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42 October 2016 Tablets & Capsules mechanisms are responsible for deag- gregation: shear flow and turbulence, particle-device impact, and particle- particle impact. As a result, different forces act on the adhesive mixture, including frictional, inertial, and drag/lift forces. The geometry of the device—narrow passages, impactor bodies (baffles, plates, internal inhaler surface), circulation and whirl or cyclone chambers—determines what kind of forces act and to what extent. Changes in the physical properties of the excipient lead to changes in the performance of the DPI. As this effect can be used in formulation develop- ment, lactose for DPIs is available in different particle size distributions. The particle size of the carrier influ- ences not only the bulk and tapped densities, flow properties, and specific surface area but also the emitted dose and FPF of the DPI. The dependence of DPI performance on the lactose car- rier's particle size has been studied extensively when high dependence on the device was found. De Boer et al. found that for the reservoir-based Novolizer device, a higher FPF was found as the particle size of the carrier increased, whereas in the Diskus device—which uses pre-metered blis- ter strips—higher FPFs were achieved when the particle size of the carrier lactose decreased [6]. These results were confirmed in a study from Hertel et al., who investigated two different carrier lactoses to assess their suitabil- ity for use with the Novolizer device [7]. The researchers found that the coarser of the two lactose grades stud- ied, InhaLac 70—which has a mean particle size (D 50 ) of 218 µm—led to a significantly higher FPF (48 percent compared to 37 percent) than did the other, InhaLac 230, which has a mean particle size of 101 µm. (Figure 3) [8]. The better performance with the coarser carrier is explained by the sep- aration mechanism of this device. The main removal forces acting on the par- ticles in this classifier-based device are inertial forces, with the powder formu- lation exposed to vibration and cen- trifugal and collision forces [9]. As coarser particles circulate at higher velocity in the classifier, higher inertial forces are available to separate the API from the carrier. Larger particles will remain in the classifier, and only the small, detached particles leave the sys- tem and become available for inhala- tion with the air stream [9]. Classifiers succeed at separating the API from the carrier, but many devices employ other mechanisms. In capsule- based devices, such as the Aerolizer or Handihaler, the air stream during inhalation causes the capsule to spin, shake, and vibrate at high frequency, enabling it to emit and disperse its con- tent through the holes pierced in the capsule [9]. A grid keeps the capsule inside the device and hinders bigger agglomerates from leaving the system. Littringer et al. investigated the effect of different lactose carriers on the performance of the Aerolizer device. In that study, three different lactose grades were mixed with an API and each was assessed according to the uniformity of the delivered dose and resulting FPF. The lactose grades in that study differed mainly in particle size distribution. For InhaLac 120, the coarsest of the investigated carriers, a D 50 of 132 µm was measured. For Inhalac 230 and InhaLac 250, the D 50 was 87 and 52 µm. As shown in Figure 4, when salbutamol sulfate was the API, the FPF increased as the particle size of the carrier decreased. This result is in line with the findings of Zeng et al., who also reported a decreasing FPF with increasing carrier particle size for a salbutamol sulfate formulation [11,12]. The superior aerosolization of smaller particles and their higher fluidization energy explain this result [1,12,13]. However, in contrast to these findings, the same investigation carried out with budes- onide instead of salbutamol sulfate led to a different result. In that study, the FPF slightly decreased as the particle size distribution of the carrier lactose decreased (Figure 4). Notably, the morphology of the APIs differed sig- nificantly: Micronized particles of salbutamol had a needle-like shape, whereas the budesonide particles were more spherical [15]. Figure 3 FPFs of two carrier lactoses 0 2.5 5 7 Amount of lactose fines (%) InhaLac 70 InhaLac 230 70 60 50 40 30 20 10 0 Notes: Adapted from Hertel et al. [7]. Shows InhaLac 70 and InhaLac 230 with different amounts of lactose fines (InhaLac 400) and 1.5 percent budesonide delivered using a Novolizer device. Values are mean particle size of n = 3 ± standard deviation. For InhaLac 70: 218.7 µm, ±1.0 µm; InhaLac 230: 101.3 µm, ±0.1 µm; InhaLac 400: 6.3 µm, ±0.0 µm; and budesonide: 1.5 µm, ±0.0 µm. Particles were measured by laser diffraction. Figure 2 In carrier-based formulations, the API detaches from the excipient when the powder is dispersed. Dispersion Excipient: 50 to 200 µm API: 1 to 5 µm Fine particle fraction (%)