Improving drug bioavailability through solid form discovery

描述(申请人提供)：提供活性药物成分(原料药)的最常见和最理想的方式是以晶体形式。原料药可配制成纯形式、盐类或多组分(溶剂酸盐、共晶体)固体，这些提供的原因是稳定性和工艺优于其他制剂。在这些形式中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诸如溶解度等因素。然而，有一个普遍存在的晶体多态问题需要考虑：给定的组合物不受限制以可预测的方式结晶，同一单元的多个堆积基序具有不同的热力学稳定性，这可能会影响生物利用度。拟议的计划将开发更快速和更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。THI将使对潜在药物的早期筛选成为可能，以确定哪种形式具有适当的溶解性和稳定性，可以配制成生物可用剂量。设计了三个相互关联的AIMS来开发和部署更高效和更健壮的多态发现方法。目的1将聚合物诱导异核化(PIHN)方法用于固相发现，使其以高通量的方式适用于多晶型发现。建议的两项关键进展是技术的微型化和固体形式筛选的自动化，这两项共同将使PIHN方法更适合于临床前候选药物的筛选。目的2解决中性分子化合物研究领域之外的晶体多态问题。由于溶剂酸盐、盐和共晶体越来越成为进入临床的药物的固体形式选择，因此迫切需要了解这些原料药的固体形式多样性。目标1中提出的方法非常适合于溶剂、盐和共晶体中的多晶型发现，因为它即使在多组分晶体形成中使用的相对较窄的一组条件下也可以产生固体形式多样性。最后，在目标3中，将引入一种新的战略，以确定晶型的靶向抑制物。该方法涉及一种新的范式，基于对PIHN如何加速成核的机理理解，重新部署以创建可溶的聚合物成核抑制剂。

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.