GOALI: CDS&E: Sensitively Quantifying Trace Crystallinity and Crystal Form within Pharmaceutical Formulations

在化学系化学测量和成像计划的支持下，以及工业创新和合作伙伴关系司的共同资助下，普渡大学的Simpson和Bouman教授、AbbVie的Danzer博士和Formulatrix的Gualtieri博士正在致力于改进用于探测多晶型晶体的光谱成像方法。多晶型晶体在化学中普遍存在。在食品科学中，土豆和意大利面中淀粉的结晶度直接决定了储存能量内容的生物利用率。在可再生能源中，生物质的生物化学降解受结晶度的影响很大。生物矿化还依赖于对晶相的仔细控制，这往往会导致亚稳结构的选择。在医药材料中，物理固体形态会对生物利用度和药物疗效产生深远影响。要可靠地测量和监测晶体如何形成和转变，需要能够报告低水平晶体含量的工具。在这笔赠款的支持下，辛普森教授和鲍曼教授与他们的工业合作伙伴密切合作，开发快速而灵敏的成像工具来实现这一点。通过与AbbVie和Formulatrix的密切合作，预计所开发的方法将对药物配方开发和其他领域产生影响，例如用于能源转换的生物质的预处理和人工生物矿化。除了与本科生和研究生在这个项目上密切合作外，辛普森教授还组织了一个关于非线性光学的密集暑期短期课程项目，在过去的十年里，有160多名学生参加了这个项目。辛普森教授现在计划制作关于短期课程节目中讨论的主题的短视频，并通过YouTube向更多的观众提供。在目前的工作中，Simpson教授、Bouman教授和他们的团队致力于将拉曼光谱的检测下限降低几个数量级，以实现对玻璃亚稳态组件的分析，目标是检测下限在百万分之几(Ppm)范围内。为了实现这一目标，我们寻求了三种互补的方法，所有这些方法都以通过降低背景来增强信噪比为中心。首先，基于手性晶体的倍频效应固有的速度和选择性，倍频效应被用来快速识别目标拉曼分析的感兴趣区域。此外，采用动态采样策略来分析配方中的SHG非活性成分，其中由先前的结果集提供信息的空间稀疏采样被用于高效的高光谱成像重建。最后，使用光电倍增管阵列的光束扫描成像的光谱稀疏采样策略允许高光谱拉曼成像的低噪声测量。作为这些光谱表征方法的补充，摩擦发光检测将被开发用于快速筛选。所有努力都极大地受益于药物配方开发(AbbVie)的合作者和仪器公司(Formulatrix)之间的密切合作伙伴关系，这些公司致力于将研究实验室的创新转化为可行的商业产品。虽然这项工作的主要重点是与工业合作者相关的亚稳态系统，但这项工作的结果为扩展到其他亚稳态生物组件提供了基础，包括用于能量转换的生物质的预处理、可食用产品的结晶度以及生物矿化的基本原理。辛普森教授为来自世界各地的研究小组的研究生组织了一个为期一周的强化项目--Chautauqua on非线性光学。该计划侧重于深入了解非线性光学的理论和实践基础，旨在建立一个在执行和解释非线性光学测量的共同框架内运作的社区。

With support from the Chemical Measurement and Imaging Program in the Division of Chemistry, and co-funding from the Division of Industrial Innovation and Partnerships, Professors Simpson and Bouman at Purdue University, Dr. Danzer at AbbVie, and Dr. Gualtieri at Formulatrix are working on advancing spectroscopic imaging methods for probing polymorph crystals. polymorph crystal forms are ubiquitous in chemistry. In food science, the crystallinity of starches within potatoes and pasta directly dictate bioavailability of the stored energy content. In renewable energy, biochemical degradation of biomass is greatly affected by the degree of crystallinity. Biomineralization also relies on careful control over crystal phase, often resulting in selection of metastable structures. In pharmaceutical materials, physical solid state form can profoundly affect bioavailability and drug efficacy. Reliably measurement and monitoring of how crystal forms and transforms requires tools capable of reporting crystalline content at low levels. With the support of this grant, Professors Simpson and Bouman work closely with their industrial partners to develop fast and sensitive imaging tools to do just that. Through close partnership with AbbVie and Formulatrix, the developed approach is expected to bring impacts in pharmaceutical formulations development and other areas, such as pretreatment of biomass for energy conversion and artificial biomineralization. In addition to working with their undergraduate and graduate students closely on the project, professor Simpson also organizes an intensive summer short-course program on nonlinear optics that more than 160 students have participated in the past ten years. Professor Simpson plans now to produce short videos on the topics discussed at the short course program and makes it available to a much broader audience through YouTube. In the present work, Professors Simpson, Bouman, and their groups work on reducing the detection limits of Raman spectroscopy by several orders of magnitude to enable analysis of glassy metastable assemblies, targeting detection limits in the parts per million (ppm) regime. Three complementary approaches are pursued to achieve this objective, all of which center on signal to noise enhancement through background reduction. In the first, SHG is used to rapidly identify regions of interest for targeted Raman analysis, building on the inherent speed and selectivity of SHG for chiral crystals. In addition, a dynamic sampling strategy is adopted for analysis of the SHG-inactive components of formulations, in which spatially sparse sampling informed by the preceding set of outcomes is used for efficient hyperspectral imaging reconstruction. Finally, a spectral sparse sampling strategy for beam-scanning imaging using a photomultiplier tube array allows low-noise measurements for hyperspectral Raman imaging. Complementing these spectral characterization approaches, triboluminescence detection will be developed for fast screening. All efforts greatly benefit from close partnership between collaborators working in pharmaceutical formulations development (AbbVie) and instrumentation companies (Formulatrix) positioned to transition innovations in the research laboratory to viable commercial products. While the primary focus of the work is on metastable systems of relevance to industrial collaborators, the results of this work provides a foundation for expansion to other metastable biological assemblies, including pretreatment of biomass for energy conversion, crystallinity in edible products, and fundamentals of biomineralization. Professor Simpson organizes a week- long intensive program, Chautauqua on Nonlinear Optics for graduate student from research groups worldwide. The program focuses on in-depth understanding of the theoretical and practical fundamentals of nonlinear optics and aims to build a community operating within a common framework for performing and interpreting nonlinear optical measurements.