Work

Nonmimetic Gels Direct Novel Crystallization Behavior of Lenalidomide

Year: 2025

Type: article

Abstract: Crystallization within supramolecular gels can yield distinct solid-state outcomes compared with conventional solution-phase methods, including the formation of novel crystal forms or selectively crystallizing one crystal form from a concomitant mixture. In several cases, tailoring the molecular structure of a gelator to mimic a pharmaceutical substrate has facilitated crystallization control, where nonmimetic gelators had no influence on the crystallization outcome compared to the solution phase. In this study, we investigate the crystallization behavior of lenalidomide within both mimetic and nonmimetic gels. Crystallization in a cyclopentanone gel using a nonmimetic gelator led to the discovery of a novel cyclopentanone hemisolvate, inaccessible via solution-phase crystallization. Additionally, an ethanol gel of the same gelator promoted selective crystallization of metastable Form 4 in ethanol, in contrast to the thermodynamically favored Form 1 obtained from solution. Gel-phase crystallization using a drug-mimetic gelator produced no deviation from the solution-phase polymorphic outcomes, in contrast to previously reported examples. Solution-state NMR studies showed no evidence of strong interactions between lenalidomide and either gelator, suggesting that the spatial arrangement of the nonmimetic gel fibers and/or possible confinement effects, rather than solution association, plays a critical role in directing crystallization behavior.

Source: Crystal Growth & Design

DOI: 10.1021/acs.cgd.5c01083