Identification and Quantitation of Plastic Additives in Medicine Containers by HR LC-MS, GC-MS and ICP-MS

Significance of the Topic

The migration of plastic additives from medicine containers into drug formulations poses potential health risks and challenges product integrity. Comprehensive extractable and leachable analysis supports patient safety, regulatory compliance, and quality control of pharmaceutical packaging.

Objectives and Study Overview

This work set out to identify and quantify plastic additives released from polypropylene pill bottles. Three complementary techniques were employed—high-resolution LC-MS, GC-MS, and ICP-MS—coupled with advanced data processing to achieve confident component detection, structure elucidation, and quantitation.

Methodology and Instrumentation

• Sample Preparation
  Polypropylene bottles were filled with isopropanol and heated at 50 °C for five days. Resulting extracts were directly injected for analysis.
• HR-LC-MS Analysis
  Orbitrap-based LC-MS acquired full-scan data at 70 000 resolution and top-3 data-dependent MS/MS at 35 000 resolution using electrospray ionization. SIEVE 2.1 and Mass Frontier 7.0 software, alongside the mzCloud spectral database, were used for component extraction, accurate-mass search, substructure matching, and fragment annotation.
• GC-MS Analysis
  Volatile and semi-volatile additives were separated on a Trace Ultra GC with split injection and detected by an ISQ single-quadrupole mass spectrometer. Spectral matching and calibration curves enabled identification and quantitation of phthalates, antioxidants, and plasticizers.
• ICP-MS Analysis
  Bottles were extracted with 2 percent nitric acid for 24 hours and analyzed by iCAP Q ICP-MS in helium KED mode. USP<232> regulated metals and additional trace elements were quantified to evaluate leachable metal content.

Used Instrumentation

• Thermo Scientific Q Exactive Orbitrap LC-MS
• Thermo Scientific ISQ Single Quadrupole GC-MS
• Thermo Scientific iCAP Q ICP-MS
• Thermo Scientific Dionex Ultimate 3000 RS UHPLC

Main Results and Discussion

• HR-LC-MS identified more than a dozen additives, including antioxidants and plasticizers, with sub-ppm mass accuracy. MS/MS fragmentation and spectral library matching confirmed proposed structures.
• GC-MS detected and quantified regulated phthalates, Irganox antioxidants, and other semi-volatile compounds. Calibration curves were linear from 1 to 1000 ppm, demonstrating robust quantitation.
• ICP-MS analysis revealed all monitored USP<232> and other trace metals below threshold limits, indicating negligible metal leaching from polypropylene containers.

Benefits and Practical Applications

• The integrated workflow streamlines extractables and leachables profiling for pharmaceutical packaging.
• High sensitivity and specificity enable thorough risk assessment of container materials.
• Compliance with regulatory guidelines is facilitated through comprehensive data processing and reporting tools.

Future Trends and Applications

Integration of artificial intelligence for spectral interpretation will enhance unknown identification. Development of on-line monitoring and miniaturized sampling may allow real-time extractables assessment during manufacturing. Broadening these approaches to biologics and combination products will expand their applicability.

Conclusion

The combined use of HR-LC-MS, GC-MS, and ICP-MS with advanced data processing and spectral libraries establishes a robust extractables and leachables workflow. This approach ensures pharmaceutical container safety, regulatory compliance, and efficient material characterization.