Hydrates in Solution - Interactions of drug compounds with water in pre-nucleation clusters

一个新的药物实体进入市场的瓶颈之一是它的配方是安全有效的药物。这一成本和时间密集的过程还因为存在多种晶型而变得复杂，这将改变材料的稳定性、加工性和溶解性。为了帮助加快药物上市的进程，该项目旨在通过研究药物在结晶过程中与水的相互作用来提高这一过程的效率，并将其与所产生的含水晶体形式(水合物)的物理稳定性联系起来。这一知识将有助于预测这些药物材料的发生和稳定性，由于它们的低水溶解度和生物利用度，这些药物材料提供给药理靶标的难度特别大。这个项目将：1.调查药物化合物和溶液中水分子之间的分子相互作用，2.确定这些相互作用的化学计量和强度，3.将这些相互作用的强度与它们各自水化结晶形式的物理稳定性联系起来，4.提出将溶液中的溶质-水相互作用与生成的水合物形式的发生和稳定性联系起来的规则。本提案是一个总体项目的一部分，旨在了解结晶前溶液结构和溶质聚集对结果结晶形式的影响，以便预测和控制结晶实验。该项目的结果将加深我们对结晶作用的基本理解。这种知识可以立即应用到配方和制造的日常业务中，例如在制药和精细化工行业。因此，它将通过缩短开发时间和加快新药上市的进程而使更广泛的公众受益。

One of the bottlenecks of a new pharmaceutical drug entity reaching the market is its formulation into a safe and effective medicine. This cost- and time-intensive process is furthermore complicated by the presence of multiple crystal forms, which will alter the stability, processability and solubility of the material. In order to help speed up the process of a drug getting onto market, this project aims to improve the efficiency of this by investigating the interaction of drug with water during crystallisation and relate this to the physical stability of the resulting water-containing crystal forms (hydrates). This knowledge will then help to predict the occurrence and stability of these pharmaceutical materials, which present an especially challenging class to deliver to the pharmacological target due to their low water solubility and, thus, bioavailability. Hydrates are generally avoided during formulation wherever possible.The project will:1. Investigate the molecular interactions between drug compounds and water molecules in solution,2. Determine the stoichiometry and strength of these interactions,3. Connect the strength of these interactions with the physical stability of their respective hydrated crystal form,4. Propose rules to connect solute-water interactions in solution with occurrence and stability of resulting hydrate forms.This proposal is part of an overarching project aiming to understand the influence of solution structure and solute aggregation before crystallisation on the resulting crystal form in order to predict and control crystallisation experiments.The results of this project will further our fundamental understanding of crystallisation. This knowledge can be immediately implemented into the day-to-day business of formulation and manufacturing, e.g. in the pharmaceutical and fine-chemical industries. It will thus benefit the broader public by shortening development times and accelerating the process of new medications reaching the market.