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: 7933382
• 负责人: Adam Jay Matzger
• 金额: $ 3万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7933382
• 关键词: Address; Azithromycin; Behavior; Bioavailable; Biological Availability; Characteristics; Chemicals; Computer Simulation; Constitution; Controlled Study; Crystallization; Development; Drug Delivery Systems; Drug Formulations; Effectiveness; Equilibrium; Event; Flutamide; Future; Ganciclovir; Goals; Growth; Isomerism; Itraconazole; Ketoconazole; Kinetics; Lead; Libraries; Methodology; Methods; Outcome; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Polymers; Production; Property; Research; Research Personnel; Role; Solid; Solubility; Spectrum Analysis; Staging; Structure; Surface; Techniques; Testing; Therapeutic Agents; aqueous; base; dehydroepiandrosterone; density; design; dosage; functional group; method development; molecular recognition; neutrophil; novel; programs; public health relevance; solid state

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 one 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)：固体形态在确定药物性质中的作用是药物输送中的一个关键问题。固体以一种以上形态存在的能力，即超分子异构体，只在堆积上不同，而不是组成上不同，造成了每种晶体形式可能具有不同的生物利用度和稳定性的情况。只有通过发现新的多晶型及其独特的性质，才能找到固体剂量最有效的形式。该提案概述了一种研究和控制晶体生长这一重要方面的方法。具体目标1-开发产生新的多态的一般方法。我们将创建能够使固体异核结晶的聚合物库。有人提出，改变聚合物表面的官能团以及这些官能团的取向和密度将允许通过产生新的杂核事件来动力学地获得新的多晶型。特定目的2-研究聚合物结构与获得的晶体多晶型之间的关系。虽然已经确定宏观上的大多数结晶都是通过异核事件进行的，但关于底物对结晶事件的影响的信息很少。使用在特定目标1中开发的方法来寻找能够产生新的多晶型的聚合物，我们将确定哪些特性对于控制多晶型的生产是重要的。具体目标3-确定新的多晶型的性质。为了找到现有药物和新药物的更有效形式，将对新多晶型的几个关键性质进行测定，包括稳定性、平衡溶解度和溶出度。 与公众健康相关的简要描述：药物物质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。这项建议为优化药物输送的这一重要方面提供了一种方法，并将导致目前和未来更有效形式的治疗剂的开发。