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

Debora Zanolla,Lara Gigli,Dritan Hasa,Beatrice Perissutti,William Jones,Mihails Arhangelskis,Dario Voinovich,Nicola Demitri,Michele R Chierotti

doi:10.3390/pharmaceutics13101606

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.

Highlights

Introduction240 million people worldwide and more than 700 million people live in endemic areas [3]
Praziquantel (PZQ, Scheme 1), ((11bRS)-2-(Cyclohexylcarbonyl)-1,2,3,6,7,11b-hexahydro4-Hpyrazino [2,1-a]isoquinolin-4-one), is the first-line drug to treat human schistosomiasis [1,2], a tropical disease caused by the Schistosoma species worm, which affects around240 million people worldwide and more than 700 million people live in endemic areas [3].For this reason, PZQ is included in World Health Organization (WHO) Model List of Essential Medicines for Adults (21st list available at [4]) and for Children (7th list available at [5])
It was found that all the new crystal forms should be assigned to PZQ solvates, which were labeled as Praziquantel acetic acid monosolvate (PZQ-AA) and Praziquantel 2-pyrrolidone monosolvate (PZQ-2P), respectively

Summary

Introduction

240 million people worldwide and more than 700 million people live in endemic areas [3]. For this reason, PZQ is included in World Health Organization (WHO) Model List of Essential Medicines for Adults (21st list available at [4]) and for Children (7th list available at [5]). The commercial form of PZQ is a racemic anhydrate structure, indexed as TELCEU in the Cambridge Structural Database (CSD) [6]. PZQ possesses two additional anhydrate polymorphic forms (Form B and Form C, indexed as TELCEU01 and GOYZOM, respectively), obtainable via neat grinding PZQ Form A [9,10]. Despite the absence of hydrogen bond donor groups in the molecular structure (Scheme 1), PZQ shows an

Methods

Results

Discussion

Conclusion