Guevara-Martínez Santiago José, Herrera-Bucio Rafael, Pérez-Cisneros Marco Antonio, Velázquez-Juárez Gilberto, Morales-Palacios Fredy Geovannini, García-Zavala Stephanie
Department of Pharmacology, School of Exact Sciences and Engineering, University of Guadalajara, Boulevard Gral. Marcelino García Barragán 1421, Olímpica, Guadalajara 44430, Jalisco, Mexico.
Instituto de Investigaciones Químico-Biológicas, Universidad Michoacana de San Nicolás de Hidalgo, Francisco J. Múgica, s/n, Morelia 58030, Michoacán, Mexico.
Molecules. 2025 Sep 8;30(17):3652. doi: 10.3390/molecules30173652.
Polymorphism critically influences the solid-state properties of organic molecules, affecting stability, solubility, and functionality. We investigated the polymorphic behavior of enantiomerically pure (+)-(6aS,11aS)-medicarpin through combined experimental and computational analyses. Single-crystal X-ray diffraction revealed two distinct chiral polymorphs: the previously reported monoclinic P2 form and a newly identified orthorhombic P222 form with a fully chiral packing arrangement. The discovery of this previously unreported polymorph underscores the subtle yet decisive effects of solvent and conformational flexibility in directing crystallization. Detailed structural analysis reveals that, whereas the P2 form is only stabilized by a single dominant electrostatic interaction, the P222 form features a more complex network comprising C-H···π contacts, bifurcated C-H···O hydrogen bonds, and aromatic edge-to-face interactions. Further investigation of a functionalized -nitrobenzoate derivative corroborates the critical influence of molecular substituents and crystallization conditions on packing motifs. Lattice energy DFT calculations confirm that each polymorph is stabilized by distinct electrostatic and dispersive interaction patterns, illustrating the complex energetic landscape of polymorph selection. Altogether, this work provides a framework for understanding and anticipating which polymorph is likely to form under specific solvent and crystallization conditions, offering insights for future strategies in materials design and guiding the pursuit of patentable crystalline forms in pharmaceutical applications.
多晶型对有机分子的固态性质有至关重要的影响，会影响稳定性、溶解性和功能性。我们通过结合实验和计算分析，研究了对映体纯的(+)-(6aS,11aS)-紫穗槐二氢黄酮的多晶型行为。单晶X射线衍射揭示了两种不同的手性多晶型：先前报道的单斜P2型和新发现的具有完全手性堆积排列的正交P222型。这种先前未报道的多晶型的发现强调了溶剂和构象灵活性在指导结晶过程中的微妙而决定性的影响。详细的结构分析表明，虽然P2型仅通过单一的主要静电相互作用稳定，但P222型具有更复杂的网络，包括C-H···π接触、分叉的C-H···O氢键和芳香边对面相互作用。对功能化的硝基苯甲酸酯衍生物的进一步研究证实了分子取代基和结晶条件对堆积模式的关键影响。晶格能密度泛函理论计算证实，每种多晶型都通过不同的静电和色散相互作用模式稳定，说明了多晶型选择的复杂能量格局。总之，这项工作提供了一个框架，用于理解和预测在特定溶剂和结晶条件下可能形成哪种多晶型，为材料设计的未来策略提供见解，并指导在药物应用中追求可专利的晶体形式。
