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

基本信息

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
项目类别：
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

项目摘要

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。