Tsarfati Yael, Biran Idan, Wiedenbeck Eduard, Houben Lothar, Cölfen Helmut, Rybtchinski Boris
Department of Molecular Chemistry and Materials Science and Department of Chemical Research Support, Weizmann Institute of Science, Rehovot 76100, Israel.
Physical Chemistry, Department of Chemistry, University of Konstanz, Universitätsstraße 10, 78457 Konstanz, Germany.
ACS Cent Sci. 2021 May 26;7(5):900-908. doi: 10.1021/acscentsci.1c00254. Epub 2021 Apr 23.
The crystallization mechanisms of organic molecules in solution are not well-understood. The mechanistic scenarios where crystalline order evolves directly from the molecularly dissolved state ("classical") and from initially formed amorphous intermediates ("nonclassical") are suggested and debated. Here, we studied crystallization mechanisms of two widely used analgesics, ibuprofen (IbuH) and etoricoxib (ETO), using direct cryogenic transmission electron microscopy (cryo-TEM) imaging. In the IbuH case, parallel crystallization pathways involved diverse phases of high and low density, in which the instantaneous formation of final crystalline order was observed. ETO crystallization started from well-defined round-shaped amorphous intermediates that gradually evolved into crystals. This mechanistic diversity is rationalized by introducing a continuum crystallization paradigm: order evolution depends on ordering in the initially formed intermediates and efficiency of molecular rearrangements within them, and there is a continuum of states related to the initial order and rearrangement rates. This model provides a unified view of crystallization mechanisms, encompassing classical and nonclassical pictures.
溶液中有机分子的结晶机制尚未得到充分理解。有人提出并讨论了晶体有序性直接从分子溶解状态（“经典”）以及从最初形成的无定形中间体（“非经典”）演化而来的机制情形。在此，我们使用直接低温透射电子显微镜（cryo-TEM）成像研究了两种广泛使用的镇痛药布洛芬（IbuH）和依托考昔（ETO）的结晶机制。在IbuH的情况中，平行的结晶途径涉及高密度和低密度的不同相，其中观察到了最终晶体有序性的瞬时形成。ETO结晶从明确的圆形无定形中间体开始，这些中间体逐渐演变成晶体。通过引入连续结晶范式，这种机制多样性得到了合理的解释：有序性演化取决于最初形成的中间体中的有序化以及其中分子重排的效率，并且存在与初始有序度和重排速率相关的连续状态。该模型提供了一个统一的结晶机制视图，涵盖了经典和非经典的情况。
