Chen Dong, Robeyns Koen, Leyssens Tom, Saikia Basanta, Van Cleuvenbergen Stijn
Department of Chemistry, Molecular Imaging and Photonics, KU Leuven, Campus KULAK Kortrijk, 8500 Kortrijk, Belgium.
Institute of Condensed Matter and Nanosciences, Université Catholique de Louvain, 1348 Louvain-La-Neuve, Belgium.
Gels. 2025 Jul 1;11(7):509. doi: 10.3390/gels11070509.
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.
芴甲氧羰基苯丙氨酰苯丙氨酸（FmocFF）是一种用途极为广泛的凝胶剂，其芴基通过π-π堆积作用以及肽主链通过氢键作用，能够在多种溶剂中形成凝胶，为晶体工程提供了丰富的支架。本研究探讨了FmocFF有机凝胶与溶剂选择对控制尼鲁米特多晶型结果的协同效应，尼鲁米特是一种具有复杂多晶型现象的非甾体抗雄激素药物。通过系统地改变诸如溶剂类型和浓度等工艺参数，我们展示了对晶体成核和生长途径的显著控制。最为重要的是，我们报告了通过基于乙腈的FmocFF有机凝胶首次在室温下分离出纯的尼鲁米特II型，突出了溶剂性质与凝胶纤维网络之间独特的相互作用。热分析表明，有机凝胶不仅选择性地模板化II型，还影响其热行为。我们还提供了令人信服的证据，证明存在一种具有二次谐波产生（SHG）活性的新多晶型。这将代表首次发现的非中心对称的尼鲁米特晶型，表明凝胶基质在结晶过程中诱导了对称性破缺。我们还通过包括粉末X射线衍射（PXRD）、差示扫描量热法（DSC）、傅里叶变换红外光谱（FTIR）、单晶X射线衍射（SXRD）和SHG显微镜等多种分析技术，对一种先前未报道的尼鲁米特 - 氯仿溶剂化物进行了表征。我们的研究结果表明，凝胶基质内特定溶剂的分子识别能够进入多晶型空间的全新区域，确立了凝胶介导的结晶作为一种在温和条件下用于药物固体形式发现的广泛适用的平台技术。
