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26 June 2022 Inhalation In both types, the surfaces are irregular at the nano- scale and micro-scale due to manufacturing process and there are micropores and indentations on the surfaces, (Figure 3). In addition, aggregated carriers have larger and wider cavities and clefts, which are able to carry considerable amounts, i.e., "chunks" of the micronized API. ese cavities provide shelter for the API particles during mixing as well as during dispersion, which is why aggregated carries behave quite differently from single crystal carriers [14]. Additional challenges with lactose as an excipient include surfaces that may be contaminated by pro- tein residues or other unwanted material [15] and that may contain amorphous regions. Such regions may negatively affect both the dispersibility and the stability of the formulation and should therefore be kept to a minimum. Lactose fines Lactose fines (or fine particles of another pharmaceu- tically inert material) can be added to the adhesive mixture. e median particle size of such grades is typically less than 10 µm. e main effect of lactose fines is to improve the dispersibility of the formula- tion and various hypotheses have been put forward to explain the effect [16]. From a "formulation mechan- ics" perspective, the effect of these inert fine particles is the same as that of the API [11, 17, 18]. erefore, added lactose fines can reduce flowability of the for- mulation, (which will be discussed in the second part of this article). Some carrier grades already on the market—in particular, the milled grades—contain fine lactose particles. Use of these may speed up formulation development as the performance of the binary API/ carrier mixture may be acceptable without further additives. However, grades with a fixed content remove the opportunity to use fine lactose content as a tool to adjust performance. properties have been identified as critical. Of these, size, shape, surface properties and content of fine particles (i.e., "carrier fines") are considered to be the most important [6, 13]. e effect of carrier particle size has been much investigated but the experimental findings are often puzzling. To date, no general theory has been estab- lished for the way in which carrier particle size affects the FPF. It is clear, however, that a larger carrier contributes to improved flowability of the formu- lation, which is particularly important for reservoir DPIs. On the other hand, a larger carrier size means a lower specific surface area, which limits the drug loading capacity. Two principal types of carriers can be identified and both have their merits. In addition, some lactose grades will exhibit properties of each: • Single crystal carriers with the typical "toma- hawk" shape • Aggregated crystal carriers Figure 3 Examples of lactose carrier particles: tomahawk type (left) and aggregated carrier type (right). Note the difference in image magnification: left image = 2.94 kx, right image = 1.50 kx. Courtesy of Anders Widelöv, Magle Chemoswed AB, Sweden.