Issue link: https://www.e-digitaleditions.com/i/1532011
14 February 2025 Inhalation puff. is difference is mainly caused by a residual droplet formed on top of the spray nozzle, which in turn is a result of the impinging jets used for aerosolization. e resulting analytical challenge is therefore to achieve a sufficient signal-to-noise ratio (SNR) suitable for deriving a robust PSD over time. In practice, it is the transmission of the laser light that serves as a surrogate for the SNR. Although optimum transmission may depend on a particular instrument, it is typically the result of the concen- tration of the particles in the laser beam. When the concentration of particles assessed is too low, one might not sample sufficient particles to derive a sta- tistically robust PSD. On the other hand, when the concentration of particles in the laser beam is too high, particle to particle scattering might be pro- nounced, which in turn will bias the PSD towards finer sizes, as the scattering angle increases with an increasing number of subsequent scattering events. Consequently, the ideal optical concentration, i.e., the particle concentration in the laser beam, should be optimized during method development and con- sidered in robustness/ruggedness validation. To address this issue, a dedicated setup (such as an inhalation module) or any accessory that channels the plume through the laser beam using a defined flow rate should be employed. To optimize the opti- cal concentration in practice, the operator can adjust the aerosol path length by incorporating or remov- ing different adapters and diffusors commonly pres- ent in these instruments. Additionally, the testing flow rate can be adjusted, however this can result in a deviating flow rate compared to delivered dose and APSD testing. Lastly, the application and amount of sizes. is becomes especially important for smaller particles compared to the laser wavelength applied. Different instrument suppliers provide different cut- off sizes from which either the Fraunhofer or Mie approach should be used. ISO 13320:2009 states that the optical properties become important where x < 40 lambda, where x is the diameter of the particle and lambda the wavelength of the laser [9]. is cor- responds to approximately 25 microns for red lasers of approximately 650 nm, which are commonly used in laser diffraction instruments. is is obviously significantly larger than the droplets of aerosols for inhalation and therefore application of the Mie the- ory is recommended for accurate results. Although some instruments utilize a second UV/blue light laser, which can measure particle diameters down to ~0.01 microns compared to ~0.1 microns using a red laser, these instruments are typically not used for spray measurements but rather for particulates. Laser diffraction is considered suitable for SMIs because the aerosol is comprised of spherical, trans- parent fluid droplets whose optical properties can be determined with reasonable accuracy and a homo- geneous solution is sprayed, in which a constant drug concentration can be assumed. While the real part of the complex refractive index can be directly measured using a refractometer, the imaginary part is notoriously difficult to measure and therefore is typically estimated using look-up tables provided by instrument suppliers. For a typical water-based, low concentration formulation, a refractive index of n = 1.33 + i*0.001 can serve as a starting point. While Respimat meters 15 mcl, the delivered vol- ume ex-device per puff is approximately 11 mcl per Figure 3 Basic principles of the Fraunhofer and Mie theories Laser Source Cell Detector Diffraction Absorption Refllection Refraction d Frauenhofer: diffraction no optical parameters required Mie: diffraction + absorption + reflection + refraction complex refractive index required φ 1 φ 2 λ sin(φ) = n*λ ;n = 1,2,3.... d