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

Significance of the Topic

Residual solvents in pharmaceutical products pose potential health risks, and stringent limits are set by pharmacopeias to ensure patient safety. High-sensitivity gas chromatography methods are essential for detecting trace levels of these solvents. With global helium shortages impacting laboratory operations, adapting headspace GC methods to use nitrogen as the carrier gas offers a practical alternative without compromising analytical performance.

Goals and Study Overview

This study evaluates compliance with the Japanese Pharmacopoeia 17th Edition Supplement II and USP <467> for Class 1 and Class 2 residual solvents in water-insoluble samples. Two procedures (A and B) differing in column type, temperature program, and split ratio were assessed using nitrogen as the carrier gas. The objective was to confirm that sensitivity, precision, and resolution meet regulatory requirements.

Methodology

Class 1 and Class 2 standard solutions were prepared according to JP17 guidelines. Headspace sampling was performed with a Shimadzu HS-20 module coupled to a Nexis GC-2030 equipped with a flame ionization detector (FID). Carrier gas control maintained a linear velocity of 35 cm/s using high-purity N₂. Procedure A employed a SH-Rxi-624 column (0.53 mm I.D. × 30 m) with a 40 °C–240 °C temperature program and split ratio 1:5. Procedure B used a SH-Stabilwax column (0.32 mm I.D. × 30 m) with a 50 °C–165 °C program and split ratio 1:10. Headspace conditions included 80 °C oven temperature, 90 °C sample line, 45 min equilibration, and 68.9 kPa vial pressure.

Used Instrumentation

• Shimadzu HS-20 headspace sampler
• Nexis GC-2030 gas chromatograph with FID-2030
• SH-Rxi-624 Sil MS and SH-Stabilwax capillary columns

Main Results and Discussion

For Class 1 solvents, Procedure A produced signal-to-noise (S/N) ratios exceeding 140 for key analytes and relative standard deviations (RSD) below 3.1 %. Procedure B achieved S/N ratios above 188 and RSD below 3.8 %. Both procedures met JP17 Supplement II criteria (S/N ≥ 5, RSD ≤ 15 %). For Class 2 mixtures, chromatographic resolution between critical peak pairs exceeded the minimum requirement of 1.0 in both procedures. Chromatograms demonstrated clear separation of residual solvents from the DMSO solvent matrix.

Benefits and Practical Applications

• Eliminates reliance on helium, reducing operational costs and supply risks.
• Maintains compliance with JP17 and USP <467> sensitivity, precision, and resolution standards.
• Applicable to quality control of water-insoluble pharmaceutical formulations.

Future Trends and Opportunities

Growing interest in alternative carrier gases may drive broader implementation of nitrogen-based methods in regulated laboratories. Further developments could include faster temperature programs, expanded method scopes for volatile impurities, and integration with automated data analytics to streamline routine QC workflows.

Conclusion

This study demonstrates that headspace GC analysis of residual solvents in water-insoluble pharmaceuticals using nitrogen as the carrier gas delivers performance equivalent to helium-based methods, fulfilling regulatory requirements and offering a robust solution amid helium supply challenges.

Reference

• Shimadzu Application Note No. G326, “Analysis of Residual Solvents in Pharmaceuticals by Water-Insoluble Samples Using N2 Carrier,” First Edition June 2020.