Simultaneous determination of known and unknown Extractables in pharmaceuticals packaging material by tandem mass spectrometry using Scan-MRM mode

Significance of the Topic

The identification and quantification of extractable compounds released from pharmaceutical packaging materials are essential to ensure drug safety and efficacy throughout shelf life. Regulatory guidelines require comprehensive extractables and leachables (E&L) studies to detect both known and unknown impurities at trace levels, guarding against patient exposure to toxicants and preserving drug product performance.

Study Objectives and Overview

This study demonstrates a robust workflow combining full-scan and multiple reaction monitoring (MRM) tandem mass spectrometry on a triple quadrupole platform. Key aims include:

• Simultaneous targeted quantification of 33 common extractables (phthalates, siloxanes, PAHs, antioxidants).
• Screening and semi-quantification of unknown impurities via Scan-MRM mode.
• Evaluation of extraction profiles under aqueous (pH 2.5–10.5) and organic reflux solvents (ethanol, hexane, isopropanol, dichloromethane).

Methodology and Sample Preparation

Extractables were studied using two complementary GC-MS/MS methods:

1. Method-1: Full-scan plus MRM for non-PAH targets. Samples refluxed in organic solvents or incubated in aqueous buffers, followed by liquid-liquid extraction with ethyl acetate, concentration under nitrogen, and reconstitution.
2. Method-2: Dedicated PAH quantification in MRM mode after organic reflux.

Calibration standards prepared in ethyl acetate covered relevant linear ranges with LOQs from 1 to 25 ppb. Aqueous extractions spanned acidic to basic conditions to simulate worst-case migration scenarios.

Used Instrumentation

• Shimadzu GCMS-TQ8040 NX triple quadrupole with AOC-20i autosampler.
• Columns: Rxi-5Sil MS (0.25 mm × 30 m, 0.25 μm) for Method-1; SH-I-PAH (0.25 mm × 30 m, 0.10 μm) for Method-2.
• Electron impact ionization, split injection, helium carrier gas.

Results and Discussion

Targeted compounds exhibited excellent linearity (r2 > 0.99) and precision at LOQ levels. Among aqueous extractions, only two targets (decamethylcyclopentasiloxane, dinonyl phthalate) were detected. In organic reflux experiments, multiple phthalates, siloxanes, PAHs, and additives were quantified, reflecting solvent polarity effects on migration. Scan-MRM data revealed approximately 88 unknown impurities, semi-quantified via average slope methods, underscoring the value of combined scan and MRM acquisition.

Practical Benefits and Applications

• High throughput: Up to 800 MRM transitions per second with 20,000 amu/s scan speed facilitates comprehensive extractables profiling.
• Sensitivity: LOQs down to 1 ppb ensure detection at regulatory thresholds.
• Versatility: Simultaneous known and unknown screening supports risk assessment for a wide range of packaging materials and drug products.

Future Trends and Applications

Advances in high-resolution and multi-dimensional mass spectrometry promise even deeper coverage of unknown extractables. Integration of automated data-processing workflows and machine learning for spectral deconvolution will accelerate identification and reduce manual interpretation. Expanding studies to real drug products under stability conditions will further link extractable profiles to leachable risk.

Conclusion

The Scan-MRM tandem MS approach on the GCMS-TQ8040 NX platform delivers a sensitive, robust, and high-throughput solution for comprehensive extractables analysis in pharmaceutical packaging. By combining targeted quantification with unknown screening in a single run, the workflow meets stringent regulatory demands and supports product safety assessments.