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

SBIR 第二阶段：基于傅里叶变换分子旋转共振 (FT-MRR) 光谱的可编程残留溶剂分析仪

• 批准号: 1556035
• 负责人: Alex Mikhonin
• 金额: $ 74.61万
• 依托单位: BrightSpec, Inc.
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-02-15 至 2019-12-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1556035&HistoricalAwards=false
• 关键词: SBIR; Phase; II; Programmable; Residual

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.

该小型企业创新研究第二阶段项目将开发一种新型分析化学仪器，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基因毒性杂质。即将开发的仪器使用傅里叶变换分子旋转共振（FT-MRR）光谱来根据分子的三维几何形状来识别分子，从而实现高化学特异性。 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，而无需事先使用色谱法进行化学分离——这是当前分析方法中一个耗时的步骤，需要大量的技术监督。 因此，基于 FT-MRR 的化学分析仪器有潜力通过将高通量药物创新过程中的分析开发周期从几周缩短到几小时来加速制药制造商的创新。 使用 FT-MRR 光谱的化学分析仪器可加快研发实验室的创新速度，并具有将方法无缝转移到在线过程监控应用以及最终产品发布的常规质量控制的额外优势。将分析方法转移到常规分析的能力是对于药品连续生产的行业目标非常重要。 FT-MRR 的实现在一定程度上（但关键）是通过第二阶段工作的两个主要目标实现的：开发 FT-MRR 的采样自动化以及设计降低成本的有针对性的 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。该项目的智力优点是引入了一种化学分析新技术，该技术基于绝对分子结构来感应化学物质，无需正交分析。 FT-MRR 光谱指纹可以区分分子异构体、构象异构体、同位素异构体，甚至对映异构体。 借助这种绝对结构信息，FT-MRR 可以实现利用位点特异性同位素比率信息和手性检测来追踪化学途径的新研究。 对于当前的技术来说，这两个概念都非常具有挑战性。 为此项目建造的 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学的最新进展，以实现时间-域，傅里叶变换（FT）测量方法。 将集成化学采样的标准方法，以最大限度地提高 FT-MRR 仪器的易用性和稳健性。