Extractables Analysis of Nasal Spray Devices Using Gas Chromatography and High- Resolution Mass Spectrometry With Soft Ionization

Significance of the Topic

The analysis of extractables and leachables (E&L) from pharmaceutical packaging and medical devices is critical for patient safety. Plastic components can release volatile and semi-volatile compounds that, if not detected and identified, may pose health risks. Combining orthogonal analytical techniques improves the comprehensiveness and confidence of E&L screening workflows.

Objectives and Study Overview

The study aimed to develop a robust screening protocol for volatile and semi-volatile E&L in commercial nasal spray systems. By integrating gas chromatography coupled to a high-resolution quadrupole time-of-flight mass spectrometer (GC-QToF HRMS) with atmospheric pressure gas chromatography (APGC) soft ionization, the goal was to extend coverage beyond traditional electron ionization (EI) GC-MS and complement existing LC-QToF data.

Applied Methodology and Instrumentation

Sample Preparation and Acquisition:

• Nasal spray containers extracted with isopropanol at 40 °C for 72 h, alongside procedural blanks and a system suitability mix.
• Triplicate injections of extracts using splitless GC inlet.

GC-QToF HRMS Conditions:

• Gas Chromatograph: Agilent 8890 with PAL RSI autosampler.
• Column: Rtx-5MS (30 m × 0.25 mm, 0.25 μm film) at 1 mL/min helium flow.
• Oven program: 40 °C hold 5 min → 330 °C at 10 °C/min, hold 14 min (total 27.75 min).
• Ionization: APGC in mixed charge transfer and protonation mode (2 µA corona, 150 °C source).
• Detection: Xevo G3 QTof MS, m/z 50–1200, 0.1 s scan time, MSE acquisition (low CE 6 V, high CE ramp 15–45 V).
• Software: MassLynx 4.2 for data collection; UNIFI in waters_connect 3.1 for data processing, screening, and elucidation.

Main Results and Discussion

System Suitability:

• Repeatable retention times (RSD < 0.01%) and accurate mass performance confirmed with E&L SST mix.

Library Screening:

• Screened against Waters E&L library with AET filtering to remove low-level noise.
• GC-QToF APGC identified compounds not detected by LC-QToF, increasing overall coverage (e.g., antioxidant 616 at RT 34.95 min, mass error 2.6 ppm).
• MSE data provided both precursor and fragment ions for confident confirmation and structural matching.

Unknown Elucidation:

• Binary comparison against procedural blanks isolated sample-specific features.
• Discovery Tool in UNIFI annotated an unknown at m/z 284.2703 as N-(2-(1-piperazinyl)ethyl)decanamide (error 2.33 ppm), using accurate mass, isotopic fit, and fragment matching.

Benefits and Practical Applications

• Soft APGC ionization preserves molecular ions for accurate formula determination, overcoming EI fragmentation limitations.
• MSE DIA acquisition delivers comprehensive precursor and fragment information in a single analysis.
• Orthogonal use of GC-QToF APGC complements LC-QToF to cover a broader chemical space of E&L.
• Streamlined UNIFI workflows facilitate system suitability checks, library screening, AET filtering, and unknown elucidation.
• Enhanced sensitivity and reduced false positives improve regulatory compliance in extractables and leachables studies.

Future Trends and Opportunities

Emerging developments in high-resolution mass spectrometry and ion mobility separation will further refine E&L profiling. Advances in soft ionization sources and integrated informatics platforms will accelerate identification of novel contaminants. Machine learning-driven spectral libraries and automated structure elucidation will enhance throughput and accuracy in pharmaceutical quality control.

Conclusion

The integration of GC-QToF HRMS with APGC soft ionization and MSE acquisition provides a powerful orthogonal approach to LC-QToF for extractables analysis. This strategy improves sensitivity, molecular ion detection, and structural elucidation capabilities, ensuring comprehensive screening of nasal spray devices. The UNIFI workflows streamline data interpretation, making the method suitable for routine QA/QC and regulatory submissions.

References

1. USP Assessment of Drug Product Leachables Associated with Pharmaceutical Packaging/Delivery Systems (USP 1664), US Pharmacopeia.
2. USP Assessment of Extractables Associated with Pharmaceutical Packaging/Delivery Systems (USP 1663), US Pharmacopeia.
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5. Stevens D. M. et al., Detection and Identification of Extractable Compounds from Polymers, Waters App. Note 720004211 (2012).
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