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

这个小型企业创新研究第二阶段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的残留化学杂质。该项目的目标应用是在制药生产的早期药物开发过程中检测遗传毒性杂质。即将开发的仪器使用傅里叶变换分子旋转共振(FT-MRR)光谱技术，根据分子的三维几何结构识别分子，这使得化学特异度很高。FT-MRR是一种高分辨率光谱技术，使得直接分析含有大量化学物质的气体混合物成为可能，而不需要事先使用色谱进行化学分离-这是当前分析方法的一个耗时的步骤，需要大量的技术监督。因此，基于FT-MRR的化学分析仪器在高通量药物创新过程中将分析开发周期从几周减少到几个小时，从而有可能加快制药制造商的创新。使用FT-MRR光谱学的化学分析仪器能够加快研发实验室的创新，并增加无缝方法转移到在线过程监控应用程序和最终产品发布的常规质量控制的好处。将分析方法转换为常规分析的能力对于实现制药连续制造的行业目标非常重要。FT-MRR在一定程度上(但至关重要)是由于这一第二阶段工作的两个主要目标：开发FT-MRR的采样自动化和设计一个成本更低、目标明确的FT-MRR系统。这两种设计的概念都在第一阶段成功地进行了测试。该项目的智力优势是引入了一种新的化学分析技术，这种技术可以根据绝对分子结构来感知化学物质，而不需要进行正交分析。FT-MRR光谱指纹可以区分分子异构体、构象、同位素，甚至是对映体。有了这种绝对结构信息，FT-MRR可以利用特定部位的同位素比率信息和手性检测来追踪化学途径的新研究。否则，这两个概念在目前的技术下都非常具有挑战性。为该项目建造的FT-MRR仪器结合了高功率固态毫米波(mm波)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，实现了一种时域傅里叶变换(FT)测量方法。将整合化学采样的标准方法，以最大限度地提高FT-MRR仪器的易用性和健壮性。

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.