GOALI: Informing Amorphous Formulations Design through Quantitative Nonlinear Optical Analysis

即使是微量的结晶度也会深刻地影响从药物成分到化学品的材料的物理行为。然而，众所周知，用现有的台式仪器检测小有机分子如活性药物成分的低水平结晶度是具有挑战性的。在这个由化学系化学测量和成像项目支持的项目中，加思·辛普森教授，他在普渡大学的研究小组，以及他们的工业合作伙伴默克公司，股份有限公司、将开发一种新的方法，晶体检测和量化的基础上，非线性光学光物质相互作用。在足够强的光场中，例如在飞秒脉冲激光的焦点中产生的光场中，通常与强度成非线性比例的弱相互作用变得显著。这些新的效应提供了显微镜的对比度，对小手性分子的晶体具有高度选择性。定量二次谐波发生（SHG）显微镜仪器结合实时数据处理将被开发和应用于表征微量结晶度在百万分之一（ppm）的水平，代表了10,000倍的降低检测下限相对于现有的常见的台式方法。将使用集成SHG显微镜和同步加速器X射线衍射的独一无二的仪器对痕量晶体检测和结晶度百分比测定进行独立确认。最初的应用将通过普渡大学研究人员和默克公司研究人员之间的合作，针对无定形制剂的分析。与默克的合作将有助于跨越“死亡之谷”--阻止药物发现向新药过渡的障碍--使手性系统非线性光学的基本发现与私营部门应用的现实相一致。如果成功，用于痕量晶体检测的可靠台式工具的开发可能直接影响药物制剂的设计和质量控制，并可能为更广泛范围的生物材料的分析提供信息。

Even trace crystallinity can profoundly affect the physical behavior of materials ranging from pharmaceutical ingredients to confectionaries. However, detection of low levels of crystallinity for small organic molecules like active pharmaceutical ingredients is notoriously challenging with existing benchtop instruments. In this project supported by the Chemical Measurement and Imaging Program of the Division of Chemistry, Professor Garth Simpson, his research group at Purdue University, and their industrial partner Merck & Co., Inc., will develop a new approach for crystal detection and quantification, based on nonlinear optical light-matter interaction. In sufficiently intense optical fields such as those arising in the focus of a femtosecond pulsed laser, normally weak interactions that scale nonlinearly with the intensity become significant. These new effects provide contrast in microscopy that is highly selective for crystals of small chiral molecules. Quantitative second harmonic generation (SHG) microscopy instrumentation incorporating real-time data processing will be developed and applied for characterizing trace crystallinity at parts-per-million (ppm) levels, representing a 10,000-fold reduction in the lower limits of detection relative to existing common benchtop methods. Independent confirmation of trace crystal detection and percent crystallinity determination will be performed using a one-of-a-kind instrument integrating SHG microscopy and synchrotron X-ray diffraction. Initial applications will target analysis of amorphous formulations through collaborations between Purdue investigators and researchers at Merck. Partnering with Merck will help span the"valley of death" - obstacles that prevent drug discoveries transition to new drugs - to align fundamental discoveries on the nonlinear optics of chiral systems with the realities of private sector applications. If successful, the development of reliable benchtop tools for trace crystal detection could directly impact the design and quality control of drug formulations and potentially inform analyses of a significantly broader scope of biological materials.