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

用于增强共晶高通量筛选的多重成核方法

• 批准号: 9134557
• 负责人: Andrew H. Bond
• 金额: $ 31.15万
• 依托单位: DENOVX, LLC
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-01 至 2018-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9134557
• 关键词: Acceleration; Acetaminophen; Benchmarking; Bioavailable; Biological Availability; Chemicals; Chemistry; Childhood; Crystal Formation; Crystallization; Decision Making; Derivation procedure; Development; Drops; Ensure; Formulation; Goals; Grant; Health Benefit; Investments; Legal patent; Licensing; Liquid substance; Marketing; Methods; Modification; Naproxen; Orphan; Outcome; Patients; Pharmaceutical Preparations; Pharmaceutical Technology; Pharmacologic Substance; Phase; Plague; Probability; Process; Proteins; Public Health; Safety; Sodium Chloride; Solid; Solubility; Solvents; Speed; Surface; System; Techniques; Technology; Time; Water; Wettability; active method; analytical method; commercial application; drug development; high throughput screening; improved; in vivo; innovation; instrument; knowledge base; monolayer; novel strategies; public health relevance; screening; small molecule; solid state; structural biology; success; technological innovation; tv watching; water solubility

 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.

 描述（由申请人提供）：活性药物成分 (API) 的水溶性差日益给药物开发带来挑战，超过 70% 的新 API 都面临这个问题，共结晶是克服这些挑战的一种新策略，特别是对于那些 API 来说。不易用亲水基团衍生化的共结晶高通量筛选 (HTS) 的改进将扩大 API 配方中易溶的新化学实体的数量。为公众健康带来新的、更安全、生物利用度更高的药物的益处 第一阶段资助的目标是开发改进的 API 共晶筛选方法，其中结合了互补的结晶方法：(1) 多重机械化学固态压缩与剪切， (2) HTS 兼容溶液结晶技术，利用表面化学修饰来增强成核，从而改善结晶结果。 DeNovX 将在 96 孔 HTS 板中使用创新的表面辅助成核技术，展示多重直接压缩固体合成和小滴溶液结晶的实用性，包括定量。使用 96 和 384 孔 HTS 的集成工作流程效率，并强调更多样化的合成子，目标是使用 HTS 处理和分析方法生成新的共晶体与儿科未满足的需求相关的组合物和选择的孤儿适应症。