Structural, Physicochemical, and Biopharmaceutical Properties of Cocrystals with RS- and R-Praziquantel─Generation and Prolongation of the Supersaturation State in the Presence of Cellulosic Polymers

Abstract

Two novel cocrystals of the pharmaceutically active enantiomer R-Praziquantel (R-PZQ) were formed with glutaric acid (R-PZQ/GA) and succinic acid (R-PZQ/SA) in a 1:1 stoichiometric ratio by liquid-assisted mechanical grinding. The characterization of the cocrystals by structural and physicochemical methods revealed properties distinct from the cocrystal analogues with racemic PZQ, i.e., RS-PZQ/GA and RS-PZQ/SA, reported previously in the literature. However, all four cocrystals exhibit improved intrinsic dissolution rates in a medium simulating the physiological conditions of the gastric fluid (pH 1.2) compared to the solid phases of the pristine drug (R-PZQ•0.5H 2 O and RS-PZQ). Nonsink powder dissolution tests showed that the cocrystals with R-and RS-PZQ can generate transient supersaturated solutions with solubility advantages of 1.3-to 2.2-fold compared to the pristine drugs. In the presence of predissolved hydrophobic polymers such as MC60HG and HPC 80,000, the supersaturation state is prolonged for 20−30 min providing solubility advantages of up to 2.7-fold and an even larger advantage compared to the pristine forms of Praziquantel.

Co-Crystalline Solid Solution Affords a High-Soluble and Fast-Absorbing Form of Praziquantel

“…In the solid, PZQ and MA molecules alternate into racemic H-bonded chains along the b axis of the orthorhombic Pbca unit cell, with the acidic oxygen of the carboxylic acid bridging between two different carbonyl oxygen atoms of two PZQ racemes. Such a monodentate synthon has been previously described as a “type III” by Herrera-Ruiz and Höpfl . The hydroxyl group of MA acts as a H-bond donor in an intramolecular H-bond for the adjacent carboxylic group (Figures and S2), while it acts as an acceptor in an additional H-bond with another MA from the nearest chains that are aligned in an antiparallel orientation in the crystal.…”

“…Such a monodentate synthon has been previously described as a “type III” by Herrera-Ruiz and Höpfl. 33 The hydroxyl group of MA acts as a H-bond donor in an intramolecular H-bond for the adjacent carboxylic group ( Figures 1 and S2 ), while it acts as an acceptor in an additional H-bond with another MA from the nearest chains that are aligned in an antiparallel orientation in the crystal.…”

Polymorphs, cocrystal and hydrate of nilutamide

“…It has been extensively reported that utilization of various pharmaceutically acceptable polymers (e.g., HPMC, PVP, and PEG) can effectively delay or suppress nucleation of drug compounds from supersaturated aqueous solutions and, therefore, inhibit precipitation of a poorly soluble component, improving the solution stability of a cocrystal. [70][71][72][73][80][81][82][83][84][85][86] In this study, we employed HPMC, a biocompatible polymer commonly used in the development of cocrystal formulations, 77 as a Nil precipitation inhibitor. Preliminary solubility studies have shown that HPMC at 0.1% concentration had virtually no effect on the thermodynamic solubility of Nil form I.…”

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

“…Finally, focusing the attention, once again, on PZQ-GLU plus also PZQ-SUC cocrystals, the same scientific group reported two novel cocrystals obtained through LAG in the presence of the above-mentioned coformers ground with enantiomerically pure (R)-PZQ in a 1:1 molar ratio [ 67 ]. The new cocrystals (i.e., (R)-PZQ-GLU and (R)-PZQ-SUC) were deeply characterized and compared with previously reported analogous cocrystals obtained with racemic PZQ (hereinafter referred as (RS)-PZQ-GLU and (RS)-PZQ-SUC), pure (R)-enantiomer hemihydrate (i.e., (R)-PZQ-HH), and pristine (RS)-PZQ.…”