Improving drug bioavailability through solid form discovery

描述（由申请人提供）：递送活性药物成分（API）的最常见和最理想的方式是结晶形式。原料药可以配制成纯的形式，如盐，或作为多组分（溶剂化物，共晶）固体，这些提供了由于稳定性和加工优势，超过其他制剂。这些形式的选择在很大程度上取决于药物分子的特定化学性质以及溶解度等因素。然而，有晶体多晶型的普遍问题要考虑：给定的组合物不限于以可预测的方式结晶，并且同一单元的多个包装基序具有不同的热力学稳定性，这可能影响生物利用度。该计划将开发更快速和全面的技术来控制生物活性有机分子的结晶，同时减少材料密集度。这将使得能够对潜在药物进行早期筛选，以确定哪种形式具有适当的溶解度和稳定性以配制成生物可利用的剂量。 三个相互关联的目标旨在开发和部署更有效和强大的多晶型发现方法。目的1使聚合物诱导的异核化（PIHn）方法适应于固体形式发现，使得其以适合于多晶型物发现的高通量方式起作用。提出的两个关键进展是技术的小型化和固体形式筛选的自动化，这两个方面将使PIHn方法更适合于筛选临床前候选药物。目标2解决了晶体多晶现象的中性分子化合物的研究领域之外的问题。由于溶剂化物、盐和共晶越来越多地成为进入临床的药物的固体形式选择，因此迫切需要了解此类API中的固体形式多样性。目的1中提出的方法完全适合于溶剂合物、盐和共晶中的多晶型物发现，因为即使在多组分晶体形成中使用的相对窄的条件组下，它也可以产生固体形式多样性。最后，在目标3中，将介绍一种用于鉴定晶体形式的靶向抑制剂的新策略。该方法涉及一种新的范式，基于PIHn如何加速成核的机械理解，重新部署用于创建可溶性聚合物成核抑制剂。

DESCRIPTION (provided by applicant): The most common and desirable way to deliver active pharmaceutical ingredients (APIs) is in the crystalline form. APIs can be formulated in pure form, as salts, or as multicomponent (solvate, cocrystal) solids and these offer due to stability and processing advantages over other formulations. The choice among these forms depends very much on the specific chemical properties of the drug molecule as well as factors such as solubility. However, there is the pervasive issue of crystal polymorphism to consider: a given composition is not constrained to crystallize in a predictable way and multiple packing motifs of the same unit possess different thermodynamic stabilities that can influence bioavailability. The proposed program will develop more rapid and comprehensive techniques to control the crystallization of bioactive organic molecules while being less material intensive. Thi will enable early stage screening of potential drugs to determine which form has the appropriate solubility and stability to be formulated into a bioavailable dosage. Three interconnected aims are designed to develop and deploy more efficient and robust polymorph discovery methodology. Aim 1 adapts the polymer-induced heteronucleation (PIHn) approach towards solid form discovery so that it functions in a high throughput manner suitable for polymorph discovery. Two of the key advances proposed are miniaturization of the technology and automation of the solid form screening, which together will make the PIHn method much better suited for the screening of preclinical drug candidates. Aim 2 addressed the issue of crystal polymorphism outside of the well-studied realm of neutral molecular compounds. Because solvates, salts, and cocrystals are increasingly the solid forms of choice for drugs entering the clinic, there is a pressing need for understanding solid form diversity in such APIs. The methodology proposed in Aim 1 is perfectly suited to polymorph discovery in solvates, salts, and cocrystals because it can generate solid form diversity even under the relatively narrow sets of conditions employed in multicomponent crystal formation. Finally, in Aim 3 a new strategy for identifying targeted inhibitors of crystal forms will be introduced. The approach involves a new paradigm, based on the mechanistic understanding of how PIHn accelerates nucleation, redeployed for creating soluble polymeric nucleation inhibitors.