## 4 Discussion
The size of microspheres in SLM dispersions is in the range of several micrometers, with the largest particles not exceeding 15 \(\upmu\)m. Dispersions with Compritol are generally characterized by a monomodal, and with stearic acid, a bi- or polymodal particle size distribution. The addition of the active substance, especially at a concentration above 1%, affects the SLM, causing a slight increase in the size of the microspheres. The particle size measured by the dry method (DPS) in powders is larger (10-20 \(\upmu\)m, most particles below 50 \(\upmu\)m) because particles in dry powders tend to agglomerate, which affects the obtained results. However, this process is reversible, as demonstrated by the redispersion tests, and the microspheres in the agglomerates formed after the drying process retain their integrity (shape and size), which was confirmed by the microscopic analyses [17; 19]. The issue of particle size and the change in this parameter in detail (particle size distributions, optical microscope and SEM images) have already been discussed in previous publications describing research on the properties of SLM dispersions and spray-dried powders [17; 19]. Moreover, thermal transformation of API is not observed regardless of the distribution of API in the SLM. It is not visible even in the case of incomplete incorporation of the drug substance into the lipid microspheres. During development studies of lipid microspheres, one of the important elements is to determine the distribution of the active substance in various phases of the SLM dispersion, such as the core of lipid particles, the surface of the microspheres or the aqueous phase of the dispersion (as described in previous reports [18]). For this purpose, in one of the stages, the drug substance localized on the surface of the lipid microspheres is dissolved while shaking the dispersion with methanol (without disturbing the structure of the microspheres and extraction of the drug substance incorporated in the lipid matrix). In the distribution studies, this fraction is isolated and quantified [18]. In the DSC study (conducted after such a process) the active substance, extracted from the particle surfaces, after evaporation of the solvent, should precipitate/crystallize outside the microspheres. Despite this, no change or drug peak was observed in the DSC curve (Figure S2). When the molecularly dispersed drug substance in the solid matrix of SLM exceeds its solubility limit, it is not fully incorporated into the SLM during the manufacturing process, and it precipitates or crystallizes out in the liquid dispersion. An example of such a formulation in our research is the SLM dispersion with 1% Ind (F11). Despite incomplete incorporation, no traces of API were found in the DSC spectrum (Figure S2). Unfortunately, DSC/TG tests do not make it possible to identify incomplete incorporation of the drug substance in the lipid matrix of the microspheres, and other techniques must be used for this purpose. On the one hand, it can be assumed that the undetectability of the drug substance in DSC tests of lipid microspheres results from low concentrations in the formulation, which is also confirmed by data from the literature [15]. On the other hand, the lack of a peak for the active substance may indicate its incorporation into the lipid matrix in the form of a molecular dispersion and interaction with the components of the dosage form (mainly lipid, but also a surfactant stabilizing the microspheres). Finally, the interaction with the lipid is confirmed by the study of physical mixtures, in which the peak intensity of the drug substance was already reduced (Figure 5). However, taking into account the fact that the active substance is not detected also in those systems, in which incomplete incorporation of the drug substance was observed, it can be assumed that the above-mentioned processes coexist.