Analysis of USP <467> Residual Solvents
using the Agilent 7697A Headspace
Sampler with the Agilent 7890B Gas
Chromatograph
Authors
Bart Tienpont, Frank David, and
Pat Sandra
Research Institute for Chromatography
Kennedypark 26
B-8500 Kortrijk
Belgium
Roger L Firor
Agilent Technologies, Inc.
2850 Centerville Rd
Wilmington, DE 19808
Application Note
Pharmaceuticals
Abstract
USP <467> residual solvents were analyzed by static headspace on the Agilent
7697A Headspace Sampler combined with the Agilent 7890B Gas Chromatograph.
The previously described method performed on an Agilent 7890A GC was directly
transferred to the 7890B GC. Excellent chromatographic performance was achieved
at USP <467> specified limits and equivalent results were obtained. This test clearly
indicated that methods can be transferred directly from an Agilent 7890A GC to the
7890B GC without modification.
2
Introduction
Residual solvent analysis is a very important quality control
procedure performed in the pharmaceutical industry. Sampling
is typically performed by static headspace and analysis is
done by GC/FID using a dedicated column. Often, a parallel
column dual channel analysis by GC/FID or GC/FID/MSD is
used. Previously, different configurations were described and
tested in terms of repeatability, sensitivity and resolution [1].
The described dual channel GC/FID method was evaluated on
the Agilent 7890B GC. The original method was transferred to
the GC, without modification. Repeatability, sensitivity, and
resolution were all tested using residual solvent solutions in
water of Class 1, Class 2A, and Class 2B compounds.
Experimental
Solutions
Three stock solutions of residual solvents in DMSO were
used:
• Residual Solvent Revised Method 467 – Class 1
(p/n 5190-0490),
• Residual Solvent Revised Method 467 – Class 2A
(p/n 5190-0492),
• Residual Solvent Revised Method 467 – Class 2B
(p/n 5190-0513).
These stock solutions were diluted in water to the USP
specified limits according to the following scheme:
Class 1 solvents
• 1.0 mL stock solution vial plus 9 mL DMSO diluted to 100 mL
• 1.0 mL from step 1 diluted to 100 mL with water
• 10 mL from step 2 diluted to 100 mL with water
• 1.0 mL from step 3 + 5 mL water in a 20-mL headspace
(HS) vial
Class 2A solvents
• 1.0 mL stock solution vial, diluted to 100 mL
• 1.0 mL from step 1 + 5 mL water in a 20-mL HS vial
Class 2B solvents
• 1.0 mL stock solution vial, diluted to 100 mL
• 5.0 mL step 1 + 1 mL water in a 20-mL HS vial
The total sample volume was thus constant at 6 mL in 20-mL
headspace vials. Assuming a 50-mg drug substance sample in
the headspace vial, the final residual solvent concentrations
correspond to the USP concentration limits (Table 1).
Table 1. Residual Solvents, Peak Number, USP Concentration Limits
(ppm = mg/kg) and Repeatability (n = 6) Obtained by HS-GC-FID
on Column 1 (VF624)
Identity USP limit (ppm) RSD (%)
Class 1
1 1,1-dichloroethene 8 2.3
2 1,1,1-trichloroethane 1,500 1.7
3 carbon tetrachloride 4 1.9
4 benzene 2 1.7
5 1,2-dichloroethane 5 2.1
Class 2A
1 methanol 3,000 0.8
2 acetonitrile 410 0.8
3 dichloromethane 600 0.3
4 trans-1,2-dichloroethene 1,870 0.8
5 cis-1,2-dichloroethene 1,870 1.4
6 tetrahydrofuran 720 1.1
7 cyclohexane 3,880 1.4
8 methylcyclohexane 1,180 1.5
9 1,4-dioxane 380 1.4
10 toluene 890 1.7
11 chlorobenzene 360 0.4
12 ethylbenzene 2,170 0.6
13,14 m-xylene, p-xylene 2,170 2.2
15 o-xylene 2,170 2.2
Class 2B
1 hexane 290 3.1
2 nitromethane 50 4.3
3 chloroform 60 1.7
4 1,2-dimethoxyethane 100 1.5
5 trichloroethene 80 2.0
6 pyridine 200 1.4
7 2-hexanone 50 1.6
8 tetralin 100 1.7