Mechanochemical activation of Praziquantel in a vibrational mill

openThe research activity presented in this PhD thesis was totally dedicated to the application of mechanochemistry to Praziquantel using a vibrational mill, taking also advantage of the wide network of the group collaborators, both national and international. Praziquantel is an antihelmintic drug used worldwide against Schistosomiasis, which is a parasitic diseases affecting more than 200.000 people, especially in the sub-saharian area. Despite being highly effective and safe, this drug has 2 major drawbacks: the first one is the low biopharmaceutical profile (i.e. solubility and bioavailability) and therefore the high dosage needed. The second one is the very bitter and disgusting taste, which makes even more difficult its administration, in particular in pediatric patients, the main involved. The research started with the study of many co-ground systems of Praziquantel with different polymers used as pharmaceutical excipients, both at RT and under cryogenic conditions, to evaluate the process and formulation variables, obtaining amorphous dispersion with enhanced solubility and maintained antischistosomal activity (in vitro). Moreover, other binary systems were investigated: when using amorphous mesoporous silica, drug amorphisation was dramatically increased, even after only 15 minutes grinding, enhancing also drug dissolution and maintaining its in vitro antischistosomal activity. The grinding of Praziquantel with natural/synthetic sweeteners led to samples with enhanced solubility and intrinsic dissolution rate, possibly ameliorating also the drug taste. The neat grinding of the drug by itself led to the discovery of two new polymorphic forms, Form B and Form C, which structures were solved from the synchrotron X-Ray powder pattern and validated by DFT calculations. Form B was fully characterized, comprehending the in vitro and in vivo antischistosomal activity and the analysis of the pharmacokinetic profile. Form C, though exhibiting the higher solubility among the polymorphic forms, presented a poor physical stability of about 3 months. In addition, Form B and a cyo-coground sample were included in Gelucire 50/13 microparticles obtained via spray congealing, with a significative increase of drug solubility and dissolution rate. During the Erasmus period at the University of Cambridge, Praziquantel was subjected to Liquid-Assisted Grinding, discovering three new forms, one hemihydrate and two solvates respectively with Acetic Acid and 2-Pyrrolidone. The hemihydrate was fully characterized, both at the solid-state and from the biopharmaceutical point of view, including in vitro antischistosomal analysis, while the other forms are still under characterization. At the end, different sucrose esters were used both at the solid state and as aqueous solutions in combination with Praziquantel during grinding and Liquid-Assisted grinding.CHIMICAembargoed_20200307Zanolla, Debor