Analysis of Residual Solvents in Pharmaceuticals - Report No. 343

Significance of the Topic

Residual solvents in pharmaceutical products pose health risks and must meet regulatory limits set by JP17 Supplement II and USP 467. Headspace GC-FID is a widely adopted approach for quantifying volatile organic compounds in water-insoluble drug formulations.

Study Objectives and Overview

This application note demonstrates a method for detecting and quantifying key chlorinated and aromatic residual solvents in pharmaceuticals. The focus is on four target analytes: 1,1-dichloroethane; 1,1,1-trichloroethane plus carbon tetrachloride; benzene; and 1,2-dichloroethane.

Methodology and Used Instrumentation

The analysis employed a Shimadzu Nexis GC-2030 gas chromatograph equipped with an FID-2030 detector and HS-20 headspace sampler. A SH-PolarWax capillary column (30 m × 0.32 mm I.D., 0.25 µm) provided separation under the following conditions:

• Column temperature program: 50 °C (20 min) ramped at 6 °C/min to 165 °C, held 20 min (total runtime 59.17 min)
• Carrier gas: nitrogen at linear velocity 35 cm/s; split injection 1:10; injection volume 1 mL
• Headspace parameters: sample line 90 °C; transfer line 105 °C; oven 80 °C; vial equilibrating 45 min; pressurization 1 min at 68.9 kPa
• FID settings: detector at 250 °C; H₂ flow 32 mL/min; air 200 mL/min; make-up N₂ 24 mL/min

Main Results and Discussion

The method achieved clear baseline separation of all four solvents with sharp peak shapes and reproducible retention times. Sensitivity met regulatory reporting limits, and nitrogen carrier gas ensured stable linear velocity and consistent detector response.

Benefits and Practical Applications

• Robust quantification of volatile residuals in water-insoluble drugs
• Compliance with JP17 and USP 467 requirements
• High throughput enabled by optimized headspace equilibration and transfer conditions

Future Trends and Potential Applications

Advances in headspace automation, faster chromatographic phases, and integration with mass spectrometry are expected to enhance sensitivity and reduce analysis time. Method adaptation for a broader range of solvent classes will support evolving regulatory frameworks.

Conclusion

This optimized GC-FID headspace method on the Nexis GC-2030 system provides reliable detection of key residual solvents in pharmaceuticals, ensuring product quality and regulatory compliance.

References

• Shimadzu Corporation. Application News G326. First Edition, September 2022.