Residual Solvents Analysis in Pharmaceuticals by HS-GC-FID with Newly Added Compounds –USP <467> Procedure A

Significance of the Topic

Residual solvent analysis is essential for ensuring pharmaceutical safety and regulatory compliance. Quantifying trace-level solvents protects patient health and aligns with international standards such as USP <467>.

Study Objectives and Overview

This work aims to validate a headspace gas chromatography–flame ionization detection (HS-GC-FID) method using nitrogen as carrier gas, following USP <467> Procedure A. It also incorporates three newly classified Class 2 solvents: cyclopentyl methyl ether, tertiary butyl alcohol, and methyl isobutyl ketone.

Methodology and Instrumentation

A Shimadzu HS-20 NX autosampler coupled with a Nexis GC-2030 system was used. Key parameters included:

• Column: SH-I-624Sil MS (30 m × 0.32 mm ID, 1.80 µm df)
• Carrier gas: Nitrogen at constant linear velocity (35 cm/s)
• Headspace conditions: split mode 5:1, pressurizing gas 75 kPa, equilibration 60 min at 80 °C
• Oven program: hold 40 °C (20 min), ramp 10 °C/min to 240 °C (20 min)
• Detector: FID at 250 °C with H2 32 mL/min, air 200 mL/min, makeup gas 24 mL/min

Results and Discussion

Class 1 solvents achieved signal-to-noise ratios well above the USP <467> requirement of 5, with carbon tetrachloride showing S/N=8 and RSD for peak areas between 3.6% and 5.3%. Class 2A standards, including the three new solvents, exhibited complete baseline separation (resolution Rs=2.2 for acetonitrile/methylene chloride) and RSD values from 0.6% to 6.7%. Class 2B solvents also met repeatability criteria with RSDs between 1.0% and 6.7%.

Benefits and Practical Applications

Switching to nitrogen carrier gas significantly reduces operating costs without compromising sensitivity or resolution. The validated HS-GC-FID method offers robust quantitation of residual solvents, streamlining quality control processes and supporting regulatory submissions.

Future Trends and Opportunities

Future developments may include alternative low-cost carrier gases, high-efficiency stationary phases for faster separations, and coupling with mass spectrometry for expanded compound coverage. Enhanced automation and data-mining algorithms could further boost throughput and analytical insight.

Conclusion

The optimized HS-GC-FID procedure using nitrogen carrier gas meets all USP <467> criteria for Class 1 and Class 2 residual solvents, including newly added compounds. This approach balances sensitivity, resolution, and cost-effectiveness, reinforcing its value for routine pharmaceutical quality control.

References

• United States Pharmacopeia, USP <467> Residual Solvents.
• International Council for Harmonisation, ICH Q3C(R8) Guideline for Residual Solvents, 2021.