Residual Solvents Analysis: Satisfying USP 467 Using a New Benchtop Time-of-Flight Mass Spectrometer

Importance of the Topic

Pharmaceutical production demands rigorous screening for residual solvents to ensure product safety and compliance with regulatory standards. USP 467 defines classification and limit thresholds for over 50 solvents, but conventional GC-FID methods require multiple columns and runs, increasing analysis time and the risk of false positives. Implementing benchtop Time-of-Flight mass spectrometry coupled with headspace GC (HS-GC-TOFMS) offers a more efficient and reliable alternative.

Objectives and Study Overview

This study evaluates a single-run HS-GC-TOFMS approach to satisfy USP 467 requirements for Class 1, 2A, and 2B solvents. It compares throughput, specificity, and identification confidence against multi-column GC-FID protocols, using pharmaceutical samples spiked with standardized solvent mixes.

Methodology and Instrumentation

One combined solvent standard was prepared at USP 467 limit concentrations. A generic ibuprofen sample was spiked at 1.5× the Class 2A limits. Headspace injections (1 mL, 80 °C, split 50:1) were performed on an Agilent 7890 GC equipped with a LECO L-PAL3 autosampler. Separation used an Rxi-624SilMS column (30 m×0.25 mm×1.4 µm) under helium at 1.5 mL/min. The oven was programmed from 35 °C to 250 °C at 25 °C/min. Mass spectra (15–650 m/z) were acquired at 10 spectra/s on a LECO Pegasus BT TOFMS. Patent-protected NonTarget Deconvolution™ algorithms resolved coelutions and apportioned spectral contributions.

Main Results and Discussion

All target solvents were resolved in a single run with retention times matching USP 467 tables. Coelutions, such as methylcyclohexane/1,4-dioxane, were deconvoluted via extracted ion chromatograms (m/z 55, 88), yielding distinct peaks. Spectral match scores exceeded 850, confirming reliable identification. Total analysis time per sample was under 10 minutes, significantly faster than traditional methods.

Benefits and Practical Applications

• Simplified workflow by eliminating multiple column setups.
• Mass spectral confirmation reduces false positives compared to FID.
• Enhanced throughput supports efficient quality control in pharmaceutical manufacturing.

Future Trends and Potential Applications

Benchtop TOFMS platforms are poised for broader adoption in pharmaceutical testing, with potential for automated non-target screening, integration with LIMS, and improved deconvolution algorithms to detect trace impurities and isomeric compounds more effectively.

Conclusion

The HS-GC-TOFMS method meets USP 467 residual solvent requirements, delivering faster analysis, higher specificity, and reliable quantitation. It represents a practical alternative to conventional GC-FID for pharmaceutical quality assurance.

References

Kelly CN; Binkley JE; Fell LM. Residual Solvents Analysis: Satisfying USP 467 Using a New Benchtop Time-of-Flight Mass Spectrometer. LECO Corporation, Saint Joseph, MI, 2023.