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性质中的作用是药物递送中的关键问题。固体以多于1种多晶型物存在的能力，即仅在包装而非构成上不同的超分子异构体，产生了每种晶型可能具有不同生物利用度和稳定性的情况。只有通过发现新的多晶型物的存在及其独特的性质，才能找到最有效的固体剂型。该提案概述了研究和控制晶体生长这一重要方面的方法。具体目标1-开发生产新多晶型物的通用方法。我们将创建聚合物库，可以异核结晶的固体。有人提出，改变聚合物表面上的官能团和这些官能团的取向和密度将允许通过创建新的异核化事件动力学访问新的多晶型物。具体目标2-研究聚合物结构和获得的晶体多晶型物之间的关系。虽然它已被确定，在宏观尺度上的大多数结晶进行通过异核化事件，有很少的信息对结晶事件的基板的影响。使用特定目标1中开发的方法来寻找产生新型多晶型物的聚合物，我们将确定哪些特性对于控制多晶型物生产是重要的。具体目标3-确定新的多晶型物的性质。最终目标是找到现有和新药物的更有效形式，将确定新多晶型物的几个关键性质，包括稳定性、平衡溶解度和溶出速率。对公共卫生相关性的简要描述：原料药的有效性不仅与其化学成分有关，还与分子在固体中的排列方式有关。该提案提供了一种优化药物递送这一重要方面的方法，并将导致开发当前和未来治疗剂的更有效形式。