Heterogeneous interfaces in confined microdomains of glycyrrhizic acid for polymorphism selection: Mechanisms and applications

Understanding the mechanisms of heterogeneous nucleation to improve the precision and applicability of polymorphism selection remains challenging. In this study, the formation of confined microdomains with heterogeneous interfaces in the micelle and gel systems were reported based on the supramolecular self-assembly of glycyrrhizic acid. The polymorph with high-purity preparation of isonicotinamide and nicotinamide was achieved due to the high degree of supersaturation and diverse nucleation pathways. In situ spectroscopy and molecular simulations provided insights into the mechanism of polymorphism selection in molecular migration and cluster aggregation, revealing the influence of a heterogeneous templated effect and protonation effect during nucleation and growth. The selective induction of dominant polymorph with chain structure (Form II of isonicotinamide and Form ε of nicotinamide) validated the efficacy and applicability of this approach. Furthermore, the effective loading (up to 4-fold), enhanced stability (up to 2 months), and pH-responsive release of the dominant polymorphs exhibited the potential of glycyrrhizic acid systems for drug delivery. This study provides a promising approach for the selective induction and efficient delivery of dominant polymorphs, which contributes to a deeper understanding of heterogeneous nucleation.