Characterization of Extractables from Common Pharmaceutical Packaging Materials with GCxGC and HR-TOFMS

Significance of the Topic

Comprehensive profiling of extractables and leachables from pharmaceutical packaging materials is critical for ensuring product safety, regulatory compliance, and patient health. Complex chemical mixtures require advanced analytical techniques to detect, separate, and identify potential impurities and breakdown products that may migrate into drug formulations.

Study Objectives and Overview

This study demonstrates the application of two-dimensional gas chromatography coupled with high-resolution time-of-flight mass spectrometry (GCxGC-HR-TOFMS) to characterize extractable compounds from butyl rubber stoppers and plastic syringes. The aim was to improve separation selectivity, increase peak capacity, and enhance confidence in analyte identification through complementary ionization modes and accurate mass measurements.

Used Instrumentation

• Pegasus GC-HRT 4D GCxGC system with QuadJet Thermal Modulator
• LECO L-PAL 3 autosampler
• Columns: Rxi-5ms primary (30 m x 0.25 mm), Rxi-17Sil MS secondary (0.9 m x 0.25 mm)
• Multi-Mode Ion Source (MMS) supporting electron ionization (EI) and methane chemical ionization (CI)
• Helium carrier gas, temperature programming from 50 °C to 340 °C, modulation period 3 s
• Mass range 35–900 m/z (EI) and 60–900 m/z (CI), acquisition rate 125 spectra/s

Methodology

Samples of butyl rubber stoppers and plastic syringes were extracted with methylene chloride at room temperature for 72 hours. Extracts were injected in splitless mode and analyzed with GCxGC-HRT 4D. Retention indices were calibrated using an alkane standard. Two-dimensional separation with nonpolar and polar columns and thermal modulation enhanced chromatographic resolution. EI and CI spectra provided library-searchable fragmentation patterns and accurate mass data for molecular formula determination.

Main Results and Discussion

• GCxGC resolved coeluted analytes that overlapped in one-dimensional GC, revealing compounds such as dodecyl acrylate and 2,4-di-tert-butyl-6-nitrophenol as separate peaks.
• High-resolution accurate mass data improved library matching and allowed selection of correct tentative identifications, as shown for an aromatic sulfur false positive replaced by a more accurate oxygen-containing compound.
• Unknown features lacking database matches were assigned to butyl rubber oligomers and chlorinated oligomers based on mass accuracy, retention behavior, and anticipated chemistry.
• Representative chromatograms from five sample types illustrated the method’s capacity to handle varied pharmaceutical contact materials and complex matrices.

Benefits and Practical Applications of the Method

• Enhanced peak capacity and cleaner spectra facilitate confident identifications of known and unknown extractables.
• Comprehensive profiling supports regulatory submissions and quality control for pharmaceutical packaging and delivery systems.
• Methodology can detect low-level impurities, degradation products, and potential toxicants in complex matrices.

Future Trends and Potential Applications

Integration of machine learning for automated feature annotation, miniaturized and high-throughput workflows, coupling with ion mobility spectrometry, and expanded applications to biologics and medical devices promise further advances in extractables and leachables analysis.

Conclusion

The combination of GCxGC and HR-TOFMS with multiple ionization modes delivers superior separation and identification capabilities for extractables characterization. This approach uncovers hidden analytes, enhances spectral clarity, and supports robust regulatory and safety assessments of pharmaceutical materials.

References

• USP 1663 Assessment of Extractables Associated with Pharmaceutical Packing/Delivery Systems