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

这个小企业创新研究二期项目将开发一种新的分析化学仪器，用于快速定量复杂混合物中残留的化学杂质。该项目的目标应用是在药物生产的早期药物开发过程中检测基因毒性杂质。待开发的仪器使用傅立叶变换分子旋转共振（FT-MRR）光谱来识别基于其三维几何形状的分子，这允许高化学特异性。FT-MRR是一种高分辨率光谱技术，可以直接分析含有大量化学物质的气体混合物，而不需要使用色谱法进行事先的化学分离，这是当前分析方法中耗时的一步，需要重要的技术监督。因此，基于FT-MRR的化学分析仪器有可能在高通量药物创新过程中将分析开发周期从数周缩短到数小时，从而加速制药商的创新。使用FT-MRR光谱的化学分析仪器使研究和开发实验室能够更快地创新，并具有无缝方法可转移到在线过程监控应用和最终产品发布的常规质量控制的附加好处。将分析方法转化为常规分析的能力对于药品连续生产的行业目标非常重要。它在一定程度上（但至关重要）通过本阶段工作的两个主要目标实现FT-MRR：开发FT-MRR的采样自动化和设计降低成本的定向FT-MRR系统。这两种设计的概念在第一阶段都得到了成功的测试。这个项目的智力优势在于引入了一种新的化学分析技术，该技术可以根据绝对分子结构来感知化学物质，而不需要正交分析。FT-MRR光谱指纹图谱可以区分分子异构体、构象、同位素，甚至对映体。有了这种绝对结构信息，FT-MRR可以通过特定位点的同位素比信息和手性检测来追踪化学途径。这两个概念对于当前的技术来说都是非常具有挑战性的。为该项目建造的FT- mrr仪器结合了高功率固态毫米波（mm-wave）光源、低成本微波合成器集成电路和高速数字电子技术的最新进展，实现了时域傅立叶变换（FT）测量方法。将整合化学取样的标准方法，以最大限度地提高FT-MRR仪器的易用性和稳健性。

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.