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Concerning Elusive Crystal Forms: The Case of Paracetamol
Journal of the American Chemical Society ( IF 14.4 ) Pub Date : 2020-03-27 , DOI: 10.1021/jacs.0c00321
Yumin Liu 1, 2 , Benjamin Gabriele 2 , Roger J. Davey 2 , Aurora J. Cruz-Cabeza 2
Affiliation  

Increasing commercial application of state of the art crystal structure prediction to aid solid form discovery of new molecular entities allows the experimentalist to target the polymorphs with desired properties. Here we remind ourselves that in this field the gap between such prediction and experimentation can be vast, the latter depending strongly on kinetic processes not accounted for in the computations. Nowhere is this gap more evident than in examples of so-called "elusive" polymorphs, forms that have been found difficult to crystallize, sometimes taking years to appear or sometimes disappearing altogether. In attempting to probe the origins of such phenomena this work targets a well-known, relatively simple molecule, paracetamol (PCM), and explores the structural and kinetic origins of its elusive nature. It is noted that in general comparisons of the kinetic factors (nucleation and crystal growth) between polymorphs have rarely been reported and of course in cases where one or more forms is "elusive" this will, by definition, be essentially impossible. PCM however offers a unique opportunity and we show how the recent discovery of the impact of metacetamol (MCM) in stabilizing PCM form II can be used to advantage, enabling otherwise impossible comparative kinetic experiments to be made. Resulting from this study we now appreciate that MCM has a selective impact in blocking the growth of the thickness and width of PCM form I while it has no impact on form II. This is interpreted in terms of strong adsorption of MCM on the {011} faces (width and thickness) of form I in orientations that inhibit crystal growth ("wrong" orientations). Of more significance here is the use of the additive in allowing an otherwise impossible comparison of linear growth rates of forms I and II. This leads to the appreciation that only through calculation of growth volumes can we finally appreciate how the relative growth kinetics lead inevitably to the elusive nature of Form II.

中文翻译:

关于难以捉摸的晶体形式:扑热息痛案例

增加最先进的晶体结构预测的商业应用,以帮助发现新分子实体的固体形式,使实验人员能够瞄准具有所需特性的多晶型物。在这里我们提醒自己,在这个领域,这种预测和实验之间的差距可能很大,后者强烈依赖于计算中未考虑的动力学过程。这种差距在所谓的“难以捉摸”的多晶型物的例子中最为明显,这些多晶型物被发现难以结晶,有时需要数年才能出现,有时甚至完全消失。在试图探索这种现象的起源时,这项工作的目标是一个众所周知的、相对简单的分子扑热息痛 (PCM),并探索其难以捉摸的性质的结构和动力学起源。值得注意的是,通常很少报道多晶型之间的动力学因素(成核和晶体生长)的比较,当然,在一种或多种形式“难以捉摸”的情况下,根据定义,这基本上是不可能的。然而,PCM 提供了一个独特的机会,我们展示了最近发现的对乙酰氨基酚 (MCM) 在稳定 PCM 形式 II 方面的影响的发现如何被利用,从而能够进行否则不可能的比较动力学实验。由于这项研究,我们现在认识到 MCM 在阻止 PCM 形式 I 的厚度和宽度的增长方面具有选择性影响,而它对形式 II 没有影响。这被解释为 MCM 在 I 型 {011} 面(宽度和厚度)上的强吸附,其取向抑制晶体生长(“错误的” 方向)。这里更重要的是使用添加剂来允许对 I 型和 II 型的线性增长率进行否则不可能的比较。这导致人们认识到,只有通过计算增长量,我们才能最终了解相对增长动力学如何不可避免地导致形式 II 难以捉摸的性质。
更新日期:2020-03-27
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