**4. Conclusions**

The interaction products PZQ–SEP and PZQ–VHS prepared with ethanol, dichloromethane and acetonitrile allowed us to carry out an effective interaction of the low water-soluble drug with the clays. Therefore, this described methodology that uses organic solvents and clays can be used to prepare drug–clay complexes, with drugs that have low aqueous solubility. The characterization using different techniques of these interaction products showed that the drug is amorphized, reducing its crystallinity.

In vitro drug release profiles of the interaction products with sepiolite compared with the pristine PZQ in sink conditions in acid aqueous medium (pH = 3) and in simulated intestinal fluid (pH = 6.8) showed that in all products the dissolution rate of the drug improved, and specifically the PZQ–SEPdic was the one that most increased the rate dissolution. In the interaction products with montmorillonite, in acid medium (pH = 3), the PZQ–VHSac improved the dissolution rate of the drug, and the PZQ–VHSdic showed a controlled release of PZQ, which can be very interesting for another type of

modified drug delivery system. In SIF medium (pH = 6.8), all the PZQ–VHS interaction products increased the dissolution rate of the drug.

Cytotoxicity and cell cycle studies were performed in the interaction products prepared with ethanol, and the interaction products with dichloromethane and acetonitrile are expected to have similar behavior. The PZQ–SEPet interaction product was biocompatible with the HTC116 line cells, and it did not produce a decrease in cell viability or alterations in the cell cycle. However, the PZQ–VHSet showed a slight loss of cell viability like pure products, but in the cell cycle study, the affectation of the cell cycle and damage of the cells were observed at the highest concentration tested, so low concentrations should be used.

Therefore, the methodology used with organic solvents is an interesting technological strategy for effective interaction between praziquantel and clays. In general, according to the results obtained, the PZQ–SEP interaction products increased more the dissolution rates of drug, without producing cytotoxicity or alterations in the cell cycle of HTC116 cells. These systems should be considered as promising pharmaceutical systems to improve the bioavailability of water low-soluble of praziquantel.

**Supplementary Materials:** The following are available online at http://www.mdpi.com/1999-4923/12/10/914/s1, Table S1: Statistical parameters corresponding to the fittings of all the experimental release results of PZQ and PZQ–SEP interaction products to the equations of distinct models, Table S2: Statistical parameters corresponding to the fittings of all the experimental release results of PZQ and PZQ–VHS interaction products to the equations of distinct models.

**Author Contributions:** Conceptualization, A.B.-S., C.V. and C.I.S.-D.; methodology, A.B.-S., C.V. and C.I.S.-D.; formal analysis, A.B.-S. and R.S.-E.; investigation, A.B.-S.; data curation, A.B.-S.; writing—original draft preparation, A.B.-S.; writing—review and editing, A.B.-S., R.S.-E., F.G.-V., C.V. and C.I.S.-D.; supervision, A.B.-S., C.V. and C.I.S.-D.; funding acquisition, C.V. and C.I.S.-D. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research was funded by Ministerio de Ciencia e Innovación government, grants numbers PCIN-2017-098, FIS2016-77692-C2-2-P and CGL2016-80833-R and by Consejería de Economía, Innovación, Ciencia y Empleo, Junta de Andalucía government, grants numbers RNM1897 and P18-RT-3786.

**Acknowledgments:** This project was supported by the Spanish research groups CTS-946 and RNM363. Technical support was provided by the Centro de Instrumentación Científica (University of Granada), the Instituto Andaluz de Ciencias de la Tierra (Consejo Superior de Investigaciones Científicas-University of Granada) and the Xtrem Biotech SL (Spin-off University of Granada).

**Conflicts of Interest:** The authors declare no conflict of interest.

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