大孔树脂吸附黄柏总生物碱的理论和应用基础研究
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摘要
出现于20世纪60年代的大孔树脂吸附技术,以其操作工序简单,溶剂单一,污染小,且产品的纯度高等独特的优越性,广泛应用于中药有效成分的分离纯化。人们对该项技术做了大量的理论和应用研究,如大孔树脂型号的筛选,吸附工艺研究,大孔树脂柱的放大,动力学和热力学研究,但缺乏系统性；且吸附的对象多是单一成分,对总有效部位的探讨较少。鉴于此,课题选择黄柏总生物碱作为研究对象,系统探讨大孔树脂对它的吸附,为总生物碱有效部位的开发和工业化生产奠定基础,同时也为大孔树脂吸附技术分离纯化中药其它有效成分提供一条思路。论文选择黄柏药材,方面因为其价廉易得,另一方面,该药材的药效物质基础研究比较成熟,最后,本课题组做了大量相关的前期基础研究工作。各项工作总结如下：
(1)采用高效液相色谱法同时测定了黄柏药材中盐酸小檗碱、盐酸巴马汀、盐酸药根碱的含量。色谱条件为：Diamonsil 5μmC18柱(250 mm×4.6mm)；流动相为乙腈-1g／L磷酸(50：50),内含1g／L十二烷基磺酸钠；流速：1mL／min；检测波长：265nm。测定结果为：盐酸小檗碱11.4mg／g药材,盐酸巴马汀5.85 mg／g药材；盐酸药根碱0.82mg／g药材,三种小檗碱型生物碱的质量占到药材中总生物碱的39.28%。
(2)采用紫外分光光度法测定了黄柏药材中总生物碱的含量。药材中总生物碱的制备方法为：取黄柏药材粉末(过40目筛)1.00g,置索氏提取器中,加90mL的甲醇加热提取至提取液无色为止,将提取液转移至100mL的量瓶中,加甲醇定容至刻度。紫外检测波长为265nm,测得总生物碱的含量以盐酸小檗碱计为46mg／g药材。
(3)通过正交实验优化了黄柏总生物碱的提取工艺。较佳的工艺条件为：乙醇浓度60%,溶媒倍量8BV,提取时间1h,提取次数3次。在此条件下,总生物碱的得量为38mg／g药材,转移率为81.88%。
(4)选取9种大孔树脂进行初筛,以黄柏提取液中总生物碱的吸附率和解吸率为指标,筛选出效果较好的3种树脂：AB-8、HP20、LD605；对这3种树脂复筛,同时以盐酸小檗碱的解吸量作为考察指标,综合各种指标发现AB-8是一种理想的树脂,可用于黄柏总生物碱的分离纯化,具有较好的推广应用价值；国内生产AB-8树脂的厂家很多,性能参数差别较大。其中天津欧瑞生物科技有限公司生产的AB-8树脂在吸附黄柏总生物碱方面效果较好,将作为后续研究的对象,进行重点讨论。
(5)对AB-8树脂吸附黄柏总生物碱和盐酸小檗碱的动力学和热力学分别进行了探讨,两者的动力学和热力学特性非常相似。黄柏提取液中的总生物碱在AB-8树脂上的吸吸附过程趋近于一级动力学过程；在总生物碱起始浓度为0.686mg／mL,温度27℃条件下,吸附速率常数K1=2.176 h-1；过程同时受液膜扩散和颗粒内扩散控制；在较低的温度、pH值,较高的起始浓度、振荡速度下,有利于吸附；盐酸小檗碱在AB-8树脂上的吸附过程也趋向于一级动力学过程,但吸附速率比黄柏提取液中总生物碱要慢；过程速率同时受液膜扩散和颗粒内扩散控制；吸附速率常数随温度的降低而升高,随初始浓度、溶液pH、振荡速度的增加而增大。实验同时发现,黄柏提取液中的盐酸小檗碱和原料药中盐酸小檗碱两者的动力学过程存在明显的差异,后者用一级动力学方程拟合较好而前者不然；在吸附的起始阶段,前者速率较后者要快很多,说明提取液中盐酸巴马汀、盐酸药根碱等其它生物碱的存在影响了盐酸小檗碱在AB-8树脂上的吸附,使其速率加快。总生物碱和盐酸小檗碱的热力学性质基本一致,吸附等温线实验表明：平衡吸附量随着浓度的增加而增加,随着温度的升高而降低,说明低温较有利于吸附；吸附等温线用Langmuir和Freundlich模型都能较好的拟合,说明二者在AB-8树脂上都是单分子层吸附；吸附是放热的物理吸附；在几个实验温度下,吸附都能自发的进行。
(6)在动力学和热力学研究的基础上,建立了大孔树脂柱的放大模型,该模型包括5个部分：①物料衡算方程(连续性方程)；②动力学方程；③相平衡方程(吸附等温线方程)；④边界条件；⑤初始条件。求解该模型得到数值解,并通过实验验证了该模型,实验测得的数据和模型模拟得出的数据吻合很好,说明建立的数学模型准确可靠,可用于大孔树脂柱的放大。
(7)对AB-8树脂动态吸附黄柏提取液中的总生物碱以及盐酸小檗碱进行了工艺考察,得到吸附总生物碱较佳的条件为：上样量50mL样品／mL树脂,上样浓度0.684mg／mL,上柱流率2BV／h,杂质洗脱剂水的用量为3BV,洗脱剂采用40%的乙醇,用量为6BV,按照此工艺条件,得到总生物碱的纯度为40.06%,比上柱之前的纯度提高了2.56倍。吸附盐酸小檗碱的工艺条件为：上样量55mL样品／mL树脂,上样浓度0.576mg／mL,洗脱剂的种类为40%的乙醇,用量为6BV。
Macroporous resin adsorption technology, first appearing in the 1960s, is widely used in the separation and purification of active ingredients for its unique advantages, such as simple operational procedures, single-solvent, low pollution, and high purity of the product. Numorous work has been conducted on the application of this techneque in traditional Chinese medicine analysis both from the theoretical and applied aspects. However, these researches are still not very systematic and too preliminary. In view of this, we will comprehensively explore the adsorption behavior of the total alkaloids on macroporous resin which may lay the foundation for the industrial production of alkaloids and provide a thread for separating other effective parts of traditional Chinese medicine. In this paper, Cortex Pheullodendri Chinensis is selected as reserch object. On the one side because it is cheap and easy to get,'on the other side, the material basic research is more mature. Finally, a lot of work has been done to this medicine.The studies are summarized as follows:
(1)Using high performance liquid chromatography method to determine berberine hydrochloride, palmatine chloride and jatrorrhizine hydrochloride 's content simultaneously in Cortex Pheullodendri Chinensis. Chromatographic conditions are:Diamonsil 5μm C18 column (250 mm×4.6mm) is used, mobile phase is acetonitrile-lg/L phosphoric acid (50:50) (containing lg/L sodium dodecyl sulfate) with flow rate 1mL/min, detection wavelength is 265nm. Determination results are as follows:berberine hydrochloride is 11.4mg/g herbs, palmatine chloride is 5.85 mg/g herbs, jatrorrhizine hydrochloride is 0.82mg/g herbs. The quality of three kinds of berberine-type alkaloid is accounted for 39.28% to total alkaloids.
(2) Using ultraviolet spectrophotometry to determine total alkaloid content in Cortex Pheullodendri Chinensis. Sample preparation is as follows: taking Cortex Pheullodendri Chinensis powder 1.OOg to Soxhlet extractor, 'then adding 90mL methanol and heating until extraction liquid is colorless. The extract liquid is transferred to container of 100mL, adding methanol to the scale volume. Selecting UV detection wavelength is 265nm. The total alkaloid content of Cortex Pheullodendri Chinens is counted as 46mg/g herbs.
(3) Extraction process of total alkaloid in Cortex Pheullodendri Chinensis was optimized by orthogonal experiments. Better process conditions are:60% ethanol as extraction solvent with 8BV, distilling 3 times, 1h per time. Under these conditions, the extraction amount of total alkaloids was 38mg/g herbs. Transfering rate is 81.88%.
(4) Nine kinds of macroporous resin was selected for screening. Three kinds of resin AB-8, HP20, LD605 have a good effect both in total alkaloid adsorption and desorption. This three kinds of resin were used for furthere selected, the desorption amount of berberine hydrochloride as an inspection-target. The result shows AB-8 is an ideal kind of resin for separating and purificating total alkaloids. AB-8 resin'performance parameters produced by different manufacturers vary in domestic. The AB-8 resin which produced by Ou Rui bio-technology Co., Ltd., Tianjin shows a good effect in absorpting total alkaloids in Cortex Pheullodendri Chinensis and will be served as study object for further research.
(5)Adsorption kinetics and thermodynamics of total alkaloids and berberine hydrochloride on AB-8 resin were discussed. Both the dynamic and thermodynamic properties are very similar. The adsorption process of total alkaloids on AB-8 resin tends to be the first order kinetics process. At the conditions of starting concentration 0.686mg/mL, temperature 27℃, the adsorption rate constant k1=2.176 h-1. Process is controled both by film diffusion and in-particle diffusion. A lower temperature, pH, a higher initial concentration, oscillation speed are favourable to adsorp. Adsorption process of berberine hydrochloride on AB-8 resin also tends to be the first order kinetics process. But the adsorption rate is slower than the total alkaloid's. Process is controled both by film diffusion and in-particle diffusion. Adsorption rate rises with the decreasing of temperature and increasing of initial concentration, solution pH, oscillation speed. Experiment also found that the kinetics of berberine hydrochloride in Cortex Pheullodendri Chinensis extraction liquid and in bulk drug were significantly different. The latter fits well first order kinetics equation but the former not. In initial stage, the former's adsorption rate is much faster than the latter's, which indicates palmatine chloride and jatrorrhizine hydrochloride and other 'alkaloids'presence affecting and promoting berberine hydrochloride adsorption on AB-8 resin. Thermodynamic properties of the two are basically the same. The isotherm adsorption experiment shows that equilibrium adsorption capacity increases with the concentration. Lower temperature is more favorable to the adsorption. The isotherm adsorption data fits well Langmuir and Freundlich isotherm which indicate the two are monolayer adsorption on AB-resin.The adsorption is spontaneous exothermic process of physical characters.
(6) On the base of dynamics and thermodynamics study, amplification model of macroporous resin column was established, which includes five parts:①mass balance equation (continuity equation);②kinetics equation;③equilibrium equation (isotherm adsorption equation);④boundary conditions;⑤initial conditions. Solving this model obtains numerical solutions and experiment was done to verificate whether the model is exact. The measured data and model simulated data are coincided, indicating the establishment of the mathematical model is accurate, reliable, and can be used for amplification of macroporous resin column.
(7)The technical conditions of dynamic adsorption of total alkaloids and berberine hydrochloride on AB-8 resin were optimized. The former is:sample volume is 50mL samples/mL resin, sample concentration is 0.684mg/mL, flow rate is 2BV/h, the amount of impurities eluant is 3BV, eluant is 40% ethanol with 6BV. In these conditions, the purity of total alkaloids is 40.06% and increases 2.56-fold prior to before purification. Berberine hydrochloride adsorption conditions are: sample volume is 55mL samples/mL resin, concentration is 0.576mg/mL, eluant·is 40% ethanol with 6BV.
(1)采用高效液相色谱法同时测定了黄柏药材中盐酸小檗碱、盐酸巴马汀、盐酸药根碱的含量。色谱条件为：Diamonsil 5μmC18柱(250 mm×4.6mm)；流动相为乙腈-1g／L磷酸(50：50),内含1g／L十二烷基磺酸钠；流速：1mL／min；检测波长：265nm。测定结果为：盐酸小檗碱11.4mg／g药材,盐酸巴马汀5.85 mg／g药材；盐酸药根碱0.82mg／g药材,三种小檗碱型生物碱的质量占到药材中总生物碱的39.28%。
(2)采用紫外分光光度法测定了黄柏药材中总生物碱的含量。药材中总生物碱的制备方法为：取黄柏药材粉末(过40目筛)1.00g,置索氏提取器中,加90mL的甲醇加热提取至提取液无色为止,将提取液转移至100mL的量瓶中,加甲醇定容至刻度。紫外检测波长为265nm,测得总生物碱的含量以盐酸小檗碱计为46mg／g药材。
(3)通过正交实验优化了黄柏总生物碱的提取工艺。较佳的工艺条件为：乙醇浓度60%,溶媒倍量8BV,提取时间1h,提取次数3次。在此条件下,总生物碱的得量为38mg／g药材,转移率为81.88%。
(4)选取9种大孔树脂进行初筛,以黄柏提取液中总生物碱的吸附率和解吸率为指标,筛选出效果较好的3种树脂：AB-8、HP20、LD605；对这3种树脂复筛,同时以盐酸小檗碱的解吸量作为考察指标,综合各种指标发现AB-8是一种理想的树脂,可用于黄柏总生物碱的分离纯化,具有较好的推广应用价值；国内生产AB-8树脂的厂家很多,性能参数差别较大。其中天津欧瑞生物科技有限公司生产的AB-8树脂在吸附黄柏总生物碱方面效果较好,将作为后续研究的对象,进行重点讨论。
(5)对AB-8树脂吸附黄柏总生物碱和盐酸小檗碱的动力学和热力学分别进行了探讨,两者的动力学和热力学特性非常相似。黄柏提取液中的总生物碱在AB-8树脂上的吸吸附过程趋近于一级动力学过程；在总生物碱起始浓度为0.686mg／mL,温度27℃条件下,吸附速率常数K1=2.176 h-1；过程同时受液膜扩散和颗粒内扩散控制；在较低的温度、pH值,较高的起始浓度、振荡速度下,有利于吸附；盐酸小檗碱在AB-8树脂上的吸附过程也趋向于一级动力学过程,但吸附速率比黄柏提取液中总生物碱要慢；过程速率同时受液膜扩散和颗粒内扩散控制；吸附速率常数随温度的降低而升高,随初始浓度、溶液pH、振荡速度的增加而增大。实验同时发现,黄柏提取液中的盐酸小檗碱和原料药中盐酸小檗碱两者的动力学过程存在明显的差异,后者用一级动力学方程拟合较好而前者不然；在吸附的起始阶段,前者速率较后者要快很多,说明提取液中盐酸巴马汀、盐酸药根碱等其它生物碱的存在影响了盐酸小檗碱在AB-8树脂上的吸附,使其速率加快。总生物碱和盐酸小檗碱的热力学性质基本一致,吸附等温线实验表明：平衡吸附量随着浓度的增加而增加,随着温度的升高而降低,说明低温较有利于吸附；吸附等温线用Langmuir和Freundlich模型都能较好的拟合,说明二者在AB-8树脂上都是单分子层吸附；吸附是放热的物理吸附；在几个实验温度下,吸附都能自发的进行。
(6)在动力学和热力学研究的基础上,建立了大孔树脂柱的放大模型,该模型包括5个部分：①物料衡算方程(连续性方程)；②动力学方程；③相平衡方程(吸附等温线方程)；④边界条件；⑤初始条件。求解该模型得到数值解,并通过实验验证了该模型,实验测得的数据和模型模拟得出的数据吻合很好,说明建立的数学模型准确可靠,可用于大孔树脂柱的放大。
(7)对AB-8树脂动态吸附黄柏提取液中的总生物碱以及盐酸小檗碱进行了工艺考察,得到吸附总生物碱较佳的条件为：上样量50mL样品／mL树脂,上样浓度0.684mg／mL,上柱流率2BV／h,杂质洗脱剂水的用量为3BV,洗脱剂采用40%的乙醇,用量为6BV,按照此工艺条件,得到总生物碱的纯度为40.06%,比上柱之前的纯度提高了2.56倍。吸附盐酸小檗碱的工艺条件为：上样量55mL样品／mL树脂,上样浓度0.576mg／mL,洗脱剂的种类为40%的乙醇,用量为6BV。
Macroporous resin adsorption technology, first appearing in the 1960s, is widely used in the separation and purification of active ingredients for its unique advantages, such as simple operational procedures, single-solvent, low pollution, and high purity of the product. Numorous work has been conducted on the application of this techneque in traditional Chinese medicine analysis both from the theoretical and applied aspects. However, these researches are still not very systematic and too preliminary. In view of this, we will comprehensively explore the adsorption behavior of the total alkaloids on macroporous resin which may lay the foundation for the industrial production of alkaloids and provide a thread for separating other effective parts of traditional Chinese medicine. In this paper, Cortex Pheullodendri Chinensis is selected as reserch object. On the one side because it is cheap and easy to get,'on the other side, the material basic research is more mature. Finally, a lot of work has been done to this medicine.The studies are summarized as follows:
(1)Using high performance liquid chromatography method to determine berberine hydrochloride, palmatine chloride and jatrorrhizine hydrochloride 's content simultaneously in Cortex Pheullodendri Chinensis. Chromatographic conditions are:Diamonsil 5μm C18 column (250 mm×4.6mm) is used, mobile phase is acetonitrile-lg/L phosphoric acid (50:50) (containing lg/L sodium dodecyl sulfate) with flow rate 1mL/min, detection wavelength is 265nm. Determination results are as follows:berberine hydrochloride is 11.4mg/g herbs, palmatine chloride is 5.85 mg/g herbs, jatrorrhizine hydrochloride is 0.82mg/g herbs. The quality of three kinds of berberine-type alkaloid is accounted for 39.28% to total alkaloids.
(2) Using ultraviolet spectrophotometry to determine total alkaloid content in Cortex Pheullodendri Chinensis. Sample preparation is as follows: taking Cortex Pheullodendri Chinensis powder 1.OOg to Soxhlet extractor, 'then adding 90mL methanol and heating until extraction liquid is colorless. The extract liquid is transferred to container of 100mL, adding methanol to the scale volume. Selecting UV detection wavelength is 265nm. The total alkaloid content of Cortex Pheullodendri Chinens is counted as 46mg/g herbs.
(3) Extraction process of total alkaloid in Cortex Pheullodendri Chinensis was optimized by orthogonal experiments. Better process conditions are:60% ethanol as extraction solvent with 8BV, distilling 3 times, 1h per time. Under these conditions, the extraction amount of total alkaloids was 38mg/g herbs. Transfering rate is 81.88%.
(4) Nine kinds of macroporous resin was selected for screening. Three kinds of resin AB-8, HP20, LD605 have a good effect both in total alkaloid adsorption and desorption. This three kinds of resin were used for furthere selected, the desorption amount of berberine hydrochloride as an inspection-target. The result shows AB-8 is an ideal kind of resin for separating and purificating total alkaloids. AB-8 resin'performance parameters produced by different manufacturers vary in domestic. The AB-8 resin which produced by Ou Rui bio-technology Co., Ltd., Tianjin shows a good effect in absorpting total alkaloids in Cortex Pheullodendri Chinensis and will be served as study object for further research.
(5)Adsorption kinetics and thermodynamics of total alkaloids and berberine hydrochloride on AB-8 resin were discussed. Both the dynamic and thermodynamic properties are very similar. The adsorption process of total alkaloids on AB-8 resin tends to be the first order kinetics process. At the conditions of starting concentration 0.686mg/mL, temperature 27℃, the adsorption rate constant k1=2.176 h-1. Process is controled both by film diffusion and in-particle diffusion. A lower temperature, pH, a higher initial concentration, oscillation speed are favourable to adsorp. Adsorption process of berberine hydrochloride on AB-8 resin also tends to be the first order kinetics process. But the adsorption rate is slower than the total alkaloid's. Process is controled both by film diffusion and in-particle diffusion. Adsorption rate rises with the decreasing of temperature and increasing of initial concentration, solution pH, oscillation speed. Experiment also found that the kinetics of berberine hydrochloride in Cortex Pheullodendri Chinensis extraction liquid and in bulk drug were significantly different. The latter fits well first order kinetics equation but the former not. In initial stage, the former's adsorption rate is much faster than the latter's, which indicates palmatine chloride and jatrorrhizine hydrochloride and other 'alkaloids'presence affecting and promoting berberine hydrochloride adsorption on AB-8 resin. Thermodynamic properties of the two are basically the same. The isotherm adsorption experiment shows that equilibrium adsorption capacity increases with the concentration. Lower temperature is more favorable to the adsorption. The isotherm adsorption data fits well Langmuir and Freundlich isotherm which indicate the two are monolayer adsorption on AB-resin.The adsorption is spontaneous exothermic process of physical characters.
(6) On the base of dynamics and thermodynamics study, amplification model of macroporous resin column was established, which includes five parts:①mass balance equation (continuity equation);②kinetics equation;③equilibrium equation (isotherm adsorption equation);④boundary conditions;⑤initial conditions. Solving this model obtains numerical solutions and experiment was done to verificate whether the model is exact. The measured data and model simulated data are coincided, indicating the establishment of the mathematical model is accurate, reliable, and can be used for amplification of macroporous resin column.
(7)The technical conditions of dynamic adsorption of total alkaloids and berberine hydrochloride on AB-8 resin were optimized. The former is:sample volume is 50mL samples/mL resin, sample concentration is 0.684mg/mL, flow rate is 2BV/h, the amount of impurities eluant is 3BV, eluant is 40% ethanol with 6BV. In these conditions, the purity of total alkaloids is 40.06% and increases 2.56-fold prior to before purification. Berberine hydrochloride adsorption conditions are: sample volume is 55mL samples/mL resin, concentration is 0.576mg/mL, eluant·is 40% ethanol with 6BV.
引文
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