Extractables & Leachables Analysis of Pharmaceutical Nasal Spray Samples using the Hi-Resolution Accurate Mass GC/QTOF

Significance of the Topic

Modern pharmaceutical products, such as nasal sprays, contact various materials during manufacturing and packaging. Compounds that migrate from these materials into the final product—known as extractables and leachables—can pose safety risks. High-resolution, accurate-mass gas chromatography coupled with quadrupole time-of-flight mass spectrometry (GC/QTOF) provides the sensitivity and selectivity needed to detect both known and unknown contaminants in complex formulations.

Study Objectives and Overview

This work aimed to develop a streamlined workflow for identifying extractable and leachable compounds in pharmaceutical nasal spray samples. Key goals included:

• Collecting samples from multiple production stages (control, container fixture, gasket, final product).
• Applying solvent extractions to packaging materials and spray formulations.
• Using accurate-mass GC/QTOF data combined with advanced software tools to detect, identify, and quantify target and unknown compounds.

Methodology

Sample Preparation:

• Packaging materials were extracted with dichloromethane.
• Spray formulations were extracted with ethyl acetate.
• A mixed standard of common plastic, elastomer, ink, and label compounds was prepared to build an initial target list.

Data Acquisition:

• Agilent 7250 GC/Q-TOF coupled to a 7890B GC system.
• Column: DB-XLB, 30 m × 0.25 mm ID, 0.25 μm film.
• Injection: 1 μL, split 100:1 at 275 °C.
• Oven program: 40 °C (2 min), ramp 5 °C/min to 320 °C, hold 15 min.
• Carrier gas: Helium at 1.0 mL/min constant flow.
• Transfer line: 280 °C; source: 250 °C; quadrupole: 150 °C.
• Spectral range: 50–750 m/z; electron energies: 70 eV and 15 eV (low energy).

Used Instrumentation

• Agilent 7250 GC/Q-TOF accurate mass spectrometer.
• Agilent 7890B gas chromatograph.
• MassHunter software suite: Unknowns Analysis, Qualitative Analysis, Quantitative Analysis.

Main Results and Discussion

Data processing leveraged the SureMass algorithm to generate cleaned spectra and detect components automatically. Library searches against NIST17 aided in tentative identification, followed by confirmation using accurate mass measurements and elemental composition analysis under low-eV conditions. Key findings included:

• Successful detection of known targets from the standard mix with quantification via automated calibration.
• Identification of 2,4-di-tert-butylphenol in the final nasal spray sample, confirmed by retention time, quant and qual ions, and mass accuracy (calculated concentration: 14 pg/μL).
• Detection of additional unknowns obscured by matrix interferences, resolved by SureMass and enhanced low-eV molecular ion signals.
• Rapid addition of newly confirmed unknowns into the quantitative method for semi-targeted analysis.

Benefits and Practical Applications

• High-resolution accurate-mass data enables confident identification of both known and unknown extractables/leachables.
• SureMass signal processing minimizes false negatives by isolating true component signals.
• Low-energy ionization enhances molecular ion detection and verifies elemental composition.
• MassHunter’s integrated workflow accelerates sample screening and method adaptation, supporting quality control and regulatory compliance.

Future Trends and Opportunities

Potential directions to enhance extractables and leachables workflows include:

• Building a Personal Compound Database and Library (PCDL) for rapid screening of historical data.
• Optimizing and shortening acquisition methods to increase sample throughput.
• Implementing MassHunter Molecular Structure Correlator (MSC) for advanced structural elucidation.

Conclusion

The combination of Agilent GC/Q-TOF accurate-mass measurements with MassHunter software and low-energy ionization provides a robust platform for comprehensive extractables and leachables analysis. This approach ensures reliable detection, identification, and quantification of both target and unknown contaminants in pharmaceutical nasal spray products, supporting safety assessments and regulatory requirements.

References

1. Degenhard Marx, Gerallt Williams and Matthias Birkhoff (June 3, 2015). Intranasal Drug Administration — An Attractive Delivery Route for Some Drugs, Drug Discovery and Development.