Analysis of Residual Solvents – Class 1, Class 2A, Class 2B – in Pharmaceuticals Using Headspace-GC/MS

Importance of the Topic

Residual solvents in pharmaceuticals are regulated impurities that can affect patient safety and drug efficacy. A robust analytical approach capable of identifying and quantifying these volatile compounds in a single analysis enhances laboratory efficiency and ensures compliance with regulatory standards.

Study Objectives and Overview

This work demonstrates the feasibility of using headspace gas chromatography–mass spectrometry (HS-GC/MS) to analyze USP <467> Class 1, Class 2A, and Class 2B residual solvents simultaneously. The goal is to reduce the number of analyses from three separate runs (by HS-GC/FID) to a single HS-GC/MS method without compromising selectivity, sensitivity, or repeatability.

Methodology and Instrumentation

Sample Preparation:

• Aqueous standard solutions for Class 1, 2A, and 2B solvents were prepared at USP <467> concentrations.
• Equilibration in sealed vials at 80 °C for 60 min to generate headspace.

Instrumental Conditions:

• Headspace Sampler: HS-20 (Shimadzu)
• Gas Chromatograph–Mass Spectrometer: GCMS-QP2010 Ultra
• Column: Rxi-624Sil MS, 30 m × 0.25 mm I.D., 1.4 µm film
• Headspace Mode: Loop injection, 1 mL volume, split 1:30
• Oven Program: 40 °C (20 min) → 10 °C/min → 240 °C (20 min)
• MS Detection: Electron ionization, SIM acquisition for target confirmation, scan range m/z 29–200

Results and Discussion

Total ion chromatograms (TICs) for each solvent class illustrated effective separation under HS-GC/MS conditions. Extracted ion chromatograms (EICs) and selected ion monitoring (SIM) provided clear peak identification, even for co-eluting analytes. Compared to HS-GC/FID, the MS method delivered an improved signal-to-noise ratio for compounds such as carbon tetrachloride. Repeatability studies (n = 6) yielded area RSDs between 1.3% and 3.9% across all classes, demonstrating high precision.

Benefits and Practical Applications

• Single-run analysis reduces total analysis time and solvent consumption.
• Mass spectrometric detection allows qualitative confirmation of unknown peaks.
• Improved sensitivity and selectivity facilitate reliable quantitation at trace levels.
• Applicable in quality control laboratories for rapid residual solvent screening.

Future Trends and Opportunities

Integration of automated sample handling and data processing will further streamline HS-GC/MS workflows. Expanding the method to include Class 3 solvents and new pharmaceutical excipients could broaden its applicability. Advances in high-throughput headspace automation and enhanced mass spectrometer resolution promise even greater sensitivity and compound identification capabilities.

Conclusion

The HS-GC/MS approach successfully achieved simultaneous analysis of USP <467> Class 1, 2A, and 2B residual solvents in pharmaceuticals with excellent repeatability and selectivity. This method offers a reliable and efficient alternative to the traditional multi-run HS-GC/FID procedure.

References

• Shimadzu Application News No. M268, Shimadzu Corporation, First Edition Oct. 2014
• United States Pharmacopeia General Chapter <467> Residual Solvents