Complementary Gel and Microemulsion Strategies for Pharmaceutical Solid Form Control

原料药的固体形式问题对英国制药业至关重要。不同的晶型具有不同的生物利用度和溶解度特征，并且晶体形状（针、板、块等）显著影响加工和压片性能。此外，所有多晶型的发现和专利是当前药物发现研究的必要部分。有许多引人注目的案例，其中未能确定药物的最稳定晶体形式导致了制造中的严重配方问题。这通常是因为稳定形式具有高的成核能垒，因此成核非常缓慢，并且仅在生产过程的后期出现，导致巨大的成本。药物固体形式是英国经济的一个主要问题，大量投资集中在计算晶体结构和通过各种结晶技术进行经验多晶型筛选。该项目将使用微乳液结晶和定制低分子量有机凝胶结晶的互补技术，以提供一种通用的固体形式发现方法以及影响晶体形状和表面特征的方法，这将大大提高制药行业中现有多晶型筛选技术的稳健性和范围。通过在微乳液中使用3D-纳米限制来最初限制晶核尺寸，新的微乳液方法允许系统地鉴定和制备最稳定的多晶型形式。在单独定制（即与特定原料药化学互补）的低分子量凝胶中结晶，将允许分离和鉴别动力学多晶型，并提供异核位点的优势，可催化开始结晶非常缓慢的形式生长。因此，在它们之间，这两种结晶策略提供了药物多晶型筛选和鉴定策略的系统方法的一步变化，因此固体形式的发现和选择。

The issue of the solid form of drug substances is of key importance to the UK pharmaceutical industry. Different crystal forms have different bioavailability and solubility characteristics, and the crystal shape (needle, plate, block etc.) significantly affects processing and tabletting behaviour. Moreover discovery and patenting of all polymorphic forms is a necessary part of current drug discovery research. There have been a number of high profile cases where failure to identify the most stable crystal form of a drug has led to severe formulation problems in manufacture. This is often because the stable form has a high nucleation energy barrier so is very slow to nucleate and only appears late in the production process, resulting in huge encumbant cost. Drug solid form is a major issue for the UK economy and tremendous investments focus on calculating crystal structure and on empirical polymorph screening by a wide variety of crystallisation techniques. This project will use the complementary techniques of crystallisation from microemulsions and crystallization within tailored low molecular weight organogels to provide a general solid form discovery method as well as a means of influencing crystal shape and surface characteristics that will greatly enhance both the robustness and scope of present polymorph screening techniques in the pharmaceutical industry. By use of the 3D-nanoconfinement in microemulsions to initially limit the crystal nucleus size, the novel microemulsion method allows systematic identification and preparation of the most thermodynamically stable polymorphic form. Crystallisation in individually tailored (i.e. chemically complementary to a particular drug substance), low molecular weight gels, will allow isolation and identification of kinetic polymorphic forms and offers the advantage of heteronucleation sites that can catalyse the growth of forms that are very slow to begin crystallising. Between them, therefore, the two crystallisation strategies offer a step change in the systematic approach to pharmaceutical polymorph screening and identification strategies and hence solid form discovery and selection.