Mechanochemical Synthesis and Physicochemical Characterization of Previously Unreported Praziquantel Solvates with 2-Pyrrolidone and Acetic Acid

Abstract

Two new solvates of the widely used anthelminthic Praziquantel (PZQ) were obtained through mechanochemical screening with different liquid additives. Specifically, 2-pyrrolidone and acetic acid gave solvates with 1:1 stoichiometry (PZQ-AA and PZQ-2P, respectively). A wide-ranging characterization of the new solid forms was carried out by means of powder X-ray diffraction, differential scanning calorimetry, FT-IR, solid-state NMR and biopharmaceutical analyses (solubility and intrinsic dissolution studies). Besides, the crystal structures of the two new solvates were solved from their Synchrotron-PXRD pattern: the solvates are isostructural, with equivalent triclinic packing. In both structures acetic acid and 2-pyrrolidone showed a strong interaction with the PZQ molecule via hydrogen bond. Even though previous studies have shown that PZQ is conformationally flexible, the same syn conformation as the PZQ Form A of the C=O groups of the piperazinone-cyclohexylcarbonyl segment is involved in these two new solid forms. In terms of biopharmaceutical properties, PZQ-AA and PZQ-2P exhibited water solubility and intrinsic dissolution rate much greater than those of anhydrous Form A.

Polymorphism of Praziquantel: Role of Cooling Crystallization in Access to Solid Forms and Discovery of New Polymorphs

“…For the experiments using acetic acid as solvent, the acetic acid solvate (PZQ-AA) was obtained in all experimental conditions, confirmed by comparison with the simulated powder pattern DAJCEA 21 (Supporting Information, Figure S2). PZQ-AA was first obtained by Zanolla et al via liquidassisted grinding using a vibrational mill.…”

“…The DSC curve of PZQ-AA (blue curve) is shown in Figure , characterized by a single endothermic event at 72.19 °C. Zanolla et al reported this event (peak at 72.26 °C) as the melting point of PZQ-AA, also confirmed by hot-stage microscopy . Before starting thermal decomposition, a mass loss of 15.60% up to 200 °C is observed in TGA.…”

“…The main investigation of new solid forms of praziquantel involved obtaining cocrystals of carboxylic acids − and using polymorph screening by mechanochemistry − The pure enantiomers of praziquantel are reported as hemihydrates, indexes under the codes SIGBUG ( S -praziquantel hemihydrate), SIGBUG01 ( R -praziquantel hemihydrate), and LIFVED ( R -praziquantel monohydrate) Table summarizes the literature survey for all reported polymorphs of PZQ (also considering the solvates).…”

Cocrystals of Praziquantel with Phenolic Acids: Discovery, Characterization, and Evaluation

“…Therefore, it is very important to improve the water solubility of praziquantel to reduce the dosage of praziquantel for better development of pediatric drug use and to reduce the probability of drug resistance and adverse reactions, as well as to protect global public health security [ 7 ].The solubility of praziquantel can be improved by preparing praziquantel solid dispersions, lipid nanoparticles or cyclodextrin inclusion compounds, but are limited by instability during preparation or storage. Considering the advantages of cocrystal technology in improving the physical and chemical properties of compounds, many researchers have carried out related studies on PRA [ 8 , 9 , 10 , 11 ]. At present, 27 cocrystals of PRA have been reported in the Cambridge Structural Database (CSD), and based on the analysis of their structural information, the cocrystal coformers (CCFs) of PRA were all carboxylic acid compounds or compounds with polyphenol hydroxyl groups.…”

A study of the heat-mediated phase transformations of praziquantel hydrates. Evaluation of their impact on the dissolution rate

“…PZQ has two known hydrates, a monohydrate (MH) [ 15 ] and a hemihydrate (HH) [ 16 ], and a hemihydrate has been reported for every drug enantiomer [ 17 , 18 ]. Other solid forms of PZQ, obtained as solvates [ 19 ], cocrystals [ 20 ], a cyclodextrin complex [ 21 ], and solid-solid dispersions [ 22 , 23 ] widen the landscape of the PZQ solid forms.…”