Chiral separation and analysis by molecular propeller effect

Solvexa, Llc, San Diego CA

Investigators

Abstract

? DESCRIPTION (provided by applicant): In this SBIR Phase I proposal we propose to test a novel chiral separation technology for rapid separation, purity analysis and identification of absolute stereochemistry. The technology will enable significant cost and time savings for chiral chemistry research and industry - (1) by eliminating the need for expensive chiral stationary phases, (2) by significantly shortening separation method development and (3) through the use of predictive software for performance prediction and stereochemistry determination. Current techniques for chiral resolution and analysis such as high-performance liquid chromatography, x-ray crystallography and vibrational circular dichroism are time consuming, expensive or low fidelity. Recently we have experimentally validated the existence of a molecular propeller effect using rotating electric fields and demonstrated both chiral separation and absolute configuration determination. In this project we propose to investigate alternative means of imposing rotation on the molecules using shear flows which offers multiple advantages such as no requirements for high dipole moment of the molecule, low polarity of the solvent and strong electric fields. Briefly, when exposed to shear flow the left and right-handed chiral molecules rotate and act as molecular propellers, propelling along the direction perpendicular to shear plane but into opposite directions due to their opposite handedness. The propeller effect, as a hydrodynamic phenomenon does not rely on specific interactions with a chemical matrix, therefore the direction and velocity of translational motion for any new chiral molecule can be reliably determined using theoretical modeling, thus providing a priori information about expected performance, as well as enabling the assignment of absolute configuration. The proposed method, relying on the molecular propeller effect will enable the development of an inexpensive and easy-to-use benchtop instrument for chiral separation and analysis. The FDA, due to the generally proven advantages of single enantiomer compounds, mandates that for most new drugs each enantiomer needs to be evaluated separately thereby increasing the need for new chiral separation and analysis techniques. The rate of drug discovery and commercialization will be positively impacted if more researchers, both in academia and industry are able to afford chiral separation and analysis at earlier stages of lead discovery. The Specific Aims are: (1) design and build a shear flow-based proof-of-principle device; and (2) demonstrate enantiomeric enrichment and absolute stereochemistry determination of at least five chiral molecules; investigate design parameter tradeoffs such as shear rate, type of the solvent, viscosity and temperature; and investigate optimal algorithms for predictive software for high fidelity absolute configuration determination. The long-term goal of the project is to develop a simple-to-use and low-cost method and device that will both accelerate the rate of drug discovery and development by pharmaceutical industry and also find applications in other industries using chiral compounds such as agricultural, food and nutraceuticals.