A cocrystal screening of the chiral drug “proxyphylline” (PXL) and achiral coformers was performed using dry or solvent assisted grinding and evaporation methods, yielding 10 different original solid forms with a 1:1 stoichiometry. Among them, three anhydrous cocrystals and a monohydrated conglomerate forming system have been identified with salicylic acid (SA). The crystal structures of the monohydrate and one of the racemic anhydrous forms were determined by X-ray single crystal experiments. The dehydration mechanism of the hydrate has been investigated by thermal analysis, X-ray powder diffraction, and water sorption–desorption cycles. The importance of water molecules in the crystal structure and the concomitant loss of both water and SA (cocrystal former) during the dehydration suggest a destructive mechanism.

The monohydrated co-crystal composed of the chiral active pharmaceutical ingredient proxyphylline, salicylic acid, and water was successfully resolved by preferential crystallization from a water/ethanol mixture. To the best of our knowledge, this is the first report of preferential crystallization applied to such a system and the results reveal that unusually high enantiomeric excess values can be attained in the mother liquor. These robust and reproducible results underline the potential of preferential crystallization to resolve co-crystal systems.Commercially available (±)-PXL purchased from TCI Europe (chemical purity > 98 %) and SA (Acros Organics; > 99 %) were All authors contributed equally to this article. Scheme 1. The monohydrate conglomerate co-crystal is composed of PXL, SA, and water.

The preparative resolution by preferential crystallization (PC) of proxyphylline has been achieved despite the existence of a stable racemic compound. This is enabled through the careful selection of a solvent in which both the racemic compound and the metastable conglomerate possess a low nucleation rate. Induction time measurements in isobutyl alcohol show that a highly supersaturated solution ( = 2.3) remains clear for almost 1 hour at 20 mL scale, revealing a slow nucleation rate. After the determination of isothermal sections in the relevant phase diagram at 10 and 25 °C, both isothermal and polythermic modes of PC could be successfully implemented. Alongside the reported case of diprophylline, this study opens opportunities to broaden the application of PC towards slowly crystallizing racemic compound.

Small non-centrosymmetric domains are observed in the racemic crystal, due to the low nucleation activation energy of the conglomerate.