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

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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.