BMSS: EXTRACTABLES ANALYSIS OF NASAL SPRAY DEVICES USING GAS CHROMATOGRAPHY AND QUADRUPOLE TIME OF FLIGHT HIGH-RESOLUTION MASS SPECTROMETRY WITH SOFT IONIZATION

Importance of the Topic

Effective screening of extractables and leachables from nasal spray packaging is critical to ensure patient safety and product quality. Materials used in device construction may release impurities, additives, or degradation products that pose health risks. Advanced analytical methods like GC-APGC-QToF-HRMS with soft ionization enable comprehensive detection and accurate identification of volatile and semi-volatile compounds, addressing limitations of traditional EI-based GC-MS.

Study Objectives and Overview

This study aimed to evaluate the performance of an atmospheric pressure gas chromatography system coupled to a high-resolution quadrupole time-of-flight mass spectrometer (GC-APGC-QToF-HRMS) operated in MSE mode for extractables profiling of commercial nasal spray devices. A dedicated extractable and leachable (E&L) workflow within UNIFI software was used to streamline data acquisition, screening, library matching, and structural elucidation.

Methodology and Instrumentation

• Sample Preparation: Three commercial nasal sprays were extracted with isopropanol at 40 °C for 72 hours; a procedural blank was included for comparison.
• GC-APGC-QToF Conditions: Agilent 8890 GC with splitless inlet at 300 °C, Rtx-5MS column (30 m × 0.25 mm × 0.25 µm), 40–330 °C temperature gradient; APGC source under dry nitrogen, corona current 2 µA, source temperature 150 °C; Xevo G3 QToF MS in MSE mode (low 6 V, high 15–45 V), mass range m/z 50–1200.
• Data Processing: MassLynx software and UNIFI application with a customized E&L workflow, using a scientific library and an analytical evaluation threshold (AET) for automated filtering of low-level signals.

Main Results and Discussion

GC-APGC-QToF-HRMS detected a broader array of extractables compared to prior LC-QToF analyses. Key findings include:

1. Identification of 7-Isopropyl-1-methyl-1,2,3,4-tetrahydrophenanthrene at retention time 29.45 min with sub-ppm mass error.
2. Discovery of unique components in sample extracts absent in blanks, visualized by difference plots in UNIFI.
3. Structural elucidation of an unknown at m/z 284.2709, identified as [(3-methylbutoxy)methyl]benzene (–0.8 ppm error), leveraging accurate precursor and fragment masses.

Benefits and Practical Applications

• Soft ionization preserves intact molecular ions, improving confidence in molecular formula assignment.
• MSE mode provides simultaneous precursor and fragment spectra, enhancing identification reliability.
• Customizable UNIFI workflow integrates library screening, blank comparison, and elucidation tools, streamlining compliance with regulatory E&L thresholds.

Future Trends and Potential Applications

Advancements in ion optics and soft ionization sources will further enhance sensitivity for labile species. Coupling with ion mobility and expanding spectral libraries will broaden compound coverage. The established workflow can be adapted to other medical devices and packaging materials, supporting comprehensive risk assessments in pharmaceutical QA/QC.

Conclusion

GC-APGC-QToF-HRMS in MSE mode offers a powerful orthogonal technique for extractables screening, delivering high-resolution mass accuracy for both precursor and fragments and enabling confident identification of a wide range of volatile and semi-volatile compounds in nasal spray devices.

References

• USP <1664> and <1663> guidelines on extractables and leachables.
• Stevens D. M. et al., Waters Application Note 720004211en (2012).
• Sanig R. et al., BMSS Poster (2022).
• Reid L. & Pickles D., Application Note 720007655 (2022).
• McCullagh M. et al., Application Note 720007794 (2022).