Residual Solvents per USP 467 using Zebron™ ZB-624PLUS™ and ZB-WAXPLUS™ GC Columns

Importance of the Topic

Residual solvents are volatile organic compounds that may remain in pharmaceutical products and pose toxicity or environmental risks. The ICH Q3C guidelines and USP <467> establish a harmonized framework for classifying these solvents by health risk and permissible limits, ensuring patient safety and regulatory compliance.

Objectives and Study Overview

This technical note evaluates two gas chromatography columns—Zebron ZB-624PLUS and Zebron ZB-WAXPLUS—for USP <467> residual solvent analysis. The goal is to demonstrate their suitability for the three prescribed procedures: identification (Procedure A), confirmation (Procedure B), and quantification (Procedure C) of Class 1, Class 2, and Class 3 solvents in drug substances, excipients, and finished products.

Applied Methodology and Instrumentation

• Static headspace extraction to introduce volatile solvents into the GC system.
• Procedure A employs a G43 phase column (ZB-624PLUS) with flame ionization detection (FID).
• Procedure B uses an orthogonal G16 phase column (ZB-WAXPLUS) for confirmation.
• Procedure C quantifies identified solvents using the column offering optimal selectivity (G43 or G16).
• Water is used to dilute water-soluble samples; dimethylformamide or dimethyl sulfoxide for water-insoluble matrices.
• System suitability criteria include signal-to-noise ratios ≥3 for all peaks, ≥5 for key analytes, and resolution ≥1.0 for critical peak pairs.

Main Results and Discussion

• On ZB-624PLUS (30 m×0.32 mm×1.8 µm), the S/N ratio for 1,1,1-trichloroethane exceeded 5 and ≥3 for other Class 1 solvents; resolution between acetonitrile and dichloromethane was ≥1.0.
• ZB-WAXPLUS (30 m×0.32 mm×0.25 µm) delivered benzene S/N >100 and resolution >1.0 between acetonitrile and cis-1,2-dichloroethene.
• Both columns achieved clear separation of Class 2 Mixtures A and B with sharp peak shapes under USP-specified GC conditions.
• The methods fully comply with USP <467> for identifying, confirming, and quantifying Classes 1–3 solvents.

Benefits and Practical Applications

• Offers a validated, regulatory-compliant approach for residual solvent testing in QA/QC laboratories.
• Enhances selectivity and reproducibility for complex solvent mixtures.
• Facilitates rapid method transfer and consistent performance across pharmaceutical workflows.

Future Trends and Opportunities

Future developments may include faster GC temperature programs, novel stationary phases for improved resolution, automated headspace sampling, and coupling with mass spectrometry to increase sensitivity and broaden the scope of detectable impurities.

Conclusion

Zebron ZB-624PLUS and ZB-WAXPLUS columns meet USP <467> requirements, providing robust, reliable separations for the identification, confirmation, and quantification of residual solvents in pharmaceutical products. Their consistent performance supports streamlined compliance and analytical confidence.

References

1. United States Pharmacopeia and National Formulary (USP 38-NF 33), USP Convention; 2018.
2. Osterberg RE. Impurities: Residual Solvents ICH Q3C. 2007 USP/PDA Joint Conference.
3. USP General Notices: <467> Organic Volatile Impurities, 2007.
4. Phenomenex Inc. Understanding Revisions to USP <467>. 2018.

Used Instrumentation

• Gas chromatograph with static headspace autosampler.
• Zebron ZB-624PLUS column (G43 phase), 30 m×0.32 mm×1.80 µm, FID at 250 °C.
• Zebron ZB-WAXPLUS column (G16 phase), 30 m×0.32 mm×0.25 µm, FID at 250 °C.
• Carrier gas: Helium (constant flow); split injection 5:1 at 140 °C.
• Diluents: Water for soluble samples; DMF or DMSO for insoluble matrices.