Differential Optical Rotation for Chiral Analysis

DESCRIPTION (provided by applicant): 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 analytical 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, the Faraday effect is utilized using a sinusoidally varying magnetic field on the sample, optical-heterodyne detection by modulating the laser source, and double modulation phase-sensitive detection. The addition of optical heterodyning decreases the observed background noise in the system by moving the signals of interest to frequencies where electronic pickup and optical noise in the system do not contribute (analogous to double-beam-double-modulation detection in laser absorption spectrometry). By observing analytical signals in electronically quiet regions, additional electronic gain can be applied prior to the analog-to-digital converter further improving system sensitivity. We call this set of techniques and the resulting device the Magneto-Optical Phase Enantiomeric Detector-Optical Rotation (MOPED). In the effort to discover and develop pharmaceutical candidates, one must consider that the vast majority of useful drugs have two or more potential geometrical forms. As the wrong geometrical form can cause harmful side effects, very high purity of therapeutics is essential for safe and effective treatment. The proposed work intends to develop a next-generation analytical technique that is suitable for non-contact, rapid, accurate, and highly sensitive screening of chiral geometries.