Residual Solvents Analysis for the Pharmaceutical Industry Using the Agilent 8697 Headspace Sampler and 8850 GC-FID System

Importance of the Topic

Residual solvents are non-therapeutic volatile organic compounds used in the manufacture of active pharmaceutical ingredients (APIs) and excipients. Regulatory authorities limit their presence due to potential toxicity and environmental impact. Reliable monitoring of residual solvents is essential to ensure product quality, patient safety, and compliance with pharmacopeial standards.

Study Objectives and Overview

This application note evaluates the performance of an Agilent 8697 headspace sampler coupled to an Agilent 8850 GC-FID system for residual solvent analysis in pharmaceuticals according to USP <467>. Both Procedure A (screening) and Procedure B (confirmation) were tested using helium and hydrogen carrier gases. The Agilent Method Translator tool was applied to convert the helium method to a hydrogen-based protocol.

Methodology

Sample preparation followed USP <467> guidelines. Class 1, 2A, and 2B solvent standards were dissolved in headspace-grade DMSO and diluted to their limit concentrations. Four additional analytes (MIBK, CPME, TBA, cumene) were spiked into Class 2A mixtures.
Oven programs and headspace parameters (85 °C oven, 40 min equilibration, 1 mL loop) were set per USP requirements. Two capillary columns were employed: DB-Select 624 UI (30 m × 0.32 mm, 1.8 µm) for Procedure A and DB-WAX UI (30 m × 0.32 mm, 0.25 µm) for Procedure B.

Instrumentation

• Agilent 8850 GC with split/splitless inlet and flame ionization detector (FID)
• Agilent 8697 headspace sampler
• Agilent OpenLab CDS version 2.8 software
• Carrier gases: helium (2 mL/min) and hydrogen (2.5 mL/min)

Main Results and Discussion

• System suitability: S/N ≥5 for 1,1,1-trichloroethane, S/N ≥3 for all Class 1 solvents; resolution >1.0 for critical Class 2 pairs (e.g., acetonitrile/methylene chloride, MIBK/CPME, xylene isomers).
• Precision: six consecutive injections yielded retention time RSD <0.04% and area RSD <3.5% for both carrier gases.
• Hydrogen method translation reduced run times by ~28% (RT ratio ~0.72) without compromising resolution or sensitivity.
• Two-dimensional retention time mapping on both columns confirmed complete separation of all 32 target solvents.

Benefits and Practical Applications

• Compact 8850 GC footprint supports dedicated process-control instruments in space-limited laboratories.
• Hydrogen carrier gas offers a cost-effective and sustainable alternative to helium with comparable analytical performance.
• Agilent Method Translator accelerates method transfer between carrier gases and simplifies regulatory compliance.
• Procedures A and B enable rapid screening and reliable confirmation of residual solvents during API production.

Future Trends and Applications

• Wider adoption of hydrogen as a primary GC carrier gas in pharmaceutical quality control.
• Integration of automated method translation for additional pharmacopeial analyses.
• Implementation of multi-dimensional GC and advanced detectors for broader impurity profiling.
• Development of real-time, inline headspace GC-FID monitoring for continuous process analytics.

Conclusion

The Agilent 8697 headspace sampler with the 8850 GC-FID system meets USP <467> requirements for residual solvent analysis using both helium and hydrogen. The translated hydrogen method delivers equivalent sensitivity and resolution with significantly shorter analysis times, facilitating efficient, compliant solvent monitoring in pharmaceutical manufacturing.

Reference

1. U.S. FDA Q3C(R8) Impurities: Guidance for Residual Solvents, 2021.
2. United States Pharmacopeia 467: Residual Solvents Monograph.
3. Zhang Y., Analysis of USP Residual Solvents Using the Agilent 8697 Headspace Sampler and Agilent 8890 GC System, Agilent Technologies Application Note, 2023.