 45 min
sampler and GCMS-QP2020 NX to analyze water-soluble Sample Line Temp. : 110 °C
samples of Class 1 and Class 2 solvents. Transfer Line Temp. : 120 °C
Vial Stirring : Off
Vial Volume : 20 mL
Vial Pressurization Time : 1 min
Vial Pressure : 75.0 kPa (He)
Loading Time : 0.5 min
Needle Flush Time : 5 min
Injection Volume : 1 mL
Load Equilib. Time : 0 min

Fig. 1 GCMS-QP 2020 NX + HS-20 NX  FID Analysis of a Class 1 Standard Solution

Table 2 shows the S/N ratio and reproducibility results for each
 Sample Preparation compound in a Class 1 standard solution.
A Class 1 standard solution, Class 2A standard solution, Class 2B These results meet the acceptance criterion for Procedure A
standard solution, and test solution were prepared according to system suitability testing cited by JP18 and USP<467>: an S/N
each method described under Procedure A for water-soluble ratio of 1,1,1-trichloroethane of not less than 5, as well as the
samples. The Class 2A standard solution was spiked with t-BuOH criterion cited by JP18: a relative standard deviation of each
and CPME, both recently recommended for classification as peak area of not more than 15 %.
Class 2 solvents in ICH Q3C (R8).
Table 2 S/N Ratio and Reproducibility of Class 1 Standard Solution
(Procedure A)
 Instrument Configuration and Analysis S/N
Relative standard
Conditions Peak No. Compound
Ratio*1
deviation (%)*1
(n=6)
An HS-20 NX headspace sampler was coupled to a GCMS- 1 1,1-Dichloroethane 190 1.92
QP2020 NX (Fig. 1) and used to perform Procedure A testing of 2 1,1,1-Trichloroethane 223 1.81
water-soluble samples based on JP18 and USP<467>. The 3 Carbon tetrachloride 12 2.61
analysis conditions are shown in Table 1. The Nexis GC-2030 was 4 Benzene 247 1.46
used for GC-FID analysis, and the GCMS-QP2020 NX was used 5 1,2-Dichloroethane 140 0.71
for GC-MS analysis. Measurements were taken with each *1 The S/N ratio and relative standard deviation values are for reference
detector using the same column for both instruments. purposes and not intended to be guaranteed values.
Application
News

 Analysis of Standard Solutions (Water-

Soluble Sample)
The results show that using the same column in both
Figures 2 to 4 show FID and MS chromatograms obtained from instruments and performing analysis in constant linear velocity
analyzing the Class 1 standard solution, Class 2A standard mode allowed peak retention times to be matched for all
solution, and Class 2B standard solution. When verifying the analytes. The results also confirm the two solvents added to the
mass spectra of peaks detected by FID, peak retention times Class 2A standard solution (Fig. 3: Compounds labeled in red)
should be matched as closely as possible between FID and MS were separated from other analytes.
chromatograms.
Note: The degrees of separation shown in these figures are for reference
purposes and not intended to be guaranteed values.

FID

1,1,1-Trichloroethane

Benzene
1,1-Dichloroethane

1,2-Dichloroethane
Carbon tetrachloride
2.0 3.0 4.0 5.0 6.0 7.0 8.0 9.0 10.0 11.0 min
MS
(TIC)

2.0 3.0 4.0 5.0 6.0 7.0 8.0 9.0 10.0 11.0 min
Fig. 2 Chromatogram of Procedure A Class 1 Standard Solution (Water-Soluble)

FID
Cyclopentyl Methyl Ether
cis-1,2-Dichloroethylene
trans-1,2-Dichoroethylene

Cyclohexane

Methyl cyclohexane

Toluene

Chlorobenzene

m,p-Xylene
Ethylbenzene
MiBK

o-Xylene
Degree of separation

Cumene
2.1 (USP)
1.9 (JP)
t-BuOH

Tetrahydrofuran
Acetonitrile

DCM

1,4-Dioxane
MeOH

2.5 5.0 7.5 10.0 12.5 15.0 17.5 20.0 22.5 25.0 27.5min
MS
(TIC)

2.5 5.0 7.5 10.0 12.5 15.0 17.5 20.0 22.5 25.0 27.5min
Fig. 3 Chromatogram of Procedure A Class 2A Standard Solution (Water-Soluble)
Tetraline

FID
1,1,2-Trichloroethylene

Methylbutylketone
Hexane

1,2-Dimethoxyethane
Nitromethane
Chloroform

Pyridine

5.0 7.5 10.0 12.5 15.0 17.5 20.0 22.5 25.0 27.5 30.0 32.5 min
MS
(TIC)

5.0 7.5 10.0 12.5 15.0 17.5 20.0 22.5 25.0 27.5 30.0 32.5 min
Fig. 4 Chromatogram of Procedure A Class 2B Standard Solution (Water-Soluble)
Application
News

 Analysis of a Sample (Water-Soluble Sample)

Fig. 5 shows chromatograms for a standard solution and of peak a revealed it to be α-pinene (Fig. 7).
pharmaceutical test solution. Although peak a eluted with almost Misidentification errors like this can be prevented by using GC-
the same retention time as cumene in the FID chromatogram and MS to check mass spectra.
was estimated to be cumene (Fig. 6), checking the mass spectrum

Class2A Standard (FID)

Sample (FID)

Cumene
a

0.0 2.5 5.0 7.5 10.0 12.5 15.0 17.5 20.0 22.5 25.0 27.5 30.0 32.5 35.0 37.5 min
Fig. 5 FID Chromatogram of a Standard Solution and Test Solution (Water-Soluble Sample)

 Using LabSolutions GCMS for Analysis

The GCMS-QP2020 NX was controlled using LabSolutions
integrated analysis software. An example analysis window is
105
shown in Fig. 8. The software uses graphical icons for more
intuitive control.
The software can be used to control both GC-FID analysis and
GC-MS analysis. LabSolutions DB/CS also provides support for
data integrity to prevent data falsification, data replacement,
120
and other issues.
79
250
39 51 65 91
128 148155162 174 189 206 218 236
50.0 75.0 100.0 125.0 150.0 175.0 200.0 225.0 m/z

Cumene

Fig. 6 Mass Spectrum of Cumene

93

Fig. 8 Analysis Window from LabSolutionsTM GCMS

77
41 53 121 136
 Conclusion
67 105 248
119 148155 169 182 205212 226 237 Tests for residual solvents in pharmaceuticals were performed
50.0 75.0 100.0 125.0 150.0 175.0 200.0 225.0 m/z using HS-GC/MS and HS-GC. Good separation was obtained for
t-BuOH and CPME, both of which were recently recommended
for classification as Class 2 solvents in ICH Q3C (R8).
α-Pinene When analyzing a test sample, GC-MS revealed accurate
qualitative information about a component that was otherwise
misidentified based on FID analysis.
Fig. 7 Mass Spectrum of Peak a LabSolutions DB/CS can also be used to support data integrity.

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01-00221A-EN First Edition: Sep. 2021
Revision A: Oct.2022
For Research Use Only. Not for use in diagnostic procedures.
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