SBIR Phase II: A Programmable Residual Solvent Analyzer based on Fourier Transform Molecular Rotational Resonance (FT-MRR) Spectroscopy

This Small Business Innovation Research Phase II project will develop a new analytical chemistry instrument for rapid quantitation of residual chemical impurities in complex mixtures. The target application for this project is the detection of genotoxic impurities during early drug development in pharmaceutical manufacturing. The instrument to be developed uses Fourier transform molecular rotational resonance (FT-MRR) spectroscopy to identify molecules based on their three dimensional geometry, which permits high chemical specificity. FT-MRR is a high-resolution spectroscopy technique that makes it possible to directly analyze gas mixtures containing a large number of chemicals without the need for prior chemical separation using chromatography - a time-consuming step of current analysis methods that requires significant technical supervision. As a result, FT-MRR based chemical analysis instruments have the potential to speed up innovation for pharmaceutical manufacturers by reducing analytical development cycles from weeks to hours during the high-throughput drug innovation process. Chemical analysis instruments using FT-MRR spectroscopy enable faster innovation in research and development labs with the added benefit of seamless method transferability to on-line process monitoring applications and routine quality control for final product release. The ability to transfer analysis methods into routine analysis is important to the industry goal of continuous manufacturing for pharmaceuticals. It is enabled for FT-MRR in part (yet critically) by the two main objectives of this Phase II effort: the development of sampling automation for FT-MRR and the design of a cost-reduced, targeted FT-MRR system. Concepts for both of these designs were successfully tested during Phase I. The intellectual merit of this project is the introduction of a new technique for chemical analysis that senses chemicals based on the absolute molecular structure, with no orthogonal analysis required. FT-MRR spectral fingerprints can distinguish molecular isomers, conformers, isotopologues, and even enantiomers. With this kind of absolute structure information, FT-MRR can enable new studies that trace chemical pathways with site-specific isotopic ratio information and chiral detection. Both concepts are otherwise very challenging with current technology. The FT-MRR instrument to be built for this project combines recent advances in high-power, solid-state millimeter wave (mm-wave) light sources, low-cost microwave synthesizer integrated circuits, and high-speed digital electronics to implement a time-domain, Fourier transform (FT) measurement approach. Standard methods for chemical sampling will be integrated to maximize the ease-of-use and robustness of FT-MRR instruments.