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.
The ability to separate chiral molecules using a very inexpensive and easy-to-operate instrument, with predictive software, will enable a benchtop, turnkey solution for all researchers, companies and academic institutions to expand their activities in chiral chemistry. Because most new pharmaceutical compounds are chiral molecules, the ability for more chemists to discern between and work with right or left-handed chirally pure molecules will increase the rate and lower the cost of drug discovery and development, including all scales from analytical up to pilot manufacturing. In short, this tool will significantly impact all industries working with chiral molecules, including pharmaceuticals, biotech, agricultural, neutraceuticals, and others.
|Clemens, Jonathon B; Kibar, Osman; Chachisvilis, Mirianas (2015) A molecular propeller effect for chiral separation and analysis. Nat Commun 6:7868|