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Inhalation August 2022 25 • Inertial forces due to: • Wall collisions (adhesive units colliding with the walls inside the inhaler) • Particle/particle collisions (collisions between adhesive units) • Drag and lift forces (when the velocity of the sur- rounding air is much higher than the velocity of the adhesive unit) • Shear and frictional forces e geometry of the flow path through the device and the inspiratory flow profile determine the types and magnitudes of the dispersion forces. Formulation design can, however, also affect which dispersion forces come into play. For instance, drag forces may not con- tribute to the dispersion of API particles residing in cavities and clefts, i.e., of an aggregated carrier, as these cannot be accessed by the airstream. Moreover, the size of the carrier particles will affect the magnitude of the impact forces, as larger carriers will accelerate slower and, therefore, impact at lower velocities. How- ever, a detailed analysis of the types and magnitudes of dispersion forces is outside of the scope of this article. Requirements for formulation flowability Formulation flowability must be assessed to ensure a good match between the formulated powder and the device. e demand on powder flowability depends on whether a device-metered (reservoir type) inhaler or a device using pre-filled doses in capsules or blisters is to be used. For device-metered inhalers, good flow- ability is a prerequisite for fulfilment of regulatory demands on delivered dose and delivered dose unifor- mity, as the powder needs to flow from the reservoir into the dosing cavity during metering of the dose. In the case of pre-metered doses, powder flowabil- ity must still be adequate to allow for industrial-scale high-speed filling. e relationship between powder properties and filling performance has been investi- gated for capsule fillers and drum fillers, respectively, in references 7 and 8. ing mixing time or speed and were analyzed using the Novolizer ® dry powder inhaler (Meda AB, Solna, Sweden). Figure 3 shows FPF data from this study, plotted as function of the mixing energy per Equation 1. It can be observed that for both mixing procedures, an exponential decay in FPF as a function of ME results. Batches mixed at different times fall on the same curve as batches mixed using different speeds, which further supports the validity of the mixing energy concept. e FPF decrease can be described by an exponential decay function (Equation 4): FPF = Ce -kx Equation 4. where x is the applied mixing energy. is is the same type of exponential decrease as that observed with extended mixing for systems including a coating agent, which points toward similar mechanisms for the two cases. For low shear mixers, there are relatively few studies of the influence of the mixing process [5, 6]. In gen- eral, a slight decrease in FPF is seen as function of mixing time. Overall, processing effects are believed to be less marked in low shear mixing. Instead, the formulation challenge resides in achieving a powder blend with good drug content uniformity [5]. Formulation interactions with the device To get the full picture, the device obviously must be considered. Conceptually, the device interacts with the entire formulation and the resulting perfor- mance, in terms of FPF, is governed by the balance between the (attractive) forces among the particles in the formulation and the dispersion forces generated via the inhaled air stream. Both the type and magni- tude of the dispersion forces matter. An overview of different dispersion mechanisms is provided in refer- ence 1. For adhesive mixtures consisting of adhesive units of carrier and fine particles, the main types of dispersion forces are: