GOALI: Tandem Computational and Experimental Combinatorics for Controlled Crystallization of Polymorphs

摘要提案标题：目标：用于多晶型物控制结晶的串联计算和实验组合学提案编号：CTS-0233696主要研究者：Michael Ward机构： 明尼苏达大学该项目的目标是开发使用适当的外延衬底进行多晶型选择和控制的技术。 将开发用于多晶型发现的计算和实验组合技术。 分子采用的不同晶体形式会影响它们的稳定性和功能。 在制药工业中，花费了相当大的努力来发现和表征多晶型物，主要是因为它们对生物利用度和稳定性的影响。 这些大学和工业研究人员将开发一种控制多晶型的策略，该策略结合了二维外延的几何晶格建模和实验组合学，目的是确定对多晶型选择性结晶有效的底物。这项工作的一个关键要素涉及使用晶格建模来构建实验上可管理的大小的基板库，基于结晶有机和无机材料，预期产生特定的多晶型物。 使用X-射线衍射和光谱方法，将筛选这些文库的多晶型选择性和它们提高结晶产率的总体能力。这些研究将伴随着实时原位原子力显微镜，直接在选定的衬底上的结晶介质中进行，这将提供成核和晶体生长的直接可视化，并确认外延的作用。该项目将导致合理和系统的控制多晶型，阐明这一现象的基本原则，发现新的多晶型，新的结晶协议，并改进结晶过程。这项工作的最终实施将提供一个重要的工具，以帮助在药物化合物的选定的晶体形式的设计和放大。 培养这方面的学生对保持美国工业的竞争优势至关重要。 这些专业研究员亦会以软件形式向社会提供计算工具。

Abstract Proposal Title: GOALI: Tandem Computational and Experimental Combinatorics for Controlled Crystallization of PolymorphsProposal Number: CTS-0233696Principal Investigator: Michael WardInstitution: University of MinnesotaThe objective of the project is to develop techniques for polymorph selection and control using appropriate epitaxial substrates. Computational and experimental combinatorial techniques for polymorph discovery will be developed. The different crystal forms that molecules adopt can affect their stability and function. In the pharmaceutical industry considerable effort is expended to discover and characterize polymorphs, largely because of their impact on bioavailability and stability. These university and industrial investigators will develop a strategy for controlling polymorphism that combines geometric lattice modeling of two-dimensional epitaxy and experimental combinatorics, with the aim of identifying substrates that are effective for selective crystallization of polymorphs. A key element of this work involves the use of lattice modeling to build substrate libraries of experimentally manageable size, based on crystalline organic and inorganic materials, expected to produce specific polymorphs. Using X-ray diffraction and spectroscopic methods, these libraries will be screened for polymorph selectivity and their overall ability to improve crystallization yields. These studies will be accompanied by real-time in situ atomic force microscopy, performed directly in crystallization media on selected substrates, which will provide direct visualization of nucleation and crystal growth and confirm the role of epitaxy. The project will lead to rational and systematic control of polymorphism, elucidation of the fundamental principles governing this phenomenon, discovery of new polymorphs, new protocols for crystallization, and improved crystallization processes. The ultimate implementation of this work will provide an important tool to aid in the design and scale-up of selected crystal forms for pharmaceutical compounds. Training students in this area is vital to keeping the competitive advantage of US industry. The PIs will also provide computation tools to the community in the form of software.