Analysis of Residual Solvents in Pharmaceuticals - Report No. 341

Importance of the Topic

Residual solvent analysis in pharmaceutical products is essential for ensuring patient safety and regulatory compliance. Volatile organic compounds may remain after manufacturing and require precise quantification to meet pharmacopeial limits such as JP17 Supplement II and USP 467.

Objectives and Overview of the Study

The study aims to establish a reliable headspace gas chromatography with flame ionization detection method for the simultaneous determination of common residual solvents in water-insoluble pharmaceutical samples. Key goals include achieving baseline separation of 24 target compounds and demonstrating compliance with international guidelines.

Methodology and Instrumentation

Sample preparation involves sealing 20 mL headspace vials with pharmaceutical samples and equilibrating at 80 °C for 45 minutes. The analytical system combines headspace sampling with GC-FID using nitrogen as carrier gas. The GC separation employs an SH-PolarWax capillary column under a temperature program from 50 °C to 165 °C over 59.17 minutes.

• Headspace unit: HS-20, oven at 80 °C, sample line at 90 °C, transfer line at 105 °C
• Gas chromatograph: Nexis GC-2030
• Detector: FID-2030, detector temperature 250 °C, hydrogen flow 32 mL/min, air flow 200 mL/min, nitrogen makeup 24 mL/min
• Column: SH-PolarWax 30 m × 0.32 mm i.d., film thickness 0.25 μm
• Carrier gas: nitrogen at linear velocity 35 cm/s
• Injection: split ratio 1:10, injection volume 1 mL

Main Results and Discussion

The method achieved clear resolution of 24 residual solvents including aliphatic, aromatic, halogenated, and polar compounds. Retention times were reproducible with sharp peak shapes and adequate separation of critical isomeric pairs such as o-, m-, and p-xylenes. Linearity and detection limits meet or exceed pharmacopeial requirements.

Benefits and Practical Applications

• High sensitivity and specificity for a broad range of solvents
• Compliance with JP17 and USP 467 guidelines
• Suitable for water-insoluble APIs and excipients
• Efficient analysis time under one hour, enabling high sample throughput

Future Trends and Possibilities

Advancements may include coupling headspace GC with mass spectrometry for enhanced identification, automation of sample handling for greater throughput, and development of shorter columns or faster temperature programs to further reduce analysis time.

Conclusion

The presented HS-GC-FID method on the SH-PolarWax column offers a robust and pharmacopeia-compliant approach for comprehensive residual solvent analysis in pharmaceuticals. Its reproducibility, sensitivity, and broad applicability make it a valuable tool for quality control laboratories.

References

Shimadzu Corporation 2022 Application News G326 JP EN