Non-classical Nucleation and Crystallization and Liquid Precursors of Pharmaceutical Compounds

本项目旨在研究三种常见止痛药双氯芬酸、布洛芬和氟比洛芬的非经典结晶途径的条件。这些药物的共同点是它们都是BCS 2类药物(水溶性差，但渗透性强)，都是羧酸。这种实验方法的基础是一个滴定装置，其中药物的水溶盐用酸滴定，使其不溶，从而增加过饱和度，直到成核和生长，同时每次都知道可溶和不溶物种的浓度。通过在不同的相关阶段(成核前、成核和生长阶段)采集样品，我们将能够通过多种技术(AUC、ESI-MS、ITC、低温(HR)透射电子显微镜、扫描电子显微镜、原子力显微镜、光/偏振显微镜、X射线衍射仪)检测结晶过程中涉及的所有物种。通过改变相关的实验条件(浓度、温度、pH、非溶剂等)。我们试图确定包括预成核团簇和液体前体在内的非经典结晶路径的条件。应调查这些前体物种在多晶型控制以及使用液体前体的更好的药物生物利用度方面的作用。还应确定相图。总体而言，通过这项研究，我们希望更好地了解到到目前为止几乎没有探索过的有机分子的非经典结晶途径，它们的机制以及相关的重要实用方面，如晶型控制和药物释放，其生物利用度比目前可能的要高得多。

This project aims to investigate conditions for non-classical crystallization pathways for three common painkiller drugs Diclofenac, Ibuprofen and Flurbiprofen. These drugs have in common that they are BCS class 2 drugs (poorly water soluble but highly permeable) and they are carboxylic acids. The basis of the experimental approach is a titration set-up where the water soluble salt of the drugs is titrated with acid to make it insoluble and thus supersaturation is increased until nucleation and growth occurs, while the concentration of soluble and insoluble species is known at each time. By taking samples at the different relevant stages (prenucleation-, nucleation- and growth phase), we will be able to detect all species involved in the crystallization process by a number of techniques (AUC, ESI-MS, ITC, Cryo-(HR)TEM, SEM, AFM, light/polarization microscopy, XRD). By varying relevant experimental conditions (concentration, temperature, pH, non-solvents etc.) we try to identify conditions for non-classical crystallization pathways involving pre-nucleation clusters and liquid precursors. The role of these precursor species for polymorph control as well as a better drug bioavailability using liquid precursors shall be investigated. The phase diagrams shall also be determined. Overall, with this study we want to achieve a better understanding of the so-far barely explored non-classical crystallization pathways of organic molecules, their mechanisms as well as related important practical aspects like polymorph control and drug delivery with a far higher bioavailability than possible so far.