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14 April 2020 Inhalation determine droplet composition. In solutions of fluori- nated propellants, droplet electron density can vary by up to 40% as the propellant evaporates, causing signifi- cant changes in scattering intensity. Since both tech- niques are volumetrically averaged, the spray need not be monodisperse. Due to the short wavelengths of X-rays, the droplet size must be small enough so the scattering angle is sufficiently large. For benchtop X-ray scattering instruments, this limits the droplet size to less than 1µm, which is too small. However, the USAXS instrument at the 9-ID beamline of the Advanced Pho- ton Source at Argonne National Laboratory 11 can achieve much smaller scattering angles, increasing the maximum droplet size above 10 µm. An example USAXS experiment is shown in Figure 5. X-rays scattered from the spray are only permitted to reach the detector within a narrow range of angles. e analyzer crystals are rotated to obtain a rocking curve over a range of angles. A large number of sprays must be repeated to build a complete set of measurements. Using focused-beam mass distribution and laser diffrac- tion sizing, the electron density contrast at a given loca- tion is determined. From this, the composition of the droplets can be calculated. A result of such a measurement is shown in Figure 6. As in the previous examples, an HFA-134a formulation with 15% ethanol co-solvent and 3.38 µg/µL ipratro- pium bromide was investigated. The measurements were made along the centerline of the spray (horizontal axis). e blue bars indicate the Sauter mean diameter of the droplets, as measured by laser diffraction. e orange bars indicate the volume fraction of co-solvent in the droplets as determined by USAXS composition measurement. At 7.5 mm from the nozzle, all the pro- pellant has evaporated and the droplet is pure co-sol- vent. Any further decrease in electron density beyond the canister and actuator after use. Focused-beam mea- surements allow determination of exactly why, when and how this is occurring. 9 is insight is now being used to inform the design of improved actuators. Ultra-small-angle X-ray scattering (USAXS) One of the complicating factors in predicting the behavior of pMDIs is that the formulation is a multi- component mixture. For solution pMDIs, in particular, differences in volatilities between propellants and co-solvents make predicting droplet composition diffi- cult, even if the formulation is well defined. Phase-con- trast imaging (Figure 2) reveals that the propellant begins to boil inside the actuator so the composition is likely different at every stage of the spray formation pro- cess. The composition and evaporation rates of the droplets are intricately connected to particle formation. Temperature and solubility changes can have drastic effects on the shape of the particles. Variations in parti- cle shape alter their aerodynamic properties and surface area, affecting deposition in the airway and rate of absorption. To understand how the actuator drives these changes, a means of measuring the local composi- tion of the droplets and particles where they are first created is required. e elastic scattering of X-rays from droplets and parti- cles at small angles depends on their surface area, vol- ume fraction and composition. If the composition is known, ultra-small-angle X-ray scattering (USAXS) can be used to measure surface area and size of droplets in environments that are too optically dense to permit laser scattering. 10 In pMDIs, however, the spray plume is sufficiently dilute to allow size distribution measure- ment using laser diffraction. is opens up the possibil- ity of using USAXS and laser diffraction together to Figure 5 Schematic of an ultra-small-angle X-ray scattering (USAXS) experiment. y x z Formulation inflow pMDI nozzle Nozzle insert Photodiode Angular filter Elastic scattering Spray Collimator Incident monochromatic X-ray beam Co-flow Figure 6 Sample results from a USAXS experiment in a solution-based pMDI spray of 85% HFA-134a, 15% ethanol, and 3.38 µg/µL ipratropium bromide. Average droplet diameter (blue) and droplet composition (orange) are shown against distance from the nozzle. 7 6 5 4 3 2 1 0 Droplet SMD (µm) 1.5 2.5 5 7.5 10 15 Distance from nozzle (mm) 1.0 0.8 0.6 0.4 0.2 0 Co-solvent volume fraction