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12 February 2024 Inhalation right panel. e X-ray measurements are integrated along the beam path (z axis) and have units of length, so the volume-integrated concentration is defined as: C V = 1 ∫∫ c(x,y) dx dy V Early results in model solution and suspension for- mulations indicate higher levels of both valve depo- sition and precipitate formation in HFO-1234ze(E) beyond that observed in glass vials. ese effects can be separated by observing the spatial distribution of the X-ray fluorescence signal. e resolution of the measurement technique permits us to identify where the tracer is adhered to the valve components or set- tled as precipitates near the valve seal, as opposed to remaining in solution in the bulk formulation. is indicates that solubility and wall-interactions are altered in HFO propellant and must be accounted for when reformulating with these propellants. ese observations correlate with observed changes in water solubility and reduced polarizability. e data shown in Figure 2 were obtained with a constant 8% w/w ethanol co-solvent but without other excipients. Plume performance: High-speed imaging e properties of the droplets produced by a pMDI (as characterized by their size, velocity and distribu- tion, for example) depend on the chemico- physical properties of the formulation. Such properties include saturated vapor pressure, density, latent heat of vaporization and surface tension, among others. No single physical property of a propellant is pre- dictive of plume metrics. However, the properties believed to be most important are shown in Table 1. sion from the iodine atom has sufficient energy to escape the aluminum canister. For suspension formu- lations, a similar approach can be obtained through the use of insoluble, micronized, barium sulfate par- ticles. With appropriate corrections for reabsorption in the formulation and canister wall, its concentra- tion can then be measured and spatially mapped [17]. A suitable tracer element is required to perform the measurements, so its behavior is first character- ized in glass vials to determine solubility and settling time. is ensures that its behavior is similar to that of conventional APIs of interest. Selection of dop- ants with appropriate size and solubility characteris- tics provides insight into the ways conventional APIs may be expected to perform. In the results shown in Figure 2, a Kindeva actuator with 0.3 mm exit orifice diameter was used. pMDI units consisting of 50 μL metal metering valves (Kin- deva Spraymiser with retaining cup, Loughborough, UK) and FEP-coated aluminum canisters with stan- dard wall thickness were used for all tests. All canis- ters were pressure-filled to 200 nominal doses. Figure 2 shows a series of X-ray images inside the canister- valve closure region of an aluminum canister with a solution formulation of 2 mg/mL KI in 8% w/w eth- anol, comparing the current HFA-134a to novel pro- pellants HFA-152a and HFO-1234ze(E). e left color panels show the local concentration of API in the highlighted region of the canister, where red indi- cates high concentration and blue indicates low con- centration. Measurements were taken after 5, 45, 85, 125 and 165 actuations (out of 200 nominal doses). From these measurements, a total volume-integrated concentration of API deposited in the canister-valve closure region can be obtained; this is shown in the HFA-134a HFA-152a HFO-1234ze(E) 0 50 100 150 200 250 Number of actuations 1.0 0.8 0.6 0.4 0.2 0.0 Fraction API mass deposition in valve region HFA-134a HFA-152a HFO-1234ze Y(mm) Y(mm) Y(mm) Y(mm) Y(mm) 40 20 0 40 20 0 40 20 0 40 20 0 40 20 0 40 20 0 40 20 0 40 20 0 40 20 0 40 20 0 40 20 0 40 20 0 40 20 0 40 20 0 40 20 0 -10 0 10 -10 0 10 -10 0 10 -10 0 10 -10 0 10 -10 0 10 -10 0 10 -10 0 10 -10 0 10 -10 0 10 -10 0 10 -10 0 10 -10 0 10 -10 0 10 -10 0 10 X (mm) X (mm) X (mm) 200 100 0 mg.mm/mL 30 mm 45 mm Figure 2 X-ray fluorescence profiles of the canister valve and closure region for various propellants, comparing the level of sedimentation and deposition over unit life. The error bars in the right panel represent a 99.7% confidence interval about the mean mass fraction of deposited API in the integrated volume indicated by the yellow box.