COMPREHENSIVE EXTRACTABLES PROFILING OF LOW-DENSITY POLYETHYLENE (LDPE) PHARMACEUTICAL PACKAGING MATERIAL USING MULTI-SOLVENT EXTRACTION AND ORTHOGONAL ANALYTICAL TECHNIQUES

Shanmugapriya R. V., Alexandar S.*, Nallakumar P., Sangeetha S.

ABSTRACT

Polymeric containers are widely used for the primary packaging of pharmaceutical products; however, chemical species can migrate from such packaging into the drug product, giving rise to extractables and leachables (E&L) that may compromise patient safety, product stability, and regulatory acceptance. The present study reports a comprehensive extractables profiling of low-density polyethylene (LDPE, Purell PE 1840H grade) pharmaceutical packaging material using a multi-solvent, multi-technique controlled extraction protocol. The test article was subjected to four independent extraction procedures - neat headspace enrichment, reflux extraction in Water for Injection (WFI), reflux extraction in dichloromethane (DCM), and microwave-assisted acid digestion - to capture volatile, semi-volatile, non-volatile organic, and inorganic (elemental) extractables. The resulting extracts were characterized using four orthogonal analytical platforms: Headspace Gas Chromatography/Mass Spectrometry (HS-GC/MS) for volatiles, Gas Chromatography/Mass Spectrometry (GC/MS) for semi-volatiles, Liquid Chromatography/Mass Spectrometry with diode array detection (LC-PDA-MS) for non-volatile organics, Inductively Coupled Plasma-Optical Emission Spectroscopy (ICP-OES) for elemental impurities, and Ion Chromatography (IC) for anions. Screening identified 10 volatile compounds above the 0.5 mg/kg reporting limit in the neat sample, 2 semi-volatile compounds in the WFI extract and 15 in the DCM extract, and 3 non-volatile organic compounds in positive-ionization LC/MS mode from the WFI extract; no metals or anions were detected above their respective reporting limits. Compounds were assigned identification confidence levels (Identified, Most Probable, Tentatively Identified, or Unidentified) based on NIST mass-spectral library matching and comparison with authentic reference standards. The resulting extractables inventory provides the scientific foundation for an Analytical Evaluation Threshold (AET)-based, risk-proportionate triage of compounds requiring confirmatory leachables monitoring in the finished drug product, in alignment with USP / and ICH Q3D expectations. The approach demonstrates a cost-effective, regulation-aligned strategy for qualifying LDPE packaging systems and strengthens indigenous analytical capability for pharmaceutical packaging safety assessment.

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