*2.3. Screening for an Absence of External Crystallization*

We investigated crystallization of nifedipine outside of the FCC particles by visual analysis of scanning electron microscopy (SEM) images (FEI Nova Nano SEM230, FEI, Hillsboro, OR, USA). Small amounts of the powders were placed on carbon adhesives and dedusted. The samples were sputtered with a 20 nm gold layer before imaging.

We used a focused ion beam scanning electron microscopy (FIB-SEM) method to visualize the internal structure of loaded FCC. To investigate the effect of phospholipid on nifedipine loading in FCC, we selected the formulations D5N20 and D20N20 as representative samples for lowest and highest phospholipid content, respectively, for FIB-SEM. Nif-FCC control formulation (without phospholipid) and pure FCC were used as reference material. To eliminate inter-particulate pores and visualize only the internal pore loading, we consolidated the powders with a compressive pressure of 50 MPa. Previous studies have shown that this pressure effectively eliminates inter-particulate pores without

affecting the intra-particle structure [37,40]. The samples were sputtered with a 20 nm gold layer before visualization. Tilt angle of 52 degrees was used for ion beam processing and further imaging (FEI Helios Nano Lab 650, FEI, Hillsboro, OR, USA). To produce trenches with a size of 20 × 10 × 8 µm, we milled down the selected regions of the samples using a 21 nA gallium ion beam. Prior to the ion-milling step, a platinum protective layer with a thickness of 0.3 µm was deposited on the location of the trench to protect the surface of the sample from deformations during the ion beam application. After milling, the surface of the cross-section was polished with a 0.79 nA ion beam and sputtered with a 3 nm platinum layer, prior to SEM imaging, to enhance conductivity of the surface and reduce imaging artifacts.
