Analysis of Extractable/Leachable Compounds from Generic Liquid Drug Formulations Using GC/MSD Systems

Significance of the Topic

Liquid drug formulations often interact with their plastic packaging, leading to migration of additives such as plasticizers, antioxidants and solvents. Identifying these extractables and leachables is critical for ensuring drug safety, efficacy and regulatory compliance under guidelines from FDA, USP, ICH and ISO.

Objectives and Study Overview

This application note investigates the migration of organic compounds from a generic pharmaceutical suspension into its packaging. Two complementary GC/MSD approaches—high-temperature headspace sampling and large-volume liquid injection—are applied to detect a broad range of volatile and semi-volatile leachables.

Applied Methodology

The drug suspension was centrifuged, separating solid and supernatant phases for headspace analysis at 250 °C to target volatile fatty-acid based plasticizers and antioxidants. Solvent extraction with dichloromethane, followed by sonication and settling, prepared samples for automatic large-volume injection using a multimode inlet in solvent-vent mode, focusing on phthalate plasticizers and semivolatile additives.

Instrumentation

• Agilent 7697A Headspace Sampler coupled to 7890A GC and 5977A MSD
• Agilent 7693A Automatic Liquid Sampler with Multimode Inlet (MMI) coupled to 7890A GC and 5977A MSD
• HP-5ms UI capillary columns (30 m × 0.25 mm, 0.5 µm and 0.25 µm)
• Helium carrier gas; full scan (15–600 amu) and single ion monitoring modes
• Data processed with MassHunter B.07.01, Unknowns Analysis B.07.00 and AMDIS 2.72

Key Results and Discussion

High-temperature headspace GC/MS identified fatty-acid plasticizers including butyl palmitate and 2-methylpropyl stearate, plus N,N-dimethyl-tetradecanamine and antioxidant residues. Large-volume liquid injection analysis revealed phthalate plasticizers such as di(2-ethylhexyl) adipate and di(2-propylpentyl) phthalate, along with common pharmaceutical excipients and flavor or fragrance trace compounds. Single ion monitoring confirmed key plasticizer identities and highlighted the need for high-resolution MS to differentiate isobaric phthalates.

Benefits and Practical Applications of the Method

This two-pronged GC/MSD workflow delivers comprehensive non-targeted screening of volatile through semi-volatile leachables in a single analysis. It is directly applicable to quality control and safety assessment of liquid pharmaceutical products across all packaging risk categories.

Future Trends and Potential Applications

Integration of high-resolution mass spectrometry and liquid chromatography will extend detection to higher molecular weight antioxidants and oligomers. Emerging non-targeted screening algorithms, in-silico toxicology prediction, and miniaturized sampling approaches promise faster, more sensitive extractables and leachables profiling for regulatory submission.

Conclusion

The complementary use of high-temperature headspace sampling and large-volume liquid injection GC/MSD enables broad identification of extractable and leachable compounds in liquid drug formulations. This robust analytical strategy supports stringent safety evaluations and regulatory compliance for pharmaceutical packaging systems.

References

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