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: 10226342
• 负责人: Andrew H. Bond
• 金额: $ 91.21万
• 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 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10226342
• 关键词: Acceleration; Acetaminophen; Acids; Address; Behavior; Benchmarking; Biological Availability; Chemicals; Coupled; Crystal Formation; Crystallization; Data; Data Collection; Development; Diabetes Mellitus; Drops; Engineering; Excipients; Excretory function; Exhibits; Failure; Goals; Helping to End Addiction Long-term; 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; detection limit; 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.

项目摘要 Denovx的技术改善了活性药物成分（API）和蛋白质的结晶。超过 70％的API表现出较差的H2O溶解度和生物利用度，导致药物衰竭。共结晶 与超分子异质的API伴侣，是创建H2O的水晶工程方法 可溶性API组成，但对于高吞吐量筛选（HTS）尚不可再现。一拳/死 HTS格式和Hydroulic Press可用于压缩机械结晶以提供可重现的 剪切力足以形成共结晶。第一阶段证明了具有48井格式的高置信度POC 用于API共晶的HTS机械晶体，并在连续变化中具有出色的可重复性 学习。显示了与压缩机械晶体结合的溶剂滴磨制定基准的比较 以后的时间可以减少81％，材料少60％，同时产生25％的样本 分析。通过斯坦福大学同步辐射光线（SSRL）和Argonne的子宣告 高级光子源（APS），II期将与同步粉末整合HTS机械构型 X射线衍射（PXRD）分析，提供无与伦比的次要构造识别，定量，结构， 和吞吐量。特定目的1：使用使用重复（n≥6）对压缩机械构图的研究 α-突出型识别最大的变量，影响API共结晶。检查两个基准和≥14 来自酸性，碱性和中性API类的共结晶适当匹配与具有异性的异质。 完全H键的行为。通过子武器和SSRL和APS收集同步器PXRD。具体目标 2：测试≥6压缩机械晶体ꞵ-prototypes可以用作易于的样品持有人 PXRD对API和共结晶的分析。四个原型要与同步加速器PXRD兼容和两个原型 较低的多路复用格式适用于实验室PXRD。多路复用持有人中的API共晶样品给出 n≥6个连续变异研究的平均值±3σ之内的同步加速器PXRD组成。具体目标3： 进行高通量同步器PXRD数据收集以证明检测限制≤0.2％（w/w） 在连续变异研究中，使用𝛾-prototype机械结构样品中的次要组成型API阶段 持有者。同时证明PXRD模式采集率≤90s，同时保留数据 质量。特定目标4：展示整洁和溶液稀疏的压缩机械构图HTS ≥6个高影响API目标的SSRL/AP的同步pxRD的共结晶与与 制药公司和NIH。确定新的共结晶阶段和准备的条件 利益相关者的溶解度/渗透率研究。 HTS API和API机械结晶的可再现工具 共结晶将通过创建新的或重新利用的API作品来使公共卫生受益 1万亿美元的药品市场的体内溶解度和生物利用度。