**4. Conclusions**

Recent developments of praziquantel formulations that are useful for the preparation of a more appropriate pediatric dosage form, were demonstrated and discussed. The mechanochemical activation, whether in the presence or in the absence of povidone, had resulted in a remarkable increase of the solubility of the starting drug. The milling at room temperature and the cryo-comilling of PZQ, with the polymer, in a 1:1 weight ratio, enabled the improvement of the biopharmaceutical properties, by obtaining either a polymorph (Form B) or an amorphous/nanocrystalline form, with a reduction in crystallinity of about 70%, respectively. The results attested the grea<sup>t</sup> potentiality and effectiveness of the method, especially by neat grinding, where the absence of the polymer avoided the dilution of the drug and fulfilled the principle of minimizing the use of excipients in pediatric formulations. However, the unfavorable technological characteristics of the activated systems, such as poor wetting and flowability, caused by electrostatic and cohesive forces, might limit their use in the pharmaceutical production process. On the contrary, Gelucire® 50/13 microspheres, in which the activated systems were encapsulated by means of the spray congealing technology, showed a further increase in solubility and a marked improvement in the rate of dissolution of the drug. After the spray congealing process, the results evidenced that the cryo-coground and the milled PZQ formed either a solid dispersion (nanocrystalline and partial amorphous phase) or a solid solution (completely amorphous state), respectively. As a consequence, the MPs containing both activated systems showed a further increase of the biopharmaceutical properties, compared to the milled powders. The in vitro antischistosomal activity showed that MPs enabled the PZQ release, while maintaining its in vitro activity.

To conclude, the approach consisting in the association of the spray congealing with the mechanochemical activation grinding, in the absence of the polymer, was the most favorable, thus, it is a promising product for designing a new praziquantel formulation and a valid option for enhancing the performance of this antischistosomal drug, possibly permitting a significant reduction in the therapeutic dose.

**Author Contributions:** Conceptualization, B.A. and B.P.; Investigation and Analysis, S.B., D.Z., E.F., and F.L.; Data Curation, S.B., B.A., and B.P.; Writing – Original Draft Preparation, B.A., S.B., and B.P.; Writing – Review & Editing, J.K. and N.P.; Project Administration, B.A. and D.V.; Funding Acquisition, D.V. and N.P.

**Funding:** This research was funded by RFO 2017 from University of Bologna.

**Acknowledgments:** The authors thank Fatro s.r.l. for the gift of praziquantel E.P. grade and Gattefossé Italy for the supply of Gelucire 50/13.

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