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12 April 2020 Inhalation Figure 3. If the composition of the spray and the sur- rounding gas are known, the total mass inside the beam at a given point in space and time can be easily deter- mined. 7 Radiography reveals the complex, rapid varia- tions that occur throughout the duration of pMDI sprays and how they are affected by the actuator and formulation. A limitation is that radiography cannot distinguish the effects of the API from the propellant; fluorescence techniques are required to achieve this and these are discussed in more detail later. By their nature, sprays of small droplets tend to be dilute so the fraction of the beam absorbed is less than 1%. This limits the quality of the data that can be obtained for a given sample size. However, when X-rays are absorbed by the spray, they are also weakly scattered. A small fraction of these can be detected by a scattering detector, 8 as shown in Figure 3. An exam- ple time-resolved, elastic scattering measurement is shown in Figure 4 (blue line, top right). Here, an HFA-134a formulation with 15% ethanol co-solvent and 3.38 µg/µL ipratropium bromide (API) is shown. e measurement is 1.5 diameters from the nozzle, in the center of the spray. e measurement reveals the unsteadiness of the spray core. When X-rays interact with the API, X-ray fluorescence can also occur. X-ray fluorescence enables tracking of a suspended or dissolved API, independently of any co-solvent, excipient or propellant. 9 e API must con- tain a suitable element that is not contained by any X-ray phase contrast images can be difficult to interpret, as complex three-dimensional features are flattened into a single image. However, it can provide valuable insight into the structure of the flow inside the pMDI and gives instant feedback on the effects of changing the actuator or formulation. For example, one can observe that the vaporization process begins inside the metering valve, well before the fluid reaches the nozzle. In addition, for- mation of droplets begins, not in the spray or at the exit of the nozzle orifice, but at the entry to the nozzle ori- fice. ese insights are now enabling the development of more physically representative models for pMDI droplet formation. Focused-beam techniques: Radiography, elastic scattering and fluorescence spectroscopy While powerful, X-ray imaging is not well suited to studying the structure of the spray outside the actuator. This task is made easier through the use of focused, monochromatic X-ray beams. 4 ese beams can pro- vide high temporal and spatial resolution, at the cost of only being able to analyze a small region of space. e beam focus is typically 5-10 µm wide. e temporal resolution can be as fast as 150 ns. Different wave- lengths and detectors enable a range of techniques, three of which are discussed here. X-ray radiography measures the fraction of X-rays transmitted through a spray. 4 An example is shown in Figure 2 Sample false-color phase contrast images inside a placebo pMDI with 15% ethanol co-solvent (left column) and pure HFA-134a propellant (right column). HFA-134a w/15% ethanol co-solvent HFA-134a (pure) 0.5 0 -0.5 -1 0.5 0 -0.5 -1 0.5 0 -0.5 -1 y (mm) y (mm) y (mm) x (mm) x (mm) 5 ms 5 ms 30 ms 30 ms 90 ms 90 ms nozzle -3 -2.5 -2 -1.5 -1 -0.5 0 0.5 -3 -2.5 -2 -1.5 -1 -0.5 0 0.5