Analysis of Residual Solvents in drug products

Significance of the Topic

Residual solvents are chemical impurities remaining in pharmaceutical products after manufacturing and purification. Their control is critical for patient safety, regulatory compliance and ensuring drug quality. The United States Pharmacopeia (USP) <467> sets limits on permitted levels of volatile organic compounds, making robust analytical methods essential for routine quality control in pharmaceutical laboratories.

Objectives and Study Overview

This study presents two analytical approaches for quantifying Class 2A residual solvents in drug products according to USP <467> Procedure A. It compares direct GC analysis with flame ionization detection (GC-FID) against headspace sampling (HS) on a Shimadzu Nexis GC-2030 system. The goal is to demonstrate method performance for 15 target solvents, including methanol, acetonitrile, dichloroethylenes, tetrahydrofuran and aromatic hydrocarbons.

Methodology and Instrumentation

The methods were designed to achieve baseline separation of all analytes within a 60-minute runtime. Key parameters include:

• GC Column and Temperature Program
  • Column: SH-I-624Sil MS, 30 m × 0.32 mm i.d., 1.8 µm film thickness
  • Oven: 40 °C hold for 20 min, ramp 10 °C/min to 240 °C, hold 20 min
• Injection and Detection
  • Injection mode: Split 1:5, injection volume 1 µL
  • Detector: FID at 250 °C
  • Carrier gas: Helium, constant linear velocity 35 cm/s
• Headspace Parameters
  • Oven temp: 80 °C, transfer line: 120 °C
  • Sample line: 110 °C, vial volume: 20 mL
  • Equilibration: 60 min, pressurization: 1 min at 75 kPa
  • Loading: 1 min, needle flush: 5 min

Used Instrumentation

• Shimadzu Nexis GC-2030 Gas Chromatograph
• FID-2030 Flame Ionization Detector
• HS-20 Headspace Sampler
• SH-I-624Sil MS capillary column (P/N: 227-36077-01)

Main Results and Discussion

Both GC-FID and headspace methods achieved complete separation of the 15 targeted Class 2A solvents within the 60-minute analysis window. Calibration curves demonstrated excellent linearity across the required concentration ranges. The headspace approach offered minimal sample preparation and reduced matrix interference, while the direct GC method provided slightly lower detection limits for low-boiling compounds. Reproducibility for retention times and peak areas met USP acceptance criteria.

Benefits and Practical Applications

These validated methods enable pharmaceutical QC laboratories to reliably monitor residual solvents, ensuring compliance with USP <467>. The HS technique streamlines workflow for routine testing of volatile organics in complex formulations. The GC-FID approach remains valuable when maximum sensitivity is required for specific analytes.

Future Trends and Potential Applications

Advances in fast GC and high-speed headspace autosamplers promise shorter runtimes and higher throughput. Coupling with mass spectrometry can enhance specificity and enable multi-class solvent screening. Integration of automated data analysis and compliance reporting will further support regulated environments.

Conclusion

The presented GC-FID and headspace methods meet USP <467> Procedure A requirements for Class 2A residual solvents in drug products. Both deliver robust performance, with headspace offering simplified sample handling and direct GC providing enhanced sensitivity. Implementation in quality control labs will ensure regulatory compliance and safeguard patient health.

References

• Shimadzu Application News G290 (JP, ENG), First Edition Sept. 2022, ERAS-1000-0309