Chiral Resolution of RS-Praziquantel via Diastereomeric Co-Crystal Pair Formation with l-Malic Acid

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·0.5H2O, 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.