金屬套管式微反應(yīng)器內(nèi)反溶劑重結(jié)晶法制備頭孢呋辛酯超細(xì)顆粒的研究
發(fā)布時(shí)間：2019-04-20 16:01
【摘要】：超細(xì)藥物具有常規(guī)藥物所無法比擬的優(yōu)點(diǎn),通過藥物的微粉化,可以改善水溶性,提高藥物生物利用度。頭孢呋辛酯是親脂性藥物,水溶性差,難于吸收,生物利用度低。為了解決溶解速率的問題,可采用超微細(xì)化加工技術(shù)。由于微反應(yīng)器具有停留時(shí)間短、混合強(qiáng)度高等優(yōu)點(diǎn),微反應(yīng)器的發(fā)展進(jìn)入納米顆粒合成的新領(lǐng)域。本文將將微反應(yīng)技術(shù)與反溶劑重結(jié)晶方法相結(jié)合,來制備頭孢呋辛酯超細(xì)顆粒。由于微反應(yīng)器本身結(jié)構(gòu)尺寸的限制,大部分微設(shè)備的處理量為微升或毫升/分鐘,這遠(yuǎn)遠(yuǎn)小于傳統(tǒng)設(shè)備的處理量,從而限制了微反應(yīng)器的工業(yè)應(yīng)用。 本文首次運(yùn)用新型的金屬套管式微通道反應(yīng)器制備有機(jī)藥物頭孢呋辛酯超細(xì)顆粒,實(shí)驗(yàn)室條件下其處理量達(dá)到升/分鐘的水平。論文詳細(xì)考察了丙酮-水體系下,無表面活性劑和添加表面活性劑制備頭孢呋辛酯顆粒的效果,發(fā)現(xiàn)加入適合的表面活性劑可以改善藥物重結(jié)晶時(shí)顆粒團(tuán)聚和聚結(jié)的現(xiàn)象,制備的藥物顆粒形貌為光滑的球形,粒度分布較為均勻,平均粒徑為1μm左右。丙酮-異丙醚體系下,通過調(diào)控溶劑/反溶劑體積比、頭孢呋辛酯溶液濃度、兩相總體積流量、微孔大小、套管環(huán)隙、混合距離、制備溫度和添加表面活性劑種類及加入量等因素,可以有效地控制顆粒的合成、大小、分布以及顆粒的結(jié)晶形態(tài)等。頭孢呋辛酯原料藥為粒徑幾十微米、大小不均勻的塊狀顆粒,而在套管式微通道反應(yīng)器中通過反溶劑重結(jié)晶方法制備出平均粒徑為290 nm左右的光滑球形顆粒�？梢娭亟Y(jié)晶后達(dá)到了細(xì)化頭孢呋辛酯顆粒的目的�；谖⑼ǖ婪磻�(yīng)器自身的結(jié)構(gòu)特點(diǎn),過程可實(shí)現(xiàn)顆粒的高通量(在本文實(shí)驗(yàn)條件下,套管式微通道反應(yīng)器的最大處理量約為6 L/min)、連續(xù)化生產(chǎn)。 本文對超細(xì)頭孢呋辛酯產(chǎn)品和原料藥進(jìn)行了表征：通過X-射線衍射和DSC分析,原料藥的晶體結(jié)構(gòu)為結(jié)晶形,而微粉化后頭孢呋辛酯顆粒晶體結(jié)構(gòu)為無定形；通過紅外吸收光譜進(jìn)行分析,超細(xì)化前后頭孢呋辛酯化學(xué)結(jié)構(gòu)未發(fā)生變化。考察了原料藥和微粉化產(chǎn)品的溶出度,試驗(yàn)測定100 min后,微粉化藥物溶出速率達(dá)到92%,為原料藥溶出速率的1.8倍左右,表明在套管式微反應(yīng)器中液相反溶劑沉淀法是降低粒度和提高難溶性藥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.
【學(xué)位授予單位】：北京化工大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2010
【分類號】：TB383.1
本文編號：2461747
[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.
【學(xué)位授予單位】：北京化工大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2010
【分類號】：TB383.1
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