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24 August 2022 Inhalation is not seen in these systems. is is illustrated in Fig- ure 2, where fine particle fractions of a 2% Bud binary formulation are compared to the 1% Bud/1% leucine formulations at different mixing energies. Further insight can be obtained from analysis of data published by researchers from the University of Kiel, who investigated high shear mixing of 1.5% Bud/lactose carrier blends, further containing 7.5% added lactose fines [3, 4]. A two-step mixing process was applied and two protocols were evaluated: one in which Bud was added first and one in which the lactose fines were added first. For each mixing proce- dure, a range of batches were manufactured by vary- • ere is a range of optimal mixing. Both too little mixing and too much mixing should be avoided. • FPF is not always higher for a higher drug load— it depends on the applied mixing energy. In Figure 1, it can be observed that 1% Bud formu- lations achieve similar or even higher FPF values than 5% Bud formulations when mixed using low mixing energies. • e size of the mixing bowl is critical, as the mix- ing force relates to the bowl radius. erefore, the mixing energy equation gives information about how to adjust speed during scale-up. • A higher concentration of coating agent is not necessarily better. e difference in maximum FPF level between Figures 1A and 1B is marginal. Our view is that the optimal mixing point should be attained shortly after reaching the maximum in FPF. An advantage of being on the (weak) slope is that it is possible to adjust FPF merely by adjusting mixing time or speed. is means that the formulator pos- sesses a quality by design tool that makes it possible to fine-tune fine particle dose independently of deliv- ered dose, thereby maintaining both key attributes within specification. Processing effects for formulations without a coating agent Formulations without a coating agent may also show important interactions between the composition and the mixing process. However, the initial increase in FPF Figure 2 Comparison of fine particle fractions between coated and uncoated batches. Squares refer to a composition with 1% Bud/1% leucine, triangles to a 2% Bud formulation without a coating agent. Lactohale LH100 was used as a carrier in both cases and no lactose fines were added. Data was derived from reference 2. 0 1 2 3 4 5 6 60 50 40 30 20 10 0 FPF [% of DD] Mixing energy (mJ/carrier) 1% Bud/1% Leucine 2% Bud Figure 3 Fine particle fraction of Bud plotted versus the applied mixing energy for a two-stage high shear mixing process. Circles and X's refer to batches where Bud was added first; circles show mixing speed was varied; X's show mixing time was varied. Squares and diamonds refer to batches where lactose fines were added first and Bud was added in the second step. In this case, only the mixing energy of the second step is relevant to Bud. Squares show varying mixing speed; diamonds show varying mixing time. Dashed lines refer to exponential decay modeling equations. Data were extracted from reference 3. 0.0 0.1 0.2 0.3 0.4 0.5 0.6 60 50 40 30 20 10 0 FPF [% of DD] Mixing energy (mJ/carrier)