Analysis of Residual Solvents in Pharmaceuticals by Water-Soluble Samples Using N2 Carrier (JP17 Supplement II, USP 467)

Importance of the Topic

The control of residual solvents in pharmaceuticals is critical due to their potential toxicity and impact on product safety. Pharmacopeial standards such as JP17 and USP <467> prescribe strict limits and analytical procedures, typically relying on headspace gas chromatography (GC) with helium carrier gas. Recent helium supply constraints have driven the need for alternative carrier gases like nitrogen to ensure uninterrupted, cost-effective, and compliant testing.

Objectives and Study Overview

This work presents a validation of JP17 Supplement II–compliant headspace GC methods using nitrogen as the carrier gas for water-soluble pharmaceutical samples. The study evaluates both Procedure A and Procedure B for Class 1 and Class 2 residual solvents, assessing sensitivity, repeatability, and chromatographic resolution against official acceptance criteria.

Methodology and Instrumentation

The analysis employed a Shimadzu HS-20 headspace sampler coupled to a Nexis GC-2030 gas chromatograph with flame ionization detector (FID). Key parameters included:

• Procedure A: SH-Rxi-624 Sil MS column (0.32 mm × 30 m, 1.8 µm), temperature program 40 °C (20 min) to 240 °C, split 1:5.
• Procedure B: SH-Stabilwax column (0.32 mm × 30 m, 0.25 µm), temperature program 50 °C (20 min) to 165 °C, split 1:10.
• Carrier gas: nitrogen at 35 cm/s linear velocity.
• Headspace conditions: oven 80 °C, sample line 110 °C, transfer line 120 °C, vial equilibration 60 min at 75 kPa.

Main Results and Discussion

For Class 1 solvents, both procedures produced signal-to-noise (S/N) ratios above 5 and relative standard deviations (RSD) below 15 % for target analytes (e.g., 1,1,1-trichloroethane, benzene), satisfying JP17 Supplement II requirements. Chromatograms showed well-resolved peaks. In Class 2 analysis, resolution between critical pairs—acetonitrile/methylene chloride (Procedure A) and acetonitrile/cis-1,2-dichloroethene (Procedure B)—exceeded the minimum threshold of 1.0, demonstrating robust chromatographic performance.

Practical Benefits and Applications

Implementing nitrogen as a carrier gas delivers:

• Relief from helium shortages and reduced operational costs.
• Compliance with pharmacopeial sensitivity and precision standards.
• Applicability in quality control and regulatory environments for routine solvent screening.

Future Trends and Applications

Emerging directions include coupling nitrogen-based headspace GC with mass spectrometry for enhanced detection limits, automated sample handling to increase throughput, and adoption of greener methodologies to minimize gas consumption and environmental impact. Extension of this approach to non-aqueous or complex dosage forms could broaden its utility.

Conclusion

The validated headspace GC methods using nitrogen achieve performance on par with helium-based protocols for analyzing Class 1 and Class 2 residual solvents in water-soluble pharmaceuticals. They meet JP17 Supplement II criteria and provide a reliable alternative in the face of helium supply limitations.

Reference

Shimadzu Application Note No. G325, First Edition June 2020; Japanese Pharmacopoeia 17th Edition Supplement II; USP General Chapter <467>.