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Inhalation April 2020 11 order of kilowatts, so exposure times are limited to mil- liseconds in order to avoid damaging the system. When X-rays pass through the actuator, the liquid for- mulation will absorb some of the X-rays while the vapor permits the beam to pass through relatively unimpeded. e surfaces of droplets and bubbles also deflect some X-rays, which interfere with parallel rays, resulting in diffraction patterns. ese are recorded on a scintillator screen some distance from the actuator. e visible light emitted by the scintillator is captured with a microscope and high-speed camera. An example of some X-ray phase contrast images in pla- cebo pMDIs are shown in Figure 2. ese experiments were conducted at the 7-ID beamline of the Advanced Photon Source at Argonne National Laboratory (Lem- ont, Illinois, US). e expansion chamber and nozzle region of a conventional pMDI are shown in false color. Dark regions represent strong absorption while bright regions indicate that the beam has passed through unimpeded. e fluid enters the expansion chamber from the top and exits through the nozzle at cen- ter-right (top left panel). ree snapshots at the start, middle and end of a spray event are shown from top to bottom. In the left column, an HFA-134a placebo for- mulation with 15% ethanol co-solvent is imaged. In the right column, a pure HFA-134a formulation is imaged. e images reveal strong swirling motions as the fluid first enters the chamber (top row). Later, significant dif- ferences between the two formulations appear. e sol- vent-containing formulation forms a fine foam, while the pure propellant formulation forms large bubbles. ese two scenarios result in different inlet conditions for the nozzle. In both cases, the bubbles grow over time as the actuator empties. is indicates decreasing cham- ber pressure and rate of delivery over time. When an active pharmaceutical ingredient (API) is introduced, settling in the bottom of the chamber can occur. Clog- ging of the nozzle between actuations can be directly observed when it occurs. ment and assessment of prototype devices. e funda- mental insights gained through these measurements can facilitate the development of models to support the design of new inhaled pharmaceutical products. X-ray techniques in pharmaceutical science X-rays have a long history in pharmaceutical science. 2 Crystallography and powder diffraction, which reveal the structure of complex molecules, are integral to the drug discovery process. e advent of synchrotron radi- ation in the late 20th century enabled many new devel- opments in pharmaceutical science that are too numer- ous to list here. 3 Synchrotron beams are thousands of times brighter than traditional X-ray tube sources, thereby enabling very fast measurements. In addition, synchrotron radia- tion can be filtered to generate monochromatic (single- wavelength) beams while retaining high throughput. Synchrotron beams, like lasers, are also highly colli- mated so light remains parallel over a long distance, enabling high resolution. Although X-rays have been used for many decades in pharmaceutical science, their use in aerosol and spray science is relatively new. Over the last 15 years, a signifi- cant effort has been invested in the development of techniques to study optically dense sprays in harsh envi- ronments, such as fuel sprays for internal combustion engines. 4 A benefit of X-rays is that they scatter weakly, compared to visible light. is means they are relatively unaffected by the high density, composition and tem- perature changes in sprays that confound traditional measurement techniques. Over the last few years, these tools have been adapted for use in pMDIs, and are now starting to be used by several research and development teams around the world 5 to aid in the design of a variety of pMDI products. is article presents an overview of some of the most commonly used synchrotron techniques for sprays, describes recent work in applying these techniques to pMDIs, and gives examples of the insights that can be gained through their use. Phase contrast imaging X-ray phase contrast imaging techniques exploit the intense, collimated nature of synchrotron light to pro- duce detailed images of the internal structure of objects. 3 X-rays reveal fluid motion inside opaque objects such as pMDI actuators, without the need for any modifications or contrast agents. e short wave- lengths of X-rays give rise to sharp images with micro- meter resolution. e short pulses produced by syn- chrotrons allow moving features like droplets to be imaged with great clarity. An example experiment in a pMDI nozzle 6 is shown in Figure 1. An X-ray beam is allowed to enter the test sec- tion through a shutter. e beam power can be on the Figure 1 Schematic diagram of the X-ray phase contrast imaging technique. Fast X-ray shutter Stem from canister Spray Image projected onto scintillator Visible light Mirror Micro- scope Camera X-ray beam pMDI Actuator

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