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（由适用提供）：活性药物成分（API）的水溶性不佳，越来越多地对药物开发构成挑战，> 70％的新API遭受了此问题。共晶化是克服这些挑战的一种新型策略，特别是对于那些不容易被亲水基团衍生的API。改进共晶的高吞吐量筛查（HTS）将扩大API配方的易于实心的新化学实体的数量，并将带来新的，安全和更多可生物利用药品的公共卫生福利。该阶段I授予的目的是为API共晶筛选开发改进的方法，该方法结合了完整的结晶方法：（1）用剪切剪切的多路复用机械化学固态压缩，以及（2）HTS兼容溶液结晶技术，这些溶液结晶技术可用表面化学修饰，从而改善了核酸核能增强结构化的结晶效果。通过将这些正交晶体成核方法纳入统一的工作流程，可以改善HTS筛选工作中共晶形成的概率和速度。 Denovx将使用创新的表面辅助成核中的96个井HTS板中的多重直接压缩固体合成和最小值溶液结晶的实用性。第二阶段的目标包括使用96和384井HTS对集成工作流程的效率进行定量，并强调更多的潜水员合成子，目的是使用HTS处理和分析方法来生成与儿科和精选孤儿指示中未满足需求相关的新共晶组成。