Multiplexed Nucleation Approaches for Enhanced High Throughput Screening of Co-Crystals

 描述（由申请人提供）：活性药物成分（API）的水溶性差越来越多地对药物开发构成挑战，超过70%的新API遭受这个问题。 共结晶是克服这些挑战的一种新策略，特别是对于那些不容易用亲水基团衍生的API。 用于共结晶的高通量筛选（HTS）的改进将扩大用于API制剂的易溶的新化学实体的数量，并且将从新的、更安全的和更生物可利用的药物中获得公共卫生益处。 该I期资助的目标是开发用于API共晶筛选的改进方法，该方法结合了互补结晶方法：（1）多重机械化学固态压缩与剪切，以及（2）HTS兼容的溶液结晶技术，该技术使用表面化学改性来提供成核增强，从而改善结晶结果。 通过将这些正交晶体成核方法合并到统一的工作流程中，可以提高HTS筛选工作中共晶形成的概率和速度。 DeNovX将在96孔HTS板中使用创新的表面辅助成核技术演示多重直接压缩固体合成和微滴溶液结晶的实用性。 第II阶段的目标包括使用96和384孔HTS对综合工作流程效率进行定量，并强调更多样化的晶体组合物，目标是使用HTS处理和分析方法生成与儿科和选定孤儿适应症中未满足的需求相关的新晶体组合物。

 DESCRIPTION (provided by applicant): Poor water solubility of active pharmaceutical ingredients (APIs) increasingly poses challenges to drug development, with >70% of new APIs suffering from this issue. Co­crystallization is a novel strategy for overcoming these challenges particularly for those APIs that are not readily derivatized with hydrophilic groups. Improvements to high throughput screening (HTS) for co­crystallization will expand the number of readily soluble, new chemical entities for API formulation, and will give Public Health benefit deriving from new, safer, and more bioavailable pharmaceuticals. The goal of this Phase I grant is to develop improved methods for API co-crystal screening that incorporate complementary crystallization approaches: (1) multiplexed mechanochemical solid state compression with shear, and (2) HTS compatible solution crystallization technologies that use surface chemistry modifications to give nucleation enhancements that improve crystallization outcomes. By incorporating these orthogonal crystal nucleation approaches into a unified workflow, the probability and speed of co-crystal formation in HTS screening efforts can be improved. DeNovX will demonstrate the utility of both multiplexed direct compression solid synthesis and mini­drop solution crystallization using innovative surface assisted nucleation in 96 well HTS plates. Objectives for Phase II include quantitation of the integrated workflow efficiencies using 96 and 384 well HTS and an emphasis on more diverse synthons with the goal of using HTS handling and analytical methods to generate new co­crystal compositions that are relevant to unmet needs in pediatric and select orphan indications.