Mechanochemical Formation of Racemic Praziquantel Hemihydrate with Improved Biopharmaceutical Properties

Abstract

Praziquantel (PZQ) is the first-line drug used against schistosomiasis, one of the most common parasitic diseases in the world. A series of crystalline structures including two new polymorphs of the pure drug and a series of cocrystals of PZQ have been discovered and deposited in the Cambridge Structural Database (CSD). This work adds to the list of multicomponent forms of PZQ a relevant example of a racemic hemihydrate (PZQ-HH), obtainable from commercial PZQ (polymorphic Form A) through mechanochemistry. Noteworthy, the formation of the new hemihydrate strongly depends on the initial polymorphic form of PZQ and on the experimental conditions used. The new PZQ-HH has been fully characterized by means of HPLC, Differential Scanning Calorimetry (DSC), Thermogravimetric Analysis (TGA), Hot-Stage Microscopy (SEM), Powder X-Ray Diffraction (PXRD), Scanning Electron Microscopy (SEM), FT-IR, polarimetry, solid-state NMR (SS-NMR), solubility and intrinsic dissolution rate (IDR), and in vitro tests on Schistosoma mansoni adults. The crystal structure was solved from the powder X-ray diffraction pattern and validated by periodic-DFT calculations. The new bioactive hemihydrate was physically stable for three months and showed peculiar biopharmaceutical features including enhanced solubility and a double intrinsic dissolution rate in water in comparison to the commercially available PZQ Form A.

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

“…The final Rietveld refinement, where soft restrains on the atom distances (±0.03 Å) and angles (±0.1 • ) were applied, was performed in TOPAS V5 resulted in an R-Bragg factor of 3.32% and 2.58% for the PZQ-AA and PZQ-2P solvates, respectively. Notwithstanding the novel solvates show a triclinic unit cell with volume, cell parameters and crystal packed similar to the hemihydrate structure already published [11] the crystal packing comparison (see Figure S5) shows the main difference is due to the slippage of PZQ layers caused by the bulkiness of acetic acid and 2-pyrrolidone compared to water and to the hydrogen bond linkage between layers in the hemihydrate. In both structures (Figure 7) the acetic acid and 2-pyrrolidone showed a strong interaction with the PZQ molecule via hydrogen bond, O1-O4 of 2.524 Å and O1-N3 of 2.760 Å for the PZQ-AA and PZQ-2P, respectively, as also attested by FT-IR analysis in both cases (see following Figure S6).…”

“…Besides, unsuccessful LAG experiments were conducted in the presence of ethanol and ethyl acetate from Form B. Similarly to the case of PZQ hemihydrate [11], the quantity of liquid added was not significant, since the same patterns were collected in all the experiments. Therefore, to simplify the preparation of the sample and the relative comparison, an equimolar ratio between the components was selected as the main production method in the case of Form B.…”

“…A series of PZQ cocrystals with different dicarboxylic acids (i.e., oxalic, malonic, succinic, maleic, fumaric, glutaric, adipic and pimelic) were attained by means of liquid-assisted grinding (LAG) with acetone or acetonitrile. Recently, our group reported a hemihydrate form of racemic PZQ (indexed as WUHQAU), obtained via LAG in a two-step mechanochemical treatment when the commercial PZQ (Form A) is used, or in a one-step in the case of PZQ Form B [11]. Both in the case of PZQ cocrystals with dicarboxylic acids and in the racemic hemihydrate, the PZQ adopts an anti-conformation of the C=O groups of the piperazinone-cyclohexylcarbonyl segment, whereas commercially available PZQ Form A has the syn stereochemistry [6,11] (Figure 1).…”

Direct Powder Extrusion 3D Printing of Praziquantel to Overcome Neglected Disease Formulation Challenges in Paediatric Populations

“…DSC, XRPD, and Raman mapping were used to characterise the solid state of the printlets. DSC thermograms confirmed the crystalline nature of the pure drug by the presence of a sharp melting endotherm at~140 • C, and the amorphous state of the polymer KOL (Figure 4), as reported previously in the literature [56][57][58][59]. Although an endothermic event was observed in the HME powdered material and mainly after milling (data not shown), its low intensity allows us to conclude that P 50 and M 50 powdered materials were predominantly amorphous before printing due to the melting process in HME.…”

“…These physical characteristics were maintained after printing for both formulations, where the P 50 remained amorphous while the DSC thermogram of the M 50 printlet shows an endothermic peak visualised in the range of 120–122 °C with ΔHfusion 2.15 J/g. However, the crystallinity is similar to that evidenced in the material before printing and cannot be attributed to the presence of the crystalline PZQ ( ~ 136 °C) or one of the polymorphs of PZQ, B, or C, for which the melting temperatures described in the literature are different (around 106 and 112 °C, respectively) [ 58 , 59 , 60 ]. The endothermic event shown in Figure 4 can be related to the effect of the polymer on lowering the melting temperature of the drug in the mixture.…”