Analysis of Residual Solvents in Pharmaceuticals - Report No. 342

Significance of the Topic

This application note presents a robust headspace gas chromatography method with flame ionization detection (HS-GC-FID) for quantifying residual solvents in water-insoluble pharmaceutical samples. Monitoring these volatile impurities is essential for patient safety, regulatory compliance (JP17, USP 467) and ensuring product quality.

Objectives and Overview

The primary goal was to develop a reliable, high-throughput procedure capable of detecting and quantifying 24 common residual solvents at trace levels. The study outlines chromatographic conditions, validation approach and demonstrates performance characteristics such as resolution, sensitivity and reproducibility.

Methodology and Instrumentation

A Shimadzu Nexis GC-2030 equipped with a headspace sampler (HS-20) and FID-2030 was employed. Key parameters included:

• Column: SH-I-624Sil MS (30 m×0.53 mm I.D., 3 µm film)
• Carrier gas: Nitrogen at 35 cm/s (linear velocity)
• Headspace conditions: 80 °C oven, 90 °C sample line, 45 min equilibration, 68.9 kPa vial pressure
• GC temperature program: 40 °C (20 min) ramp 10 °C/min to 240 °C (20 min)
• Injection: split 1:5, 1.0 mL, FID at 250 °C with H2, air and makeup flows

Key Results and Discussion

The method achieved baseline separation of all 24 analytes within a 60-minute run. Calibration curves demonstrated linearity across typical residual solvent concentration ranges, with limits of detection below regulatory thresholds. Repeatability tests showed relative standard deviations under 5% for most compounds. The use of nitrogen carrier gas minimized peak broadening and improved sensitivity for low‐boilingpoint solvents.

Benefits and Practical Applications

This HS-GC-FID method offers:

• High specificity for volatile solvents in complex matrices
• Compliance with global pharmacopeial standards
• Simple sample preparation and minimal solvent usage
• Scalability for routine quality control laboratories

Future Trends and Potential Applications

Advancements may include coupling with mass spectrometry for enhanced selectivity, automation for high-throughput screening and miniaturized headspace modules for on-site testing. Integration with data analytics can further streamline regulatory reporting and trend analysis.

Conclusion

The described HS-GC-FID procedure provides a validated, sensitive and reproducible approach for residual solvent analysis in pharmaceuticals. Its alignment with JP17 Supplement II and USP 467 ensures effective quality assurance and regulatory compliance.

Reference

Shimadzu Corporation. Application News G326: Analysis of Residual Solvents in Pharmaceuticals. First Edition: September 2022.