Analysis of Residual Solvents in Pharmaceuticals - Report No. 344

Significance of the Topic

Analysis of residual solvents in pharmaceuticals is critical to ensure patient safety and compliance with regulatory guidelines such as USP 467 and JP17. Organic solvents used during drug synthesis may remain as impurities that pose toxicity risks or affect drug stability; accurate quantification supports quality control and risk management.

Objectives and Study Overview

This study demonstrates a headspace gas chromatography method using the Shimadzu Nexis GC-2030 system with FID detection and the SH-I-624Sil MS capillary column. Five chlorinated solvents commonly found as residuals were evaluated: 1,1-dichloroethane, 1,1,1-trichloroethane, carbon tetrachloride, benzene and 1,2-dichloroethane. Method development focused on achieving reliable separation, sensitivity and compliance with JP17 Supplement II and USP 467.

Methodology and Instrumentation

• Gas chromatograph: Nexis GC-2030
• Detector: FID-2030 flame ionization detector at 250 °C
• Column: SH-I-624Sil MS, 30 m × 0.53 mm, 3 μm film thickness
• Oven temperature program: 40 °C (20 min) → 10 °C/min → 240 °C (20 min), total 60 min
• Injection mode: Split 1:5, 1 μL injection volume
• Carrier gas: Nitrogen, linear velocity 35 cm/s
• Headspace sampler: HS-20, vial equilibrated at 90 °C for 45 min, pressurization at 68.9 kPa
• Transfer line: 105 °C; sample line: 90 °C; no vial shaking

Main Results and Discussion

The method achieved baseline separation of all target solvents within the 60-minute run. FID response was linear across typical concentration ranges, enabling accurate quantification above specified detection limits. No significant interference from water-insoluble sample matrices was observed. Chromatograms showed consistent retention times and peak shapes, supporting method repeatability.

Benefits and Practical Applications of the Method

• Validated compliance with international pharmacopeial standards
• High sensitivity and selectivity for volatile chlorinated solvents
• Minimal sample preparation using static headspace
• Robust performance suitable for routine QC laboratories

Future Trends and Applications

Future developments may include reduced analysis times through faster temperature programs, coupling headspace GC with mass spectrometry for enhanced identification, and adopting greener carrier gases. Automation and integration with laboratory information systems will streamline workflows, while emerging regulations may expand solvent lists and tighten limits.

Conclusion

The presented headspace GC-FID method provides a reliable, pharmacopeia-compliant procedure for quantifying chlorinated residual solvents in pharmaceuticals. Its robustness and sensitivity make it well suited for routine quality control and regulatory testing.

Reference

Application News G326, ERAS-1000-0344, Shimadzu Corporation, First Edition September 2022.