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

Significance of the Topic

Monitoring residual solvents in pharmaceutical products is critical for patient safety and regulatory compliance. The United States Pharmacopeia (USP) General Chapter <467> defines stringent limits and analytical methods for Class 1–3 solvents. Traditionally, helium has been the carrier gas of choice in headspace gas chromatography (HS-GC), but global shortages and rising costs have driven interest in hydrogen as an alternative. This study demonstrates hydrogen’s capability to deliver USP-compliant analyses while reducing laboratory expenses.

Study Objectives and Overview

The primary goal was to validate hydrogen as a carrier gas in HS-GC for water-insoluble pharmaceutical samples under USP General Chapter <467> (residual solvents) and to verify method performance per USP <1467>. Analysis focused on Class 1 and Class 2 standard solutions using Procedure A, comparing signal-to-noise ratios, repeatability, and chromatographic resolution between hydrogen and helium carriers.

Methods and Instrumentation

Analysis employed a Shimadzu Nexis GC-2030 gas chromatograph fitted with an FID-2030 detector, coupled to an HS-20 NX headspace sampler. Key GC parameters included:

• Column: SH-Rxi™-624Sil MS (0.32 mm×30 m, 1.8 µm)
• Temperature program: 40 °C (20 min) → 240 °C at 10 °C/min (20 min)
• Carrier modes: constant linear velocity at 35 cm/s using H2 or He
• FID gases: H2 32 mL/min, N2 makeup 24 mL/min, air 200 mL/min

Headspace conditions included 80 °C oven, 45 min equilibration, 68.9 kPa N2 pressurization, and 1 mL injection.

Main Results and Discussion

For the Class 1 solution, hydrogen provided signal-to-noise ratios above USP thresholds (e.g., ≥211 for 1,1,1-trichloroethane) and relative standard deviations below 5 %. Comparable or slightly higher S/N values were obtained versus helium. In Class 2A, resolution between acetonitrile and methylene chloride exceeded the USP requirement of 1.0 with hydrogen. Chromatograms for Class 2B also showed equivalent peak separation and reproducibility, confirming hydrogen’s suitability.

Benefits and Practical Applications

• Cost efficiency: hydrogen is less expensive and more readily available than helium.
• Regulatory compliance: meets USP <467> and <1467> criteria for residual solvent analysis.
• Safety assurance: integrated hydrogen sensor in the GC system detects leaks and automatically disables power to mitigate risk.
• Reliability: HS-20 NX headspace sampler ensures consistent sample introduction and robust performance.

Future Trends and Potential Applications

Wider adoption of hydrogen as a GC carrier may extend to diverse pharmaceutical matrices and other regulated industries. Advances in leak-detection technology, automated method validation workflows, and hybrid carrier-gas systems will further streamline solvent analyses. Integration with mass spectrometric detection could enhance sensitivity and broaden scope.

Conclusion

This work confirms that hydrogen is a viable, cost-effective carrier gas for USP-compliant HS-GC analysis of water-insoluble pharmaceutical samples. It achieves requisite performance metrics for Class 1 and Class 2 solvents while offering safety features and operational savings, making it an attractive alternative to helium.