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

Significance of the topic

The reliable quantification of residual solvents in pharmaceutical materials is a regulatory and quality-critical task. Headspace gas chromatography (HS-GC) is the standard approach for assessing Class 1 and Class 2 solvents under USP <467> and JP18. Recent global constraints on helium supply and cost have driven demand for validated procedures using nitrogen (N2) as carrier gas. The presented application demonstrates a practical N2-based HS-GC workflow that meets pharmacopeial sensitivity and precision requirements for water-insoluble samples, enabling cost-effective routine testing in QC and R&D laboratories.

Objectives and overview of the study

The study aimed to evaluate 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-insoluble pharmaceutical samples using N2 carrier gas. Specific objectives included:

• Demonstrate compliance with JP18 and USP <467> criteria for system suitability, sensitivity and repeatability.
• Compare two validated procedures (Procedure A and Procedure B) employing different columns and GC conditions for Class 1 and Class 2 solvents.
• Confirm capability to measure solvents recently added in ICH Q3C (R8), such as tert-butyl alcohol (TBA) and cyclopentyl methyl ether (CPME).

Methodology and analytical conditions

Samples: Water-insoluble standards and mixed standards prepared in DMSO (dimethyl sulfoxide); some deviations from USP/JP sample-preparation protocols were noted for method adaptation.

Two procedural variants were used to cover the broad solvent set and to optimize separation and detection:

Procedure A (broad, non-polar column):

• Column: SH-I-624Sil MS, 0.53 mm I.D. × 30 m, 3.0 µm film
• Temperature program: 40 °C (20 min) → 10 °C/min → 240 °C (20 min); total ~60 min
• Injection mode: Split 1:5

Procedure B (polar column):

• Column: SH-PolarWax, 0.32 mm I.D. × 30 m, 0.25 µm film
• Temperature program: 50 °C (20 min) → 6 °C/min → 165 °C (20 min); total ~59.17 min
• Injection mode: Split 1:10

Carrier gas and GC parameters (common):

• Carrier gas: Nitrogen (N2) controlled by linear velocity; target linear velocity 35 cm/s
• Instrument: Nexis GC-2060
• Detector: Newly designed FID; detector temperature 250 °C
• FID gas flows: H2 40 mL/min; makeup flow 30 mL/min (N2); air 170 mL/min

Headspace sampler (common):

• Sampler: HS-20 NX
• Oven 80 °C; sample line 90 °C; transfer line 105 °C
• Vial volume 20 mL; equilibration 45 min; vial pressurizing 68.9 kPa; injection 1 mL

Used instrumentation

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

Main results and discussion

Sensitivity and repeatability: Both procedures produced high signal-to-noise (S/N) ratios and low relative standard deviations (%RSD) across multiple injections, indicating robust detection performance using N2 carrier gas and the Nexis GC-2060 FID.

Selected performance highlights (reference values):

• Procedure A (Class 1 standards): Carbon tetrachloride S/N ≈ 15; individual-peak %RSD ≤ ~2%.
• Procedure B (Class 1 standards): 1,2-dichloroethane S/N ≈ 99; individual-peak %RSD ≤ ~3%.

Separation and system suitability:

• Procedure A achieved resolution ≥1.0 between acetonitrile and dichloromethane for Class 2 mixtures.
• Procedure B achieved resolution ≥1.0 between acetonitrile and cis-1,2-dichloroethene.

Class 2 analytes, including the separately prepared mixture containing TBA, CPME and MiBK, were resolved satisfactorily under the chosen conditions. Chromatograms were shown at differing magnifications to illustrate both major and trace components. Minor peaks attributable to DMSO-derived impurities were observed and acknowledged as matrix-related artifacts.

Overall, the new FID design provided the necessary sensitivity to meet pharmacopeial acceptance criteria using nitrogen carrier gas rather than helium, addressing both analytical and operational challenges.

Benefits and practical applications

• Regulatory compliance: Methods meet JP18 and USP <467> suitability criteria for residual solvent testing of water-insoluble samples.
• Cost and supply resilience: N2 is a viable and economical alternative to helium, mitigating the impact of helium shortages.
• Expanded analyte coverage: Capability demonstrated for newly emphasized solvents in ICH Q3C (R8), including tert-butyl alcohol and CPME.
• Routine QC suitability: High repeatability and sensitivity support adoption in quality control laboratories and stability testing workflows.

Future trends and possibilities for application

• Wider adoption of N2 carrier methods across pharmaceutical QC as laboratories seek to reduce reliance on helium.
• Further method transfer and inter-laboratory validation to establish broad regulatory confidence in N2-based HS-GC procedures.
• Integration with automated sample preparation and data-processing workflows to increase throughput and traceability for routine release testing.
• Investigation of alternate detectors or enhanced FID configurations to broaden dynamic range and lower limits of quantitation for challenging analytes.
• Continued attention to matrix effects (e.g., solvent-derived impurities such as those from DMSO) and refinement of sample-prep strategies to minimize interference.

Conclusion

The Nexis GC-2060 combined with HS-20 NX successfully performs residual solvent analysis for water-insoluble pharmaceutical samples using nitrogen carrier gas. The system achieves pharmacopeial-level sensitivity, repeatability and separation for both Class 1 and Class 2 solvents, including recently added analytes such as TBA and CPME. Adoption of N2 methods can offer cost and supply advantages while maintaining analytical performance suitable for QC environments.

Reference

• Shimadzu Corporation, Application News: Residual Solvent Analysis in Pharmaceuticals with N2 Carrier Gas Using Nexis GC-2060 and HS-20 NX — JP 18 and USP <467> / Water-Insoluble Samples, First Edition Aug. 2026.