Stereochemical Purification of an Anti-Inflammatory Drug in an Enzyme Membrane Reactor

酶拆分是一种分离立体异构体的有效方法。脂肪酶和羧酸酯酶已被广泛研究用于这一目的。许多脂肪酶底物是具有手性中心的复杂分子，在水中很难溶解。因此，生物转化必须在多相乳液型酶反应器中进行，存在三个相--有机酶、水相和固定化酶。基于中空纤维组件的多相和萃取膜反应器，通过促进有效的传质和简化相和产物的分离，提供了比传统反应器更多的工程优势。这一二期方案旨在优化膜生物反应器的性能(生产率和酶的稳定性)，在大规模模块中展示酶促拆分，并对集成的重要止痛药(S)-布洛芬进行技术和经济评估。正在开发的新药在结构上越来越复杂，在许多情况下需要更复杂的纯化方案。人体在识别药物的三维结构(即链异构体)方面具有高度的特异性，因此，药物需要具有较高的立体化学纯度才能起作用。人们对使用酶来分离混合的立体异构体进行了广泛的研究。然而，这项技术的商业化必须克服某些工程障碍，才能在经济上可行。基于膜的新型酶反应器的使用已被证明成功地解决了第一阶段研究中的许多问题。这一第二阶段的提案旨在优化膜生物反应器的性能，在大规模系统中展示酶促拆分，并对生产(S)-布洛芬的集成酶促拆分过程进行技术和经济评估。

Enzymatic resolution is a potentially powerful approach for the separation of the stereoisomers. Lipases and carboxyesterases have been extensively studied for this purpose. Many lipase substrates, complex molecules with chiral centers, are poorly soluble in water. Thus bioconversions must be performed in multiphase, emulsion-type enzyme reactors with three phases present--organic, aqueous, and immobilized enzyme. Multiphase and extractive membrane reactors, based on hollow- fiber modules, offer several engineering advantages over conventional reactors by promoting efficient mass transfer and simplifying phase and product separation. This Phase II proposal seeks to optimize membrane bioreactor performance (productivity and enzyme stability), demonstrate enzymatic resolution in a large-scale module, and conduct both a technical and economic evaluation of an integrated important analgesic, (S)-Ibuprofen. New drugs under development are increasingly more complex in structure and require, in many cases, more elaborate purification schemes. The body is highly specific in regard to the recognition of the three-dimensional structure (i.e., streoisomers) of a pharmaceutical and, therefore, the drug needs to be of high stereochemical purity for it to be active. Extensive research has been conducted on the use of enzymes for the separation of mixtures of steroisomers. However, the commercialization of this technology must overcome certain engineering roadblocks to be economically feasible. The use of a novel enzyme reactor, based on membranes, has been shown to successfully address many of these problems in Phase I studies. This Phase II proposal seeks to optimize membrane bioreactor performance, demonstrate enzymatic resolution in a large-scale system, and conduct both a technical and economic evaluation of an integrated, enzymatic-resolution process for the production of (S)-Ibuprofen.