金属套管式微反应器内反溶剂重结晶法制备头孢呋辛酯超细颗粒的研究

发布时间：2019-04-20 16:01

【摘要】：超细药物具有常规药物所无法比拟的优点,通过药物的微粉化,可以改善水溶性,提高药物生物利用度。头孢呋辛酯是亲脂性药物,水溶性差,难于吸收,生物利用度低。为了解决溶解速率的问题,可采用超微细化加工技术。由于微反应器具有停留时间短、混合强度高等优点,微反应器的发展进入纳米颗粒合成的新领域。本文将将微反应技术与反溶剂重结晶方法相结合,来制备头孢呋辛酯超细颗粒。由于微反应器本身结构尺寸的限制,大部分微设备的处理量为微升或毫升/分钟,这远远小于传统设备的处理量,从而限制了微反应器的工业应用。本文首次运用新型的金属套管式微通道反应器制备有机药物头孢呋辛酯超细颗粒,实验室条件下其处理量达到升/分钟的水平。论文详细考察了丙酮-水体系下,无表面活性剂和添加表面活性剂制备头孢呋辛酯颗粒的效果,发现加入适合的表面活性剂可以改善药物重结晶时颗粒团聚和聚结的现象,制备的药物颗粒形貌为光滑的球形,粒度分布较为均匀,平均粒径为1μm左右。丙酮-异丙醚体系下,通过调控溶剂/反溶剂体积比、头孢呋辛酯溶液浓度、两相总体积流量、微孔大小、套管环隙、混合距离、制备温度和添加表面活性剂种类及加入量等因素,可以有效地控制颗粒的合成、大小、分布以及颗粒的结晶形态等。头孢呋辛酯原料药为粒径几十微米、大小不均匀的块状颗粒,而在套管式微通道反应器中通过反溶剂重结晶方法制备出平均粒径为290 nm左右的光滑球形颗粒。可见重结晶后达到了细化头孢呋辛酯颗粒的目的。基于微通道反应器自身的结构特点,过程可实现颗粒的高通量(在本文实验条件下,套管式微通道反应器的最大处理量约为6 L/min)、连续化生产。本文对超细头孢呋辛酯产品和原料药进行了表征：通过X-射线衍射和DSC分析,原料药的晶体结构为结晶形,而微粉化后头孢呋辛酯颗粒晶体结构为无定形；通过红外吸收光谱进行分析,超细化前后头孢呋辛酯化学结构未发生变化。考察了原料药和微粉化产品的溶出度,试验测定100 min后,微粉化药物溶出速率达到92%,为原料药溶出速率的1.8倍左右,表明在套管式微反应器中液相反溶剂沉淀法是降低粒度和提高难溶性药物溶解度的有效方法。
[Abstract]:Ultra-fine drugs have more advantages than conventional drugs. Micro-pulverization of drugs can improve water solubility and bioavailability of drugs. Cefuroxime is a lipophilic drug with poor water solubility difficult to absorb and low bioavailability. In order to solve the problem of dissolution rate, ultra-fine processing technology can be used. Because the micro-reactor has the advantages of short residence time and high mixing strength, the development of micro-reactor has entered a new field of nano-particle synthesis. In this paper, the preparation of cefuroxime ester ultrafine particles by the combination of micro-reaction technique and reverse solvent recrystallization method. Due to the limitation of micro-reactor structure and size, the capacity of most micro-devices is micro-liter or milliliter / min, which is much smaller than that of traditional equipment, which limits the industrial application of micro-reactors. In this paper, the ultra-fine particles of cefuroxime ester were prepared by a new metal tube microchannel reactor for the first time. The treatment capacity of cefuroxime ester reached the level of L / min under the laboratory conditions for the first time. In this paper, the preparation effect of cefuroxime axetil particles without or with surfactants in acetone-water system was investigated in detail. It was found that adding suitable surfactants could improve the agglomeration and coalescence of cefuroxime esters during drug recrystallization. The morphology of the prepared drug particles is smooth spherical, the particle size distribution is more uniform, the average particle size is about 1 渭 m. In acetone-isopropyl ether system, the volume ratio of solvent / antisolvent, the concentration of cefuroxime axetil solution, the total volume flow rate of two-phase, the micropore size, the annulus of casing, the mixing distance, and the concentration of cefuroxime were adjusted. The synthesis, size, distribution and crystal morphology of the particles can be effectively controlled by the factors such as the preparation temperature and the type and amount of surfactants added. The raw drug of cefuroxime axetil is a massive particle with a diameter of dozens of microns and uneven size. Smooth spherical particles with an average diameter of about 290nm were prepared by reverse solvent recrystallization in a tube-tube micro-channel reactor. It can be seen that the purpose of refining cefuroxime axetil granules is achieved after recrystallization. Based on the structural characteristics of the micro-channel reactor, the process can achieve high throughput of particles (the maximum capacity of the tube-tube micro-channel reactor is about 6 L/min under the experimental conditions in this paper), and the continuous production can be achieved. In this paper, the ultra-fine cefuroxime ester products and raw materials were characterized. By X-ray diffraction and DSC analysis, the crystal structure of the drug was crystalline, while the crystal structure of cefuroxime axetil particles was amorphous after micro-powder. The crystal structure of cefuroxime axetil was characterized by X-ray diffraction and DSC analysis. The chemical structure of cefuroxime axetil did not change before and after ultra-refinement by infrared absorption spectrum. The dissolution rate of raw drug and micro-powdered product was investigated. After 100 min, the dissolution rate of micronized drug was 92%, about 1.8 times of that of raw drug, and the dissolution rate of micronized drug reached 92%, which was about 1. 8 times as high as that of raw drug. The results show that liquid reverse solvent precipitation is an effective method to reduce particle size and increase solubility of insoluble drugs in tubular microreactor.
【学位授予单位】：北京化工大学
【学位级别】：硕士
【学位授予年份】：2010
【分类号】：TB383.1

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