Analysis of Residual Solvents in Pharmaceuticals - No. 382

Significance of Topic

Residual solvents in pharmaceutical products pose health risks and must be controlled to meet regulatory standards. Reliable analysis of these volatile organic compounds ensures patient safety, product consistency and compliance with international guidelines.

Study Objectives and Overview

The primary goal of this work was to develop and demonstrate a robust headspace gas chromatography method coupled with mass spectrometry and flame ionization detection for simultaneous identification and quantification of eight common residual solvents in drug substances. A model mixture was analyzed to assess separation, sensitivity and reproducibility.

Methodology and Instrumentation

• Sampling mode: Headspace loop injection (1 mL) with split ratio 1:5
• Equilibration conditions: vial at 90 °C for 45 min, pressurization at 76.4 kPa
• Instrument configuration: Shimadzu GCMS-QP 2020 coupled to FID-2010 Plus and HS-20 autosampler
• GC column: SH-I-624Sil MS, 30 m × 0.32 mm I.D., 1.8 µm film
• Oven program: 40 °C hold 20 min, ramp 10 °C/min to 240 °C, hold 20 min
• Carrier gas: Helium under constant pressure (89.4 kPa)
• Detection details:
  • FID at 250 °C (H2 40 mL/min, air 400 mL/min, make-up He 30 mL/min)
  • MS scan range m/z 29–250, ion source 200 °C, interface 250 °C

Main Results and Discussion

The developed method achieved baseline separation of eight target solvents—including n-hexane, chloroform and trichloroethene—within 35 min. The GC-MS data provided reliable compound identification, while FID delivered stable quantitation. Reproducibility was demonstrated by retention time RSDs below 0.5% and consistent response factors. Sensitivity met typical regulatory reporting thresholds.

Benefits and Practical Application

• Simultaneous GC-MS confirmation and FID quantification reduces analysis time.
• Automated headspace sampling enhances throughput and minimizes sample prep variability.
• Method applies to a wide range of volatile solvents, supporting routine quality control.

Future Trends and Potential Applications

• Integration with high-throughput screening platforms for process monitoring.
• Miniaturized micro-headspace modules to lower sample volume and waste.
• Advanced data analytics for automated peak assignment and impurity profiling.

Conclusion

The headspace GC-MS/FID approach outlined delivers a sensitive, reproducible and compliance-ready solution for residual solvent analysis in pharmaceuticals. Its dual-detector design offers both confirmatory identification and accurate quantitation, streamlining QC workflows.

Reference

Application News M272 (JP, ENG), Shimadzu Corporation, First Edition Sep. 2022