硫酸妥布霉素精制过程研究
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摘要
硫酸妥布霉素属氨基糖苷类抗生素,在我国工业生产中存在着最终产品纯度低,收率低,残留溶媒含量高,制备过程容易聚结凝胶等问题。本工作对其精制过程进行了较系统的研究,开发了新型硫酸妥布霉素溶析工艺,并结合真空冷冻和喷雾干燥技术,制备出了符合美国药典要求的产品。
考察了硫酸妥布霉素在14种纯溶剂中的固液平衡行为,采用激光法测定了硫酸妥布霉素在四种纯溶剂及两种二元混合体系中的溶解度,确定了溶析过程溶剂体系。分别应用Apelblat和CNIBS/RK经验方程对硫酸妥布霉素在纯溶剂及乙醇—水二元溶剂体系中的溶解度数据进行关联,建立了相应的数学模型。
采用激光法动态测定了硫酸妥布霉素在水-乙醇二元体系下的超溶解度和诱导期。考察了硫酸妥布霉素在溶液中的浓度,搅拌速度以及超声波对硫酸妥布霉素超溶解度同溶解度宽度的影响,并考察了诱导期与过饱和度比的关系。
在热力学、超溶解度的研究基础上,采用显微镜观测、X射线粉末衍射(XRPD)、扫描电镜(SEM)、红外光谱(FT-IR)等测试手段对硫酸妥布霉素精制过程中出现的凝胶现象进行了分析。通过工艺实验对各种因素进行了研究。考察了pH值,溶液浓度,溶液温度,冷却温度,搅拌强度,溶析剂流加方式和流加速率以及产品洗涤方式对收率、产品残留溶媒、效价和成胶现象的影响情况,确定了硫酸妥布霉素溶析过程的经验优化操作条件。
根据真空冷冻干燥原理,系统的对硫酸妥布霉素水溶液以及加入赋形剂后的体系进行了分析。利用喷雾干燥方法对硫酸妥布霉素产品进行干燥,分析了干燥前原料液浓度以及原料液来源和pH值对产品残留溶媒和效价的指标。改进了硫酸妥布霉素水分析方法,建立了一种新的快速、准确确定硫酸妥布霉素水份的分析方法。
通过本文开发的硫酸妥布霉素溶析工艺以及干燥工艺生产的实验产品,较原工艺产品指标有较大提高,平均收率达到95%以上,平均效价达到698μg/mg,残留溶媒指标达到0.17%以下,各项指标均已达到美国药典USP24的要求。
Tobramycin sulfate is an aminoglycoside antibiotic. There are some serious problems in the productions processes of tobramycin sulfate, such as low purity of the product, low yield, high residual solvent content of product, forming gel during the process of purification etc.. In this these, a better manufacturing scheme for tobramycin sulfate was presented based on a systematic study of purification process. By means of the new delution technology and vacuum freeze-drying and spray drying in this work, the high quality products were produced under the optimum schedule of purification, and all indexes have surpassed the United States Pharmacopoeia standards.
The solid-liquid equilibrium behavior of tobramycin sulfate in 14 solvents was investigated. The solubilities in 4 pure solvents and two binary solvents systems were determined and the dilution solvent system was choosen according to the properties of solutility. The Apelblat empirical equation was used to correlate the data of the solubilities of tobramycin sulfate in pure solvents system and the model equations were estabilished. And the data of solubilities in water + ethanol binary mixtures was corelated by CNIBS/Redlich-Kister equation and the mathematical model was estabilished.
The supersolubility and induction time of tobramycin sulfate in water + ethanol binary mixtures were determined by laser monitoring method. The influence of width between the supersolubility curve and solubility curve was investigated by regulating the concentration of tobramycin sulfate in the solution and agitation rate, also with the ultrasonic apparatus. The induction time under different relative supersaturation degree was researched.
By means of observartion in microscope、XRPD、SEM and FT-IR technology, the phenomenon of forming gel during the process of delution has been researched. Optimization of operating conditions was determined by means of regulating the addition rate and mode of antisolvent, adjusting the temperature program, etc, and the gelation phenomenon in the purification process has been avoided efficiently.
The system of tobramycin salfate in aqueous solution with excipient was researched according to the principle of vacuum freeze drying. The spray drying was applied in the process of drying the product. The influence of residual solvent and purity of product was researched by investigating concentration, the source of feed and pH value. A new rapid, accurate method was developed to measure the water content of tobramycin sulfate product.
Through this development of tobramycin sulfate delution and drying craft, the product quality has been improved greatly. The average yield has reached 95%, mean purity reached 698μg/mg, the content of residual solvent was below the 0.17% level.. All the quality index of tobramycin sulfate product reached the requirements of the United States Pharmacopoeia USP24.
考察了硫酸妥布霉素在14种纯溶剂中的固液平衡行为,采用激光法测定了硫酸妥布霉素在四种纯溶剂及两种二元混合体系中的溶解度,确定了溶析过程溶剂体系。分别应用Apelblat和CNIBS/RK经验方程对硫酸妥布霉素在纯溶剂及乙醇—水二元溶剂体系中的溶解度数据进行关联,建立了相应的数学模型。
采用激光法动态测定了硫酸妥布霉素在水-乙醇二元体系下的超溶解度和诱导期。考察了硫酸妥布霉素在溶液中的浓度,搅拌速度以及超声波对硫酸妥布霉素超溶解度同溶解度宽度的影响,并考察了诱导期与过饱和度比的关系。
在热力学、超溶解度的研究基础上,采用显微镜观测、X射线粉末衍射(XRPD)、扫描电镜(SEM)、红外光谱(FT-IR)等测试手段对硫酸妥布霉素精制过程中出现的凝胶现象进行了分析。通过工艺实验对各种因素进行了研究。考察了pH值,溶液浓度,溶液温度,冷却温度,搅拌强度,溶析剂流加方式和流加速率以及产品洗涤方式对收率、产品残留溶媒、效价和成胶现象的影响情况,确定了硫酸妥布霉素溶析过程的经验优化操作条件。
根据真空冷冻干燥原理,系统的对硫酸妥布霉素水溶液以及加入赋形剂后的体系进行了分析。利用喷雾干燥方法对硫酸妥布霉素产品进行干燥,分析了干燥前原料液浓度以及原料液来源和pH值对产品残留溶媒和效价的指标。改进了硫酸妥布霉素水分析方法,建立了一种新的快速、准确确定硫酸妥布霉素水份的分析方法。
通过本文开发的硫酸妥布霉素溶析工艺以及干燥工艺生产的实验产品,较原工艺产品指标有较大提高,平均收率达到95%以上,平均效价达到698μg/mg,残留溶媒指标达到0.17%以下,各项指标均已达到美国药典USP24的要求。
Tobramycin sulfate is an aminoglycoside antibiotic. There are some serious problems in the productions processes of tobramycin sulfate, such as low purity of the product, low yield, high residual solvent content of product, forming gel during the process of purification etc.. In this these, a better manufacturing scheme for tobramycin sulfate was presented based on a systematic study of purification process. By means of the new delution technology and vacuum freeze-drying and spray drying in this work, the high quality products were produced under the optimum schedule of purification, and all indexes have surpassed the United States Pharmacopoeia standards.
The solid-liquid equilibrium behavior of tobramycin sulfate in 14 solvents was investigated. The solubilities in 4 pure solvents and two binary solvents systems were determined and the dilution solvent system was choosen according to the properties of solutility. The Apelblat empirical equation was used to correlate the data of the solubilities of tobramycin sulfate in pure solvents system and the model equations were estabilished. And the data of solubilities in water + ethanol binary mixtures was corelated by CNIBS/Redlich-Kister equation and the mathematical model was estabilished.
The supersolubility and induction time of tobramycin sulfate in water + ethanol binary mixtures were determined by laser monitoring method. The influence of width between the supersolubility curve and solubility curve was investigated by regulating the concentration of tobramycin sulfate in the solution and agitation rate, also with the ultrasonic apparatus. The induction time under different relative supersaturation degree was researched.
By means of observartion in microscope、XRPD、SEM and FT-IR technology, the phenomenon of forming gel during the process of delution has been researched. Optimization of operating conditions was determined by means of regulating the addition rate and mode of antisolvent, adjusting the temperature program, etc, and the gelation phenomenon in the purification process has been avoided efficiently.
The system of tobramycin salfate in aqueous solution with excipient was researched according to the principle of vacuum freeze drying. The spray drying was applied in the process of drying the product. The influence of residual solvent and purity of product was researched by investigating concentration, the source of feed and pH value. A new rapid, accurate method was developed to measure the water content of tobramycin sulfate product.
Through this development of tobramycin sulfate delution and drying craft, the product quality has been improved greatly. The average yield has reached 95%, mean purity reached 698μg/mg, the content of residual solvent was below the 0.17% level.. All the quality index of tobramycin sulfate product reached the requirements of the United States Pharmacopoeia USP24.
引文
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[11]李秀荣.旋光法快速测定硫酸妥布霉素注射液半成品的含量,海峡药学杂志,2002,14(4)：56-58
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[2]顾觉奋.钟琼.反相HPLC快速分析妥布霉素的方法建立.药学世界,1994,2：7
[3]张四维.抗生素分离精制工作中若干问题的探讨.医药工业,1988；19(3)：137
[4]杨春娥,李桂珍,妥布霉素的药理学特点及其临床应用,中国药房,2002,11：695
[5]洪文荣,郭养浩,石贤爱,等,中国药科大学学报,2000,31：304
[6]李德培,妥布霉素的药理和临床,天津药学,1989,6：10
[7]Sakchai, Wittaya A., Freeze-drying of tert-Butanol/water cosolvent systems:A case report on formation of a friable freeze-dried powder of tobramycin sulfate, J. Pharm. Sci.,2002,4:1147-1155
[8]鲁敏,倪建平,妥布霉素结晶工艺的研究,山东医药工业,2002,2：33-35
[9]王弘,于淑娟,高大维,妥布霉素结晶工艺的改进,中国医药工业杂志,2003,34：13-14
[10]赵凤琴.硫酸妥布霉素的含量测定,沈阳药科大学学报,1997,14(2)：120-121
[11]李秀荣.旋光法快速测定硫酸妥布霉素注射液半成品的含量,海峡药学杂志,2002,14(4)：56-58
[12]熊敏玲.再论旋光度测定法测定硫酸妥布霉素注射液含量,海南医学杂志,1998,4：295
[13]庞克坚,李永平,魏永玲.快速比色法测定硫酸妥布霉素注射液中间体的含量,佳木斯医学院学报,1998,21(2)：22-23
[14]郑昌亮,唐秋瑾.使用高效液相色谱分析检测抗生素[J].中国抗生素杂志1986,11(2)：261-266
[15]胡云明,张康,于华生.高效液相色谱法测定注射用硫酸妥布霉素的含量,海峡药学,2002,14(5)：56-57
[16]朱自强,姚善泾,金彰礼编著.流体相平衡原理及其应用[M].浙江：浙江大学出版社,1990年4月第1版：214-282
[17]Walas S M.化工相平衡[M].韩世钧等译.北京：中国石化出版社,1991年10月第1版,444-450
[18]胡英.流体的分子热力学[M].北京：高等教育出版社,1982年5月第1版：310-497
[19]黄承遇,陈钟秀,顾飞燕.化工热力学[M].北京：化学工业出版社,1990年 6月第1版：208-238
[20]Prausnitz JM, Lichenthaler R N, Azevedo E G.流体相平衡的分子热力学[M].骆赞椿,吕瑞乐,刘国杰,谭子明译.北京：化学工业出版社,1990年6月第1版：338-483
[21]金克新,赵传钧,马沛生,化工热力学,天津：天津大学出版社,1990,137-139.
[22]Domanska U, Hofman T, Rolinska J. Solubility and Vapour Pressures in Saturated Solutions of High-Molecular-Weight Hydrocarbons[J]. Fluid Phase Equilibria,1987,32:273-293
[23]陈钟秀,顾飞燕,化工热力学,北京：化学工业出版社,1993,151
[24]Muir R. F., Howart C. S., Predicting solid-liquid equilibrium data from vapor-liquid data, Chem. Eng.,1982,89(4):89
[25]Preston G. T., Prausnitz J. M., Ind Eng Chem Process Des Dev,1970,9:264
[26]Acree W. E. J., Comments concerning "model for solubility estimation in mixed solvent system",Int. J. Pharm.,1996,127:27-30.
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