The pharmaceutical respiratory inhalation sector is entering its second major propellant transition. In response to the Montreal Protocol requirements, the first transition moved pressurised metereddose inhalers (pMDIs) away from ozonedepleting chlorofluorocarbons (CFCs such as CFC-11) to hydrofluoroalkanes (HFAs), principally HFA-134a and HFA-227ea. These HFAs eliminated the ozone-depletion concern but unfortunately retained high global warming potential (GWP).
Climate change regulation is now driving a further transition. Following the Montreal Protocol, the Kyoto Protocol and the related Kigali Amendment established a global hydrofluorocarbon phasedown trajectory, implemented regionally in the EU through Regulation (EU) 2024/573, which removed the previous quota exemption for HFA-based pMDIs, and in the United States through the American Innovation and Manufacturing (AIM) Act and its implementing allowance programme at 40 CFR Part 84.1,2,3 For pMDIs, the challenge is to decarbonise without compromising patient access, inhaler performance, or therapeutic continuity.
This review summarises HFO-1234ze(E) as a successfully approved next-generation propellant, assessing its physical properties, formulation compatibility, toxicological profile, clinical evidence, and regulatory readiness.
Technical and Formulation Considerations
Medical Propellant HFO-1234ze(E), GMP is a hydrofluoroolefin propellant for pMDIs, reducing propellant greenhouse gas emissions by up to 99.9% relative to the incumbent HFAs.4,5 Its liquid density of 1.17 g/ mL is comparable to HFA-134a at 1.22 g/mL so that suspension sedimentation and creaming behaviour carry across the transition without wholesale reformulation, in contrast to the substantially less dense HFA-152a.4,5 HFO1234ze(E) exhibits no vapor flame limits under standard test conditions and is classified nonflammable under EC Testing Method A11, ISO 10156 and the US DOT standard (ASTM E681), and in the ASTM flame projection, ignition distance and enclosed-space ignition tests.4 A narrow flammable range can be observed only where temperature is at or above 30°C, relative humidity at or above 50%, and a high-energy ignition source is present.7 The propellant is thermally and hydrolytically stable, showing no breakdown and no effect on metals after two weeks at 200°C in the presence of water and metals, and remaining within specification after several years of storage in steel cylinders. Compatibility has been demonstrated with aluminium, tin plate and PET-lined canisters and with common valve gasket materials including grades of butyl rubber, Buna and neoprene, with pMDI valve compatibility testing conducted by Aptar Pharma.4 Nonetheless, the best approach is to conduct confirmatory testing with the specific container closure system used.
