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26 August 2022 Inhalation In part 1 of this two-part series, we saw that both increased drug load and addition of fine lactose can improve the dispersibility of a formulation [9]. At the same time, however, both of these measures can entail a reduction in powder flow, with associated risks for issues in filling and dosing as mentioned above. e challenge for the formulator is to find the optimal balance between the two approaches. Again, this emphasizes the need for careful selection of a device and filling method, and assessment of a good match between a device and the formulation. Prediction of optimal dispersibility Models have been put forward for selection of excip- ients (carriers and fines) as well as composition, in order to maximize formulation performance. Shalash, et al., developed a model in which dispersibility can be predicted from measurement of the nano- and micro-porosity of the carrier in combination with the fluidization energy of the formulation [10, 11]. e model was tested using 1% fluticasone propionate formulations with a range of different carrier mate- rials and good correlation was obtained (however, a mannitol carrier was an outlier) [11, 12]. Hertel, et al., used permeability data from a powder rheometer to investigate optimum composition with respect to addition of lactose fines [13]. While basically sound, the generality of these models remains to be proven, e.g., for inhalers with different dispersion principles. Moreover, formulations with a coating agent may not be applicable, as the surface properties of the carriers will be extensively changed after processing. To circumvent the uncertainties associated with these models, it is recommended that studies be performed early in project development, in the relevant mixer, to map out dispersibility as well as delivered dose uniformity for the selected device. Furthermore, if a high shear mixer is to be used, such mapping should include the effect of the applied mixing energy. Flow rate and formulation performance A primary parameter of an inhalation device is its air flow resistance, as this determines the flow rate at which DPI performance should be assessed. A pressure drop of 4 kPa over the device is recommended by the Euro- pean Pharmacopoeia for testing [14]. Still, patients will use DPI products over a wide range of pressure drops/flow rates. e flow rate behavior is, therefore, important and has been investigated by several groups, as reviewed by Elsayed and Shalash [12]. Both mono- tonic and sigmoidal curves have been reported for FPF as a function of flow rate, and in some cases, even bi-exponential curves have been observed [15]. To date, a general understanding of flow rate depen- dence has not been obtained, which, in part, may be due to the extensive differences in design and, there- fore, different modes of dispersion of various DPI Once the inhaler is filled, sufficient powder flowabil- ity is needed for entrainment of the dose from the dose-holding compartment (such as a cavity or cap- sule). Incomplete entrainment obviously would lead to compromised doses and issues with delivered dose uniformity. For capsule devices, there may be a risk of incomplete emptying from the capsules when using large carrier particles since piercing of the capsules, per- formed in use by the patient, will not always be ideal. Figure 4 The percentage of salbutamol sulfate, SBS, detached from the carrier in a cyclone inhaler prototype, for systems of 0.4% SBS plus carrier (circles) and 4.0% SBS plus carrier (squares) as function of air flow rate. At flow rates below 35 L/min, the 0.4% formulation shows better dispersibility, while at flow rates higher than 35 L/min the 4.0% formulation gives higher FPF values. It should be noted that the percent of drug detached from the carrier is not the same as the FPF, but it can be anticipated that the two measures correlate. 0 20 40 60 80 100 90 80 70 60 50 40 30 20 10 0 Percent of drug detached Flow rate [L/min] 0.4% SBS 4% SBS