Analysis of Residual Solvents in Pharmaceutical Products by Headspace-GC-FID with Nitrogen Carrier Gas Following USP<467> - Procedure B

Significance of the Topic

Residual solvent testing is essential for pharmaceutical safety and regulatory compliance under USP<467>. Traditional use of helium as carrier gas can be costly and in limited supply. Evaluating nitrogen as an alternative carrier offers a practical solution without compromising analytical performance.

Objectives and Study Overview

The study aimed to assess the feasibility of headspace GC-FID using nitrogen carrier gas for residual solvent analysis in water-soluble pharmaceutical products following USP<467> Procedure B. Key performance metrics included sensitivity, precision, and chromatographic resolution.

Methodology and Used Instrumentation

• Instrumentation
  • Headspace autosampler HS-20
  • Nexis GC-2030 GC with flame ionization detector
  • SH-Stabilwax column, 30 m × 0.32 mm, 0.25 μm
• Headspace parameters
  • Oven temperature 80 °C
  • Sample line 110 °C, transfer line 120 °C
  • Equilibration 60 minutes, shaking level 2, pressurizing gas pressure 75 kPa
  • Injection time 1 minute, split ratio 10:1
• GC-FID conditions
  • Nitrogen carrier gas at constant linear velocity 35 cm/s
  • Oven program: 50 °C hold 20 min, ramp 6 °C/min to 165 °C hold 20 min
  • Detector temperature 250 °C, hydrogen flow 32 mL/min, synthetic air flow 200 mL/min, make-up gas flow 24 mL/min

Main Results and Discussion

• Class 1 standards showed repeatability (%RSD) between 1.8% and 5.1% and signal-to-noise ratios well above USP requirements (lowest S/N for benzene was 93).
• Co-elution of carbon tetrachloride with 1,1,1-trichloroethane was noted but did not affect compliance.
• Class 2 standards (2A and 2B) achieved %RSD values from 0.7% to 9.1% and a critical resolution of 2.9 for cis-1,2-dichloroethene versus acetonitrile, exceeding the minimum Rs of 1.

Practical Benefits and Applications

• Reduced operational costs by replacing helium with nitrogen.
• Meets USP<467> Procedure B criteria for water-soluble pharmaceutical products.
• Suitable for routine QC environments with robust and reproducible performance.

Future Trends and Opportunities

• Extension of the nitrogen-based HS-GC method to a wider range of solvent classes and complex matrices.
• Integration into high-throughput and automated quality control systems.
• Potential coupling with mass spectrometric detection for enhanced selectivity and confirmation.

Conclusion

Nitrogen has been shown to be an effective carrier gas substitute in HS-GC-FID analysis of residual solvents under USP<467> Procedure B, delivering required sensitivity, precision, and resolution while reducing costs.

References

1. The United States Pharmacopeia, USP <467> Residual Solvents
2. Shimadzu Application News AD-0209 Analysis of Residual Solvents in Pharmaceutical Products by Headspace-GC-FID with Nitrogen Carrier Gas Following USP<467> - Procedure A