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Inhalation February 2025 13 inside typical rheometers (especially with respect to shear rate). erefore, testing the formulation in a modified device is recommended, as this can allow direct observation of the metering mechanism and subsequent dosing, in terms of piston movement including acceleration and deceleration. Particle size distribution (PSD) Analytical perspective Compared to pMDIs, the spray duration of Respimat is relatively long, i.e., approximately 1.5 seconds vs. 0.15-0.36 seconds for a typical pMDI [5]. is implies that the consistency of the particle size dis- tribution (PSD) should be assessed over time since maintaining a consistent PSD over the compara- tively long spray-duration requires a robust energy supply by the device over its lifespan. In fact, the time- resolved PSD assessment also serves as a sur- rogate test for the mechanical performance of the pump inside the SMI. Alternatively, the speed of the piston motion can be checked. e mechanical chal- lenges are the start and the end of the piston stroke, going from zero to full speed and from full speed to zero. Also, the spring force is not constant but will decrease during piston motion. A common technique for assessing the PSD of an inhaler is laser diffraction. Here, the aerosol is entrained into a laser beam and the diffraction pat- tern is recorded by a detector over time. From this diffraction pattern, the particle size distribution is deduced using either the Fraunhofer or the Mie the- ory/approximation. Furthermore, different method- ologies yield different distributions. For example, a geometric PSD obtained from laser diffraction differs from an aerodynamic PSD from cascade impaction. Fraunhofer and Mie theories differ in their approach to derive a geometric PSD from a recorded diffrac- tion pattern. e Fraunhofer theory relies on a comparatively simple derivation of a particle size from a scattering angle and was therefore widely used historically. However, it neglects the laser light which is absorbed, reflected and refracted by the particles (Figure 3). To take these effects into account, the optical prop- erties, in terms of the complex refractive index, are required. Here, the real part describes the ratio of the speed of light in the corresponding media, whereas the imaginary part is a measure for the absorption of light. Both parts are important to yield accurate results. is is due to the transparent nature of most pharmaceutical aerosols that allow for refraction. Due to refraction, additional light is detected at larger scat- tering angles, which is interpreted as smaller droplets. Contrary to the Fraunhofer approach, the Mie the- ory is based on an analytical solution of the Maxwell equations and therefore represents the most accu- rate diffraction pattern and consequently accurate spray pattern) and nebulizers (aerodynamic particle size distribution (APSD) testing using cooled cascade impactors) (Table 1). Although a PSG is designed to guide the industry through an abbreviated new drug application (ANDA), it is conceivable that the char- acteristics and testing conditions highlighted in the Tiotropium Bromide PSG may become a standard approach for SMI development. e following sections will discuss pharmaceuti- cal plume testing ex-device in terms of particle size distribution by laser diffraction, delivered dose and aerodynamic particle size distribution by cascade impaction testing. During early development, a precise analysis of the liquid flow through the nozzle under operating con- ditions is essential. Non-Newtonian liquids may be present and the flow inside the microchannels may deviate considerably from the testing conditions Table 1 Test characteristics described in tiotropium Respimat product specific guidance (PSG) Characteristic Test Design Single actuation content (SAC) Beginning, middle and end of life, DUSA 28.3 L/min Aerodynamic particle size distribution (APSD) Beginning and end of life, water evaporation should be minimized, 28.3 L/min Spray pattern Only beginning of life, two distances at least 3 cm apart, in the range between 3 and 7 cm Plume geometry Only beginning of life, plume angle and width should be measured. Width to be measured at equal to the greater distance selected for spray pattern testing. Priming and repriming Emitted dose (ex-mouthpiece) after defined time periods of non-use Spray duration Beginning and end of life, high-speed camera, laser light diffraction, particle image velocimetry, phase Doppler anemometry or other suitable method Spray velocity Beginning and end of life, high speed imaging, particle image velocimetry, phase doppler anemometry or other suitable method. Position for measuring the velocity is important. Because patients do inhale, velocity at a relevant air flow rate should be investigated.