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

项目总结 DeNovX的技术改善了活性药物成分(API)和蛋白质的结晶。完毕 70%的原料药表现出较差的H2O溶解性和生物利用度，这是导致药物失败的原因。共结晶 将原料药与超分子异构体配对，是一种产生H2O的晶体工程方法 可溶的原料药成分，但还不能用于高通量筛选(HTS)。冲压/冲模在…中 HTS格式和水压机可用于压缩机械结晶，以获得可重现的 足以形成共晶的剪切力。第一阶段演示了48孔格式的高置信度POC 用于API共晶体的高温超导机械结晶，并在连续变化中提供优异的重现性 学习。溶剂滴磨基准与压缩机械结晶的比较表明 后者可以用更少的材料减少81%的时间，同时产生更多25%的样品 分析。通过授予斯坦福大学同步辐射光源(SSRL)和阿贡的子奖 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，提供无与伦比的次要成分鉴定、定量、结构、 和吞吐量。具体目标1：进行重复(n≥6)的压缩机械结晶研究 原型法-确定对原料药共结晶影响最大的变量。检查两个基准测试和≥14 来自酸性、碱性和中性原料药类别的共晶与具有 互补的氢键行为。通过授予SSRL和APS的子奖收集同步加速器PXRD。特定目标 2：测试≥6压缩机械结晶ꞵ-可用作以下消耗品样品架的原型 原料药和共晶的X射线衍射分析。四个与同步加速器PXRD兼容的原型和两个 较低的多路复用格式，适合实验室PXRD。API共晶样品在多路复用器上给出 同步加速器X射线衍射物相组成在nσ6连续变化研究的平均值的±3≥内。具体目标3： 进行高通量同步加速器X射线衍射仪数据采集，以验证≤0.2%(w/w)的检测限值 使用𝛾-原型机械结晶样品的连续变化研究中的次要组分API相 持有者。同时演示每个样本的X射线衍射图采集率≤90 S，同时保留数据 质量。具体目标4：演示整齐和溶剂稀疏的压缩机械结晶HTS 在SSRL/APS上用同步加速器X射线衍射法对与以下相关的≥6高冲击原料药靶材进行共晶 制药公司和美国国立卫生研究院。确定新的共晶相和制备条件，使 利益相关者进行的溶解度/渗透率研究。用于原料药和原料药的HTS机械结晶的可重复工具 共晶体将通过创造新的或改变用途的原料药组合物来造福公共健康，在 1万亿美元药品市场的体内溶解度和生物利用度。

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.