Rapid and cost-effective determination of Class 3 residual solvents in pharmaceutical products by HS-GC with hydrogen as carrier gas

Importance of the topic

Pharmaceutical products require stringent control of residual organic solvents to ensure patient safety and regulatory compliance. Among these, Class 3 solvents are favored for their low toxicity and environmental benignity. Analytical methods that rapidly and reliably quantify these solvents support green chemistry initiatives and streamline quality control in high-throughput laboratory environments.

Objectives and Study Overview

This study aimed to demonstrate the suitability of a Thermo Scientific TriPlus 500 static headspace autosampler coupled to a TRACE 1610 gas chromatograph, using hydrogen as carrier gas, for rapid and cost-effective determination of Class 3 residual solvents in pharmaceutical matrices. Dual detection by flame ionization (FID) and mass spectrometry (MS) was employed to enable both accurate quantitation and spectral identification of targeted and unknown compounds.

Methodology and Instrumentation

• Headspace sampling: TriPlus 500 valve-and-loop static autosampler (240-vial capacity) with direct headspace-to-column interface.
• Gas chromatography: TRACE 1610 GC equipped with an iConnect split/splitless injector bypassed during analysis.
• Analytical column: TraceGOLD TG-624SilMS (30 m × 0.32 mm × 1.8 µm) for high inertness and thermal stability up to 320 °C.
• Carrier gas: Hydrogen at constant pressure (70 kPa) for faster separation and reduced environmental footprint.
• Detection: Dual-path microfluidic split (1:1) feeding FID and TSQ 9610 triple quadrupole MS in full-scan mode.
• Sample preparation: Matrix-matched calibration standards (100–15 000 µg/g) in aqueous solution; model aspirin sample (20 mg nominal) in water for method validation.

Main Results and Discussion

Baseline chromatographic separation of 24 Class 3 solvents was achieved in less than 11 minutes, with resolution >1.1 for most analyte pairs. Calibration over 100–15 000 µg/g showed excellent linearity (R² > 0.992; AvCF %RSD < 14%). Calculated MDLs were below 100 µg/g for most compounds, and peak area repeatability averaged 2.6 % RSD. Analysis of the aspirin sample revealed residual acetone well below the 5 000 µg/g limit and identified D-limonene as an excipient trace using NIST20 spectral matching. The same chromatographic conditions also met USP <467> system suitability requirements for Class 1 and Class 2 solvents, delivering a fourfold reduction in analysis time compared to official USP protocols.

Benefits and Practical Application

• Rapid cycle times (<20 min total) increase throughput in QA/QC laboratories.
• Dual FID/MS detection ensures robust quantitation and confident compound identification, including unknown screening.
• Use of hydrogen carrier gas aligns with green chemistry principles and lowers operating costs.
• Automated sampling and processing with Chromeleon 7.3 CDS support FDA 21 CFR Part 11 and EU Annex 11 compliance, ensuring data integrity and streamlined workflows.

Future Trends and Potential Applications

Integration of hydrogen-based GC methods with advanced headspace automation is expected to expand into multi-analyte screening (e.g., pesticides, environmental contaminants). Further improvements in data deconvolution and AI-driven spectral matching will streamline unknown identification. Development of more inert microfluidic interfaces and sustainable gas alternatives will support greener, high-throughput workflows across pharmaceutical and industrial analytics.

Conclusion

The presented HS-GC method, combining hydrogen carrier gas with dual FID/MS detection, provides a robust, fast, and eco-friendly solution for residual solvent analysis in pharmaceuticals. It achieves high sensitivity, linearity, and full compliance with USP <467> requirements while reducing run times and operational costs, thus addressing both regulatory and sustainability challenges.

References

1. Design for the Environment Program Announces: Alternative Synthetic Design for Pollution Prevention. U.S. EPA, 1993.
2. United States Pharmacopeia, USP General Chapter <467> Organic Volatile Impurities, 2019.
3. International Council for Harmonization, ICH Q3C(R6) Guideline for Residual Solvents, 2016.
4. Capello C.; Fischer U.; Hungerbühler K. What is a green solvent? Green Chemistry 2007, 9, 927–934.
5. Byrne F.P.; Jin S.; Paggiola G.; Petchey T.H.M.; Clark J.H.; Farmer T.J.; Hunt A.J.; McElroy C.R.; Sherwood J. Tools and techniques for solvent selection: green solvent selection guides. Sustainable Chemical Processes 2016, 4, 7.
6. Thermo Fisher Scientific. TriPlus 500 Gas Chromatography Headspace Autosampler – Productivity from all Angles. Brochure AN002014-EN, 2023.
7. Thermo Fisher Scientific. Application Note 10676: Residual solvents determination according to USP <467>, 2022.
8. Thermo Fisher Scientific. Application Note 73374: Method validation based on ICH guidelines of a USP assay method of acetaminophen, 2021.
9. United States Pharmacopeia, USP General Notices and Requirements <38>, 2015.