Analysis of Residual Solvents in Pharmaceuticals - Report No. 339

Importance of the Topic

Volatile residual solvents are often used in pharmaceutical manufacturing and can pose serious health and safety risks if present above regulatory limits. Accurate quantification of these solvents is essential for quality control, safeguarding patient health, and meeting global pharmacopeial standards such as JP17 and USP 467.

Study Objectives and Overview

This application note details a headspace gas chromatography method with flame ionization detection (HS-GC-FID) for the simultaneous analysis of key residual solvents in water-soluble pharmaceutical samples. The protocol aims to achieve robust separation, reliable quantitation, and compliance with pharmacopeial requirements.

Methodology and Instrumentation

The method employs nitrogen as the carrier gas and a headspace sampler to introduce volatiles into a GC-2030 system equipped with an FID-2030 detector. A SH-PolarWax capillary column (30 m × 0.32 mm, df = 0.25 μm) is used under a temperature program starting at 50 °C (20 min), ramping at 6 °C/min to 165 °C (20 min), for a total run time of 59.17 min. Split injection (1:10) of 1 mL sample is performed after 60 min equilibration at 75 kPa. Instrument parameters such as gas flows, transfer line and oven temperatures, and vial handling are optimized for reproducibility.
Instrument Configuration:

• GC System: Nexis GC-2030
• Headspace Sampler: HS-20
• Detector: FID-2030
• Column: SH-PolarWax (P/N 221-75972-30)

Main Results and Discussion

Baseline separation of four target solvents—1,1-dichloroethane; 1,1,1-trichloroethane with carbon tetrachloride; benzene; and 1,2-dichloroethane—was achieved within the defined run time. The method demonstrated consistent retention times, sharp peak shapes, and adequate sensitivity for quantitation at pharmacopeial acceptance criteria. The use of a polar wax column facilitated resolution of structurally similar chlorinated hydrocarbons.

Benefits and Practical Applications

The protocol provides a streamlined workflow for routine QC analysis of residual solvents in pharmaceuticals. Its robustness, compliance with JP17 and USP 467, and compatibility with standard laboratory instrumentation make it suitable for adoption in pharmaceutical quality assurance and regulatory laboratories.

Future Trends and Potential Applications

Advances in headspace automation, faster temperature ramps, and multidimensional GC approaches promise further reduction in analysis time and enhancement of separation power. Integration with mass spectrometric detectors could extend the method to wider solvent panels and trace-level detection. Continuous method optimization will support evolving regulatory requirements and emerging pharmaceutical formulations.

Conclusion

The described HS-GC-FID method on a SH-PolarWax column offers reliable, pharmacopeial-compliant analysis of key residual solvents in water-soluble drug products. Its validated performance and straightforward implementation underscore its value for routine quality control.

References

• Application News G325, Shimadzu Corporation, First Edition: Sep. 2022