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

药物化合物的非经典成核和结晶以及液体前体

基本信息

批准号：
383718951
负责人：
Professor Dr. Helmut Cölfen (†)
金额：
--
依托单位：
Arbeitsgruppe Physikalische Chemie (AG Cölfen)
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2017
资助国家：
德国
起止时间：
2016-12-31 至 2019-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/383718951?language=en
关键词：
Non classical Nucleation Crystallization Liquid

项目摘要

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.

本项目旨在研究三种常用止痛药双氯芬酸、伊诺明和氟比洛芬非经典结晶途径的条件。这些药物的共同点是它们是BCS 2类药物（水溶性差但渗透性高），并且它们是羧酸。实验方法的基础是滴定装置，其中药物的水溶性盐用酸滴定以使其不溶，因此过饱和度增加直到成核和生长发生，而可溶性和不溶性物质的浓度在每次都是已知的。通过在不同的相关阶段（成核前阶段、成核阶段和生长阶段）取样，我们将能够通过多种技术（AUC、ESI-MS、ITC、Cryo-（HR）TEM、SEM、AFM、光/偏振显微镜、XRD）检测结晶过程中涉及的所有物质。通过改变相关实验条件（浓度、温度、pH、非溶剂等），我们试图确定涉及预成核簇和液体前体的非经典结晶途径的条件。应研究这些前体物质对多晶型控制的作用以及使用液体前体的更好的药物生物利用度。还应确定相图。总的来说，通过这项研究，我们希望更好地了解迄今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践方面，如多晶型控制和药物递送，其生物利用度远远高于迄今为止的可能性。