Many diseases are still without an effective treatment today, and others have evolved resistances requiring new therapeutic agents to be developed. In the effort to develop discovery candidates for medical applications, an important observation is that the vast majority of useful drugs contain one or several chiral centers. Since the wrong enantiomer can cause harmful side effects, very high enantiomeric purity of therapeutics is essential for safe and effective treatment. Thus, both producing enantiomerically pure formulations and testing for enantiomeric purity are critical. Unfortunately, both of these activities remain significant challenges, even with the current """"""""state of the art"""""""" analytical instrumentation. The proposed work intends to develop a next-generation chiral analysis technique that is suitable for non-contact, rapid, accurate, and highly sensitive screening of chiral samples. This approach utilizes several experimentally simple, but scientifically sophisticated techniques from """"""""state of the art"""""""" optics research first developed for nonlinear-optical spectroscopy, but which we now apply to simple polarimetry. The method transforms the detection of optical rotation into a dual-beam technique that utilizes the advantages of differential signal detection. In addition, advances in components such as digital lock-in detection, wavelength tunable sources, polarization modulation, and polarizing optics are utilized to extend the utility of the technique into the UV region. A prototype device will be constructed and tested with several chiral substrates, products, and mixtures of pharmaceutical interest to establish limits of detection (LOD), limits of quantitation (LOQ), and demonstrate superior determination of enantiomeric excess (ee%) as compared to current chiral detectors. Chiral enzymatic reactions will also be investigated to demonstrate examples of real-time kinetic analysis. Particular emphasis will be placed on demonstrating utility for analyzing multiple chiral species present in mixtures, which is particularly difficult for current methods to analyze directly.
