Hydrodynamic Chirality: A novel method for chiral separation and analysis

描述(申请人提供)：在此SBIR Fast Track中，我们重点介绍了一种新颖的手性化学处理技术，该技术能够在一台仪器中实现基线分离、绝对立体化学鉴定和纯度分析，所有这些都在一台仪器中完成，只需几分钟。这项技术通过廉价的组件和预测软件在手性化学处理方面节省了大量的成本和时间。简而言之，当被放置在毛细管中并暴露在旋转电场(REF)中时，左手和右手手性分子随场旋转，并相对于它们的溶剂充当纳米级的推进器。由于它们用的是相反的手，它们沿着场的旋转轴朝相反的方向推进，从而能够进行隔离和分析，包括绝对的构型确定。目前的手性分析和分离技术，如高压液相色谱、X射线结晶学和振动圆二色谱等，往往费时、昂贵、保真度低，普遍阻碍了手性化学的广泛研究。这项拟议的新技术依赖于流体动力学手性和物理学原理，有望创造出一种易于使用、价格低廉数量级的台式手性分析和分离仪器。随着越来越多的研究人员、公司和大学能够负担得起手性分析和分离，手性药物的研究、发现和商业化的步伐必然会加快。由于单一对映异构体化合物普遍证明的好处，FDA要求大多数新药是对映异构体，这增加了对新的手性分离和分析技术的需求。在第一阶段，我们的具体目标是：1)设计和建造一个运行频率高达300 MHz和100V p-p的坚固可靠的REF分离室；2)定量演示99%的纯对映体分离和高保真的绝对构型测定；以及3)研究设计参数之间的权衡，包括电压和频率的依赖关系以及每天高达克的处理量。我们将利用旋转电场、微流体和手性检测来实现手性分析和分离。一旦技术在第一阶段得到验证，第二阶段的具体目标是1)设计和制造板级集成分离组件；2)设计分析规模的一次性分离室，产品成本低于10美元；3)开发和集成预测软件，高保真且易于非专家使用；4)展示至少100个手性分子在极性和非极性溶剂中的广泛适用性；以及5)展示毫克规模的基线分离。除了第一阶段的方法外，我们还将使用从头计算、分子力学和分子动力学模拟来确定推进方向和速度。

DESCRIPTION (provided by applicant): In this SBIR Fast Track we focus on a novel chiral chemistry process technology that enables baseline separation, identification of absolute stereochemistry and purity analysis, all in one instrument and within minutes. The technology offers significant cost and time savings in chiral chemistry processing through inexpensive components and predictive software. Briefly, when placed in a capillary and exposed to a Rotating Electric Field (REF), left and right-handed chiral molecules rotate with the field and act as nanoscale propellers with respect to their solvent. Due to their opposite handedness, they propel along the axis of field rotation in opposite directions, enabling both isolation and analysis, including absolute configuration determination. Current techniques for chiral analysis and isolation such as high pressure liquid chromatography, x-ray crystallography and vibrational circular dichromism are frequently time consuming, expensive, low fidelity and are generally hindrances to the widespread study of chiral chemistry. This proposed new technique, relying on hydrodynamic chirality and principles of physics, promises to enable the creation of an easy-to-use, order of magnitude less expensive, benchtop instrument for chiral analysis and isolation. With more researchers, companies and universities able to afford chiral analysis and isolation, the pace of chiral drug study, discovery and commercialization is bound to increase. The FDA, due to the generally proven benefits of single enanatiomer compounds, mandates that most new drugs be enantiospecific, increasing the need for new chiral separation and analysis techniques. In Phase I, the Specific Aims are to 1) Design and build a robust and reliable REF separation chamber operating at up to 300MHz and 100V p-p; 2) Demonstrate quantitatively, 99% pure enantiomeric separation and high fidelity absolute configuration determination of at least two chiral molecules in both polar and nonpolar solvents; and 3) Investigate design parameter tradeoffs including voltage and frequency dependence and throughput up to gram per day scale. We will use rotating electric fields, microfluidics and chiral detection to achieve chiral analysis and isolation. Once the technique is proven in Phase I, for Phase II the Specific Aims 1) Design & build a board- level-integrated separation assembly; 2) Design a disposable separation chamber with cost of goods less than $10 at analytical scale; 3) Develop and integrate predictive software with high fidelity and ease-of-use for non-experts; 4) Demonstrate broad applicability for at least 100 chiral molecules in polar and nonpolar solvents; and 5) Demonstrate baseline separation at milligram scale. In addition to Phase I methods, we will use ab initio, molecular mechanics and molecular dynamics simulations to determine propulsion direction and velocity.