Analysis of USP <467> Residual Solvents of Class 1, Class 2, and Class 3 using the Agilent 8890 GC/ FID /5977B MSD System

Importance of the Topic

Analysis of residual solvents in pharmaceutical products is critical for patient safety and regulatory compliance. United States Pharmacopeia (USP) Method <467> classifies these solvents by risk (Class 1, 2, and 3) and restricts their levels in drug substances and excipients. Robust, sensitive, and efficient analytical solutions are needed to monitor over sixty volatile organic compounds and ensure quality control in drug manufacturing.

Objectives and Study Overview

This application note demonstrates a streamlined workflow using a single Agilent 8890 Gas Chromatograph fitted with both a flame ionization detector (FID) and a 5977B mass selective detector (MSD). Low–boiling point solvents (52 compounds) were analyzed by headspace injection on a DB-624 column, while higher–boiling point and polar solvents (10 compounds) were introduced by liquid injection on a DB-WAX UI column. A purged two-way capillary flow technology (CFT) splitter directed effluent 1:1 to FID and MSD, enabling concurrent qualitative and quantitative measurements.

Methodology and Instrumentation

• Agilent 8890 GC with Agilent 7697A Headspace Sampler and 7693A Automatic Liquid Sampler
• Columns: DB-624 (60 m × 0.25 mm, 1.4 µm) for headspace and DB-WAX UI (30 m × 0.25 mm, 0.25 µm) for liquid injection
• CFT splitter (G3180-60501) with 1:1 MSD:FID split
• Headspace parameters: 85 °C oven, 95 °C loop, 30 min equilibration, 1 mL loop volume
• Liquid injection parameters: SSL inlet at 250 °C, split ratios 10:1 (headspace) or 30:1 (liquid), 0.5 µL injection
• FID: H₂ 30 mL/min, air 300 mL/min, makeup N₂ 25 mL/min, 250 °C
• MSD: EI source at 230 °C, quad at 150 °C, scan mode

Results and Discussion

Both detectors achieved excellent linearity (R² > 0.99) across compound ranges. Repeatability (n=8) yielded area RSD ≤ 5% on MSD and ≤ 2.3% on FID. Method detection limits were in the sub-µg/mL range for most solvents. Dual detection resolved coelutions: unknown peaks were identified by library matching on MSD, while FID provided robust quantification. For higher–boiling solvents and water-soluble acids, liquid injection improved sensitivity. Retention times of formic and acetic acids shifted with DMSO concentration, requiring constant solvent composition across calibration levels.

Benefits and Practical Applications

• Single-instrument workflow reduces analysis time and method transfers
• Simultaneous MSD and FID detection allows unambiguous identification and quantification
• Flexibility to analyze diverse compounds from low- to high-boiling points
• Compliance with USP <467> and pharmacopeial standards
• High throughput for routine QA/QC and new drug development laboratories

Future Trends and Potential Applications

Advances in capillary flow technology and automated sample introduction may further increase throughput. Alternative stationary phases can address coelution challenges for specific solvent pairs. Integration of automated data processing and AI-based library searches will streamline unknown identification. Expansion of this dual-channel approach to other impurity analyses (e.g., pesticides, residual reactants) can enhance overall laboratory efficiency.

Conclusion

The Agilent 8890 GC/FID/5977B MSD system with headspace and liquid injection provides a powerful, versatile solution for comprehensive residual solvent analysis according to USP <467>. Excellent linearity, repeatability, and sensitivity across more than sixty solvents support reliable identification and quantification in pharmaceutical quality control.

References

1. United States Pharmacopeia 32-NF 27, General Chapter USP <467> Organic Volatile Impurities, USP Convention Inc., Rockville, MD, 2009.
2. Chinese Pharmacopoeia (2015), Appendix ⅥⅤ Solvent Residue Determination, China.