Analysis of USP <467> Residual Solvents Using the Agilent 8697XL Headspace Sampler and Agilent 8890 GC

Importance of the Topic

Residual solvents represent volatile organic chemicals introduced during pharmaceutical manufacturing. Monitoring these analytes ensures product safety and regulatory compliance under USP <467> and ICH Q3C guidelines. Headspace GC analysis plays a critical role in quality control and risk assessment of drug substances and excipients.

Objectives and Study Overview

This study evaluated the performance of an integrated headspace sampler coupled to a dual-channel GC/FID system for analyzing USP <467> class 1, 2A, and 2B residual solvents at their limit concentrations. Both helium and nitrogen carriers were benchmarked, with a focus on resolution, sensitivity, and repeatability.

Methodology

The analytical configuration combined an Agilent 8697XL headspace sampler with an Agilent 8890 GC hosting two parallel FID channels. Two capillary columns (DB-Select 624 UI and DB-WAX UI) enabled simultaneous procedure A and procedure B analyses. Sample vials were equilibrated at 85 °C for 40 min, with loop pressurization and split ratios optimized per USP recommendations.

Used Instrumentation

• Agilent 8697XL Headspace Sampler
• Agilent 8890 GC with two FID detectors
• DB-Select 624 UI column (30 m × 0.32 mm, 1.8 μm)
• DB-WAX UI column (30 m × 0.32 mm, 0.25 μm)

Results and Discussion

Both carrier gases met USP <467> acceptance criteria. Using helium, resolutions exceeded minimum requirements (e.g., acetonitrile/MIBK R=1.68; MIBK/cis-dichloroethene R>5). Nitrogen also provided comparable separation after adjusting oven temperature (38 °C initial) and reduced column flow, achieving R=1.17 for acetonitrile/MIBK. Area repeatability (n=10) was typically below 2.5% with helium and under 4.5% with nitrogen. Retention time RSDs remained under 0.03% for all analytes, demonstrating robust system performance. Automated headspace diagnostics on the 8890 GC minimized leaks and ensured consistent sampling integrity.

Benefits and Practical Applications

• Simultaneous dual-column analysis reduces total run time compared to separate injections.
• Nitrogen carrier gas offers a cost-effective alternative during helium shortages without compromising analytical quality.
• Integrated diagnostics improve uptime and reliability in regulated environments.

Future Trends and Opportunities

• Expansion to automated quantitation workflows with software integration and data trending.
• Adoption of alternative carrier gases to mitigate resource constraints.
• Development of headspace–MS coupling for enhanced selectivity and trace-level detection.

Conclusion

The Agilent 8697XL/8890 dual-channel GC/FID system efficiently quantifies USP <467> residual solvents, offering high resolution, repeatability, and flexibility with helium or nitrogen carrier gas. This integrated approach streamlines compliance testing and supports robust quality control operations.

References

1. USP <467> Residual Solvents.
2. ICH Q3C(R8) Impurities: Guidance for Residual Solvents.
3. Eisele I. Residual Solvents Analysis Using an Agilent Intuvo 9000 GC with 8697 Headspace Sampler. Agilent Technologies Application Note, 2021.