【作者】 李玉；

【导师】 王福安；

【作者基本信息】 郑州大学 ， 化学工艺， 2011， 博士

【摘要】 头孢类药物是一类来源于头孢菌素C、多为半合成的广谱抗生素。由于其疗效好、抗菌谱广、抗菌活性强,而成为目前抗生素研发和应用最为活跃的一类品种。但国产头孢类药物产品质量差,毒副作用、过敏反应时有发生,相关基础研究相当活跃。作为河南省教育厅自然科学基金项目(2008A530004),本文进行模拟生物溶液中头孢类药物溶解度及溶解过程热力学、折射率、电导率、体积性质、粘度性质及相应热力学行为研究,具有重要学术理论意义和工程应用前景。采用激光监视动态法测定了278.15K～308.15K温度范围内盐酸头孢吡肟、头孢地嗪钠、硫酸头孢匹罗3种头孢类药物在水、甲醇+水、乙醇+水、正丙醇+水、异丙醇+水中的溶解度。运用基于流体相平衡分子热力学的双参数溶解度模型关联了溶解度数据,确定了模型参数。根据化工热力学原理,由溶解度实验数据计算出3种头孢类药物在水和醇+水混合溶剂中的溶解焓△solH和溶解熵△solS.△solSH>0,表明头孢类药物分子与溶剂分子之间的交互作用弱于溶剂分子间的缔合作用,头孢类药物溶于溶剂的过程中缔合键的断裂占主导地位,为吸热过程。△solSH、△solS均为正值,说明头孢类药物在水和醇+水混合溶剂中的溶解为熵变驱动过程。ΔsolS>0,表明头孢类药物分子溶解进入溶剂中时扰乱了溶剂分子的排列,使体系的有序度降低,混乱度增加,熵增加。实验测定了278.15K～313.15K温度范围内盐酸头孢吡肟、头孢曲松钠、头孢地嗪钠、头孢噻肟钠等4种头孢类药物与水和0.9%生理盐水所组成二元、三元溶液的密度。对所研究体系的密度随温度和浓度的变化用Vogel-Tamman-Fulcher方程进行了关联,确定了方程参数。由密度实验数据计算出头孢类药物在水溶液和0.9%生理盐水溶液中的表观摩尔体积、标准偏摩尔体积、标准偏摩尔体积膨胀率等体积性质。运用Heple准则探讨了溶质—溶质、溶质—溶剂的相互作用和头孢类药物的结构破坏效应。实验测定了278.15K-313.15K温度范围内盐酸头孢吡肟、头孢曲松钠、头孢地嗪钠、头孢噻肟钠与水和0.9%生理盐水所组成的二元、三元溶液的粘度。计算出盐酸头孢吡肟、头孢曲松钠、头孢地嗪钠、头孢噻肟钠与水和0.9%生理盐水所组成溶液的相对粘度变化、粘度B系数等粘度性质。运用Jones-Dole方程探讨了溶质—溶质和溶质—溶剂相互作用以及盐酸头孢吡肟、头孢曲松钠、头孢地嗪钠、头孢噻肟钠的结构破坏效应。实验测定了278.15K～313.15K温度范围内,盐酸头孢吡肟、头孢曲松钠、头孢地嗪钠、头孢噻肟钠与水或0.9%生理盐水所组成的二元、三元溶液的折射率数据。建立了适用于头孢类药物溶液折射率的分子热力学模型,并确定了模型参数。模型计算值与实验值相比较8个体系536个数据点的总标准偏差为1.095×10-4。实验测定了278.15K～313.15K温度范围内盐酸头孢吡肟、头孢噻肟钠和头孢曲松钠生理盐水溶液的电导率,算出摩尔电导率。摩尔电导率随溶液浓度的变化服从改进的Kohlrausch经验方程,计算得到极限摩尔电导率。极限摩尔电导率和温度呈直线关系。摩尔电导率和温度的关系遵从Arrhenius方程。据此,求得迁移过程活化能和极限迁移过程活化能。研究结果既为头孢类药物在醇水、生理盐水等模拟生物溶液中的热力学行为研究奠定基础,还将为头孢类药物生产技术进步、药效行为和相关溶液热力学研究提供依据,也将在一定程度上促进相关学科发展。更多还原

【Abstract】 Cephalosporins are semi-synthetic broad-spectrum antibiotics which are modified by cephalosporin C. Currently, more and more researches and developments are focused on cephalosporins because of its high efficacy, broad spectrum antimicrobial and antibacterial activity. However some byeffects and anaphylactic reaction occurred occasionally due to domestic cephalosporins poor quality control. Suported by Natural Science Foundation of Henan Education Department (2008A530004), the solubilities and the thermodynamics for dissolving process, refractive indices, electrical conductivity, the volume properties as density and transferring properties as viscositiy of cephalosporins in simulated biological solutions are studied systematically in this paper. The results will have a great significance in scientific theory and engineering applications.Using the laser monitoring observation technique, the solubilities of three cephalosporins including cefepime hydrochloride, cefodizime sodium and cefpirome sulfate in water, water+methanol, water+ethanol, water+1-propanol and water+ 2-propanol were measured in the temperature range from 278.15 K to 308.15 K. The experimental data were correlated with a simple model of molecular thermodynamics for solubilities of solid in liquid and the model parameters were obtained completely. The dissolution enthalpies△solH and dissolution entropies△solS of the three cephalosporins in water and water+alcohol were estimated.△solH> 0 reveals that the interactions between the cephalosporins and solvent molecules are weaker than those between the solvent molecules. The dissolved process is endothermic and the break of association bond is principal. The positive△solH and△solS reveal that the dissolution process of the three cephalosporins in the studied systems were entropy-driven processes.△solS> 0 shows that when cephalosporins dissolved into solvents, the array of solvents molecular was disturbed, the degree of order decrease, randomness increases and entropy increases.The densities, viscosities and refractive indices of cefepime hydrochloride (or cefodizime sodium, ceftriaxone sodium and cefotaxime sodium)+water (or 0.9 mass % normal saline) binary and ternary solutions were measured at different concentrations in the tempreture range from 278.15K to 313.15 K.The Vogel-Tamman-Fulcher Equation was used to correlate the densities variation with temperatures and concentrations successfully by least square method. Apparent molar volumes, standard partial molar volumes, standard partial molar volume expansivities of cephalosporins in binary or ternary solutions were calculated based on experimental densities. Changes in relative viscosity and viscosity B-coefficient of the four cephalosporins were calculated from viscosity experimental data. The variation rules of volume properties and viscosity properties were discussed from the aspect of molecular interactions. Solute-solvent interaction, solute-solute interaction and structure-breaking effect of the four cephalosporins have been discussed using the Helper rule and Jones-Dole equation.A molecular thermodynamic model of refractive indices for multicomponent solutions was proposed, based on the molecular model for solution structure and equation for the excess enthalpy of a binary solution. The model parameters were determined by nonlinear least square method from the experimental measurements. Compared the calculated data by model with the experimental data, the total standard deviation of the 536 data points in 81 systems is 1.095×104.The conductivity of cefepime hydrochloride (cefotaxime sodium or ceftriaxone sodium)+saline water ternary solutions were determined in the tempreture range from 278.15K to 313.15 K and the molar conductivity was calculated. The molar conductivity depending on the molality of solutions were correlated with the modified Kohlrausch equation, and the limiting molar conductivities were obtained at different temperatures for the three systems. The limiting molar conductivities were linearly correlated with temperatures. The relationship between the molar conductivity and temperature submits to Arrhenius Equation. In view of the above, the activation energy for conductivity and the limiting activation energy for conductivity can be obtained.The results not only provide the academic datas for the behavior of thermodynamics of cephalosporins in simulated biological solutions such as water+ alcohol and normal saline, but also provide foundations for the improvement of production technology, the studies of pharmacodynamics and relevant molecular thermodynamics as well. The research will be sure to promote the development of relevant subjects.更多还原