Analysis of USP <467> Residual Solvents using the Agilent 7697A Headspace Sampler with the Agilent 7890B Gas Chromatograph

Significance of the Topic

The analysis of residual solvents according to USP <467> is critical for pharmaceutical quality control to ensure patient safety and compliance with regulatory standards. Static headspace GC/FID methods enable trace-level detection of volatile impurities in drug substances.

Objectives and Study Overview

This application note describes the direct transfer of a USP <467> residual solvent method from an Agilent 7890A GC to an Agilent 7890B GC equipped with a 7697A Headspace Sampler. The study evaluates repeatability, sensitivity, and chromatographic resolution for Class 1, 2A, and 2B solvents at USP-defined concentration limits.

Methodology and Instrumentation

Static headspace sampling was performed at 85 °C for 40 min using 20 mL vials containing residual solvents in DMSO/water, maintaining a 6 mL sample volume. The system combined an Agilent 7697A Headspace Sampler with a 7890B GC operating in parallel dual-column mode. Column A was a VF-624ms (30 m × 0.32 mm, 1.8 µm), and Column B was an HP-INNOWax (30 m × 0.32 mm, 0.25 µm). Helium at 104 kPa served as carrier gas. Injection was split/splitless at 140 °C with a 1:5 split ratio, and the oven was programmed from 40 °C (5 min) to 240 °C at 18 °C/min. Detection on both channels was performed by FID at 250 °C.

Used Instrumentation

• Agilent 7697A Headspace Sampler
• Agilent 7890B Gas Chromatograph
• Columns: VF-624ms and HP-INNOWax
• Ultra Inert split/splitless inlet liner (p/n 5190-2295)
• Thermal zones with Capillary Flow Technology

Main Results and Discussion

• Chromatographic performance on the 7890B matched that of the 7890A, with equivalent elution order, resolution, and sensitivity.
• Class 1 solvents achieved baseline separation on VF-624ms; signal-to-noise ratios ranged from 4 to 42, exceeding the USP threshold of S/N > 3.
• Six replicate injections yielded an average RSD of 1.6% on VF-624ms, demonstrating excellent precision for static headspace sampling.

Benefits and Practical Applications

• Seamless method transfer reduces validation workload and accelerates regulatory compliance.
• Parallel dual-column detection enhances reliability and peak identification.
• Stable thermal control and inert flow paths contribute to reproducible performance.

Future Trends and Potential Applications

Enhancements in automated headspace workflows, advanced flow control, and integration with mass spectrometry are expected to improve sensitivity and throughput. Dual-channel and multiplexed analyses may extend applications to complex samples in pharmaceutical development and beyond.

Conclusion

This study confirms that USP <467> residual solvent methods can be directly migrated from Agilent 7890A to 7890B systems without performance loss, providing a robust protocol for pharmaceutical QC laboratories.

References

1. Firor RL Analysis of USP <467> residual solvents with improved repeatability using the Agilent 7697A Headspace Sampler Application Note 5990-7625EN 2012
2. United States Pharmacopeia General Chapter USP <467> Organic Volatile Impurities USP 32-NF 27 Rockville MD 2009