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Inhalation April 2020 15 this point is entirely due to ethanol evaporation, at which point precipitation of the API inside the droplets can begin. ese data reveal the regions of the spray in which co-solvent evaporation (and precipitation pro- cesses) are occurring. Evaporation affects the precipita- tion rates of particles, and thus their size, shape, and surface area. All these parameters affect the clinical effi- cacy of the formulation. ese insights enable the devel- opment of precipitation models for new formulations. USAXS techniques are also capable of similar measure- ments in suspension pMDI sprays and in the future may also be applied to DPIs. Supporting the development of new inhalers Table 1 lists synchrotron radiation techniques, their purposes, benefits and disadvantages. Depending on Technique Evaluates/Determines Purpose Benefits Disadvantages X-ray Phase Contrast Evaluates/Determines: Internal structure of liquid flow inside devices Purpose: Rapid assessment of flow in prototypes • Correlates internal geometry to changes in spray properties • Does not require modification to device • Suitable for all liquid-based delivery devices • Investigate causes of clogging and deposition • Difficult to determine quantitative properties, such as liquid density or droplet size • Requires specialized synchrotron facility • Not suitable for DPIs X-ray Radiography Evaluates/Determines: Accurate measurements of local spray density at high speed Purpose: Link changes in impactor measurements to changes in spray, due to formulation and/or device • Does not require a synchrotron source; a lab-scale X-ray source fitted with a polycapillary optic could also be used • High temporal resolution, enabling observation of fast- moving droplets and particles • Suitable for all liquid-based delivery devices • Enables assessment of effects of formulation changes in regions where environmental and patient- use factors are not yet influential • Weak absorption of X-rays limits precision of data • Requires a specific range of X-ray energies (6-8 keV) • Requires many repeated sprays • Not well-suited to DPIs • Cannot be conducted simultaneously with X-ray fluorescence unless X-ray beam is polychromatic X-ray Elastic Scattering Evaluates/Determines: Accurate and precise measurements of spray density Purpose: Demonstrate equivalence of spray between devices and formulations, independent of environmental factors • Does not require a synchrotron source; a lab-scale X-ray source could also be used • Better signal quality than radiography and can be performed simultaneously with X-ray fluorescence • With X-ray fluorescence, enables drug mass loading in droplets to be quantitatively assessed inside the spray; this is not possible using conventional measurement tools • Requires complex calibration procedure • Limited time resolution compared to radiography; can only observe average densities, not individual particles or droplets X-ray Fluorescence Evaluates/Determines: Local drug concentration in droplets and particles Purpose: An unequivocal means of demonstrating equivalence of drug delivery capacity of new devices and formulations, independent of environmental factors • Combined with elastic scattering, enables drug mass loading in droplets to be quantitatively assessed inside the spray; this is not possible using conventional measurement tools • Unaffected by co-solvent, propellant and ambient conditions • Suitable for liquid sprays, nebulizers and dry powders • Requires careful calibration • Requires specialized detector equipment Ultra-Small Angle X-ray Scattering Evaluates/Determines: Droplet composition and evaporation rates Purpose: Determine in situ evaporation and precipitation rates for the prediction of particle structure and translation of single-droplet measurements • With radiography, enables evaporation rates and composition of droplets to be determined inside the spray; this is not possible using conventional measurement tools • Unaffected by co-solvent, propellant and ambient conditions • Suitable for liquid sprays, nebulizers and dry powders • Requires a specialized synchrotron beamline • Requires careful calibration • Not stand-alone; must be supported by other measurements (i.e., radiography) to obtain quantitative results Table 1 Summary of X-ray measurement techniques and their purposes, benefits and disadvantages