The combination of racemic praziquantel, (RS)-PZQ, with aliphatic dicarboxylic acids of the homologous series HOOC−(CH 2 ) n −COOH (with n = 0−8) and the unsaturated analogues of succinic acid as cocrystal formers via liquid-assisted grinding provided a total of nine 1:1 and 2:1 cocrystals with oxalic acid, malonic acid, succinic acid (two polymorphic phases), maleic acid, fumaric acid, glutaric acid, adipic acid, and pimelic acid. The cocrystalline phases were identified first by XRPD analysis and then structurally characterized by IR spectroscopy and, as far as possible, by single-crystal X-ray diffraction analysis. Crystals suitable for XRD analysis were obtained for seven cocrystals and, additionally, for (RS)-PZQ. The analysis of the supramolecular interactions in the crystal structures has shown that the dominant hydrogen bonding patterns within the cocrystals are heterodimeric motifs formed through O−H•••O hydrogen bonds between PZQ and the dicarboxylic acids, which mostly contain additionally at least one secondary C−H•••O contact. In all crystal structures, the PZQ molecules are connected with each other through cyclic homodimeric hydrogen bonding interactions formed mainly through C−H•••O, but also through C−H•••π contacts, giving overall 1D, 2D or 3D hydrogen bonded networks. The crystallographic study also allowed us to establish that there are two main rotational conformers for PZQ, which differ in the configuration of the CO groups in the piperazinone−cyclohexylcarbonyl segment. In the crystal structure of (RS)-PZQ, all four independent molecules in the asymmetric unit have the syn-conformation, which in the hemihydrates, viz. (R)-PZQ•0.5H 2 O and (S)-PZQ•0.5H 2 O, and all cocrystals except for one are switched to the anti-antagonist.

Praziquantel (PZQ) is an important chiral active pharmaceutical ingredient for the treatment of gastrointestinal parasites, which is commercially available only in the form of its racemate. In this article, on the basis of co-crystallization experiments a convenient two-step protocol for the chiral resolution of RS-PZQ is described. Screening experiments with RS-PZQ using the liquid-assisted grinding technique revealed the formation of a diastereomeric co-crystal pair with L-malic acid (L-MA) of the compositions R-PZA:L-MA and S-PZQ:L-MA. Both co-crystals have been examined by single-crystal X-ray diffraction analysis, revealing similar unit cell parameters but differences in the supramolecular organization. Particularly the analysis of the hydrogen bonding patterns indicated overall stronger intermolecular interactions in the case of R-PZA:L-MA, which was confirmed by thermogravimetric−differential scanning calorimetry analysis giving a substantial difference in the melting point when compared to S-PZA:L-MA. After synthesis of R-and S-PZQ in enantiomerically pure form for the selective preparation of both R-PZA:L-MA and S-PZQ:L-MA, comparative solubilization experiments were carried out. Since significant variations in the solubility were found in some solvents, a procedure could be established allowing for the separation of R-PZA:L-MA by fractional crystallization. In a subsequent reaction step, the biologically active enantiomer R-PZQ was liberated from the co-crystal in the form of its hemihydrate by stirring with water. Comparison of the intrinsic dissolution rates for RS-PZQ, R-PZA•0.5H 2 O, and R-PZA:L-MA indicated that the co-crystalline phase exhibits a significantly larger rate constant than praziquantel in its enantiomerically pure form or as a racemate.

A total of 20 co-crystal formers have been combined with acetazolamide (ACZ) via solvent drop grinding in acetone, acetonitrile, and water. The screening experiments provided co-crystals with 4-hydroxybenzoic acid (4HBA) and nicotinamide (NA) (ACZ-4HBA and ACZ-NA-H 2 O), which were identified by X-ray powder diffraction (XRPD) and further characterized by IR spectroscopy and differential scanning calorimetry-thermogravimetric analysis (DSC-TGA). Both co-crystals could be prepared also by neat grinding (NG) and reaction crystallization (RC). Single-crystal X-ray diffraction analyses allowed for an examination of the dominant hydrogen bonding patterns in the co-crystals, showing that 4HBA binds to the thiadiazole acetamide fragment of ACZ via C(N)NH···HOOC and O−H···N interactions, while NA is linked through N−H···N and N−H···O contacts. In ACZ-NA-H 2 O, the components are connected further by crystal lattice water molecules through N−H···Ow and Ow−H···N hydrogen bonds. Phase stability assays in water at physiological pH values ranging from 1.2 to 6.8 showed that for ACZ-4HBA the crystalline solid phase did not transform to ACZ within 72 h, while for ACZ-NA-H 2 O a gradual transformation occurred. Thermal treatment of ACZ-NA-H 2 O and reaction crystallization experiments in methanol and anhydrous ethanol gave the dehydrated crystalline phase ACZ-NA, which is stable at ambient conditions for at least four months but transforms to the corresponding co-crystal monohydrate when stirred with deionized water.

Acetazolamide (ACZ) has been combined via liquid-assisted grinding in water with a library of cocrystal formers derived from benzoic and nicotinic acid, which provided novel cocrystals with 2-hydroxybenzamide, 2-aminobenzamide, picolinamide, and 2,3-dihydroxybenzoic acid. The cocrystalline phases were identified first by XRPD analysis and then structurally characterized by IR spectroscopy and single-crystal X-ray diffraction analysis. These cocrystals and the previously reported cocrystalline phases obtained from 4-hydroxybenzoic acid and nicotinamide constitute a series of six cocrystals of varied stoichiometric ratios (3:1, 2:1, 1:1, and 1:2), which allowed for a profound analysis of the structural and chemical factors that govern their formation. The structural analysis has shown that the ACZ molecules participate in the dominant hydrogen-bonding patterns within the crystal structures: three cocrystal structures exhibit extended supramolecular aggregates of ACZ having channels, pores, or semispherical voids, in which the cocrystal formers are included as guest molecules, and can, therefore, be described as inclusion or clathrate complexes. One cocrystal can be considered as a pillared or intercalation compound, and the remaining two cocrystals are true two-component 2D or 3D networks. In addition, a variety of alternative preparative methods (liquid-assisted grinding, neat grinding, reaction crystallization, solution-mediated phase transformation, and solution crystallization) have been employed, showing that four of the six cocrystals required the presence of water for successful cocrystal formation.

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