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

Abstract

Solvent-assisted grinding (SAG) and solution slow evaporation (SSE) methods are generally used for the preparation of cocrystals. However, even by using the same solvent, active pharmaceutical ingredient (API), and cocrystal coformer (CCF), the cocrystals prepared using the two methods above are sometimes inconsistent. In the present study, in the cocrystal synthesis of praziquantel (PRA) with polyhydroxy phenolic acid, including protocatechuic acid (PA), gallic acid (GA), and ferulic acid (FA), five different cocrystals were prepared using SAG and SSE. Three of the cocrystals prepared using the SAG method have the structural characteristics of carboxylic acid dimer, and two cocrystals prepared using the SSE method formed cocrystal solvates with the structural characteristics of carboxylic acid monomer. For phenolic acids containing only one phenolic hydroxyl group (ferulic acid), when preparing cocrystals with PRA by using SAG and SSE, the same product was obtained. In addition, the weak molecular interactions that were observed in the cocrystal are explained at the molecular level by using theoretical calculation methods. Finally, the in vitro solubility of cocrystals without crystal solvents and in vivo bioavailability of PRA-FA were evaluated to further understand the influence on the physicochemical properties of API for the introduction of CCF.

Praziquantel Fifty Years on: A Comprehensive Overview of Its Solid State

“…RDkit molecular descriptors computed from the input SMILES strings were used as the features of the corresponding compound, which were computed by the ChemDes website [ 128 ]. This model, applied to PZQ cocrystallization, predicted that PZQ could form cocrystals with all eight coformers, which was consistent with experimental results [ 69 , 71 , 72 ], thus revealing the model as a powerful tool for cocrystal prediction and design in the field of drug research.…”

“…In 2022, the same scientific group also reported PZQ cocrystallization in the presence of polyhydroxy phenolic acids, namely protocathecuic acid (PA), gallic acid (GA), and ferulic acid (FA) [ 72 ]. They prepared five different cocrystals through LAG and SE methods: precisely, PZQ-PA, PZQ-GA, and PZQ-FA were obtained by grinding in a mortar a 1:1 molar ratio of PZQ and each coformer in the presence of a certain amount of ACN ( Figure 9 ); SE, performed with the same solvent, facilitated obtaining two cocrystal solvates, i.e., PZQ-PA-ACN and PZQ-GA-ACN, plus the same PZQ-FA cocrystal of LAG.…”

“…Recently, Yang et al reported another work with the application of artificial intelligence in cocrystal screening [ 127 ]. Precisely, they provided a data-driven cocrystal prediction method based on the eXtreme Gradient Boosting (XGBoost) machine learning model of the scikit-learning package applied to their eight previously and experimentally obtained PZQ cocrystals [ 69 , 71 , 72 ]. The cocrystal data in the CSD and the data recorded as no cocrystal formation in experimental screening were used as data sets for model training.…”

Comparing and Quantifying the Efficiency of Cocrystal Screening Methods for Praziquantel

“…Praziquantel (PZQ) (shown in Figure ), the model chiral compound of this study, presents several challenges that could be solved by multicomponent crystal formation. PZQ is the standard medicine for a parasitic worm infection named schistosomiasis causing the death of about 280,000 people annually in underdeveloped regions of Africa, South America, and Asia. − Searches for multicomponent crystals are performed either to improve the drug physicochemical properties − or to separate enantiomers with the purpose to produce an enantiopure drug . Indeed, chiral resolution strategies are sought for PZQ, − currently marketed as a racemic compound, as only its R -enantiomer possesses the desired pharmaceutical action, whereas the S -enantiomer causes side effects such as a bitter taste.…”

Salification-driven strategy toward the hydrophobic molecular salt of the antifungal drug 5-fluorocytosine and protocatechuic acid with triple-helix structure offers an innovative insight for conquering adverse drug reactions

“…However, these bands are moved to 1730 and 3291 cm −1 in the molecular salt, indicating that these groups take part in the hydrogen-bonding formation due to the band displacements being less than 50 cm −1 . 58,59 Furthermore, the characteristic vibration peak [ v (COOH)] for free PCA molecule is found at 1683 cm −1 , 60 which splits into two bands at 1364 [ v s (COO − )] and 1539 cm −1 [ v as (COO − )] in the molecular salt FYT–PCA respectively, hinting at the involvement of PCA molecule in the proton exchange reaction with the FYT molecule. Of particular note, more than 50 cm −1 in wavenumber changes of the carboxyl suggest that a molecular salt instead of a cocrystal is formed between FYT and PCA molecules.…”