Residual Solvent Analysis in Pharmaceuticals with N2 Carrier Gas Using Nexis GC-2060 and HS-20 NX

Significance of the topic

Residual solvent testing by headspace gas chromatography (HS-GC) is a mandatory quality control step in pharmaceutical development and release. Regulatory monographs such as USP General Chapter <467> and JP18 define limits and test procedures for Class 1 and Class 2 solvents. High sensitivity, reproducibility and robust system suitability are required to ensure patient safety and regulatory compliance. Recent helium supply constraints have increased interest in nitrogen (N2) as an alternative GC carrier gas; evaluating instrumentation and methods that deliver required performance with N2 is therefore important for routine QC laboratories.

Objectives and overview of the study

This application note evaluated the performance of the Nexis GC-2060 equipped with a newly designed flame ionization detector (FID) and the HS-20 NX headspace sampler for residual solvent analysis of water-soluble pharmaceutical samples using nitrogen as carrier gas. Specific aims were:

• Demonstrate compliance with JP18 and USP <467> requirements for Class 1 and Class 2 solvents using N2 carrier gas.
• Compare two analytical procedures (Procedure A and Procedure B) that use different columns, temperature programs and split ratios.
• Assess sensitivity (signal-to-noise, S/N), repeatability (%RSD), and chromatographic resolution for key solvent pairs, including newly relevant solvents such as tert-butyl alcohol (TBA) and cyclopentyl methyl ether (CPME).

Methodology

Analyses targeted Class 1 and Class 2 residual solvents in water-soluble matrices using DMSO as the sample solvent. Two GC procedures were developed to meet JP/USP system requirements and to accommodate varying volatility and polarity among solvents.

• Procedure A: non-polar column (SH-I-624Sil MS, 0.53 mm I.D., 30 m, 3.0 µm), temperature program starting at 40 °C (20 min) then ramp to 240 °C; split 1:5.
• Procedure B: polar column (SH-PolarWax, 0.32 mm I.D., 30 m, 0.25 µm), temperature program starting at 50 °C (20 min) then ramp to 165 °C; split 1:10.
• Carrier gas: nitrogen at linear velocity equivalent to 35 cm/s.
• FID conditions: detector temp 250 °C; H2 flow 40 mL/min; make-up gas 30 mL/min (N2); air 170 mL/min.
• Headspace sampling (HS-20 NX) conditions (common to both procedures): oven 80 °C; sample line 110 °C; transfer line 120 °C; vial 20 mL; equilibration 60 min; vial pressurizing 1 min at 75 kPa; injection volume 1 mL; needle flush 5 min.

Some minor modifications were made to the published USP/JP sample preparation protocols to accommodate instrument configuration and N2 carrier gas operation.

Used instrumentation

• Nexis GC-2060 gas chromatograph with newly designed FID.
• HS-20 NX headspace sampler.
• Columns: SH-I-624Sil MS (0.53 mm I.D. × 30 m, 3.0 µm) and SH-PolarWax (0.32 mm I.D. × 30 m, 0.25 µm).

Main results and discussion

Key analytical performance observations are summarized below:

• Class 1 solvents: Both procedures produced clear chromatograms with acceptable sensitivity and repeatability. In Procedure A carbon tetrachloride showed an average S/N of 23 and individual peak area %RSD values ≤ 2% (n = 6). In Procedure B 1,2-dichloroethane reached an average S/N of 198 with %RSD ≤ 3% (n = 6), highlighting the strong sensitivity achievable with the new FID even when using N2 carrier gas.
• Class 2 solvents: Chromatograms for Class 2A/2B mixtures demonstrated good separation and system suitability. Procedure A delivered resolution ≥ 1.0 between acetonitrile and dichloromethane; Procedure B delivered resolution ≥ 1.0 between acetonitrile and cis-1,2-dichloroethene. Reference resolution values of approximately 2.1 and 2.5 were reported for specific peak pairs (not guaranteed).
• Additional solvents: The method successfully included recently emphasized solvents such as tert-butyl alcohol (TBA) and cyclopentyl methyl ether (CPME); mixture containing TBA/CPME/MiBK was prepared separately to match target concentrations.
• Repeatability and S/N: Across both procedures, repeatability and S/N performance met or exceeded typical QC expectations for JP/USP residual solvent testing when using N2 carrier gas. Reported S/N ratios and %RSD values are reference values from the study and not guaranteed for all laboratory setups.

Overall, the Nexis GC-2060 combined with the HS-20 NX produced robust HS-GC results for water-soluble samples using nitrogen, supporting its suitability for regulated residual solvent analysis under resource-constrained carrier gas conditions.

Benefits and practical applications

• Carrier gas flexibility: Using nitrogen mitigates dependence on helium supplies and reduces operating cost while maintaining required analytical performance for JP/USP methods.
• Improved sensitivity: The redesigned FID improved detectability for low-level residual solvents, enabling reliable quantitation and system suitability testing.
• Regulatory alignment: The procedures demonstrated compatibility with JP18 and USP <467> expectations for Class 1 and Class 2 solvents in water-soluble matrices, facilitating implementation in QC laboratories.
• Expanded solvent scope: Capability to analyze solvents added to recent ICH updates (e.g., TBA, CPME) supports contemporary pharmacopeial requirements.

Future trends and opportunities

• Extended validation: Multi-site method validation and robustness testing across different matrix types (including water-insoluble samples) will strengthen method transferability.
• Detector and MS coupling: Combining optimized FID performance with selective detectors (e.g., GC–MS) can provide orthogonal confirmation for challenging co-elutions or trace-level identification.
• Green analytical practices: Continued transition to sustainable gases and reduced sample volumes can lower environmental footprint and operational costs.
• Automation and data integrity: Integration of automated sample preparation, instrument qualification workflows and electronic record-keeping will streamline routine QC implementation.

Conclusion

The study demonstrates that the Nexis GC-2060 with its improved FID and the HS-20 NX headspace sampler can perform pharmacopeial residual solvent testing for water-soluble samples using nitrogen as the carrier gas while achieving the sensitivity, repeatability and chromatographic resolution required by JP18 and USP <467>. This provides a viable, cost-effective alternative to helium-based workflows for regulated laboratories, including the ability to analyze newly emphasized solvents such as TBA and CPME.

References

• Shimadzu Corporation. Residual Solvent Analysis in Pharmaceuticals with N2 Carrier Gas Using Nexis GC-2060 and HS-20 NX — JP18 and USP <467>: Application Note (2026).
• Japanese Pharmacopoeia, 18th Edition (JP18).
• United States Pharmacopeia. General Chapter <467> — Residual Solvents.