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Unlike many traditional measurement techniques, synchrotron measurements can provide direct evidence of the effects of changes to actuator design and formulation composition on the behavior of a device, a formulation or both. This can shorten the design feedback loop and allow for more rapid development and assessment of prototype devices. 10 April 2020 Inhalation Gaining new insights into pressurized metered dose inhaler (pMDI) design using synchrotron radiation New laboratory tools use X-rays to reveal the inner workings of pMDIs, accelerating the development of new devices and formulations Daniel J. Duke, PhD Monash University the propellant in the spray causes significant evapora- tive cooling, resulting in the formation of cold, dense clouds of vaporized propellant gas around the droplets, at temperatures below -25°C. Large temperature gradi- ents and high droplet number densities conspire to limit the capabilities of traditional, laser-based aerosol testing tools. While they can provide useful measure- ments of velocity and size, 1 many other droplet proper- ties (such as composition, temperature and drug distri- bution) are difficult to measure. A response to this challenge is to move away from reli- ance on visible light, and instead use a synchrotron X-ray beam to reveal the inner workings of devices such as pMDIs. Synchrotron radiation is produced by turn- ing energetic electron beams in magnetic fields. is produces bright, high resolution X-ray beams that can be tuned to specific wavelengths. Complex, specialized beamlines are required and experiments must be con- ducted remotely in a heavily shielded room. is article hopes to demonstrate that the benefits of using syn- chrotron radiation far outweigh the costs of providing this type of facility. Depending on how they are used, synchrotron X-rays can provide valuable quantitative information on drug distribution, spray density, droplet and particle proper- ties; metrics that are difficult or virtually impossible to obtain by other means. Unlike many traditional mea- surement techniques, synchrotron measurements can provide direct evidence of the effects of changes to actu- ator design and formulation composition on the behav- ior of a device, a formulation or both, rather than sim- ply indicating a change in the end result (such as deter- mination of fine particle fraction). is can shorten the design feedback loop and allow for more rapid develop- The development of new devices for the delivery of inhaled drugs depends on the ability to demonstrate equivalence with existing products. A common feature of all measures of equivalence is that they are an end result of a complex chain of events which begins with the formulation, and includes all the components of the delivery device, and environmental conditions. Ana- lytic tools such as cascade impaction can provide valu- able information on the nature of the drug particles produced, but cannot reveal the underlying processes inside the device that lead to these outcomes. To address this challenge, new laboratory tools are required that can quickly reveal the inner workings of prototype devices and accurately measure the properties of the droplets or particles produced. A concrete exam- ple that underlines the need for such tools is the phase down of chlorofluorocarbons (CFCs) in pMDIs, which necessitated design changes in dose metering, use of different valves and seals, co-solvents and filling pro- cesses, etc. Another major transition is approaching, from hydrofluorocarbons (HFCs) to less green- house-intensive propellants. Detailed device and for- mulation modifications will be required to achieve this. e magnitude of the challenge in developing the new tools required to produce the next generation of devices is exemplified by the operational principles of the pMDI. Vaporisation of the propellant in a pMDI results in significant variations in the quality of the spray, at scales on the order of millimeters and millisec- onds. ese processes, which begin inside the actuator itself, ultimately determine the nature of the final parti- cles and the efficacy of the device. pMDI sprays are an exceptionally difficult environment in which to make accurate scientific measurements. Rapid evaporation of

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