*4.1. Impact of Drug Loading*

All synthesized formulations were found to be homogeneous and achieved high FEN loading efficiency regardless of the type of silica or lipid. Thus, this validates the efficiency of the simple mixing technique in minimizing drug/lipid loss during the fabrication process. The small amount of drug loss (<6% *w*/*w*) (Table S1) can be attributed to lipid solution of the drug sticking to the vial and not being adsorbed into the nanopores.

Both FS and MPS, silica microparticles were able to maintain FEN in a non-crystalline state at a sub-saturation level of 80% Seq, regardless of the lipid type. DSC and XRPD data confirmed the presence of a greater extent of FEN crystallinity in all 600% Seq formulations, compared to 400% Seq (Figure 2). This correlated with reduced in vitro dissolution performance (Figure 5). Furthermore, FEN dissolution and aqueous solubilization from unsaturated (80% Seq) and super-SLH (200, 400 and 600% Seq) was dependent on the type of silica and lipid utilized. The overall trend was that an increase in drug load resulted in an increase in FEN crystallization and aggregation of the silica microparticles.

It is important to note that, for FEN-SLH formulations, the endothermic peak observed in DSC thermographs were at a lower temperature than the melting point of crystalline FEN. The depression in melting point was previously reported in IBU-loaded super-SLH formulations and was attributed to the confinement of the drug crystallites in the nanopores [29]. The authors postulated that the presence of the drug outside of the pores and on the surface on the silica will not cause any depression in melting point, which implies the successful imbibition of drug and lipid into the nanopores of the silica microparticles. Based on this hypothesis and supported by XRPD data, it was confirmed that crystalline FEN is present in the formulations where display shifted endothermic peaks at 45–60 ◦C. Furthermore, it was hypothesized that the heating process during DSC analysis caused crystalline FEN present to re-dissolve in the lipid component of the SLH formulations displaying a shifted endothermic peak. However, further investigations are required to fully validate this hypothesis.
