Analysis of Residual Solvents in Pharmaceuticals - Report No. 337

Importance of the Topic

Residual solvents in pharmaceuticals pose potential health risks and must be rigorously monitored to meet global regulatory standards such as USP 467 and JP 17 Supplement II. Headspace gas chromatography with flame ionization detection offers a reliable approach for volatile organic compound analysis in complex dosage forms.

Objectives and Study Overview

This application note describes the development and validation of a headspace GC-FID method using a SH-PolarWax capillary column for simultaneous determination of 24 common residual solvents. The goal is to achieve baseline separation, robust quantitation, and compliance with pharmacopeial limits.

Methodology and Instrumentation

The analysis was performed on a Shimadzu Nexis GC-2030 gas chromatograph equipped with an FID-2030 detector and HS-20 headspace sampler. Key operating conditions included:

• Column: SH-PolarWax, 30 m × 0.32 mm I.D., film thickness 0.25 µm
• GC oven program: 50 °C hold 20 min, ramp 6 °C/min to 165 °C, hold 20 min (total 59.17 min)
• Carrier gas: nitrogen at linear velocity 35 cm/s
• Headspace oven: 80 °C, sample line 110 °C, transfer line 120 °C
• Equilibration: 60 min at 75 kPa before 0.5 min loading
• Injection: split ratio 1:10, 1 mL vial volume, needle flush 5 min
• FID conditions: detector 250 °C, H2 32 mL/min, N2 makeup 24 mL/min, air 200 mL/min

Main Results and Discussion

The optimized method achieved clear separation of all 24 analytes including critical pairs such as trans-1,2-dichloroethylene and tetrahydrofuran. Retention times were reproducible with relative standard deviations below 1.5%. Calibration curves for each solvent displayed linearity over relevant concentration ranges with correlation coefficients above 0.995. Method detection limits met or exceeded pharmacopeial requirements, ensuring trace-level quantitation.

Benefits and Practical Applications

This headspace GC-FID approach combines simplicity and high throughput for routine quality control laboratories. Advantages include minimal sample preparation, compatibility with water-soluble matrices, and robust performance under varied sample loads. The method supports compliance verification for residual solvent specifications in active pharmaceutical ingredients and finished products.

Future Trends and Opportunities

Ongoing developments may include coupling headspace sampling with mass spectrometric detection for enhanced selectivity, integrating automated sample preparation for higher throughput, and exploring green carrier gases to reduce environmental impact. Advances in stationary phase technology could further shorten analysis times while maintaining resolution.

Conclusion

The presented headspace GC-FID method using a SH-PolarWax column offers a validated, reliable solution for comprehensive residual solvent analysis in pharmaceuticals. Its compliance with USP and JP guidelines, combined with strong analytical performance, makes it well suited for routine QA/QC applications.

Instrumentation Used

• Shimadzu Nexis GC-2030 gas chromatograph
• FID-2030 flame ionization detector
• HS-20 headspace sampler
• SH-PolarWax capillary column

References

Shimadzu Application News G325 (JP, ENG); Shimadzu Corporation First Edition Sep. 2022 ERAS-1000-0337