Analysis for Residual Solvents in Pharmaceuticals -JP18, USP467 : Class 1 Standard Solution

Importance of the Topic

The control of residual solvents in pharmaceutical products is essential to ensure patient safety and regulatory compliance. Class 1 solvents, identified by ICH Q3C guidelines, pose significant toxicity risks even at trace levels. Reliable detection and quantification of these impurities are therefore critical for quality assurance in drug manufacturing.

Objectives and Study Overview

This application note describes the development and validation of a headspace gas chromatography method with dual detection (FID and mass spectrometry) for the analysis of Class 1 residual solvents in pharmaceuticals. The study follows JP 18 and USP <467> requirements, using a standard solution containing five representative solvents: 1,1-dichloroethane, 1,1,1-trichloroethane, carbon tetrachloride, benzene and 1,2-dichloroethane.

Methodology and Instrumentation Used

The analysis was conducted using a Shimadzu GCMS-QP 2010 NX coupled to an HS-20 NX headspace sampler and an FID-2030 detector. Key parameters include:

• Column: SH-I-624Sil MS (30 m × 0.32 mm I.D., 1.8 µm stationary phase).
• Oven program: 40 °C (20 min) ramp to 240 °C at 10 °C/min, hold 20 min (total run time 60 min).
• Carrier gas: helium at 40 cm/s linear velocity.
• Injection: split ratio 1:5; injection volume 1 mL.
• Headspace conditions: vial temp. 80 °C; equilibration time 45 min; vial pressure 75 kPa; loading 0.5 min; transfer line 120 °C.
• FID settings: detector 250 °C; H2 flow 32 mL/min; makeup He 24 mL/min; air 200 mL/min.
• MS settings: ion source 200 °C; interface 250 °C; scan range m/z 30–250; event time 0.3 s.

Main Results and Discussion

The method achieved baseline separation of all five Class 1 solvents within 11 minutes. FID provided sensitive quantification with stable response factors, while MS confirmed compound identity through characteristic mass spectra. Calibration curves showed linearity over the required concentration range, with detection limits well below regulatory thresholds. Peak shapes were sharp and reproducible, and no significant matrix interference was observed.

Benefits and Practical Applications

This dual-detection approach offers high confidence in both quantification and confirmation of residual solvents. Implementation in quality control laboratories ensures compliance with ICH Q3C and pharmacopeial standards. The method’s robustness and long run time stability make it suitable for routine batch release testing.

Future Trends and Potential Applications

Advances in sample preparation, such as automated micro-extraction techniques, and enhanced MS libraries will further streamline residual solvent analysis. Emerging technologies like fast GC and multidimensional GC-MS can reduce analysis time and increase throughput. Integration with laboratory information management systems (LIMS) will improve data traceability and regulatory reporting.

Conclusion

The headspace GC-FID/MS method using the SH-I-624Sil MS column provides a reliable, sensitive and compliant solution for Class 1 residual solvent analysis in pharmaceuticals, meeting current regulatory requirements while offering flexibility for future enhancements.

Reference

Application News 01-00221-JP (JP, ENG)