Analysis of Residual Solvents in Pharmaceuticals - Report No. 335

Significance of the Topic

The presence of residual solvents in pharmaceutical products can pose safety and quality risks. Regulatory guidelines such as JP17 Supplement II and USP 467 set strict limits for these compounds. Reliable analytical methods are essential to ensure compliance and protect patient health.

Objectives and Study Overview

This study demonstrates a headspace gas chromatography method with flame ionization detection for the simultaneous analysis of 16 common residual solvents in drug substances and formulations. The aim is to achieve clear separation, reproducible quantitation, and alignment with pharmacopoeial criteria.

Methodology and Instrumentation

The analysis employs static headspace sampling coupled to gas chromatography with a flame ionization detector. Key parameters include:

• Gas chromatograph: Shimadzu Nexis GC-2030 with HS-20 headspace sampler
• Column: SH-I-624Sil MS, 30 m length, 0.53 mm inner diameter, 3 μm film thickness
• Oven program: 40 °C hold 20 min, ramp 10 °C/min to 240 °C, hold 20 min
• Carrier gas: helium at linear velocity 35 cm/s
• Headspace conditions: vial equilibration at 80 °C for 45 min, pressurization at 68.9 kPa for 1 min
• Injection mode: split ratio 1 to 5, injection volume 1 mL
• Detector: flame ionization at 250 °C, gases hydrogen 32 mL/min, air 200 mL/min, makeup helium 24 mL/min

Main Results and Discussion

The method achieved baseline resolution of all 16 residual solvents including methanol, acetonitrile, chlorinated solvents and aromatic hydrocarbons. Retention times were consistent across replicate injections. Peak shapes were sharp and symmetric, enabling reliable integration. The headspace sampling conditions minimized matrix interferences, and the split injection prevented detector overload for high‐volatility analytes.

Practical Benefits and Applications

This headspace GC-FID approach provides a robust solution for quality control laboratories in pharmaceutical development and manufacturing. It offers:

• High throughput through unattended batch analysis
• Compliance with pharmacopeial guidelines
• Broad applicability to diverse formulation matrices
• Low operational complexity compared to mass spectrometry options

Future Trends and Opportunities

Advances in detector technology and automation may further shorten analysis time and improve sensitivity. Coupling with mass spectrometry could extend the scope to unknown volatile impurities. Integration with laboratory information management systems will streamline data handling and regulatory reporting.

Conclusion

The described headspace gas chromatography with flame ionization detection meets regulatory requirements for residual solvent testing in pharmaceuticals. The method delivers reliable separation, reproducible quantitation, and operational ease, making it well suited for routine quality control.

Reference

Application News G324, Shimadzu Corporation, First Edition Sep. 2022 ERAS-1000-0335