Cocrystallization has been promoted as an attractive early development tool as it can change the physicochemical properties of a target compound and possibly enable the purification of single enantiomers from racemic compounds. In general, the identification of adequate cocrystallization candidates (or coformers) is troublesome and hampers the exploration of the solid-state landscape. For this reason, several computational tools have been introduced over the last two decades. In this study, cocrystals of Praziquantel (PZQ), an anthelmintic drug used to treat schistosomiasis, are predicted with network-based link prediction and experimentally explored. Single crystals of 12 experimental cocrystal indications were grown and subjected to a structural analysis with single-crystal X-ray diffraction. This case study illustrates the power of the link-prediction approach and its ability to suggest a diverse set of new coformer candidates for a target compound when starting from only a limited number of known cocrystals.

We tap into an unexplored area of preferential crystallization, being the first to develop simultaneous chiral resolution of two racemic compounds by preferential cocrystallization. We highlight how the two racemic compounds RS‐mandelic acid (MAN) and RS‐etiracetam (ETI) can be combined together as enantiospecific R‐MAN⋅R‐ETI and S‐MAN⋅S‐ETI cocrystals forming a stable conglomerate system and subsequently develop a cyclic preferential crystallization allowing to simultaneous resolve both compounds. The developed process leads to excellent enantiopurity both for etiracetam (ee>98 %) and mandelic acid (ee≈95 %) enantiomers.

Pharmaceutical cocrystals are highly interesting due to their effect on physicochemical properties and their role in separation technologies, particularly for chiral molecules. Detection of new cocrystals is a challenge, and robust screening methods are required. As numerous techniques exist that differ in their crystallization mechanisms, their efficiencies depend on the coformers investigated. The most important parameters characterizing the methods are the (a) screenable coformer fraction, (b) coformer success rate, (c) ability to give several cocrystals per successful coformer, (d) identification of new stable phases, and (e) experimental convenience. Based on these parameters, we compare and quantify the performance of three methods: liquid-assisted grinding, solvent evaporation, and saturation temperature measurements of mixtures. These methods were used to screen 30 molecules, predicted by a network-based link prediction algorithm (described in Cryst. Growth Des. 2021, 21(6), 3428−3437) as potential coformers for the target molecule praziquantel. The solvent evaporation method presented more drawbacks than advantages, liquid-assisted grinding emerged as the most successful and the quickest, while saturation temperature measurements provided equally good results in a slower route yielding additional solubility information relevant for future screenings, single-crystal growth, and cocrystal production processes. Seventeen cocrystals were found, with 14 showing stability and 12 structures resolved.