Identification of plastic additives in pharmaceutical packaging using a fully automated parallel extraction evaporator system and UHPLC-HRMS

Significance of the Topic

Polymeric components in pharmaceutical packaging can release additives and degradation products into drug formulations, posing risks to safety and efficacy. Regulatory authorities such as the FDA and USP require rigorous extractables and leachables (E&L) testing to ensure container–closure systems do not compromise drug quality.

Objectives and Study Overview

• Develop and validate an automated extraction method for plastic additives in inhaler packaging using the Thermo Scientific EXTREVA ASE Accelerated Solvent Extractor.
• Compare extraction efficiency and analyte integrity with traditional static liquid extraction (SLE) and existing accelerated solvent extraction (ASE) protocols.

Instrumentation Used

• Thermo Scientific EXTREVA ASE Accelerated Solvent Extractor for combined extraction and evaporation.
• Thermo Scientific Vanquish Flex UHPLC system (quaternary pump, split sampler, column compartment, diode array detector).
• Thermo Scientific Q Exactive HF Hybrid Quadrupole–Orbitrap mass spectrometer with positive/negative electrospray ionization.

Methodology

Inhaler samples were cut into small pieces, loaded into cellulose thimbles with Ottawa sand, and processed on the EXTREVA ASE system. Extraction variables were optimized by comparing solvents (hexane vs isopropanol), temperatures (90 °C vs 100 °C), and durations (20 vs 25 minutes). Extracts were evaporated in situ, reconstituted in acetonitrile, then analyzed by UHPLC–HRMS using a C18 column and data‐dependent MS/MS acquisition.

Results and Discussion

Using hexane at 100 °C for 25 minutes provided the highest yields of the three major additives—tris(2,4-di-tert-butylphenyl) phosphite (Irgafos 168), its oxidized form, and bis(2,4-di-tert-butylphenyl) phosphate degradation product—as well as Irganox 1010. Hexane outperformed isopropanol in extraction efficiency, while the integrated gas‐assisted extraction and evaporation of the EXTREVA ASE system minimized additive oxidation compared to a 10 h SLE protocol. Parallel processing of four samples reduced solvent consumption and labor.

Benefits and Practical Applications

• Automated extraction and evaporation in one instrument accelerates sample throughput.
• Parallel processing of up to four cells conserves solvent and reduces manual labor.
• Optimized conditions maintain analyte stability and yield comparable or improved recoveries versus traditional methods.
• UHPLC–HRMS screening enables confident identification of target and non‐target E&L species.

Future Trends and Opportunities

Further integration of machine‐vision controlled evaporation, expansion of solvent selection for greener extraction, and advanced HRMS libraries will enhance E&L screening. Emerging regulatory updates and AI‐driven data analysis promise more comprehensive risk assessments for container–closure systems.

Conclusion

The EXTREVA ASE Accelerated Solvent Extractor offers a robust, fully automated platform for E&L studies in pharmaceutical packaging, delivering efficient plastic additive extraction, reduced solvent use, and minimized analyte degradation compared to conventional approaches.

References

1. U.S. FDA, Code of Federal Regulations, 21 CFR 211.94.
2. FDA Guidance for Industry: Container Closure Systems for Packing Human Drugs and Biologics, 1999.
3. PQRI Recommendations to FDA on E&L Testing for Orally Inhaled and Nasal Drug Products, 2006.
4. USP General Chapters <1663> and <1664> on Extractables and Leachables, 2015.
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6. U.S. Pharmacopeial Convention, <1663> Assessment of Extractables Associated with Pharmaceutical Packaging/Delivery Systems, USP 40, 2017.
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8. Thermo Scientific Application Note 1108: Comparison of Soxhlet and Accelerated Solvent Extraction for Leachable and Extractable Analysis, 2016.
9. Srinivasan K, Ullah R, US Patent 9,440,166 B2, 2016.
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