School of Chemical Engineering and Technology, Collaborative Innovation Center of Chemical Science and Chemical Engineering, Tianjin University, Tianjin 300072, P. R. China.
Department of Chemical Engineering and Analytical Science, University of Manchester, Manchester M13 9PL, United Kingdom.
J Am Chem Soc. 2020 Apr 8;142(14):6682-6689. doi: 10.1021/jacs.0c00321. Epub 2020 Mar 27.
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.
日益增多的最先进晶体结构预测在商业上的应用，有助于发现新的分子实体的固态形式，这使得实验人员能够针对具有所需性质的多晶型物。在这里，我们提醒自己，在这个领域，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到的动力学过程。在所谓的“难以捉摸”多晶型物的例子中，这种差距最为明显，这些形式很难结晶，有时需要数年时间才会出现，有时甚至完全消失。在试图探究这种现象的起源时，这项工作以一种众所周知的、相对简单的分子对乙酰氨基酚（PCM）为目标，探索了其难以捉摸的性质的结构和动力学起源。值得注意的是，一般来说，很少有报道比较多晶型物之间的动力学因素（成核和晶体生长），当然，在一种或多种形式是“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，我们展示了如何利用最近发现的邻乙酰氨基酚（MCM）对 PCM 形式 II 的稳定作用，这可以带来优势，使原本不可能进行的比较动力学实验得以进行。通过这项研究，我们现在意识到 MCM 对 PCM 形式 I 的厚度和宽度的生长具有选择性的阻碍作用，而对形式 II 则没有影响。这可以解释为 MCM 在形式 I 的{011}面上（宽度和厚度）具有强烈的吸附作用，这些取向会抑制晶体生长（“错误”取向）。更重要的是，在这里，添加剂的使用允许对形式 I 和 II 的线性生长速率进行原本不可能的比较。这使得我们认识到，只有通过计算生长体积，我们才能最终理解相对生长动力学如何不可避免地导致形式 II 的难以捉摸的性质。
