# Nonmimetic Gels Direct Novel Crystallization Behavior of Lenalidomide

## TL;DR

This study shows that nonmimetic gels can lead to new crystallization outcomes for lenalidomide, including a novel hemisolvate and selective formation of a metastable crystal form.

## Contribution

The discovery of a novel cyclopentanone hemisolvate and selective crystallization of metastable Form 4 using nonmimetic gels.

## Key findings

- A novel cyclopentanone hemisolvate of lenalidomide was formed in a nonmimetic gel, not achievable via solution-phase crystallization.
- An ethanol gel promoted selective crystallization of metastable Form 4, unlike the thermodynamically favored Form 1 from solution.
- No strong interactions between lenalidomide and gelators were observed, suggesting spatial arrangement or confinement effects drive crystallization.

## 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.