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Tablets & Capsules October 2016 43 after lactose fines were added. For both of the carrier lactoses investi- gated, InhaLac 230 and InhaLac 70, the addition of fine-milled lactose (InhaLac 400) led the FPF to increase. In the range we investigated—2.5 to 7.0 percent of lactose fines—the FPF increased as the amount of fines grew. Theories of dispersion behavior Several mechanisms are believed to account for this improved dispersion behavior. They include the active-sites hypothesis, the agglomeration hypo- thesis, the buffer hypothesis, and the fluidization hypothesis. Active-sites hypothesis. This model states that the fines occupy areas on the carrier surface that have the strongest binding characteristics (active sites), leaving only areas with weaker binding properties for the API. This, in turn, facilitates deaggregation of the API from the carrier [19]. Agglomeration hypothesis. This model states that agglomerates of lac- tose fines and micronized API detach from the carrier surface more easily than an API monolayer [18]. Buffer hypothesis. This model holds that the mixing process offers protection from press-on forces. It is applicable when the lactose fines are coarser than the API particles [20]. Fluidization hypothesis. Propo- nents of this model contend that the added fines can increase the tensile strength of the bulk powder, leading to an increase in the minimum energy The reservoir-based Clickhaler device was investigated using these same two APIs. Unlike the Novolizer, it has no classifier to support deaggre- gation. Rather, the aerosol collides with impact bodies inside the device [15]. Even so, FPFs exceeding 40 per- cent could be achieved with salbuta- mol sulfate (Figure 4). In the case of salbutamol sulfate, the device worked significantly better when smaller excipient particles were used. The best results were achieved with InhaLac 250, which contains intrinsic fines. Loaded with a budesonide-lactose mixture, no significant differences were seen between the three carrier lactoses investigated. Moreover, the resulting FPFs of the budesonide for- mulations were significantly lower than those obtained from the Aerolizer device, a difference of slightly more than 10 percent. In addition to the more or less coarse carrier lactose and the API- excipient fines, many DPI formula- tions contain ternary mixtures. Indeed, several studies have shown that the addition of a third, fine-milled compo- nent improves the dispersion of car- rier-based DPI formulations [1,16]. In principal, this third substance could be any number of different excipients, especially sugars like mannitol, sor- bitol, and trehalose. But in general, the ternary agent is a fine-milled lactose monohydrate [17]. Figure 3 shows that the dispersion of budesonide formulations improved needed for fluidization, and thus the energy available for dispersion [13]. However, the addition of fines comes with a decrease in the mixture's flow properties, as the fines exhibit poor flow behavior on their own and will, additionally, fill the voids between the coarser carrier particles. This promotes packing and powder densification [20]. The addition of more than 15 to 20 percent of excipient fines is not rec- ommended, and the final concentra- tion of fines should be adjusted to obtain the most beneficial effect. Lactose selection As the cited studies show, selecting lactose for use in DPI formulation development is an important step. Choosing the "correct" lactose remains a challenge due to the many and diverse factors that influence DPI per- formance, the device, and the nature of the API. Nevertheless, it is possible to give a rough guide for lactose selection based on the device. In general, for reservoir- based devices using mainly inertial forces for API separation, coarse carri- ers like InhaLac 70 are suitable. For reservoir-based devices like the Turbohaler, in which the API separates from the carrier mainly due to drag/lift or shear/friction forces, finer yet good- flowing lactose carriers—such as InhaLac 120—are recommended. DPIs that use pre-metered doses of Figure 4 Relationship between carrier size, device, and API InhaLac 120 InhaLac 230 InhaLac 250 InhaLac 120 InhaLac 230 InhaLac 250 Salbutamol sulfate Aerolizer Budesonide Fine particle fraction (%) Fine particle fraction (%) 50 40 30 20 10 0 50 40 30 20 10 0 Notes: Adapted from Littringer et al. [13]. Three carrier lactoses (InhaLac 120, InhaLac 230, and InhaLac 250) were used for formulation with budesonide or salbutamol sulfate. NGI impactor was used to calculate fine particle fractions. For InhaLac 120, a D50 of 132 µm was measured (laser diffraction); for Inhalac 230 and InhaLac 250, the D50 was 87 µm and 52 µm. Plotted data are means of n = 3 ± standard deviation. Clickhaler