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

项目名称：目标：多晶型控制结晶的串联计算和实验组合方法项目编号：cts -0233696项目负责人：Michael ward机构：明尼苏达大学项目目标是开发使用合适外延衬底的多晶型选择和控制技术。计算和实验相结合的技术，多晶发现将发展。分子所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，花了相当大的努力来发现和表征多态，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态性的策略，该策略结合了二维外延的几何晶格建模和实验组合学，目的是确定对多晶晶的选择性结晶有效的衬底。这项工作的一个关键要素是使用晶格建模来构建实验可管理尺寸的基板库，基于晶体有机和无机材料，预计会产生特定的多晶型。使用x射线衍射和光谱方法，这些文库将筛选多晶型选择性和它们提高结晶收率的整体能力。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。该项目将导致对多态性的合理和系统的控制，阐明控制这一现象的基本原理，发现新的多态性，新的结晶协议，改进结晶工艺。这项工作的最终实施将为药物化合物的选定晶体形式的设计和放大提供重要的工具。在这一领域培训学生对于保持美国工业的竞争优势至关重要。这些项目还将以软件的形式向社区提供计算工具。

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.