Polymer-Based Approaches for Exploring Polymorph Space

描述（由申请人提供）：固态形式在决定药物性质中的作用是药物传递中的关键问题。固体以多种多晶形态存在的能力，即仅在包装而非结构上不同的超分子异构体，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体的存在及其独特的性质，才能找到固体剂型的最有效形式。本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：开发一种生产新多态性的通用方法。我们将创建可使固体异核结晶的聚合物库。研究人员提出，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异核事件来获得新的多晶态。目的2：研究聚合物结构与晶体形貌之间的关系。虽然已经确定，在宏观尺度上，大多数结晶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Specific Aim 1中开发的方法来寻找产生新的多晶型的聚合物，我们将确定哪些特征对于控制多晶型的产生是重要的。具体目标3-确定新多态性的性质。为了找到现有药物和新药物的更有效形式的最终目标，将确定新多晶型的几个关键性质，包括稳定性，平衡溶解度和溶解速率。

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.