Liquid Metastable Precursors of Ibuprofen as Aqueous Nucleation Intermediates
Liquid Metastable Precursors of Ibuprofen as Aqueous Nucleation Intermediates
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DOI：
10.1002/anie.201910986
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发表时间：
2019-11-06
影响因子：
16.6
通讯作者：
Coelfen, Helmut
中科院分区：
文献类型：
--
作者：
Wiedenbeck, Eduard;Kovermann, Michael;Coelfen, Helmut
有机小分子晶体的成核机制，基于计算机模拟假设，仍然缺乏实验证据。在这项研究中，我们设计了一个实验方法来监测布洛芬结晶的早期阶段作为一个模型系统的小有机分子。布洛芬在成核之前经历液-液相分离。分析并确定了相应的液-液互溶间隙的双结点和旋结点极限。粘度的增加维持了稠密液体中间体的动力学稳定性。由于在致密液相内布洛芬分子之间的距离与晶体形式中的那些相似，因此该致密液相被鉴定为布洛芬成核中的前体相，其中致密化之后是结构有序的生成。这一发现可能使其能够丰富的难溶性药物超出经典的溶解度限制，在水性环境中。
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.