Polymorphic Control in Pharmaceutical Gel-Mediated Crystallization: Exploiting Solvent–Gelator Synergy in FmocFF Organogels

TL;DR

This study shows how using FmocFF organogels with specific solvents can control the crystal forms of nilutamide, a drug, and discover new polymorphs under mild conditions.

Contribution

The first ambient-temperature isolation of nilutamide Form II and discovery of a new SHG-active polymorph using FmocFF organogels.

Findings

Nilutamide Form II was isolated at ambient temperature using acetonitrile-based FmocFF organogel.

A new nilutamide polymorph with second-harmonic generation (SHG) activity was discovered.

A nilutamide–chloroform solvate was characterized using PXRD, DSC, FTIR, SXRD, and SHG microscopy.

Abstract

FmocFF is a highly versatile gelator whose π–π-stacking fluorenyl group and hydrogen-bonded peptide backbone permit gelation in a wide spectrum of solvents, providing a rich scaffold for crystal engineering. This study explores the synergistic effects of FmocFF organogels and solvent selection on controlling the polymorphic outcomes of nilutamide, a nonsteroidal antiandrogen drug with complex polymorphism. By systematically varying process parameters such as solvent type and concentration, we demonstrate remarkable control over crystal nucleation and growth pathways. Most significantly, we report the first ambient-temperature isolation of pure nilutamide Form II through acetonitrile-based FmocFF organogel, highlighting the unique interplay between solvent properties and gel fiber networks. Thermal analysis reveals that the organogel not only selectively templates Form II but also affects its thermal pathway. We also present compelling evidence for a new polymorph exhibiting second-harmonic generation (SHG) activity. This would represent the first non-centrosymmetric nilutamide form discovered, suggesting the gel matrix induces symmetry breaking during crystallization. We also characterize a previously unreported nilutamide–chloroform solvate through multiple analytical techniques including PXRD, DSC, FTIR, SXRD, and SHG microscopy. Our findings demonstrate that solvent-specific molecular recognition within gel matrices enables access to entirely new regions of polymorphic space, establishing gel-mediated crystallization as a broadly applicable platform technology for pharmaceutical solid form discovery under mild conditions.

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