Selective Co-Crystallization and Co-Amorphous Formation of Flavanones from Licorice Leaves

Flavanones retrieved in the leaves of Glycyrrhiza glabra (licorice), specifically glabranin (GLA), pinocembrin (PIN) and licoflavanone (LIC), represent a valuable source of bioactive natural products, although their isolation and handling are often complicated by their structural similarity and unfavorable physical properties. In this work, crystal engineering strategies were explored both to facilitate the selective separation of licorice flavanones and to improve their solid-state characteristics. Co-crystallization was investigated as a tool for the selective recognition of PIN from a GLA-rich chromatographic fraction. Guided by structural considerations and predictive analyses performed using the Co-Crystal Design and Hydrogen Bond Propensity (HBP) tools in CCDC Mercury (within CCDC-Materials), co-crystallization experiments were performed with pyridinic co-formers. 4,4′-Bipyridine (BPY) selectively formed a new co-crystal with PIN, enabling the capture of traces of this flavanone directly from the GLA-rich fraction. In contrast, nicotinic acid (NIC) did not form a co-crystal with PIN, consistently with the predicted preference for NIC self-association. In addition, a co-amorphous system between LIC and BPY was obtained by quench cooling, yielding a fully amorphous solid with improved handling properties compared to the waxy precursor. These results highlight the potential of crystal engineering approaches for the selective separation and solid-state modification of natural flavanones.