Near-Infrared VCD of Chiral Pharmaceuticals

申请人的描述：拟议研究的目的是应用 傅里叶变换近红外振动圆二色性（FT-near-IRVCD）， 作为一种新的分子手性原位探针， 药物分子和最终配制的药物产品。 目前，还没有可用的技术来确定 对映体纯度、手性化合物的绝对构型或构象状态 药物分子原位作为配制产品。我们建议将联合收割机 现有的FT中红外VCD光谱相关技术，传统的 FT近红外吸收和反射光谱，以及固相中红外和 紫外-可见CD采样方法，以产生探测手性的新方法 大药厂中红外波段的FT-VCD仪器最近已 作为分子结构的灵敏探针变得可商购获得， 手性FT-near-IR光谱显示出显著的灵敏度， 近年来取样灵活，用于质量控制的测定 食品、化学品和食品等多种产品中的各种因素 大药厂由此产生的新的光谱技术，傅立叶变换近红外VCD， 将具备探测对映体纯度、绝对 构型、分子构象和粒度分布 固体，在最终配制的手性药物中，以及任何先前的步骤 在合成和生产过程中。除了溶液相 抽样，我们将调查使用的研磨，颗粒，粉末，电影和 旋涂样品。利用双偏振调制方法研制的 最近由主要研究者自动校正CD基线， 将抑制所有固体样品中的双折射效应，从而消除许多 固相CD取样的再现性问题。如果可能，近红外 VCD将使用频率分配与中红外VCD相关， 2D-FT-中红外/近红外相关光谱。这项研究将在 逐步的方式从现有的中红外仪器和方法， 开发新的近红外仪器和方法。带FT近红外VCD 技术在手，我们将开发敏感的分析措施，首先 纯手性药物样品，包括蛋白质药物，然后 各种赋形剂。特别感兴趣的药物分子 是普萘洛尔、麻黄碱、去甲麻黄碱、 伪麻黄碱、去甲伪麻黄碱、N-甲基麻黄碱和N-甲基麻黄碱 伪麻黄碱，止痛药布洛芬和萘普生，环孢菌素， 选择蛋白质药物。待研究的赋形剂包括葡萄糖 （葡萄糖）、蔗糖、乳糖、环糊精和纤维素。在这些研究之后， 我们将测量赋形剂支撑的最终药物的FT-近红外-VCD， 产品. FT-near-IR VCD对粒径、含水率的敏感性 并测定蛋白质药物中的聚集。的比率 药物与赋形剂的比例将发生变化，直至 实现了用于人施用的那些。这将允许在原地 最后阶段手性和物理性质的控制质量 医药产品。

APPLICANT'S DESCRIPTION: The objective of the proposed research is to apply Fourier transform near-infrared vibrational circular dichroism (FT-near-IRVCD), as a new in situ probe of molecular chirality, to the analysis of pharmaceutical molecules and final formulated pharmaceutical products. Currently, there is no available technology for the determination of enantiomeric purity, absolute configuration or conformational states of chiral pharmaceutical molecules in situ as formulated products. We propose to combine the existing related technologies of FT mid-IR VCD spectroscopy, conventional FT near-IR absorption and reflection spectroscopy, and solid-phase mid-IR and UV-visible CD sampling methods to yield a new methodology for probing chiral pharmaceuticals. FT-VCD instrumentation in the mid-infrared region has recently become commercially available as a sensitive probe of molecular structure and chirality. FT-near-IR spectroscopy has shown remarkable sensitivity and sampling flexibility in recent years for the determination of quality-control factors in wide varieties of products, such as food, chemicals and pharmaceuticals. The resulting new spectroscopic technique, FT-near-IR VCD, will possess the analytical capability to probe enantiomeric purity, absolute configuration, molecular conformation, and particle-size distribution in solids, in final formulated chiral pharmaceuticals, as well as any prior step in the synthesis and production process. In addition to solution-phase sampling, we will investigate the use of mulls, pellets, powders, films and spin-coated samples. The use of dual polarization modulation methods developed recently by the principal investigator to automatically correct CD baselines, will suppress birefringence effects in all solid samples, thus eliminating many problems of reproducibility in solid-phase CD sampling. Where possible, near-IR VCD will be correlated to mid-IR VCD using frequency assignments and 2D-FT-mid-IR/near-IR correlation spectroscopy. The research will proceed in step-wise fashion from existing mid-IR instrumentation and methods to the development of new near-IR instrumentation and methods. With FT-near-IR-VCD technology in hand, we will then develop sensitive analytical measures of first pure chiral pharmaceutical samples, including protein pharmaceuticals, and then excipients of various kinds. Pharmaceutical molecules of particular interest are propranolol, ephedra drugs, including ephedrine, norephedrine, pseudoephedrine, norpseudoephedrine, N-methyl ephedrine and N-methyl pseudoephedrine, the analgesics ibuprofen and naproxen, and cyclosporins and selected protein pharmaceuticals. The excipients to be studied include dextrose (glucose), sucrose, lactose, cyclodextrins and cellulose. After these studies, we will measure FT-near-IR-VCD of excipient-supported final pharmaceutical products. The sensitivity of FT-near-IR VCD to particle size, moisture Content and aggregation in protein pharmaceuticals will be determined. The ratio of pharmaceutical to excipient will be varied until proportions equivalent to those used for human administration are achieved. This will permit in situ quality of control of chiral and physical properties in final-stage pharmaceutical products.