*3.1. X-ray Di*ff*raction*

The interaction products were prepared following the methodology described above in drug–clay. These materials and raw materials were characterized by powder XRD, showing the results in Figure 1. PZQ drug revealed the most intense reflection at around 16.5◦ (2θ units) and other intense reflections at approximately 8.0◦, 19.1◦ and 23.3◦ (2θ units) in accordance with that previously reported [41].

**Figure 1.** XRPD patterns of the studied samples with sepiolite (**a**) and montmorillonite (**b**).

After interaction with the clay minerals, a practically complete absence of drug reflection was observed, probably due to a loss of crystallinity of PZQ (Figure 1). In previous works, similar behavior of PZQ was observed in the formation of a solid dispersion with polyvinylpyrrolidone [24], with sodium starch glycolate [29], and with glycyrrhizic acid–forming micelles [42].

The interaction product of PZQ with sepiolite using different solvents in the preparation method (Figure 1a) showed an XRD pattern similar in all the cases. In the profiles, clear peaks of the PZQ drug were not observed; only the peaks of sepiolite were observed. Therefore, after the interaction, a loss of drug crystallinity was found.

In the oriented aggregate powder X–ray diffraction pattern of the interaction products of PZQ with montmorillonite (Figure 1b), the peaks of PZQ were not observed either in any of the products. However, the (001) reflection peak of the VHS increased in the interaction products, confirming the intercalation and the presence of PZQ in the interlayer space of the clay.

The interaction product PZQ–VHSet showed an increase in the interlayer space of montmorillonite from 1.26 nm to *d*(001) = 1.50–1.61 nm in accordance with that reported previously [33,43]. The interaction product PZQ–VHSdic increased to *d*(001) = 1.47 nm; and the spacing of PZQ–VHSac increased to *d*(001) = 1.51 nm (Figure 1b). These results corroborated that the PZQ is present in the interaction products and the peaks of PZQ were not observed probably due to the complete intercalation of the drug in the interlayer space of the clay and the loss of crystallinity of the drug. The PZQ molecules intercalate in the confined space of montmorillonite as individual molecules where no recrystallization is possible. Nevertheless, the *d*(001) reflection peaks are wider in the interaction products than in the pristine VHS. This indicates than a range of different *d*(001) spacings can be produced, especially in PZQ–VHSdic, where two peaks can be distinguished. In previous modeling studies, we observed the formation of a monolayer of PZQ in the interlayer space of VHS, where different densities of the drug can be found and several conformations of the adsorbate molecule can happen [44]. These differences can be responsible for the variation of *d*(001) spacing widening this (001) peak, maintaining the monolayer configuration.
