Analysis of Residual Solvents in Pharmaceuticals by Water-Soluble Samples Using H2 Carrier (USP 467)

Importance of the Topic

The analysis of residual solvents in pharmaceuticals is critical for ensuring product safety and compliance with regulatory standards. USP General Chapter <467> defines headspace GC methods to categorize and limit Class 1–3 solvents in drug products. Due to global helium shortages, hydrogen offers an inexpensive and readily available alternative carrier gas.

Goals and Study Overview

This study aims to validate the substitution of helium with hydrogen as a carrier gas in headspace GC analysis for water-soluble samples in accordance with USP Chapter <467>. The performance evaluation covers sensitivity, repeatability, and resolution for Class 1, 2A, and 2B standard solutions, comparing hydrogen and helium carriers.

Methodology and Instrumentation

The experiments were conducted on a Shimadzu Nexis GC-2030 equipped with an HS-20 NX headspace sampler and FID-2030 detector. A SH-Rxi™-624 Sil MS column (0.32 mm I.D. × 30 m, 1.8 µm) was used under a temperature program from 40 °C (20 min) to 240 °C at 10 °C/min. Headspace conditions included 80 °C oven temperature, 20 mL vial volume, 75 kPa vial pressurization with nitrogen, and 45 min heat-retention. Both hydrogen and helium carriers operated at a constant linear velocity of 35 cm/s. A built-in hydrogen sensor ensures safe operation and automatic shutdown upon leak detection.

Main Results and Discussion

• Class 1 solvents: Using hydrogen achieved signal-to-noise ratios above USP requirements (e.g., 1,1,1-trichloroethane S/N ≥ 5) with repeatability RSD < 4%, comparable to helium.
• Class 2A solvents: Chromatograms showed clear separation of critical pairs such as acetonitrile/methylene chloride, meeting USP resolution criteria (≥ 1.0) using hydrogen.
• Class 2B solvents: All target compounds, including newly added methyl isobutyl ketone (MiBK), were baseline resolved with hydrogen; performance matched or exceeded that of helium in peak shape and resolution.

Benefits and Practical Applications

• Cost reduction by replacing scarce helium with an inexpensive hydrogen source.
• Regulatory compliance: Meets USP General Chapters <467> and <1467> requirements for sensitivity, repeatability, and resolution.
• Enhanced safety: Integrated hydrogen sensor provides early leak detection and automatic system shutdown.
• High throughput and reliability: Advanced headspace sampling enables consistent measurement of residual solvents in various pharmaceutical matrices.

Future Trends and Potential Applications

Broader adoption of hydrogen carriers in QA/QC laboratories is expected, driven by cost savings and sustainability. Future developments may include integration with real-time monitoring, automation, coupling headspace GC with mass spectrometry, and microfluidic GC systems to further improve sensitivity, reduce analysis time, and handle diverse sample types.

Conclusion

This study demonstrates that hydrogen is a viable, cost-effective alternative to helium for USP-compliant residual solvent analysis by headspace GC. Shimadzu’s Nexis GC-2030 and HS-20 NX system deliver reliable performance with essential safety features.

Reference

Mikota Y, Kobayashi E, Miyamoto A. Analysis of Residual Solvents in Pharmaceuticals by Water-Soluble Samples Using H2 Carrier (USP 467). Application News 01-00176-EN, Shimadzu Corporation, 2021.