Analysis of Volatile Compounds Identified in Rubber Gasket Extracts Using GC/MSD and High-Resolution GC/Q-TOF

Importance of the Topic

Elastomeric closures can leach chemicals into drug products, jeopardizing safety and efficacy. Detailed characterization of extractable and leachable (E&L) compounds from rubber gaskets is essential for regulatory compliance and patient health.

Objectives and Study Overview

This study aimed to develop and compare workflows for identifying volatile and semivolatile E&L compounds from rubber syringe gaskets using unit-mass GC/MSD and high-resolution GC/Q-TOF. It sought to demonstrate improved compound coverage, confidence in identifications, and structure elucidation capabilities introduced by high-resolution mass spectrometry and a novel low-bleed GC column.

Methodology and Instrumentation

• Sample Preparation: Gasket extraction in tetrahydrofuran at room temperature for six months.
• Chromatography: Agilent 8890 GC equipped with either a 30 m×0.25 mm DB-5Q column (0.25 µm) or a 30 m×0.25 mm DB-5ms Ultra Inert column. Pulsed splitless injection, 45 °C initial oven ramp to 325 °C.
• Mass Spectrometry:
  • GC/MSD: Agilent 5977C MSD in full-scan EI mode (m/z 45–450).
  • GC/Q-TOF: Agilent 7250 Q-TOF in standard and low-energy EI modes (m/z 50–1000), enabling accurate mass measurement and MS/MS experiments.
• Data Processing:
  • Chromatographic deconvolution and library search against NIST23 using MassHunter Unknowns Analysis.
  • Retention time (RT) locking and RI filtering to improve match confidence.
  • ExactMass and Molecular Structure Correlator (MSC) software for formula confirmation and structure elucidation.

Main Results and Discussion

• DB-5Q vs. DB-5ms UI: The new DB-5Q column exhibited significantly lower bleed at high oven temperatures, improving detection of high-boiling additives such as antioxidants, stabilizers, and UV absorbers.
• RT/RIs: Consistency between DB-5Q and DB-5ms UI was demonstrated, with average RI deviations <1 unit for 70 reference compounds and closely matched alkane RTs.
• Compound Identification:
  • GC/MSD identified over 100 E&L compounds, including acids, phenols, phthalates, and long-chain hydrocarbons.
  • GC/Q-TOF confirmed ~80 of these and revealed additional extractables (solvents, accelerators, plasticizers, UV stabilizers).
• Unknowns and Structure Elucidation:
  • Low-energy EI increased molecular ion visibility for unknowns, facilitating formula assignment.
  • MS/MS with targeted precursors and MSC software enabled tentative structural proposals for several unknown E&L degradants.

Benefits and Practical Applications of the Method

• Compliant data acquisition with audit trails and RT locking supports regulatory requirements (21 CFR 11, EU Annex 11).
• Low-bleed column enables reliable detection of late-eluting, high-boiling additives in E&L studies.
• Combination of unit-mass and high-resolution mass spectrometry enhances compound coverage, confidence in identifications, and unknown elucidation.
• Workflow is applicable to quality control and safety assessment of pharmaceutical packaging materials.

Future Trends and Opportunities

• Integration of alternative soft ionization techniques (e.g., CI) to further improve molecular ion detection.
• Enhanced MS/MS libraries and machine-learning–driven deconvolution for automated unknown identification.
• Development of targeted screening panels for common E&L compounds in various elastomeric materials.
• Implementation of high-throughput autosamplers and advanced data analytics for large-scale E&L screening.

Conclusion

The combined GC/MSD and high-resolution GC/Q-TOF workflow with a low-bleed DB-5Q column provides a robust, compliant platform for comprehensive analysis of volatile and semivolatile extractables and leachables from rubber gaskets. The approach improves compound coverage, reduces background interferences, and enables structural elucidation of unknowns, supporting safety assessments and regulatory compliance in pharmaceutical packaging analysis.

Reference

1. Zhang F et al., J. Pharm. Biomed. Anal. 2004, 34, 841–849.
2. Baneshi M et al., Molecules 2023, 29(1), 106.
3. Taylor R, Son PN, Encyclopedia of Chemical Technology 1982.
4. Bohrer D et al., JPEN 2016, 41(6), 1037–1044.
5. Agilent OpenLab ECM XT White Paper 2024, 5994-7586EN.
6. Agilent DB-5Q Technical Overview 2024, 5994-3228EN.