Efficient Analysis of Residual Solvents in Pharmaceuticals Using the Compact Model, Brevis GC-2050 (1) —JP18 and USP467, Water-Soluble Samples—

Importance of the Topic

Residual solvents in pharmaceutical products must be carefully monitored to ensure patient safety and regulatory compliance. The headspace gas chromatography (HS-GC) approach is a pivotal technique for detecting and quantifying volatile organic compounds (VOCs) carried over from synthesis or formulation steps. Recent helium shortages have intensified the need for reliable alternative carrier gases without compromising analytical performance.

Objectives and Study Overview

This study evaluates the compact Brevis™ GC-2050 coupled with the HS-20 NX USTL headspace system for the analysis of Class 1 and Class 2 residual solvents in water-soluble pharmaceutical samples. Key goals include:

• Demonstrate compliance with JP18 and USP <467> guidelines using helium, hydrogen, and nitrogen as carrier gases.
• Assess chromatographic resolution and sensitivity for both Class 1 (e.g., dichloroethane, benzene) and Class 2 (e.g., acetonitrile, methylene chloride) solvent mixtures.
• Compare performance under two standardized temperature programs (Procedure A and B).

Methodology and Instrumentation

The analytical workflow integrates the HS-20 NX USTL (Ultra Short Transfer Line) headspace sampler and Brevis GC-2050 system equipped with a flame ionization detector (FID). Key configuration and operating parameters:

• Columns: SH-I-624Sil MS (0.32 mm×30 m, 1.8 µm) and SH-PolarWax (0.32 mm×30 m, 0.25 µm).
• Temperature Programs: Procedure A – 40 °C (20 min) to 240 °C at 10 °C/min; Procedure B – 50 °C (20 min) to 165 °C at 6 °C/min.
• Carrier Gases: He, H₂, N₂ controlled at 35 cm/s linear velocity.
• Headspace Conditions: Oven 80 °C; sample line 110 °C; transfer line 120 °C; 20 mL vial; 60 min equilibration; 75 kPa pressurization.
• Detection: FID at 250 °C with H₂ (32 mL/min), N₂ makeup (24 mL/min), and air (200 mL/min).

Main Results and Discussion

Class 1 Analysis:
Under both Procedures A and B, benzene, dichloroethane isomers, and carbon tetrachloride were baseline resolved. Using nitrogen or hydrogen in Procedure A, resolution between 1,1-trichloroethane and carbon tetrachloride remained above 2.0, meeting system suitability.

Class 2 Analysis:
Procedure A separated acetonitrile and methylene chloride with a resolution ≥1.0, in line with JP18 requirements. For Procedure B, the cis-1,2-dichloroethene and acetonitrile pair achieved resolution values >2.8. The inclusion of tert-butyl alcohol, cyclopentyl methyl ether, and methyl isobutyl ketone (Class 2B) demonstrated consistent retention and sharp peaks across carrier gases.

Use of H₂ and N₂:
Alternative gases yielded chromatographic performance comparable to helium. Slight adjustments in linear velocity maintained retention times while preserving critical pair separations. All gas options passed USP <1467> operational checks before quantitation.

Benefits and Practical Applications

This compact GC system offers:

• Laboratory footprint reduction, enabling multiple units for high-throughput screening.
• Flexibility to switch among helium, hydrogen, and nitrogen, alleviating supply constraints.
• Compliance with international pharmacopoeial standards for residual solvent analysis.

It is particularly suited for QC laboratories in pharmaceutical development and manufacturing, where rapid, reliable VOC profiling is essential.

Future Trends and Opportunities

Advancements may include automated method transfer between labs, expanded solvent libraries for emerging impurities, and enhanced data analytics with AI-driven peak identification. Integration with lab informatics systems could further streamline regulatory reporting and trend monitoring.

Conclusion

The Brevis™ GC-2050 paired with HS-20 NX USTL provides a robust, compact solution for residual solvent analysis in pharmaceuticals. It satisfies JP18 and USP <467> requirements with helium, hydrogen, or nitrogen carrier gases, ensuring analytical performance even amid helium shortages. Its modular design supports high-throughput environments and flexible method deployment.

Instrument Configuration and Analytical Conditions

The study utilized the following instrumentation:

• Gas Chromatograph: Brevis GC-2050 with FID.
• Headspace Sampler: HS-20 NX USTL (80–120 °C gradient).
• Columns: SH-I-624Sil MS and SH-PolarWax.
• Carrier Gas Controller: Linear velocity mode for He, H₂, N₂ at 35 cm/s.