Analysis of Extractable Compounds from a Pressurized Metered-Dose Inhaler (pMDI) Using GC/MSD Systems

Significance of the topic

A pressurized metered-dose inhaler (pMDI) is widely used to deliver precise doses of respiratory drugs directly to the lungs. Elastomeric and plastic parts within the device may release chemical compounds into the active pharmaceutical formulation, posing potential safety and efficacy concerns. Regulatory bodies and industry groups have established guidelines for extractables and leachables testing to ensure patient safety and product quality.

Objectives and overview of the study

This application note reports a nondirected screening of volatile and semivolatile extractable compounds in expired pMDI components. The goal was to identify potential migrants from metal, plastic, and rubber parts by combining high-temperature headspace GC/MS with large-volume liquid injection GC/MS using a multimode inlet.

Methodology and Instrumentation

The study employed two complementary GC/MS systems:

• Headspace analysis: Agilent 7697A Headspace Sampler coupled to a 7890 GC and 5977A MSD, equilibrated at 250 °C for 25 min to detect highly volatile species directly from intact components.
• Liquid injection analysis: Agilent 7693A Automatic Liquid Sampler with a multimode inlet on a 7890 GC and 5977A MSD, operated in solvent-vent mode to inject large volumes of ethanol, dichloromethane (DCM) or hexane extracts.

Sample preparation involved cutting each component into ~1 cm2 pieces, extracting with selected solvents under sonication, and allowing thermal equilibration or solvent removal per technique.

Main results and discussion

Analysis revealed an array of extractables including monomers, plasticizers, antioxidants, lubricants, surfactants, stabilizers, residual solvents, fragrance additives, curing agents and by-products of polymer processing. Key findings included:

• Rubber seals released siloxane oligomers, fatty acids (palmitic, stearic, oleic), amides, and low-molecular-weight cyclic siloxanes detectable by both headspace and solvent extraction.
• Plastic parts such as the retaining cup and metering valve yielded phthalate esters, benzene derivatives, and proprietary slip agents detectable primarily by DCM or hexane extraction.
• Headspace sampling uniquely identified volatile species like dioxolane softeners, furans, pyridine, and residual monomers at elevated temperature without solvent.
• Large-volume injection enhanced sensitivity for low-level migrants including photoinitiators, UV stabilizers (Irganox, Irgafos), and dye precursors.

Most compounds were technique-dependent, underscoring the value of combining headspace and solvent-based GC/MS to build a comprehensive extractables profile.

Benefits and practical applications

The combined analytical approach enables broad chemical coverage from intact device components through aggressive solvent extraction. It supports risk assessments for inhalation devices, informs material selection and formulation design, and helps meet regulatory expectations for extractables and leachables testing in orally inhaled drug products.

Future trends and applications

Future work may include high-resolution GC/Q-TOF or tandem MS methods for targeted quantitation of identified extractables. Development of shared databases and standardized workflows will improve cross-laboratory consistency. Novel valve technologies and low-extractable materials are anticipated to reduce chemical migration in next-generation inhalation devices.

Conclusion

This study demonstrates that headspace GC/MS and multimode-inlet GC/MS are complementary tools for nondirected extractables screening of pMDI components. Together they yield a detailed chemical profile necessary for safety assessment, regulatory compliance, and material optimization.

References

1. Ball DJ, et al. Leachables and Extractables Handbook. John Wiley & Sons; 2012.
2. Feilden A. Update on Undertaking Extractable and Leachable Testing. Smithers-Rapra; 2011.
3. Jenke D, Carlson T. PDA J Pharm Sci Technol. 2014;68:407–455.
4. Norwood DL, et al. Pharm Res. 2008;25:727–739.
5. IPAC-RS Materials Webinar. Best Practices of Routine Extractables Testing; 2012.
6. Nagao LM, et al. Pharm Outsources. 2011 Nov 1.
7. US FDA. Guidance for Industry: Container Closure Systems for Packaging Human Drug and Biologics. 1999.
8. Wildhaber JH, et al. J Pediatr. 1999;135:28–33.
9. Chan J, Shuang F. Agilent Application Note 5990-9510EN; 2012.
10. Ye X, et al. Anal Methods. 2014;6:4083–4089.