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: 10081479
• 负责人: Andrew H. Bond
• 金额: $ 107.87万
• 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 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10081479
• 关键词: Acceleration; Acetaminophen; Acids; Address; Behavior; Benchmarking; Biological Availability; Chemicals; Coupled; Crystal Formation; Crystallization; Data; Data Collection; Detection; Development; Diabetes Mellitus; Drops; Engineering; Excipients; Excretory function; Exhibits; Failure; Goals; Hydrogen Bonding; Laboratories; Metabolism; Microscopy; Minor; Mole the mammal; National Institute of Diabetes and Digestive and Kidney Diseases; National Institute of Drug Abuse; National Institute of General Medical Sciences; Outcome; Partner in relationship; Pattern; Performance; Permeability; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Photons; Powder dose form; Preparation; Proteins; Public Health; Reproducibility; Safety; Sampling; Side; Solid; Solubility; Solvents; Source; Structure; Synchrotrons; Technology; Temperature; Testing; Time; United States National Institutes of Health; Variant; X ray diffraction analysis; absorption; commercial application; data quality; design; high throughput screening; improved; in vivo; innovation; novel; pressure; prototype; public health research; screening; stoichiometry; synchrotron radiation; tool; water solubility

PROJECT SUMMARY DeNovX’s technologies improve crystallization of active pharmaceutical ingredients (APIs) and proteins. Over 70% of APIs exhibit poor H2O solubility and bioavailability that contribute to drug failures. Co-crystallization mates an API with a supramolecular heterosynthon and is a crystal engineering approach to creating H2O soluble API compositions, but it is not yet reproducible for high throughput screening (HTS). A punch/die in an HTS format and a hydraulic press can be used for compressive mechanocrystallization to give reproducible shear forces adequate to form co-crystals. Phase I demonstrated a high confidence POC with a 48 well format for HTS mechanocrystallization of an API co-crystal and gave excellent reproducibility in a continuous variation study. A comparison of the solvent drop grinding benchmark with compressive mechanocrystallization showed that the latter can be conducted in 81% less time with 60% less material while yielding 25% more sample for analysis. Through subawards to Stanford’s Synchrotron Radiation Lightsource (SSRL) and Argonne’s Advanced Photon Source (APS), Phase II will integrate HTS mechanocrystallization with synchrotron powder X-ray diffraction (PXRD) analysis to give unparalleled minor constituent identification, quantitation, structure, and throughput. Specific Aim 1: Conduct replicate (n ≥ 6) studies of compressive mechanocrystallization using α-prototypes to identify variables most impacting API co-crystallization. Examine two benchmarks and ≥ 14 co-crystals from the acidic, basic, and neutral API classes matched appropriately to heterosynthons having complementary H-bonding behavior. Collect synchrotron PXRD by subawards to SSRL and APS. Specific Aim 2: Test ≥ 6 compressive mechanocrystallization ꞵ-prototypes that can serve as consumable sample holders for PXRD analyses of APIs and co-crystals. Four prototypes to be compatible with synchrotron PXRD and two lower multiplexed formats suitable for laboratory PXRD. API co-crystal samples in multiplexed holders to give synchrotron PXRD compositions within ±3σ of averages for n ≥ 6 continuous variation studies. Specific Aim 3: Conduct high throughput synchrotron PXRD data collection to demonstrate limit of detection ≤ 0.2% (w/w) for minor constituent API phases in a continuous variation study using 𝛾-prototype mechanocrystallization sample holders. Concurrently demonstrate PXRD pattern acquisition rates ≤ 90 s per sample while retaining data quality. Specific Aim 4: Demonstrate neat and solvent sparse compressive mechanocrystallization HTS of co-crystals with synchrotron PXRD at SSRL/APS for each of ≥ 6 high impact API targets relevant to pharmaceutical companies and NIH. Identify new co-crystal phases and preparative conditions enabling solubility/permeability studies by stakeholders. Reproducible tools for HTS mechanocrystallization of APIs and co-crystals will benefit Public Health by creating new or repurposed API compositions exhibiting superior in vivo solubility and bioavailability for a $1 trillion pharmaceuticals market.

项目概要 DeNovX 的技术改善了活性药物成分 (API) 和蛋白质的结晶。 70% 的 API 的水溶解度和生物利用度较差，导致药物共结晶失败。 将 API 与超分子异质合成物相结合，是一种制造 H2O 的晶体工程方法 可溶性 API 组合物，但尚不能在冲头/模具中进行高通量筛选 (HTS) 重现。 HTS 格式和液压机可用于压缩机械结晶，以提供可重复的结果 剪切力足以形成共晶，第一阶段展示了 48 孔格式的高置信度 POC。 用于 API 共晶的高温超导机械结晶，并在连续变化中提供出色的再现性 研究表明，溶剂滴研磨基准与压缩机械结晶。 后者可以在减少 81% 的时间、减少 60% 的材料的情况下进行，同时多产生 25% 的样品 通过对斯坦福大学同步辐射光源（SSRL）和阿贡国家实验室的子奖项进行分析。 先进光子源 (APS) 第二阶段将高温超导机械结晶与同步加速器粉末相结合 X 射线衍射 (PXRD) 分析可提供无与伦比的次要成分鉴定、定量、结构、 具体目标 1：使用压缩机械结晶进行重复 (n ≥ 6) 研究。 α-原型以确定对 API 共结晶影响最大的变量 检查两个基准并且 ≥ 14。 酸性、碱性和中性 API 类别的共晶与具有以下特征的异质合成物适当匹配 通过 SSRL 和 APS 的子奖励收集互补的氢键行为。 2：测试 ≥ 6 个压缩机械结晶 ꞵ 原型，可用作消耗性样品支架 API 和共晶的 PXRD 分析 四个原型与同步加速器 PXRD 兼容，还有两个原型。 较低的多重格式适用于多重支架中的实验室 PXRD API 共晶样品。 n ≥ 6 次连续变化研究的同步加速器 PXRD 成分在平均值的 ±3σ 范围内。 进行高通量同步加速器 PXRD 数据收集，以证明检测限 ≤ 0.2% (w/w) 使用 𝛾 原型机械结晶样品进行连续变化研究中的次要成分 API 相 同时展示每个样品的 PXRD 图案采集率 ≤ 90 秒，同时保留数据。 具体目标 4：展示纯且溶剂稀疏的压缩机械结晶 HTS。 在 SSRL/APS 下使用同步加速器 PXRD 进行共晶，针对 ≥ 6 个与相关的高影响 API 目标中的每一个 制药公司和 NIH 确定新的共晶相和制备条件。 利益相关者进行的溶解度/渗透率研究 可重复的 API 和 HTS 机械结晶工具。 共晶将通过创造新的或重新利用的 API 组合物来造福公众健康，这些组合物在以下方面表现出优异的性能： 价值 1 万亿美元的药品市场的体内溶解度和生物利用度。