*3.1. Hybrid Preparation and Characterization*

The hybrid ZnAl-KET was obtained by ion exchange mechanism (Scheme 1) using ZnAl-NO3, having the following formula obtained by ICP-OES analysis: [Zn0.70 Al0.30 (OH)2](NO3)0.30·0.4 H2O.

**Scheme 1.** Schematic representation of the ion exchange between NO3 − ions in the pristine ZnAl-HTlc (ZnAl-hydrotalcite) and KET− (ketoprofen).

The XRPD analysis confirmed KET- intercalation into HTlc lamellae. In fact, the hybrid pattern showed a reflection at 2.19 nm, which was increased in comparison to pristine ZnAl-NO3 that shows a reflection at 0.89 nm, typical of nitrate anion (Figure 1A). Combining the results coming from ICP-OES and TGA analyses, the final formula was calculated as [Zn0.70 Al0.30 (OH)2] (KET)0.30·0.98 H2O (ZnAl-KET); drug loading was 41.89% *wt.*/*wt*.

KET intercalated into HTlc in the anionic form (KET−) showed a different solid-state compared to the pristine crystalline form. In fact, the reflection of the crystalline form disappeared in the intercalation product XRPD spectrum, testifying the lack of the crystalline form (Figure 1A). This was confirmed also by the thermal profile obtained by differential scanning calorimetry analysis. In fact, while crystalline KETH (alone) showed a sharp endothermic peak at 94 ◦C, corresponding to the melting point, this was not detectable in the ZnAl-KET profile, meaning that the crystallinity form was not present in this product (Figure 1B).

**Figure 1.** (**A**) XRPD pattern (X-ray diffraction patterns) of crystalline ketoprofen (KET) (acid form), pristine ZnAl-NO3, and the hybrid ZnAl-KET. (**B**) Thermal profiles measured by differential scanning calorimetry of ZnAl-NO3, crystalline KET, ZnAl-KET, and KET/ZnAl-NO3 physical mixture.

The morphological analysis carried out by scanning electron microscopy (SEM) showed the typical desert-like rose structure of pristine ZnAl-NO3 crystals (Figure 2A,B) [24] having dimensions in the range of 1–10 μm. The intercalation procedure induced the modification of this morphology, as can be observed from the micrographs reported in Figure 2C,D appearing fragmented with rounded edges, while the dimensions were maintained in the same range of the raw ZnAl-NO3.

**Figure 2.** Micrographs obtained by scanning electron microscopy of pristine ZnAl-NO3 (**A**,**B**) and ZnAl-KET (**C**,**D**).
