Physical Chemistry, University of Konstanz, Universitätsstraße 10, 78457, Konstanz, Germany.
Leibniz University of Hannover, Institute of Inorganic Chemistry, Callinstraße 9, 30167, Hannover, Germany.
Angew Chem Int Ed Engl. 2019 Dec 19;58(52):19103-19109. doi: 10.1002/anie.201910986. Epub 2019 Nov 6.
The nucleation mechanism of crystals of small organic molecules, postulated based on computer simulations, still lacks experimental evidence. In this study we designed an experimental approach to monitor the early stages of the crystallization of ibuprofen as a model system for small organic molecules. Ibuprofen undergoes liquid-liquid phase separation prior to nucleation. The binodal and spinodal limits of the corresponding liquid-liquid miscibility gap were analyzed and confirmed. An increase in viscosity sustains the kinetic stability of the dense liquid intermediate. Since the distances between ibuprofen molecules within the dense liquid phase are similar to those in the crystal forms, this dense liquid phase is identified as a precursor phase in the nucleation of ibuprofen, in which densification is followed by generation of structural order. This discovery may make it possible to enrich poorly soluble pharmaceuticals beyond classical solubility limitations in aqueous environments.
基于计算机模拟提出的小分子晶体成核机制仍缺乏实验证据。在本研究中，我们设计了一种实验方法来监测布洛芬结晶的早期阶段，将其作为小分子的模型体系。布洛芬在成核前经历液-液相分离。分析并确认了相应的液-液相混合不溶区间的双节点和旋节线限制。粘度的增加维持了稠密液相中间物的动力学稳定性。由于稠密液相中布洛芬分子之间的距离与晶体形式中的相似，因此将这种稠密液相鉴定为布洛芬成核的前体相，其中致密化之后产生结构有序。这一发现可能使在水溶液环境中超越经典溶解度限制来富集难溶性药物成为可能。
