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

在化学系化学测量和成像项目的支持下，以及工业创新和合作伙伴关系部的共同资助下，普渡大学的Simpson和Bouman教授、艾伯维的Danzer博士和Formulatrix的Gualtieri博士正在研究用于探测多晶型晶体的先进光谱成像方法。多晶型在化学中是普遍存在的。在食品科学中，土豆和面食中淀粉的结晶度直接决定了储存能量的生物利用度。在可再生能源中，生物质的生化降解受结晶度的影响很大。生物矿化还依赖于对晶体相的仔细控制，通常导致亚稳结构的选择。在药用材料中，物理固态形态对生物利用度和药效有着深远的影响。可靠地测量和监测晶体的形成和转变需要能够报告低水平晶体含量的工具。在这笔拨款的支持下，辛普森教授和鲍曼教授与他们的工业合作伙伴密切合作，开发快速灵敏的成像工具来做到这一点。通过与AbbVie和Formulatrix的密切合作，开发的方法有望在药物配方开发和其他领域带来影响，例如生物质预处理用于能量转换和人工生物矿化。除了与本科生和研究生密切合作外，辛普森教授还组织了一个关于非线性光学的暑期短期课程，在过去十年中有160多名学生参加了该课程。辛普森教授现在计划就短期课程中讨论的主题制作短视频，并通过YouTube将其提供给更广泛的受众。在目前的工作中，辛普森教授、鲍曼教授和他们的团队致力于将拉曼光谱的检测限降低几个数量级，从而能够分析玻璃状亚稳态组装体，目标是百万分之一（ppm）的检测限。为了实现这一目标，采用了三种互补的方法，所有这些方法都以通过背景减小来增强信号噪声为中心。首先，基于SHG对手性晶体固有的速度和选择性，SHG被用于快速识别目标拉曼分析感兴趣的区域。此外，采用动态采样策略对配方中不含shg的成分进行分析，利用上述结果集合的空间稀疏采样进行高效的高光谱成像重建。最后，使用光电倍增管阵列进行波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，摩擦发光检测将用于快速筛选。所有的努力都得益于药物配方开发（AbbVie）和仪器公司（Formulatrix）之间的密切合作，这些公司定位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，包括生物质的能量转换预处理，可食用产品的结晶度和生物矿化的基础。教授辛普森组织了一个为期一周的密集课程，肖陶夸非线性光学的研究小组的研究生来自世界各地。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.