离子交换树脂分离米格列醇的应用基础研究

【作者】 章结兵；

【导师】 张小里；

【作者基本信息】 西北大学 ， 化学工程， 2012， 博士

【摘要】 米格列醇作为一种重要的糖尿病治疗药物,可利用化学全合成法和化学与生物组合法进行制备,而化学与生物组合法合成米格列醇路线因具有流程短、条件温和、收率高等优势受到重视。同时,高纯度分离是作为原料药物使用的前提,因此针对化学与生物组合法特点开展的米格列醇分离工艺过程研究是十分关键的课题,但鉴于米格列醇及其相关物质特殊的化学结构,其分离和纯化方面的基础数据相对欠缺。本文以米格列醇和离子交换树脂间的相互作用作为对象,研究米格列醇吸附分离纯化过程的基本规律及工艺条件。主要研究内容及结论如下：1.通过对波长、吸光度与浓度间关系等分光光度计测试条件研究,确立了可用于工艺过程监控的米格列醇及N-羟乙基葡萄糖胺浓度简便测试方法,通过准确度和精密度分析,证明了该测试方法的可行性。2.研究米格列醇吸附平衡规律,获得了吸附介质类型、浓度、温度和溶液pH值对离子交换吸附平衡影响关系,并运用热力学、平衡吸附模型、SEM和孔结构测试去分析米格列醇与树脂间的吸附平衡行为。结果表明：米格列醇在树脂D001上具有较高的吸附量,不同米格列醇初始浓度下的等温吸附平衡遵循Langmuir方程。该离子交换过程为放热过程,温度越高,越不利于米格列醇在树脂D001上的吸附。相同起始浓度下的吸附平衡研究发现：随着温度的升高,树脂表面覆盖分数(0)值逐渐下降。相同温度条件下,随着米格列醇溶液浓度的增加,树脂表面覆盖分数0值逐渐加大。米格列醇溶液在中性条件下,树脂对其具有较高吸附量且树脂吸附后表面积增大,而树脂内孔面积、孔容和孔直径呈下降趋势。3.通过考察米格列醇浓度、温度和震荡速率外在因素去研究米格列醇在树脂D001上的离子交换过程。结果表明：米格列醇在D001树脂上吸附交换3h即可达到吸附平衡。溶液初始浓度越大,吸附速率越快,树脂平衡吸附量也越大。温度越高,离子交换达到吸附平衡的时间越短。恒温振荡器的震荡速率越快,吸附速率越大,但震荡速率对吸附过程的影响有临界值。动力学模型拟合分析表明该离子交换过程符合类型1的伪二级动力学模型。米格列醇在树脂D001上的离子交换过程为膜扩散控制,溶液浓度、温度和震荡速率值的改变对米格列醇在D001树脂上的吸附传质扩散过程控制影响较弱。相关物质N-羟乙基葡萄糖胺相对米格列醇在树脂上具有更强的离子交换吸附能力,该等温吸附平衡过程也符合Langmuir吸附方程,且两者都具有相似的离子交换动力学方程。4.考察米格列醇上样液浓度、流速、温度、高径比、床层堆积高度以及洗脱剂类型、浓度和流速影响因素去研究固定床中米格列醇的吸、脱附规律。结果表明：随着上样液浓度的增大,达到树脂吸附平衡饱和点的时间缩短,固定床传质区高度(MTZ)增大,固定床树脂吸附率(A)变小,上样液浓度为8mg/mL和流速为0.7mL/min时的吸附量最大。动力学模型对离子交换过程拟合分析结果显示：Thomas模型和Yoon-Nelson模型对其具有较好的拟合度。上样液的溶液温度对吸附过程影响较小。固定床高径比(H/D)越小,对应的固定床吸附效率(AE)和A值越大。床层堆积高度越大,吸附量越大。BDST模型拟合度高,对应的理论计算值N0和Ka与实验值相差小。筛选氨水作为洗脱剂,当氨水浓度越大,流速越低时所对应的物质洗脱量越大。固定床堆积高度为1.5cm时,洗脱剂的洗脱效率(EE)达到最大。5.以上样液混合物的不同流速、固定床高径比、床层树脂堆积高度以及洗脱剂浓度和流速等影响因素来研究米格列醇和N-羟乙基葡萄糖胺不同质量比下混合物在固定床上的离子交换分离过程。结果表明：随着上样混合溶液中米格列醇含量的提高,AE值逐渐增大,而A值下降。上样液流速较大时具有较小的固定床MTZ值,其对应的AE值和A值都明显增大。固定床高径比越大,其对应的固定床树脂吸附量越小,AE和A值都较小。固定床堆积高度越大,树脂吸附量、AE值和A值都增大。对于米格列醇与N-羟乙基葡萄糖胺质量比固定的混合物上样液,在设定吸附条件下进行洗脱,结果显示：氨水浓度越大,流速越小,洗脱混合物中米格列醇与N-羟乙基葡萄胺质量比值越大。针对不同质量比下的混合物吸附洗脱实验发现：上样液混合物中米格列醇质量比值越高,氨水对其洗脱影响越明显,当上样液混合物中米格列醇与N-羟乙基葡萄糖胺质量比值为9：1时,经过氨水洗脱后可使洗脱混合物溶液中两者质量比值提高到62.6,米格列醇由最初纯度90.0%提高到98.0%以上。同样以氨水对固定床树脂不同堆积高度下吸附米格列醇的洗脱实验研究结果表明：氨水对固定床树脂堆积高度为1.5cm的床层树脂上吸附离子洗脱效果较好,这时洗脱液中米格列醇与N-羟乙基葡萄糖胺质量比值达到最大。同时通过明显提高固定床层高度下的洗脱实验研究,优化了米格列醇与N-羟乙基葡萄糖胺间的洗脱曲线,建立了洗脱动力学模型,归纳了组分间的分离规律。更多还原

【Abstract】 Chemical method and chemical-biological method are mainly used to synthesize miglitol as an important diabetes drug, The chemical-biological method synthesis route of miglitol is paid more attention due to superiority of the short of synthesis route.mild conditions and the higher yield. Meanwhile, high purity of the product is application prerequisite as raw drug. Therefore, it is an important key issue to study separation process of miglitol for characteristics of chemical-biological method. In view of the special chemical structure of miglitol and related substance, the basic data in the separation and purification is relative lack. In this paper, the basic rules and the technology conditions of the adsorption purification process are investigated with the interaction of miglitol and ion exchange resin as object.The main research contents and conclusions are as follows:1. The test conditions of wavelength, absorbency and concentration in spectrophotometer were investigated to establish simpler test method for the monitoring technology process of miglitol and N-hydroxyethyl glucosamine concentration.The test method is proved feasible by the method of the accuracy and precision analysis.2. In the adsorption equilibrium experiment, the types of adsorption medium, initial concentrations of miglitol, temperatures, pH values were discussed to study adsorption equilibrium effects for miglitol adsorbed onto resin. Furthermore, adsorption thermodynamics, equilibrium adsorption models, scanning electron microscope and pore structure analysis were investigated to analysize adorption behaviors of miglitol and resins.The results showed that there is high adsorption capacity of D001resin as separation medium.The adsorption equilibrium at different initial concentrations of miglitol is followed by Langmuir model. The higher is the temperature, the more is unfavourable to miglitol adsorbed onto the resin D001.and the ion exchange process is exothermic chemical process.The values of surface coverage fraction of resin(θ) gradually decline with increasing temperature.The values of θ gradually increase with increasing miglitol concentration.There is high adsorption capacity of resin for miglitol in neutral condition and the surface of absorbed resin increases, and meanwhile, the values of the pore area,pore volumn and pore diameter fall.3. The external effect factors of resin adsorption capacity including initial concentration of miglitol, temperature and stirring rates were investigated respectively to study ion exchange process of miglitol onto resin. The results showed that the adsorption time for miglitol onto D001resins continues3hours and can reach adsorption equilibrium.The greater is the initial concentration, the faster is absorption rate and equilibrium adsorption capacity of resin is also bigger. The higher are the temperature and stirring rate, ion exchange equilibrium time is shorter and the adsorption rate is faster correspondingly. Nevertheless, there is a critical value for stirring rate on effect of ion exchange adsorption process.In addition, the ion exchange process is in accord with typel pseudo-second order kinetic model and is mainly controlled by film diffusion.The value changes of concentration, temperature and stirring rate are affected weakly to control mass transfer diffusion process during the ion exhange process. The related substance N-hydroxyethyl glucosamine is more easy to be adsorbed onto resins D001in contrast to that of miglitol, the adsorption equilibrium at different initial concentrations of N-hydroxyethyl glucosamine is also followed by Langmuir mathmetics model. Meanwhile, their ion exchange kinetic models are similar.4. The factors of concentration, flow rate, temperature, height to diameter ratio (H/D), fixed bed stacking height and the types of eluents, concentration and flow rate of eluent were separately discussed to study adsorption and elution law of miglitol in the fixed bed.The results showed that the saturation point of time is shortened with increasing influent concentration, height of mass transfer zone (MTZ) increases and the value of adsorption ratio (A) decreases. The influent concentration8mg/mL and flow rate0.7mL/min for adsorption capacity is the maximum. The kinetic model fitting analysis for the ion exchange process in the fixed bed shows that Thomas model and Yoon-Nelson model has better fitting degree.The solution temperature on effect of adsorption process is weak. The value of height to diameter ratio is smaller, the corresponding adsorption efficiency (AE) and value of A is larger. The higher is the stacking height of the fixed bed, the greater is the adsorption capacity of resin. The ion exchange process is fitted by bed depth service time (BDST) model and reachs good fit degree, the calculated value of the volume adsorption capacity (No) and rate constant of BDST model (Ka) differ little. The ammonia water is selected as eluent, the greater is concentration of ammonia water and the flow rate is lower, the elution quantity is also biger. In addition, the stacking height of the fixed bed is1.5cm and the value of elution efficiency reaches the largest.5. The ion exchange separation process in the fixed bed for the different mass ratios of miglitol to N-hydroxyethyl glucosamine was discussed by influent concentrations, flow rate, height to diameter ratio, stacking height, concentration and flow rate of eluent, respectively. The results showed that the values of adsorption efficiency gradually increases and the values of adsorption ratio declines with increasing miglitol concentration. There is a small value of mass transfer zone with the greater flow rate, the corresponding values of adsorption efficiency and adsorption ratio obviously augments. The greater is the value of height to diameter ratio and corresponds with the small value of D001resin adsorption capacity, the values of adsorption efficiency and adsorption ratio are all smaller. The bigger is the stacking heigh in fixed bed. the adsorption capacity, the values of adsorption efficiency and adsorption ratio are all increasing. The adsorbed ions were eluted for the fixed mass ratio mixture. The results showed that there are a higher mass ratio of miglitol to N-hydroxyethyl glucosamine in effluent solution mixture with a greater concentration and a lower flow ratio of ammonia water.The different mass ratios mixture were eluted and investigated by ammonia water, it was found that the adsorbed samples are eluted more obvious with the higher miglitol mass ratio in the influent mixture.The mass ratio of miglitol to N-hydroxyethyl glucosamine in the effluent solution mixture reaches62.6:1when the influent mass ratio of miglitol to N-hydroxyethyl glucosamine is9:1,the purity of miglitol is from90.0%to over98.0%. In addition, the adsorbed samples in different fixed bed stacking heights were also eluted and found that the elution results is better when the stacking height is1.5cm in the fixed bed, the mass ratio of miglitol to N-hydroxyethyl glucosamine in effluent solution mixture is the best. The elution curves of miglitol and N-hydroxyethyl glucosamine are obviously optimized by prolonging the stacking height in the fixed bed, establishs elution kinetic model and summarizes the separation law of the matters.更多还原