Polymer-Based Approaches for Exploring Polymorph Space

基于聚合物的多晶型空间探索方法

• 批准号: 7144245
• 负责人: Adam Jay Matzger
• 金额: $ 22.96万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7144245
• 关键词: X ray crystallography; chemical kinetics; chemical registry /resource; chemical stability; chemical structure; chemical structure function; chemical synthesis; combinatorial chemistry; computer simulation; crystallization; drug discovery /isolation; isomer; pharmacokinetics; polymers; scanning electron microscopy; solubility; spectrometry; stereochemistry

DESCRIPTION (provided by applicant): The role of solid-state form in determining the properties of Pharmaceuticals is a critical issue in drug delivery. The ability of a solid to exist as more than 1 polymorph, supramolecular isomers that differ only in packing and not constitution, creates a situation where each crystal form may have different bioavailability and stability. Only by discovering the presence of new polymorphs and their unique properties can the most efficacious form for a solid dosage be found. This proposal outlines a method for studying and controlling this important aspect of crystal growth. Specific Aim 1-Develop a general methodology for producing new polymorphs. We will create libraries of polymers that can heteronucleate crystallization of solids. It is proposed that varying the functional groups on the surface of the polymer and the orientation and density of these functional groups will allow kinetic access to new polymorphs by creating novel heteronucleation events. Specific Aim 2-lnvestigate the relationship between polymer structure and crystal polymorph obtained. Though it has been established that the majority of crystallizations on a macroscopic scale proceed through heteronucleation events, there is little information about the influence of the substrate on crystallization events. Using the approach developed in Specific Aim 1 to find polymers that create novel polymorphs, we will determine which characteristics are important for controlling polymorph production. Specific Aim 3-Determine the properties of novel polymorphs. With the ultimate goal of finding more efficacious forms of existing and new Pharmaceuticals, the determination of several key properties of the new polymorphs will be undertaken including stability, equilibrium solubility and dissolution rate. Brief description of public health relevance: The effectiveness of a drug substance is not solely related to its chemical composition but also to how the molecules arrange in the solid. This proposal offers a method for optimizing this important aspect of drug delivery and will lead to the development of more effective forms of current and future therapeutic agents.

描述（由申请人提供）：固态形式在确定药物特性中的作用是药物输送的关键问题。固体存在的能力是超过1个多晶型物，超分子异构体，仅在包装而不构成方面有所不同，会产生每种晶体形式可能具有不同生物利用度和稳定性的情况。只有发现存在新的多晶型物及其独特的特性，才能找到最有效的固体剂量。该建议概述了研究和控制晶体生长这一重要方面的方法。特定的目标1开发一种用于产生新多晶型物的一般方法。我们将创建可以异核核酸结晶的聚合物库。有人提出，在聚合物表面上改变官能团，这些官能团的方向和密度将通过创建新型的异核核事件，从而使动力学访问新的多晶型物。特定的AIM 2-LNVEST，可以在获得的聚合物结构与获得的晶体多晶之间的关系。尽管已经确定，宏观量表上的大多数结晶通过异核事件进行，但关于底物对结晶事件的影响的信息很少。使用特定目标1中开发的方法来查找产生新型多晶型物的聚合物，我们将确定哪些特征对于控制多晶型物的生产很重要。特定目标3确定性新型多晶型物的特性。为了找到现有和新药物的更有效形式的最终目标，将确定新多晶型物的几种关键特性，包括稳定性，平衡溶解度和溶解速率。公共卫生相关性的简要描述：药物的有效性与其化学成分有关，而与分子如何在固体中排列的方式有关。该建议提供了一种优化药物输送这一重要方面的方法，并将导致开发更有效的当前和未来治疗剂。