Characterizing Extractables from Common Pharmaceutical Packaging Material by High Resolution Time-of-Flight Mass Spectrometry and Enhanced Gas Chromatography Separations

Importance of the Topic

Characterization of extractables and leachables from pharmaceutical packaging is critical for ensuring product safety and regulatory compliance. Comprehensive analysis informs risk assessment, supports FDA submissions under USP 1663 guidance, and helps manufacturers identify potential contaminants from closures and delivery systems.

Objectives and Study Overview

This study demonstrates a robust workflow combining comprehensive two-dimensional gas chromatography (GCxGC) with high-resolution time-of-flight mass spectrometry (HR-TOFMS) to identify unknown extractables from plastic syringes and rubber stoppers. Key goals include improving chromatographic separation, enhancing spectral clarity, and achieving confident molecular formula determinations.

Methodology and Instrumentation

Samples of butyl rubber stoppers and plastic syringes (with and without rubber) were extracted in methylene chloride at room temperature for 72 hours. Analytical conditions:

• GCxGC-TOFMS system: LECO Pegasus HRT+ 4D with QuadJet thermal modulation
• Columns: Rxi-5ms primary, Rxi-17Sil MS secondary
• Ionization: simultaneous electron ionization (EI) and methane chemical ionization (CI)
• Mass range: 35–900 m/z (EI), 60–900 m/z (CI); acquisition rate 125 spectra/s

Main Results and Discussion

GCxGC delivered significant gains in peak capacity, uncovering coeluted analytes that one-dimensional GC could not resolve. Examples include separation of phenol and dodecyl acrylate. Structured chromatograms and second-dimension retention behavior aided identification. Combining EI and CI data provided molecular ion support and formula confirmation for phthalates, oligomers, antioxidants, and processing additives. High-resolution accurate mass measurements enabled differentiation between candidate library matches and determination of formulas for features absent from spectral libraries.

Benefits and Practical Applications

The GCxGC-HR-TOFMS workflow offers:

• Enhanced resolution of complex mixtures in packaging extracts
• Cleaner spectra through chromatographic isolation, reducing interferences
• Accurate mass determination for confident unknown identification
• Support for regulatory submissions and quality control in pharmaceutical manufacturing

Future Trends and Opportunities

Advances in multidimensional separations and data processing will further expand detection of trace contaminants. Integration with automated spectral deconvolution and machine learning promises more rapid identification workflows. Emerging stationary phases and ion mobility spectrometry could complement GCxGC-TOFMS for even greater chemical space coverage.

Conclusion

This work validates GCxGC-HR-TOFMS as a powerful strategy for thorough characterization of extractables from pharmaceutical packaging materials. The combination of enhanced chromatographic separation and high-resolution accurate mass detection addresses both sample complexity and stringent identification requirements, supporting safer drug delivery systems.