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

Significance of Extractables Analysis in Nasal Spray Devices

Assessing chemical species that migrate from packaging or delivery systems into pharmaceutical products is essential to ensure patient safety and product quality. This study focuses on screening extractable compounds in nasal spray devices to identify potentially harmful substances prior to patient exposure.

Objectives and Study Overview

The investigation aimed to apply gas chromatography coupled with high-resolution mass spectrometry and soft ionization to detect volatile and semi-volatile extractables in nasal spray containers. Key goals included benchmarking system performance, comparing results to traditional electron ionization approaches, and demonstrating comprehensive compound coverage with accurate mass measurements.

Methodology and Instrumentation

Sample Preparation

• Three commercial nasal spray devices extracted with isopropanol at 40 °C for 72 hours alongside procedural blanks.
• System suitability mix used to evaluate retention time reproducibility and mass accuracy.

Chromatographic and Mass Spectrometry Conditions

• GC system with splitless inlet at 300 °C and Rtx-5MS column (30 m × 0.25 mm, 0.25 μm film).
• Atmospheric pressure gas chromatography interface operated under dry nitrogen to promote soft ionization, generating radical cation and protonated molecular ions.
• Xevo G3 quadrupole time-of-flight mass spectrometer using alternating low and high collision energies (MSE mode) for precursor and fragment ion acquisition.
• Data acquisition with MassLynx software and processing with UNIFI application employing a customizable extractables and leachables workflow.

Main Results and Discussion

System Suitability and Method Performance

• Retention time RSD below 0.01 % for test mix compounds, confirming excellent reproducibility.
• Mass error typically within ±1 ppm for both precursor and fragment ions, supporting confident formula assignments.

Identification of Extractables

• Soft ionization enabled detection of intact molecular ions facilitating library screening and accurate mass matching.
• Comparison plots highlighted unique peaks in extracted samples relative to blanks, guiding targeted elucidation.
• Example unknown at m/z 284.2709 assigned as (3-methylbutoxy)methylbenzene based on elemental composition, isotopic fit, and fragment ion matches.

Benefits and Practical Applications

• Enhanced sensitivity and compound coverage compared to traditional electron ionization methods.
• Integrated workflow streamlines data interpretation with screening, binary comparison, and structural elucidation tools.
• Accurate mass measurement of both precursor and fragment ions improves confidence in identification of known and unknown extractables.

Future Trends and Potential Applications

The combination of atmospheric pressure gas chromatography with high-resolution time-of-flight mass spectrometry is poised to expand applications in regulated extractables and leachables workflows. Further integration of ion mobility separation and advanced spectral libraries will enhance identification of complex polymers and low-abundance contaminants. Artificial intelligence-driven data mining and automated reporting within unified software platforms will accelerate laboratory throughput and regulatory compliance.

Conclusion

This study demonstrates that GC-APGC soft ionization coupled with QToF high-resolution mass spectrometry delivers robust, sensitive, and reliable screening of extractables in nasal spray devices. The approach provides accurate mass data for both precursor and fragment ions, streamlining compound identification and structural elucidation within a single software environment.

Reference

ISO 10993-18 Biological evaluation of medical devices Part 18 Chemical characterization of medical device materials within a risk management process