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The pressurized metered dose inhaler (pMDI) has undergone many changes in its 68-year history. Some of the most significant in pMDI formulation and design have been driven by regulatory restrictions on the liquefied gas propellants that the pMDI relies upon to produce…. 10 February 2024 Inhalation Environmentally friendly metered dose inhaler propellants: Challenges for inhaler design Timely conversion to low-GWP propellants involves a number of tradeoffs but the challenge is surmountable. Daniel Duke, PhD Monash University Introduction e pressurized metered dose inhaler (pMDI) has undergone many changes in its 68-year history. Some of the most significant in pMDI formulation and design have been driven by regulatory restrictions on the liquefied gas propellants that the pMDI relies upon to produce a fine aerosol [1]. Starting thirty years ago, the substitution of chlorofluorocarbon (CFC) propellants with hydrofluoroalkane (HFA) propellants was undertaken in response to the Mon- treal Protocol's phase-out of ozone-depleting CFCs [2]. To achieve this goal, many complex challenges had to be overcome, such as the replacement of seals, canister coatings, new toxicity studies and product reformulation due to changes in propellant chemis- try and interactions with drugs and hardware com- ponents. Despite many changes to materials and formulations, the chemico-physical properties of the new HFA propellants were such that the pMDI actu- ator geometry did not need to change significantly, remaining relatively similar to its original design [3]. e transition to CFC-free propellants was com- pleted in 2001, and now a second major shift in pMDI propellants is already underway due to the need to phase out HFA propellants with high global warming potential (GWP). e most popular HFA pMDI propellants are potent greenhouse gases; 1 kg of HFA-134a is equivalent to 1,430 kg of CO 2 , and 1 kg of HFA-227 is equivalent to 3,220 kg of CO 2 . e Kigali Amendment to the Montreal Protocol, which was ratified in 2016 and came into force in 2019, manages the phase-down of HFA usage to reduce greenhouse emissions from these fluorinated products ("F-gases"). e European Union is lead- ing the phase-down with the goal of reducing con- sumption to 20% of 2014 levels by 2030. Although the metered dose inhaler industry only accounts for about 2.3% of worldwide F-gas emissions, a com- bination of regulatory pressures, economic pressures and changing customer priorities are driving the inhaled drug delivery market towards more environ- mentally friendly alternatives [4]. Some high-GWP pMDI products may be replaced by dry powder inhalers and soft mist inhalers, but a low-GWP propellant-option may be justified for some pMDIs that cannot be transitioned to these platforms for technical, medical and economic rea- sons. A discussion of these factors, along with the history of the CFC-HFA transition and lessons that can be learned from that process, is neatly summa- rized in a recent review by Buttini, Glieca, Sonvico and Lewis [5]. Propellant manufacturers have developed two pri- mary low-GWP alternatives that are currently in clin- ical trials. HFA-152a (difluoroethane) from Koura Global (Boston, Massachusetts, US) is a low molecu- lar weight hydrofluoroalkane with chemico- physical properties similar to HFA-134a [6]. HFA-152a con- tains fewer fluorine atoms than the HFAs it replaces, affording it a lower GWP (124 kg CO 2 -equivalent). However, its low specific gravity, 25% less than HFA- 134a [7], makes formulating suspensions challenging due to insoluble sedimentation of the active pharma- ceutical ingredient (API) in the time between shaking and inhaling. ere are some concerns around flam- mability. HFA-152a is less flammable than hydrocar-