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 series of 2:1 fluorinated arylboronic ester adducts with 4,4′-bipyridine sustained by N→B dative bonds have been synthesized. The degree of fluorination in the arylboronic esters derived from catechol is shown to modulate the molecular conformation of the coordinated boronic ester moieties and the intermolecular interactions by means of C−H•••F and F•••F contacts that sustain the crystal lattices. The adduct derived from the catechol ester of 2,4-difluorophenylboronic acid was chosen to examine the formation of inclusion complexes with a large number of aromatic guests, affording solvates, cocrystals, and a cocrystal solvate. Six different crystal structure types with 1:1, 1:2, and 1:2:2 N→B adduct−guest ratios were observed, whose supramolecular organization is strongly influenced by the formation of sandwich-type complexes between the host and guest molecules. The host−guest interactions involve π•••π interactions with the bipyridine linkers and additional contacts with the catecholate and Baryl F substituents, indicating a large flexibility of the N→B adducts to adapt to the guest stereochemistry. The versatility of the crystallization system was employed to isolate o-xylene from an equimolar mixture of o-, m-, and p-xylene.

The effect of hydroxypropyl methylcellulose (HPMC) and methylcellulose (Methocel ® 60 HG) on the dissolution behavior of two cocrystals derived from nitazoxanide (NTZ), viz., nitazoxanide-glutaric acid (NTZ-GLU, 1:1) and nitazoxanide-succinic acid (NTZ-SUC, 2:1), was explored. Powder dissolution experiments under non-sink conditions showed similar dissolution profiles for the cocrystals and pure NTZ. However, pre-dissolved cellulosic polymer in the phosphate dissolution medium (pH 7.5) modified the dissolution profile of NTZ when starting from the cocrystals, achieving transient drug supersaturation. Subsequent dissolution studies under sink conditions of polymer-based pharmaceutical powder formulations with NTZ-SUC cocrystals gave a significant improvement of the apparent solubility of NTZ when compared with analogous formulations of pure NTZ and the physical mixture of NTZ and SUC. Scanning electron microscopy and powder X-ray diffraction analysis of samples recovered after the powder dissolution studies showed that the cocrystals undergo fast dissolution, drug supersaturation and precipitation both in the absence and presence of polymer, suggesting that the solubilization enhancement is due to polymer-induced delay of nucleation and crystal growth of the less soluble NTZ form. The study demonstrates that the incorporation of an appropriate excipient in adequate concentration can be a key factor for inducing and maintaining the solubilization of poorly soluble drugs starting from co-crystallized solid forms. In such a way, cocrystals can be suitable for the development of solid dosage forms with improved bioavailability and efficacy in the treatment of important parasitic and viral diseases, among others.

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Baclofen (BAC) is an important chiral active pharmaceutical ingredient for the treatment of specific neurological disorders that is commercially available only as RS-BAC (racemate). Using the liquid-assisted grinding technique, combination of RS-BAC with DL-MA in 1:1 stoichiometric ratio yielded a crystalline solid phase mixture of the enantiomeric salts R-BAC:L-MA and S-BAC:D-MA. Single-crystals suitable for SCXRD analysis of R-BAC:L-MA were obtained by fractional crystallization from a solution of RS-BAC and L-MA in a solvent mixture of ethyl acetate and water. Analysis of the supramolecular interaction patterns revealed that the crystal structure is stabilized by strong N+–H···–O, N+–H···O and O–H···–O hydrogen-bonding interactions. A comparative study with structurally related compounds enabled to identify common homo- and heterosynthons involving RNH3 +, OH, and COOH/COO– groups. The spectroscopic, structural and thermogravimetric studies of the enantiomeric solid phase mixture of R-BAC:L-MA and S-BAC:D-MA was accomplished by examination of some basic pharmaceutically relevant physicochemical properties. Phase stability studies in aqueous media simulating the gastrointestinal tract physiological conditions (pH 1.2 and 4.5) showed that R-BAC:L-MA/S-BAC:D-MA transforms into BAC within a few minutes. However, upon exposure to standard thermal/humidity stress conditions, the phases were stable. The decomposition changes the kinetics of the dissolution process under sink conditions, but the calculated intrinsic dissolution rates of RS-BAC and R-BAC:L-MA/S-BAC:L-MA resulted to be quite similar.