USP<467> residual solvents

Significance of the Topic

Residual solvents in pharmaceutical products can affect safety, bioavailability, and stability. Regulatory bodies such as the United States Pharmacopeia (USP) impose strict limits (USP <467>) to ensure that volatile impurities are controlled. Robust analytical methods are essential for quality assurance in both drug development and manufacturing processes.

Objectives and Overview of the Study

This work evaluates the analytical performance of the Agilent 7697A headspace sampler coupled with the Agilent 7890B GC and 5977A MSD for USP <467> residual solvents using Procedure A. Key goals include assessing repeatability, sensitivity, and system robustness at regulatory limit concentrations for Class 1, 2A, and 2B solvents.

Methodology and Applied Instrumentation

Sample Preparation and Procedure

• Solvent standards for Class 1, 2A, and 2B were prepared in purified water at USP limits.
• 6 mL aliquots were transferred into 20 mL vials with PTFE-lined septa; no salt was added.

Headspace Conditions

• Vial equilibration at 85 °C with shaker level 1.
• Pressurization to 15 psi, vent controlled to 10 psi at 20 psi/min.
• Helium carrier and pressurization gas; 1.0 mL loop volume.

GC/MS Parameters

• Agilent 7890B GC with multimode inlet at 140 °C, constant flow 1.3 mL/min; split ratios 20:1 (scan) and 100:1 (SIM).
• 30 m × 0.25 mm VF-624ms column, 1.4 µm film; oven ramp from 40 °C (5 min) to 240 °C at 18 °C/min.
• 5977A MSD with source 250 °C, quad 200 °C; SIM and scan acquisition modes.

Main Results and Discussion

Repeatability and Sensitivity

• Scan mode RSDs for all classes were below 2.5 % for most compounds; SIM mode further improved precision for Class 2A.
• Baseline separation of critical Class 1 analytes (e.g., benzene, 1,2-dichloroethane) was achieved on the VF-624ms phase.
• High split ratios in SIM yielded excellent signal-to-noise even for low-response solvents (e.g., acetonitrile, 1,4-dioxane).

System Robustness

• Inert sample path and controlled venting eliminated carryover.
• Pneumatic control modules provided precise pressure and timing for reproducible headspace sampling.

Benefits and Practical Applications of the Method

The described GC/MS system offers high precision and sensitivity ideal for QA/QC laboratories, method development, and troubleshooting unknown residual solvents. The integrated MassHunter software simplifies SIM table setup, data analysis, and conversion of legacy methods.

Future Trends and Potential Applications

Integration with laboratory information management systems (LIMS), further automation of sample prep and data processing, and expansion to nonaqueous matrices (e.g., DMSO, DMAc) will extend the utility of headspace GC/MS. Advances in high-throughput screening and miniaturized headspace modules may accelerate routine residual solvent testing.

Conclusion

The Agilent 7697A headspace sampler combined with the 7890B GC and 5977A MSD delivers reliable, repeatable analysis of USP <467> residual solvents at regulatory limits. Controlled pneumatic sampling, inert flow paths, and versatile acquisition modes make this system well suited for pharmaceutical quality control and method development.

Applied Instrumentation

• Agilent 7697A Headspace Sampler
• Agilent 7890B Gas Chromatograph with multimode inlet and Ultra Inert 1 mm liner (p/n 5190-4047)
• Agilent 5977A Mass Selective Detector
• VF-624ms, 30 m × 0.25 mm, 1.4 µm column
• Agilent MassHunter and MSD ChemStation software suites

References

1. United States Pharmacopeia. General Chapter USP<467> Organic volatile impurities. USP 32-NF 27. Pharmacopoeia Convention Inc., Rockville, MD, 2009.
2. Gudat AE, Firor RL. Improved Retention Time, Area Repeatability, and Sensitivity for Analysis of Residual Solvents. Agilent Technologies Application Note 5989-6079EN.
3. Firor RL. Analysis of USP<467> Residual Solvents with Improved Repeatability Using the Agilent 7697A Headspace Sampler. Application Note 5990-7625EN.
4. Tienpont B, et al. Analysis of USP<467> Residual Solvents using the Agilent 7697A Headspace Sampler with the Agilent 7890B GC. Application Note 5991-1834EN.
5. Firor RL. Fast Analysis of USP 467 Residual Solvents using the Agilent 7890A GC and Low Thermal Mass System. Application Note 5990-5094EN.
6. Firor RL. Optimizing Vial Pressurization Parameters for the Analysis of USP<467> Residual Solvents Using the 7697A Headspace Sampler. Application Note 5990-9106EN.