Analysis of Extractable/Leachable Compounds from Transdermal Patches Using GC/MSD Systems

Importance of the Topic

Recent regulatory and quality demands in pharmaceuticals require thorough profiling of extractable and leachable compounds from transdermal patches to safeguard patient safety and product integrity. Transdermal systems deliver drugs through the skin over time, raising concerns about migrant additives from packaging or adhesive matrices.

Study Objectives and Overview

The study used a 5 % lidocaine adhesive patch to characterize extractable and leachable compounds. Solvents—acetone, dichloromethane (DCM), and hexane—were applied to extract potential migrants. Analytical techniques included high-temperature headspace GC/MS and large-volume liquid injection GC/MS to detect volatile, semivolatile, and low-level compounds.

Methodology and Instrumentation

• Sample Preparation: 1 cm² patch pieces (300 mg) and film liner pieces were extracted with 5 mL solvent via sonication and 24 h equilibration.
• Headspace GC/MS: Agilent 7697A Headspace Sampler coupled with 7890A GC and 5977A MSD. Equilibration at 250 °C, loop size 1 mL.
• ALS GC/MS: Agilent 7693A Automatic Liquid Sampler with Multimode Inlet for large-volume solvent vent injection into 7890A GC and 5977A MSD.

Main Results and Discussion

• Over 80 compounds were identified across techniques, including plasticizers (phthalates, adipates), adhesives (acetophenone, benzophenone), antioxidants and stabilizers, pharmaceutical excipients (parabens, glycerin, sorbitol), and lidocaine.
• Acetone extracts highlighted glycerin, urea, parabens, terephthalates, and fatty acids.
• DCM extracts revealed benzophenone, bis(2-ethylhexyl)phthalate, squalene, and tributyl acetylcitrate.
• Hexane extracts targeted nonpolar plasticizers like bis(2-ethylhexyl)adipate and various phthalates.
• Headspace analysis detected volatile additives and residual monomers such as furfural, glycidol, and formamide derivatives, and high-boiling compounds like palmitic and stearic acid esters.
• Large-volume injection proved essential for low-level phthalate detection, while headspace sampling allowed straightforward volatile profiling.

Benefits and Practical Applications

• Comprehensive extractable and leachable profiling supports regulatory compliance (USP <87>/USP <88>/ICH Q6A).
• Method flexibility allows targeted analysis of solvent-selective migrants and volatile contaminants.
• Optimized headspace and ALS GC/MS workflows offer efficient detection across a broad polarity range, enhancing quality control in transdermal product development.

Future Trends and Opportunities

• Integration of high-resolution mass spectrometry for improved identification of unknown leachables.
• Non-targeted screening with data-mining algorithms to detect unforeseen migrants.
• Miniaturized and in-line sampling techniques for real-time leachable monitoring during storage.
• Green chemistry approaches to reduce solvent use and environmental impact in extractables testing.

Conclusion

This study demonstrated robust analytical workflows combining headspace and large-volume injection GC/MS for comprehensive extractable and leachable analysis of lidocaine transdermal patches. The solvent-specific and thermal sampling methods provide a toolbox for detecting a wide spectrum of potential migrants, enabling safer and more reliable transdermal drug delivery.

References

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