基于微流控芯片纳米电化学的药物杂质检测研究

Drug impurities are a critical factor that strongly affects the quality of pharmaceuticals. Reliable analytical techniques for impurities test can provide essential guarantee for drug development and clinical practice. Detection of drug impurities is facing a long-standing challenge, as the intricate drug impurities to be assayed in pharmaceuticals are usually at fairly low quantity level. Conventional analytical methods such as high performance liquid chromatography (HPLC), gas chromatography (GC), and thin layer chromatography (TLC) have some intrinsic drawbacks, which include unfavorable analytical time and expensive instruments cost; yet they are not environmentally friendly. Herein, we are ready to dedicate efforts to fabricating microanalytical systems based on the assembly of capillary electrophoresis microchip and nanoelectrochemical detectors, through which we design and construct simple, facile and feasible microchip-electrochemistry devices for the detection of drug impurities. The established microanalytical systems take several advantages such as rapidity, high efficiency, and economical consumption originating from microfluidic chips; meanwhile reap favorable analytical sensitivity and specificity by using novel nanoelectrochemical detectors. Nanomaterials including carbon nanotubes, graphene, and metal nanoparticles are used to assemble remarkable functional interface for electrochemical sensing, and the electrocatalytic reactions and electrochemical behaviors of drug impurities are to be investigated. Thus, the improved detection sensitivity and analytical reproducibility can be expected. Moreover, heterogeneous electron transfer on nanostructures in the microscale fluid environment would be inspected to enhance the mass transfer and chemical molecules recognition, thereby ameliorating the resolution of electrophoretic elutes. Presumably, nanomaterial-functionalized electrochemical detectors coupled to microfluidic platform promise to offer an avenue for impurity test and quality control of pharmaceuticals. Further, this project will present fundamental research strategies for constructing microanalytical devices in common drug laboratories.

药物杂质是影响药品质量的关键因素，可靠的杂质检测技术能够为药物研发和临床用药提供必要的质量安全保障。药物杂质分析面临的主要问题是：杂质种类多、含量低。传统的分析技术如HPLC、GC和TLC成本高、耗时长，且不利于环保。我们拟通过构建微流控芯片纳米电化学检测装置，将快速、高效、低成本的微芯片与灵敏度高、专属性强的纳米电化学检测器联用，设计出简便、灵活，实用性强的芯片电化学分析平台，用于药物杂质检测。通过构筑并优化功能化的纳米（如碳纳米管、石墨烯、金属纳米粒等）电化学传感界面，探讨药物杂质分子的电催化反应和电化学行为，以提高检测的灵敏度和重现性。进一步地，探讨微尺度流体环境下纳米界面的传质过程和化学识别，增强电泳组分在检测器上的异相电子传输速率，从而改善电泳谱带的分辨率。该研究有望为药物杂质检查和药品质量控制提供一种新的途径，并为在普通药学实验室构建新型的微型分析仪器提供一定的研究思路。

本项目以纳米电化学和纳流控体系的设计和构建为基础，探讨用于药物杂质检测的分析策略和技术手段，并注重方法的灵敏性、稳定性和实用性。研究内容包括：.(1) 纳米电化学和电分析.① 合成了还原石墨烯/金纳米粒（rGO/GNPs）杂合材料。以聚电解质PDDA为还原剂，氧化石墨烯和氯金酸为前驱物质，采用化学还原法实现了该纳米杂合物的合成。另外，PDDA还可以稳定金纳米粒，防止团聚；增加导电性，提高传感界面的电子传递能力。实验表明rGO/GNPs具有出色的电化学催化活性，可以同时检测氨基酚异构体；根据电化学理论推测了对氨基酚的电化学行为和反应机理。该方法用于检测对乙酰氨基酚制剂中的有毒性杂质对氨基酚。.② 探讨了电化学法制备还原石墨烯/铁氰酸钴（rGO/CoHCF）纳米复合物，该方法摒弃了肼还原策略。实验表明rGO/CoHCF具有一定的电催化协同效应，可有效降低肼和亚硝酸盐的氧化过电位，增强其电流响应。通过电化学测试和计算推测了两种组分的电化学转化过程，并实现了高灵敏度检测（肼和亚硝酸盐检出限分别为2.2 ppb和12.4 ppb）。.③ 研究了镍纳米粒/多壁碳纳米管/铜复合传感界面，实现了葡萄糖的直接电催化氧化。实验揭示了葡萄糖的电氧化是一个扩散控制的过程，且浓度响应范围宽、灵敏度高、特异性好，电极易于制备、成本低廉，可用于血液中葡萄糖的定量检测。.④ 制备了铂-钯双金属纳米粒，结合氮掺杂石墨烯构建了新的纳米传感界面。该复合纳米材料能显著降低亚硫酸和草酸的氧化过电位，并能同时检测抗坏血酸、亚硫酸和草酸。该方法可望用于维生素C注射液的总体质量控制（如主成分定量分析和杂质监测）。.(2) 纳流控-纳米孔道电化学系统.设计了一种集成有工作电极/对电极的纳米孔道-电化学-纳流控体系，从而实现了流体操控、分子识别以及信号输出三种功能在固态纳米孔道的一体化。该分析平台被用于非标记电化学检测DNA和蛋白质。