Analysis of Thermal Extracts from an Eye Drop Container via the Trapped Headspace (THS) Method

Significance of the Topic

Continuous exposure to extractables and leachables from pharmaceutical packaging poses potential health risks. High-sensitivity analysis of volatile and semi-volatile compounds is essential for quality control and regulatory compliance in pharmaceutical production. The trapped headspace (THS) method coupled with GC-MS offers a promising approach for efficient screening of packaging materials.

Objectives and Study Overview

This study compares static headspace (SHS), trapped headspace (THS), and thermal desorption (TD) methods for analyzing thermal extracts from an eye drop container composed of LDPE nozzle and HDPE cap. Target compounds include nonanal, naphthalene, 2,6-bis(tert-butyl)-4-ethylphenol, di‐ethyl phthalate (DEP), di-iso-butyl phthalate (DiBP), and di-n-butyl phthalate (DBP).

Used Instrumentation

• GC-MS system: GCMS-QP2020 NX
• Headspace sampler: HS-20 NX Trap with electronic cooling trap (down to ‑10 °C)
• Trap adsorbent: Tenax TA (60/80 mesh, 37 mg)
• Headspace vials: 20 mL wide-mouth glass vials

Applied Methodology

The GC-MS analysis employed a SH-I-5Sil MS capillary column (30 m × 0.25 mm i.d., 0.25 µm film) with a temperature program of 50 °C (2 min) ramped at 10 °C/min to 320 °C (6 min). Helium carrier gas was used at a constant linear velocity of 44.4 cm/s. SHS, THS, and TD methods were evaluated as follows:

• SHS: Direct sampling of 20 mL vial headspace at 150 °C after 15 min equilibration.
• THS: Concentration of the entire vial headspace onto Tenax TA trap at ‑10 °C, then rapid heating to 250 °C for desorption.
• TD: Thermal desorption tubes loaded with 20 mg sample, desorbed at up to 400 °C.

Main Results and Discussion

THS achieved more than 20-fold higher sensitivity compared to SHS and reached approximately one-tenth the signal intensity of TD, despite using a 1/30 gas concentrate volume. Nonanal, which was undetectable by SHS, was clearly identified by THS with library matching. Differences in pyrolytic compound intensity were observed between LDPE nozzle and HDPE cap. THS provided sufficient sensitivity to detect all target analytes under practical conditions.

Benefits and Practical Applications

THS offers high sensitivity comparable to TD while requiring minimal sample preparation and lower cost. Wide-mouth vials facilitate easier sample loading and reduce contamination risk. The ability to switch between trap (THS) and loop (SHS) modes allows flexible adaptation to varying analyte concentrations. This approach is suitable for routine quality assurance of extractables and leachables, residual solvents, and impurity profiling.

Future Trends and Potential Applications

Advancements may include integration of automated trap cooling and heating, miniaturization of adsorption devices, coupling with high-resolution mass spectrometry for enhanced compound identification, and expansion into real-time monitoring of diffused gases and environmental contaminants. Data analytics and machine learning could further improve screening workflows and predictive risk assessments.

Conclusion

The THS-GC-MS method demonstrated robust performance for detecting thermal extractables from pharmaceutical packaging, combining sensitivity, speed, and cost-effectiveness. Its flexibility and high throughput make it a valuable tool for comprehensive E&L analysis and broader analytical applications.