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

了解小有机分子如何聚集在一起形成结晶固体是一项基本的科学挑战。不仅同一个分子可以以不止一种方式包装（多态性），而且其他分子，通常是水，可以参与结构，显着增加固体形式的多样性。对于制药工业来说，了解他们生产的药物分子的固态行为尤为重要，因为不同的固体形式通常具有不同的溶解速率，因此具有不同的药物特性。药品监管机构要求所用剂型的物理性质得到充分表征，未表征的剂型可能会在专利保护方面存在漏洞。溶剂化物（即固体形式，包括水或其他溶剂分子）在不适合无水形式（例如，容易随时间改变形式）时广泛使用。然而，水合物的物理性质差别很大：有些非常稳定，有些则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基本的科学挑战。这项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，从而消除一些谜团。其他技术，如x射线衍射，能够识别相对不动的溶剂分子，但在溶剂分子运动的（有趣的）情况下挣扎。相反，核磁共振实验通常对运动的影响非常敏感。我们将专注于应用氢核磁共振（1H和2H）的新技术，这在固体中通常是困难的。然而，在这种情况下，我们对氢在结构（氢键）和运动中的氢的作用感兴趣，我们相信识别溶剂信号是可行的。这将辅以计算工作来计算我们在实验中测量的量。这将使我们能够更好地将我们的测量与结构特征联系起来，例如氢键的长度。我们将研究一些系统，这些系统是与学术界和制药行业的合作伙伴合作选择的，它们表现出不同的行为。充分表征溶剂的结构作用和流动性（以及相关特征，如氢键），使用固态核磁共振和互补技术（如x射线衍射），将对理解溶剂化物形式的行为做出重大贡献。除了回答基本的科学问题外，这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，而不是浪费时间和金钱在后来被证明是不良行为的形式上。

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.