Analysis of Residual Solvents in Pharmaceuticals - Report No. 340

Importance of the Topic

Residual solvents in pharmaceuticals can pose safety risks and must be controlled to meet regulatory guidelines such as JP17 Supplement II and USP 467. Headspace gas chromatography with flame ionization detection (HS-GC-FID) provides a sensitive and selective approach for quantifying trace levels of volatile organic impurities in water-soluble drug formulations.

Study Objectives and Overview

This application note describes a validated HS-GC-FID method for simultaneous analysis of five chlorinated residual solvents (1,1-dichloroethane; 1,1,1-trichloroethane; carbon tetrachloride; benzene; 1,2-dichloroethane) in pharmaceutical samples. The work demonstrates compliance with pharmacopeial limits and practical utility for routine quality control.

Methodology and Instrumentation

The analysis was performed on a Nexis™ GC-2030 equipped with an FID-2030 detector and Shimadzu HS-20 headspace sampler. A 30 m × 0.32 mm I.D. SH-I-624Sil MS column (1.8 µm film) was used for separation. Key parameters included:

• Carrier gas: nitrogen at linear velocity 35 cm/s
• Oven program: 40 °C hold 20 min, ramp 10 °C/min to 240 °C hold 20 min (total 60 min)
• Headspace oven: 80 °C; transfer line: 120 °C; sample line: 110 °C
• Injection: split ratio 1:5, volume 1 mL
• FID conditions: 250 °C; H₂ flow 32 mL/min; air flow 200 mL/min; makeup N₂ 24 mL/min
• HS settings: 20 mL vial, equilibrate 60 min, pressurize at 75 kPa for 1 min, load 0.5 min, needle flush 5 min

Main Findings and Discussion

The method achieved baseline resolution of all target solvents with retention times that met pharmacopeial criteria. Calibration curves exhibited excellent linearity across relevant concentration ranges. The repeatability, expressed as relative standard deviation, was within acceptable limits, confirming robustness for routine analysis.

Benefits and Practical Applications

This HS-GC-FID approach offers:

• High sensitivity for trace solvent detection
• Reduced sample preparation complexity for water-soluble formulations
• Compliance with JP and USP standards
• Reliable throughput suitable for QA/QC laboratories

Future Trends and Applications

Advances in column technology and detector sensitivity may shorten analysis times and improve detection limits. Integration with automated sample prep and data processing platforms will further enhance laboratory efficiency. The method can be extended to additional solvent classes and new regulatory guidelines.

Conclusion

The presented HS-GC-FID method on the Nexis GC-2030 system provides a robust, compliant, and user-friendly solution for monitoring residual chlorinated solvents in pharmaceuticals. Its validated performance supports quality control requirements and regulatory compliance.

Reference

• Application News G325 JP, ENG; First Edition Sep. 2022; Shimadzu Corporation