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Inhalation February 2024 11 e latter two categories in Figure 1 involve the external aerosol, previously described as Phase I and II of the aerosol maturation process by Stein and Myrdal [15]. e second category concerns the performance of the spray plume beyond the orifice, which drives spray pattern, plume geometry, drop- let size and velocity. It is dominated by atomization, mixing and evaporative processes. e third cate- gory is the performance of the matured aerosol par- ticles, as measured by their delivered dose and size distribution. All three of these categories represent a complex interaction of hardware, propellant and formulation chemistry. In our studies, we have not considered varying ambient conditions, preferring to hold these constant in order to investigate the effect of the propellant change. Investigating in-canister stability, sedimentation and adhesion (among other factors) often requires the use of transparent vials or destructive testing of samples. is limits the amount of information that can be obtained. In response to this challenge, we have devel- oped a non-destructive, confocal X-ray fluorescence technique capable of measuring API distribution for both suspended and dissolved surrogate drugs in a model formulation through the wall of an aluminum canister. is allows us to study formulation interac- tions with canister, valve and actuator components. For example, we can evaluate API deposition in the actuator orifice. In previous work, we demonstrated the use of synchrotron X-ray fluorescence to measure the distribution of ipratropium bromide in a pMDI spray plume [16]. In this new work, we used a higher X-ray beam energy (42 keV compared to 15 keV) capable of penetrating the aluminum canister wall. To obtain a strong signal, potassium iodide (KI) was used as a surrogate API to make a model solution for- mulation. e characteristic X-ray fluorescence emis- bon aerosol propellants, but requires additional safety considerations during filling and transport compared to propellants previously commercialized in pMDIs [8]. HFA-152a has demonstrated analogous mate- rial compatibility and similar plume properties com- pared to current HFAs. It is also a favorable solvent for lipophilic drugs [9]. e second propellant of note is HFO-1234ze(E) (tetrafluoropropene) from Honeywell International, Inc. (Charlotte, North Carolina, US). Unlike the HFAs discussed above, this propellant is a hydro- fluoroolefin; a different class of molecule. It there- fore has different chemical behavior and interactions compared to the propellants it proposes to replace. Its carbon-carbon double bond gives it a GWP approaching that of CO 2 , while retaining a high liq- uid density likely to facilitate suspension stability [10]. However, it has a lower vapor pressure (simi- lar to HFA-227ea) and a higher surface tension than HFA-134a, and is therefore likely to produce a nar- rower aerosol plume with larger droplets if delivered using equivalent actuator hardware [11]. ere are also some concerns regarding its breakdown products once emitted into the upper atmosphere, and its via- bility due to perfluoroalkyl (PFAs) restrictions cur- rently under consideration [12]. Given the long lead time required for new products to come to market, the development of entirely new low-GWP products within the HFA phase-down period will prove challenging. e rapidly shifting economics of HFA production in response to the accelerated phase-down timelines proposed by the European Union, and the desires of consumers to reduce their carbon footprint drive the need for a faster response [13]. is may be achieved by alter- native development pathways to demonstrate in vitro equivalence via the weight of evidence approach, which may include tests such as spray pattern, plume geometry and droplet size and velocity [14]. We have investigated how the change from current- generation to next-generation pMDI propellants might affect the technical performance of currently used pMDI hardware, with a particular focus on actuator designs that assist with the achievement of in vitro equivalence. In-canister performance: X-ray fluorescence spectroscopy When considering the in vitro performance of novel pMDI propellants, we can divide our studies into three broad categories as illustrated in Figure 1. e first category is consideration of performance inside the canister. is includes factors such as API solu- bility (for solutions), sedimentation or creaming time (for suspensions), material compatibility, and adhe- sion or loss of the drug onto the canister valve and wall surfaces (both physical forms). Propellant choice HFO-1234ze(E) HFA-227 HFA-134a HFA-152a F F F F F F F F F F F F F F F F F Thermophysical properties Formulation chemistry Particle properties Plume dynamics and structure In-canister effects 1 2 3 Figure 1 Schematic diagram of a pressurized metered dose inhaler showing regions that could be affected by propellant choice.