Elucidating structure and dynamics in solvates by NMR: applications to pharmaceutical solids

了解有机小分子如何堆积在一起形成结晶固体是一项根本性的科学挑战。不仅相同的分子通常以多种方式(多态)堆积，而且其他分子，通常是水，也可以参与结构，显著增加固体形式的多样性。对于制药行业来说，了解它们所产生的药物分子的固态行为尤其重要，因为不同的固体形式往往具有不同的溶解速度，因此具有不同的药物特性。药品监管机构要求，过去使用的剂型的物理性质必须完全特征化，而不具体化的剂型可能会在专利保护方面提供漏洞。当无水形式不合适(例如，随着时间的推移容易改变形式)时，广泛使用溶剂酸盐(即包括水或其他溶剂分子在内的固体形式)。然而，水合物的物理性质差异很大：一些非常稳定，另一些容易失去溶剂而变成无定形。试图预测一种给定材料的行为是一项根本性的科学挑战。这一提议旨在通过使用核磁共振(NMR)来识别和表征固体形式的溶剂分子，从而解开这一谜团。其他技术，如X射线衍射，能够识别相对静止的溶剂分子，但在(有趣的)溶剂分子运动的情况下难以识别。相比之下，核磁共振实验通常对运动的影响非常敏感。我们将集中精力应用新的氢核磁共振技术(1H和2H)，这在固体中通常是困难的。然而，在这种情况下，我们感兴趣的是氢在结构中的作用(氢键)和运动中的氢，我们相信识别溶剂信号将是可行的。这将得到计算工作的补充，以计算我们通过实验测量的量。这将使我们能够更好地将我们测量的内容与结构特征联系起来，例如氢键的长度。我们将研究与学术界和制药业合作伙伴共同选择的一些系统，这些系统表现出不同的行为。充分表征溶剂的结构作用和流动性(以及相关特征，如氢键)，结合使用固体核磁共振和补充技术(如X射线衍射)，将对了解溶剂型的行为作出重大贡献。除了回答基本的科学问题外，这还将对制药行业大有裨益，因为他们试图提前预测不同固体形式的适用性，而不是将时间和金钱浪费在后来被证明表现不佳的形式上。

Understanding how small organic molecules pack together to form crystalline solids is a fundamental scientific challenge. Not only can the same molecule often pack in more than one way ( polymorphism ), but other molecules, often water, can be involved in the structure, significantly increasing the variety of solid forms. It is particularly important for the pharmaceutical industry to understand the solid-state behaviour of the drug molecules they produce, since the different solid forms often have different dissolution rates and so different pharmaceutical characteristics. Drug regulatory agencies require that the physical properties of the form used to be fully characterised, and uncharacterised forms may provide loopholes in patent protection. Solvates (that is solid forms including water or other solvent molecules) are widely used when anhydrous forms are unsuitable (e.g. prone to change form over time). However, the physical properties of hydrates vary widely: some are very stable, others tend to lose solvent and become amorphous. Trying to predict how a given material will behave is a fundamental scientific challenge.This proposal aims to remove some of this mystery by using nuclear magnetic resonance (NMR) to identify and characterise solvent molecules in solid forms. Other techniques, such as X-ray diffraction are able to identify solvent molecules that are relatively immobile, but struggles with the (interesting) cases where the solvent molecules are in motion. In contrast, NMR experiments are usually very sensitive to the effects of motion. We will be concentrating on applying new techniques for hydrogen NMR (both 1H and 2H), which is generally difficult in solids. In this case, however, we are interested in looking at the role of hydrogens in the structure ( hydrogen bonding ) and hydrogens in motion, and we believe that identifying the solvent signals will be feasible. This will be complemented by computational work to calculate the quantities we measure experimentally. This will allow us to better relate what we measure to structural features e.g. the length of hydrogen bonds. We will be studying a number of systems, chosen in collaboration with partners in academia and the pharmaceutical industry, which show different behaviour. Fully characterising the structural role and mobility of the solvent (and related features, such as hydrogen bonding), using solid-state NMR together with complementary techniques (such as X-ray diffraction), will make a major contribution towards understanding the behaviour of solvate forms. As well as answering fundamental scientific questions, this will be of great benefit to the pharmaceutical industry as they try to predict the suitability of different solid forms in advance, rather wasting time and money on forms that later turn out to be badly behaved.