Impact of mesoporous silica on the chemical degradation of Praziquantel upon grinding

Praziquantel and Syloid 244 FP (amorphous silicon dioxide) were ground in a vibrational mill in standard conditions (15 or 30 min at 25 Hz). Amorphous solid dispersions were obtained in a very short grinding time (15 min), as testified by DSC, PXRD and ESEM analyses. Samples ground at 15 min and 30 min showed the presence of the same degradation product, as was evident from UPLC, MS and NMR analyses. This short paper brings to light the tremendous lattice de-structuration ability of Syloid 244 FP upon grinding toward Praziquantel as well as its detrimental influence on promoting chemical degradation through ring opening and oxidation

Impact of mesoporous silica on the chemical degradation of Praziquantel upon grinding

Praziquantel and Syloid 244 FP (amorphous silicon dioxide) were ground in a vibrational mill in standard conditions ($15^{\prime}$ or $30^{\prime}$ at 25 Hz). Amorphous solid dispersions were obtained in a very short grinding time (15 min), as testified by DSC, PXRD and ESEM analyses. Samples ground at $15^{\prime}$ and $30^{\prime}$ showed the presence of the same degradation product, as was evident from UPLC, MS and NMR analyses. This short paper brings to light the tremendous lattice de-structuration ability of Syloid 244 FP upon grinding toward Praziquantel as well as its detrimental influence on promoting chemical degradation through ring opening and oxidation

From Bitter to Sweet: a preliminary study towards a patient-friendly Praziquantel dosage form

Praziquantel (PZQ) is an antihelmintic drug used worldwide against Schistosomiasis, despite its low solubility, bioavailability and the disgusting taste. This research represents a preliminary screening of 6 selected sweeteners in terms of their aptitude to be ground with PZQ, towards the development of a patient-friendly dosage form, capable of overcoming both dissolution and taste drawbacks. A vibrational mill was used to process equimolar mixtures of PZQ and each sweetener, and the dispersions were characterized by means of Differential Scanning Calorimetry, Powder X-ray Diffraction, Fourier Transform-Infrared Spectrometry, water solubility and Intrinsic Dissolution Rate. Physical stability of the coground systems was checked over a period of 1 year. The grinding for a short period (such as 30 min) of PZQ and selected sweeteners led to several very interesting products, with prevalent amorphous character, enhanced solubility and Intrinsic Dissolution Rate comparing to the raw drug. Peculiar behavior was found in the case of xylitol:PZQ ground mixtures where the appearance of traces of PZQ anhydrous Form B was noticed. Therefore, this research highlights the possibility of using binary premixes of PZQ and sweeteners in order to obtain an increase in the biopharmaceutical and organoleptic properties of the anthelmintic drug, underlining also the need for a careful screening of sweetener to design a PZQ patient-friendly dosage form

From Bitter to Sweet: a preliminary study towards a patient-friendly Praziquantel dosage form

Praziquantel (PZQ) is an antihelmintic drug used worldwide against Schistosomiasis, despite its low solubility, bioavailability and the disgusting taste. This research represents a preliminary screening of 6 selected sweeteners in terms of their aptitude to be ground with PZQ, towards the development of a patient-friendly dosage form, capable of overcoming both dissolution and taste drawbacks. A vibrational mill was used to process equimolar mixtures of PZQ and each sweetener, and the dispersions were characterized by means of Differential Scanning Calorimetry, Powder X-ray Diffraction, Fourier Transform-Infrared Spectrometry, water solubility and Intrinsic Dissolution Rate. Physical stability of the coground systems was checked over a period of 1 year. The grinding for a short period (such as 30 min) of PZQ and selected sweeteners led to several very interesting products, with prevalent amorphous character, enhanced solubility and Intrinsic Dissolution Rate comparing to the raw drug. Peculiar behavior was found in the case of xylitol:PZQ ground mixtures where the appearance of traces of PZQ anhydrous Form B was noticed. Therefore, this research highlights the possibility of using binary premixes of PZQ and sweeteners in order to obtain an increase in the biopharmaceutical and organoleptic properties of the anthelmintic drug, underlining also the need for a careful screening of sweetener to design a PZQ patient-friendly dosage form

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

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

Mechanochemical Formation of Racemic Praziquantel Hemihydrate with Improved Biopharmaceutical Properties.

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 activation of Praziquantel in a vibrational mill

The 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

Identification of degradation products of praziquantel during the mechanochemical activation

Praziquantel (PZQ) is an inexpensive, low toxicity BCS II class anthelmintic drug used for the treatment of neglected tropical diseases. In earlier papers a mechanochemical activation has been used to induce physical transformations on the drug which would ameliorate its solubility and hence its bioavailability and a systematic study of the effects of varying temperature, frequency and time of milling on drug melting enthalpy and drug recovery was given. In this communication, the focus is on the degradation products that are formed during this mechanical treatment of Praziquantel. In the cogrinding process with povidone and crospovidone several degradation products are formed. Different degradation products are formed, which depend on the type of polymer rather than the process conditions. Two of the most prominent degradation products were identified and their structure proposed on the basis of information obtained from GC\u2013MS, UPLC-MS and 1H NMR techniques

An explorative analysis of process and formulation variables affecting comilling in a vibrational mill: The case of praziquantel

Praziquantel, a BCS II class anthelmintic drug used for the treatment of schistosome infections, was coground in a vibrational mill with different polymers (linear and crosslinked povidone, copovidone and sodium starch glycolate). An explorative analysis of formulation variables (drug-polymer wt ratio and polymer type) and process parameters (type of grinding media, grinding time and frequency) was carried out with the help of an experimental screening design. The influence of the above mentioned factors on three PZQ characteristics (residual crystallinity, water solubility enhancement and drug recovery) was studied. The variation of carrier amount proved to be by far the most important variable affecting all the experimental responses. A lower impact and, in some cases, rather null effect, had the variation of the process variables. All coground systems were characterized by a high amorphous degree and a solubility significantly higher than the API. A very promising product was obtained by processing at 20 Hz for 4 h, using 3 spheres of 15 mm as grinding media, i.e. a coground having a 50% API content, showing a 4.6-fold greater solubility at 20 °C than pure praziquantel. This product maintained the same antischistosomal activity of pure API and was both physically and chemically stable for at least 6 months