Near-Infrared VCD of Chiral Pharmaceuticals

申请者描述：拟议研究的目标是应用 傅里叶变换近红外振动圆二色谱(FT-NEAR-IRVCD)， 作为一种新的分子手性原位探针，用于分子手性分析 药物分子和最终配方药物产品。 目前，还没有可用的技术来确定 手性化合物的对映体纯度、绝对构型或构象状态 药物分子就地作为配方产品。我们建议联合 傅立叶变换中红外VCD光谱现有相关技术，常规 FT近红外吸收和反射光谱，固相中红外光谱和 紫外可见CD采样方法为手性检测提供了一种新的方法 制药公司。中红外区域的FT-VCD仪器最近 成为一种可用于商业用途的敏感的分子结构和 手性。FT-近红外光谱显示出显著的灵敏度和 近几年用于确定质量控制的抽样灵活性 各种产品中的因素，如食品、化学品和 制药公司。由此产生的新光谱技术--FT-近红外VCD， 将拥有探测对映体纯度的分析能力，绝对 晶体的构型、分子构象和粒度分布 最终配方手性药物中的固体，以及之前的任何步骤 在合成和生产过程中。除了解决方案阶段之外 抽样，我们将调查使用毛毯，颗粒，粉末，薄膜和 旋涂样品。开发的双偏振调制方法的使用 最近由首席调查员自动校正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 固相镉采样的重现性问题。在可能的情况下，近红外线 VCD将使用频率分配与中IR VCD相关联 2D-FT-MID-IR/近红外相关光谱。研究将在#年进行。 从现有的中红外仪器和方法逐步发展到 发展新的近红外仪器和方法。带FT-近红外-VCD 技术，然后我们将制定灵敏的分析措施，首先 纯手性药物样本，包括蛋白质药物，然后 各种赋形剂。特别感兴趣的药物分子 有心得安、麻黄类药物，包括麻黄碱、去甲麻黄碱、 伪麻黄碱、去甲麻黄碱、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，环孢菌素和 精选蛋白质药物。要研究的辅料包括葡萄糖。 (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持的最终药物的FT-近红外-VCD 产品。FT-近红外VCD对颗粒大小、水分的敏感性 蛋白质药物中的聚集性将被确定。的比例 药物与赋形剂的比例将发生变化，直到相当于 实现了用于人类管理的那些。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.