【作者】 蒋雪梅；

【导师】 夏之宁；

【作者基本信息】 重庆大学 ， 药物化学， 2006， 硕士

【摘要】 微乳液毛细管电动色谱法（MEEKC）是一种毛细管电泳的新方法。它利用药物在微乳液滴相和水连续相中的分配性质，而引起其电泳迁移行为的差异，已被发展为药物疏水参数logP_ow测定的一种新技术。MEEKC中迁移时间t_m测定的准确与否，决定着能否得到准确的logP_ow值。然而，我们发现试样中作为待测化合物（药物）的迁移行为受其在试样中浓度、进样量以及电泳高电场的影响，即迁移时间t_m值的大小由化合物浓度、进样量以及电泳高电场决定。而前人的工作忽略了上述因素对t_m的影响，导致测定药物logP_ow时存在较大误差。因此，建立一种经过改进的MEEKC方法，保证t_m测定的可靠性，对药物疏水参数值的测定是非常必要的。本论文通过考察化合物浓度、进样量和高电场对其迁移行为的影响及其规律，探讨了化合物分配于微乳后改变微乳内相性质的原因，以及电泳高电场致使微乳液性质变化的机理。在此基础上，建立了一种测定药物疏水参数的改进型MEEKC方法（I-MEEKC）。并尝试采用迭代拟合的方法计算微乳相的迁移时间，以克服以往采用微乳相标记物标记其迁移时间的困难和不足，从而进一步提高MEEKC方法测定疏水参数的准确度。本研究详细考察了该改进方法的可行性和可靠性，并进行了其应用研究。主要研究内容如下： 1) 建立了能更准确测定化合物疏水参数的I-MEEKC方法。通过详细考察5种苯胺类化合物的浓度、进样量和高电场对其迁移行为的影响及其规律，探讨了化合物分配于微乳后改变微乳内相性质的原因，以及电泳高电场致使微乳液性质变化的机理，提出了相应的解决方法。在此基础上，建立了同时扣除待测化合物浓度、进样量以及高电场影响的测定化合物疏水参数的I-MEEKC方法。将I-MEEKC方法应用于苯、甲苯、乙苯、阿昔洛韦以及扑热息痛5种化合物的疏水参数的测定，测定值与文献值平均相差0.16个对数单位，比现行的MEEKC方法所测值与文献值的平均差值0.40小，准确度有了一定的提高，验证了I-MEEKC方法的可行性和可靠性。 2) 探讨了一种不使用微乳相标记物的技术，使MEEKC法测定logP_ow更为方便。即以系列化合物在MEEKC中的迁移时间t_m与其已知的logP_ow值之间的非线性关系，迭代计算得到t_me，并同时建立了logP_ow，与logk的标准曲线。以该MEEKC方法对阿昔洛韦、扑热息痛、多沙唑嗪以及氯雷他定4种电中性药物的logP_ow值进行了测定，其测定值与采用经典的摇瓶法测得的logP_ow值较接近，平均差值为0.15。并以迁移时间测量误差⊿t_m对logP_ow值影响的数学推导，从理论上对该方法测得结果的准确度进行了分析评价。更多还原

【Abstract】 Microemulsion electrokinetic chromatography （MEEKC） has been used as a powerful method for indirect measuring the hydrophobic parameters (logP_ow) of various kinds of compounds. In order to obtain a correct value, the migration time of the solute （t_m） in MEEKC must be accurately required, because the t_m is an important parameter in measuring hydrophobicity with MEEKC. However, in our studies on conventional MEEKC, the influence of concentrations, injection volumes of compounds and high electric-field on their migration behavior was found, which may bring some problems when determining the logP_ow values. Therefore, an improved MEEKC is expected to be established to ensure the accuracy of t_m, which can obtain more accurate logP_ow values.In this paper, an improved method of MEEKC （I-MEEKC） that can solve the problems of determining logP_ow by conventional MEEKC was developed, In addition, a new method of MEEKC without microemulsion phase marker was studied. In this method, the migration time of microemulsion phase (t_me) was obtained by multiline fitting program, which can avoid the error from tracing t_me.The preparation process, feasibility and reliability of I-MEEKC were studied in detail and several applications with satisfactory results were performed. The main research and results are listed below:1. A novel method of MEEKC （I-MEEKC） was established, and its feasibility and reliability were studied. The concentrations, injection volumes of 5 anilines and high electric-field impacting on their migration behavior were studied. The reason and mechanism were also studied. Based on the study above, the I-MEEKC method was then developed. The logP_ow values of benzene, toluene, ethyl benzene, acilovir and acetaminophen by I-MEEKC were obtained: the average error between logP_ow values estimated using I-MEEKC and the ones from literature was 0.16 logarithm units.2. The migration time of microemulsion phase (t_me ) was obtained by non-linearity fitting with logP_ow, values from literature and measured migration time （t_m） of a series of organic compounds, a calibration curve for estimating logP_ow of pharmaceuticals was thus set up. The logP_ow values of 4 pharmaceuticals that are electric neutral measured by this method were close to those determined by shake-flask method, and the average error between values from two methods was 0.15 logarithm units. Furthermore, according to the suggested theory, the measurement accuracy of logP_ow is correlated更多还原