Satisfy Requirements for Residual Solvent Analysis - Agilent J&W DB-Select 624 Ultra Inert for <467> and DB-WAX Ultra Inert capillary GC columns

Importance of the Topic

Residual solvent analysis in pharmaceutical manufacturing is critical to ensure product safety, stability, bioavailability, and compliance with global regulatory guidelines such as USP <467> and ICH Q3C. Monitoring trace levels of organic solvents remaining in active pharmaceutical ingredients (APIs) protects patients from toxic exposures and preserves drug quality.

Objectives and Study Overview

This application note evaluates the performance of Agilent J&W DB-Select 624 Ultra Inert (UI) and DB-WAX UI capillary columns in conjunction with headspace GC/FID analysis for USP <467> Procedures A (identification/limit test), B (confirmation), and C (quantification). It examines single-column and dual-column configurations, compares Agilent columns with competitive offerings, and demonstrates improvements in resolution, sensitivity, and throughput.

Methodology

Static headspace sampling was performed using an Agilent 7697A headspace sampler at controlled temperatures and equilibration times. GC separations employed:

• DB-Select 624 UI, 30 m × 0.53 mm, 3.0 µm for Procedure C and dual-channel analysis
• DB-Select 624 UI, 30 m × 0.32 mm, 1.8 µm for Procedure A
• DB-WAX UI, 30 m × 0.32 mm, 0.25 µm for Procedure B

Oven programs were tailored to each procedure, with initial holds at 40 °C, followed by ramps to 170–240 °C. Carrier gas (helium) flow was maintained in constant flow mode. FID detection used hydrogen and air flows optimized for sensitivity. Resolution criteria required Rs > 1.0 between critical solvent pairs (e.g., acetonitrile/dichloromethane).

Instrumentation

• Agilent 7890B GC system
• Agilent Intuvo 9000 GC system (dual-channel configuration)
• Agilent 7697A headspace sampler
• Flame ionization detector (FID)
• Ultra inert column liners, gold seals, deactivated fused-silica transfer lines

Main Results and Discussion

Procedure A separations on the DB-Select 624 UI column achieved high repeatability (< 2.5% RSD) and resolution (Rs 3.1 between acetonitrile and dichloromethane; Rs 1.1 for benzene/1,2-dichloroethane). Procedure B on the DB-WAX UI column provided clean confirmation of Class 1, 2A, and 2B solvents with minimal tailing (USP tailing factors ~1.0–1.3). Dual-channel analysis combined both columns in a single run, halving cycle time and enhancing confidence through orthogonal selectivities.

Comparisons with competitor G43 columns demonstrated superior peak shape, higher signal-to-noise ratios, and more robust resolution for Agilent UI phases. Application-specific flow chips and headspace sampling routines further improved throughput and reduced carryover.

Benefits and Practical Applications

• Meets or exceeds USP <467> requirements for residual solvent detection
• High inertness and stable thermal zones yield reproducible results
• Single-run dual-column method streamlines Procedures A and B
• Preconfigured Intuvo analyzers accelerate method deployment and validation
• Agilent headspace sampler and GC supplies simplify routine QA/QC workflows

Future Trends and Applications

The field is moving toward faster, more automated workflows including: comprehensive two-dimensional GC (GC×GC) for complex matrices; hyphenated techniques (GC-MS) for enhanced specificity; real-time monitoring in continuous manufacturing; and eco-friendly carrier gas alternatives. Method optimization software and digital twins are expected to further shorten development cycles.

Conclusion

Agilent J&W Ultra Inert GC columns combined with the Agilent 7697A headspace sampler provide a robust, high-throughput solution for USP <467> residual solvent analysis. Both single- and dual-column approaches deliver excellent resolution, sensitivity, and repeatability, ensuring regulatory compliance and operational efficiency in pharmaceutical quality control.

References

• Agilent Application Note 5991-0616: Single-Column USP <467> Analysis
• Agilent Application Note 5991-7531: Dual-Column GC/FID Residual Solvent Analysis
• USP Q3C—Tables and List Guidance for Industry, FDA, June 2017