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16 February 2024 Inhalation a means of measuring and demonstrating equivalent or improved in-canister formulation stability, plume performance and aerosol size distributions through the following means: • For solution formulations, adjustment of co- solvent concentration. Small changes in co-solvent level can alter the vapor pressure and density of the formulation to compensate for some changes in chemico-physical properties. • For solution or suspension formulations, adjust- ment of the spray orifice. Changes in vapor pres- sure and density lead to changes in spray duration, stability and spreading rate, which can be compen- sated for by small alterations in diameter, length and shape. • For solution or suspension formulations, adjust- ment of the mouthpiece. Less stable sprays, such as those produced by HFA-152a propellant, lead to increased mouthpiece deposition. Altering the shape and length of the mouthpiece may be able to compensate for these effects. (is is a matter of ongoing research). e above modifications open up a range of new possibilities in the realm of actuator design that were not necessary and therefore not widely investigated during the CFC to HFA transition era. e ability to take advantage of these optimizations requires a deep understanding of the physics of pMDI sprays, and tools that can provide the high-resolution data required to do so. Many challenges remain for the development of low-GWP pMDIs beyond simply matching aerosol performance. ese will be driven by regulatory and formulation needs rather than engineering consid- erations [5]. However, with additional engineering design variables at our disposal, the metered dose inhaler can continue to be adapted to serve the needs of clinicians and patients for decades to come. Acknowledgements and declaration of interests e author's research is funded by the Australian Research Council (grant numbers LP190100138 and DP200102016). e author also receives fund- ing support from Kindeva Drug Delivery. e views in this article are the author's own. e author would like to acknowledge the contribu- tions of Lingzhe Rao, Swetha Vutlapalli and Anesu Kusangaya (Monash University, Australia); Alan Kastengren (Argonne National Laboratory, Illi- nois, US); Paul Young, Hui Xin Ong and Nirmal Marasini (Woolcock Institute, Sydney, Australia); Benjamin Myatt, Phil Cocks and Stephen Stein (Kindeva Drug Delivery). e author acknowledges the use of high- performance computing facilities provided by the Laboratory Computing Resource Centre (Argonne National Laboratory, Illinois, US) and the National Computational Infrastructure (Australia). References 1. Prokopovich P, editor. Inhaler devices: Fundamen- tals, design and drug delivery. Oxford: Woodhead Publ; 2013. 175 p. (Woodhead Publishing Series in Biomaterials). 2. Byron P, Dalby R. Formulation for delivery of drugs by metered dose inhalers with reduced or no chlorofluorocarbon content. Virginia Com- monwealth University, Richmond, VA, US. Patent 5,190,029, 1993. 3. iel CG. From Susie's question to CFC-free: An inventor's perspective on forty years of MDI devel- opment and regulation. In: Dalby R, Byron P, Farr S, editors. Proc Respiratory Drug Delivery V. Virginia Commonwealth University; 1996. p. 115-123. 4. Pritchard JN. e climate is changing for metered dose inhalers and action is needed. Drug Des Devel er. 2022;14:3043-3055. 5. Buttini F, Glieca S, Sonvico F, Lewis DA. Metered dose inhalers in the transition to low GWP propel- lants: What we know and what is missing to make it happen. Expert Opin Drug Deliv. 2023 Sep 28;17425247.2023.2264184. 6. Noakes T, Corr S. e future of propellants for pMDIs. In: Proc Drug Delivery to the Lungs. Edin- burgh, UK: e Aerosol Society; 2016. 7. Sato H, Uematsu M, Watanabe K, Okada M. Sat- urated liquid density of 1,1 difluoroethane (R 152a) and thermodynamic properties along the vapor liq- uid coexistence curve. Fluid Phase Equilibria. 1987 Oct;36:167-181. 8. Dalby RN. Prediction and assessment of flamma- bility hazards associated with metered dose inhal- ers containing flammable propellants. Pharm Res. 1992;09(5):636-642. 9. Williams RO, Rogers TL, Liu J. Study of solubility of steroids in hydrofluoroalkane propellants. Drug Dev Ind Pharm. 1999 Jan;25(12):1227-1234. 10. Katsuyuki T. Measurements of vapor pressure and saturated liquid density for HFO-1234ze(E) and HFO-1234ze(Z). J Chem Eng Data. 2016 Apr 14;61(4):1645-1648. 11. Zhao X, Duan W, Zeng X, Liu Y. Measurements of surface tension of R1234yf and R1234ze(E). J Chem Eng Data. 2018 Jan 11;63(1):21-26. 12. Simonetti R. Will PFAS be a barrier to the use of HFO refrigerants? [Internet]. 2021 Mar. https://www.carel.com/blog/-/blogs/will-pfas- be-a-barrier-to-the-use-of-hfo-refrigerants-. 13. Wilkinson AJK, Braggins R, Steinbach I, Smith J. Costs of switching to low global warming potential inhalers. An economic and carbon footprint analysis