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High throughput x-ray diffraction and second order nonlinear optical imaging of crystals.

机译：高通量X射线衍射和晶体的二阶非线性光学成像。

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摘要

Active pharmaceutical ingredients (APIs) are typically required to be sufficiently hydrophobic to pass through lipid membranes and ultimately reach their targets, yet aqueously soluble enough to dissolve in the body. Approximately 40% of potential API candidates are currently abandoned due to poor systemic exposure at an estimated industry wide cost in the hundreds of millions of dollars annually. Packaging the ingredient into an amorphous solid is an attractive option for increasing the solubility and bioavailability of APIs, though the higher free energy comes at a price; amorphous APIs are typically metastable and can spontaneously crystallize, which significantly alters their bioavailability. A common compromise is to crystallize the API into a high energy state to balance the drug stability and bioavailability, but designing and manufacturing high energy API crystals is challenging, since there are many variables that determine the final structural form upon API crystallization. Since the API crystal structure, distribution of crystal structures, and percent crystallinity of the final dosage form is critical to the bioavailability and shelf life, having a rapid measurement throughput for crystal screening is highly desirable. X-ray diffraction is the current gold standard for determining crystal structures, but is expensive and slow. Other higher speed measurements (e.g. Raman, brightfield, calorimetry, and others) can be used to discriminate among previously diffracted structures in the late stages of the drug design process. Second harmonic generation (SHG) microscopy has previously been shown to be sensitive to crystals of smaller than 1 micron, can discriminate different crystal structures, and can quickly determine percent crystallinity with many orders of magnitude higher sensitivity than the common methods of X-ray powder diffraction or calorimetry.;In the work here, instrumentation and signal processing techniques were developed to increase the information content and measurement throughput of X-ray diffraction and SHG microscopy. A high throughput (GByte/second), multi-channel, computerized platform and optical circuitry interfacial electronics were developed in chapter 2, with parallelized computer algorithms implemented capable of realtime analysis of the datastream. A Lissajous trajectory beam-scanning microscope was developed in chapter 3 to quickly scan the field of view and increase the overhead available amount of laser power before thermal sample damage. From the synchronous high speed analog to digital conversion datastream, access was available to the full distribution of photomultiplier voltage measurements. The relationship connecting the photon counting and signal averaging techniques was developed through a statistical derivation in chapter 4, and resulted in a high speed algorithm that recovered 90% to approaching 100% of the theoretical maximum Poisson signal/noise. The counting statistics research was generalized in chapter 5 to the case of X-ray photon counting with silicon counting arrays for X-ray diffraction, where spectral information is natively present in the detected signal, and can be exploited for multiwavelength anomalous dispersion measurements; an algorithm was developed for mathematically extracting spectral information, calibrating the sensor, and increasing the measurement dynamic range.
机译：通常要求活性药物成分（API）具有足够的疏水性，以穿过脂质膜并最终达到其目标，但水溶性足以溶解在体内。由于系统暴露不良，目前约有40％的潜在API候选者被放弃，估计整个行业每年要花费数亿美元。将成分包装到无定形固体中是增加API的溶解度和生物利用度的一种有吸引力的选择，尽管更高的自由能是有代价的。无定形原料药通常是亚稳态的，可以自发结晶，从而大大改变其生物利用度。常见的折衷方案是使API结晶成高能态，以平衡药物的稳定性和生物利用度，但是设计和制造高能API晶体具有挑战性，因为有许多变量决定API结晶后的最终结构形式。由于API晶体结构，晶体结构的分布以及最终剂型的结晶度百分比对生物利用度和保质期至关重要，因此非常需要具有用于晶体筛选的快速测量通量。 X射线衍射是用于确定晶体结构的当前金标准，但是昂贵且缓慢。在药物设计过程的后期，可以使用其他更高速度的测量（例如拉曼，明场，量热法等）来区分先前衍射的结构。先前已证明，二次谐波（SHG）显微镜对小于1微米的晶体敏感，可以区分不同的晶体结构，并且可以快速确定结晶度百分比，且灵敏度比X射线粉末的常用方法高许多个数量级。 ；在这里的工作中，开发了仪器和信号处理技术以增加X射线衍射和SHG显微镜的信息含量和测量通量。第2章开发了高吞吐量（千兆字节/秒），多通道，计算机化平台和光学电路接口电子设备，并实现了能够实时分析数据流的并行计算机算法。在第3章中开发了Lissajous轨迹光束扫描显微镜，以快速扫描视野并增加热样品损坏之前的可用激光功率开销。从同步高速模拟到数字转换数据流，可以访问光电倍增管电压测量的全部分布。通过第4章中的统计推导开发了连接光子计数和信号平均技术的关系，并导致了一种高速算法，该算法将90％恢复到接近理论最大泊松信号/噪声的100％。计数统计研究在第5章中进行了概括，涉及使用硅计数阵列进行X射线衍射的X射线光子计数的情况，其中光谱信息固有地存在于检测到的信号中，可用于多波长异常色散测量；开发了一种算法，可通过数学方法提取光谱信息，校准传感器并增加测量动态范围。

著录项

  • 作者

    Muir, Ryan D.;

  • 作者单位

    Purdue University.;

  • 授予单位 Purdue University.;
  • 学科 Analytical chemistry.
  • 学位 Ph.D.
  • 年度 2014
  • 页码 135 p.
  • 总页数 135
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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