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  • 學位論文

含氮藥物於超臨界二氧化碳程序中溶解度 與微粒化之研究

Investigation on Solubility and Micronization of Nitrogen-Containing Drugs Using Supercritical Carbon Dioxide Process

指導教授 : 陳延平
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摘要


摘要 本研究主要是針對藥物於超臨界二氧化碳中之固體溶解度,進行實驗量測與使用半經驗模式進行廻歸計算,最後以超臨界溶液快速膨脹法 (RESS)搭配旋風分離器(Cyclone separator)做為收集瓶 與超臨界反溶劑法 (SAS) 對藥物進行再結晶與微粒化研究。 首先研究第一部分為固體溶解度實驗量測,本研究中建立一半流動式量測設備,搭配使用HPLC的非線上分析方法,選擇3種肌肉鬆弛劑,分別為Chlormezanone、Metaxalone與Methocarbamol;與3種血管舒張劑,分別為Cinnarizine、Pentoxifylline與Piracetam,進行其於超臨界二氧化碳中之固體溶解度量測。量測溫度為308.2、318.2與328.2 K,每個固定溫度下,於12~24 MPa之間各7組量測壓力,共可得到126個實驗數據點。接著使用3種半經驗式分別為MST、Chrastil與Bartle等進行迴歸計算,從研究結果得到三種半經驗式對溶解度實驗數據皆能得到良好的迴歸計算結果。 在研究的第二部份,首先建立一超臨界溶液快速膨脹法微粒化設備,在研究中選擇用於治療多發性硬化症及阿茲海默症之藥物Fampridine,在超臨界溶液快速膨脹法微粒化過後,外觀由透明結晶型態轉變為白色粉體,同時,平均粒徑由532.3大幅減小至0.32 μm。在研究中選用旋風分離器做為藥物收集瓶,將藥物經由噴嘴噴入其中,最後可得到球狀微粒。而經由微粒化後,藥物的多晶型態並沒有造成改變。在經過超臨界溶液快速膨脹法處理後的藥物微粒,其溶離速率有顯著的提升,最高可比原始藥物快2.90倍。 第三部份中,本研究接著建立一半連續式超臨界反溶劑法微粒化設備,將治療高血壓之利尿劑Chlorothiazide進行再結晶與微粒化程序,在使用DMSO、DMSO:EtAc(volume ratio= 1:4)或DMSO:EtOH(volume ration 1:4)為溶劑時,藥物晶型由原始藥物Form I轉變為擬態多晶型(Pseudopolymorph)形成Chlorothiazide DMSO Solvate的結晶,其利用所得計量係數莫耳數比約為Chlorothiazide:DMSO (1:1),而在使用丙酮為溶劑時,則無晶型轉變仍為穩定的Form I晶型,平均粒徑由原始的43.1減小至0.21 μm,且其溶離速率亦有顯著的提升,可比原始藥物快1.4倍。在超臨界反溶劑法的研究中也搭配結晶動力學MSMPR模式對成核成長模式進行探討。

並列摘要


Abstract In this study, measurement and correlation of solid solubility for active pharmaceutical ingredients (APIs) in supercritical carbon dioxide were investigated. And re-crystallization and micronization for APIs were also investigated using rapid expansion of supercritical solution (RESS) with cyclone separation as collector and supercritical anti-solvent (SAS) processes. The solid solubilities of three skeletal muscle relaxants of chlormezanone, metaxalone, methocarbamol, and three vasodilators of cinnarizine, pentoxifylline, piracetam in supercritical carbon dioxide were measured using a semi-flow apparatus. Total 126 data points were obtained. These experimental results were correlated by three semi-empirical models of Mendez-Santiago-Teja, Chrastil and Bartle. The measured data satisfied the self-consistency test, and the parameters in the semi-empirical models are feasible for data extrapolation. Fampridine is used to cure multiple sclerosis and Alzheimer’s disease. In this study, it was re-crystallized and micronized using rapid expansion of supercritical solution (RESS) process. The mean particle size of fampridine was reduced from its original 532.3 to 0.32 μm under the optimal operation conditions. Its dissolution rate enhanced by 2.90 times after the RESS processed in a simulated gastric buffer (pH6.8). Finally, re-crystallization and micronization for a thiazide diuretic chlorothiazide was investigated using semi-continuous supercritical anti-solvent (SAS) process. The chlorothiazide DMSO solvate (chlorothiazide: DMSO(mole ration=1:1.2)) was prepared via a SAS process by using DMSO, DMSO:EtAc (1:4),or DMSO:EtOH (1:4) as a solvent. Then the solvent effect of acetone was also used in SAS process. It was the same polymorph (form I) with original. The mean particle size of chlorothiazide was reduced from its original 43.1 to 0.21 μm under the optimal operation conditions. It also presented an enhanced dissolution rate by 1.40 times after the SAS processed. In this study, the kinetic model of MSMPR (Mixed Suspension, Mixed-Product-Removal ) was also developed.

參考文獻


林柏青,利用超臨界快速膨脹法進行Gemfibrozil、Lidocaine、Ethosuximide及Tolbutamide藥物微粒化之研究,國立台灣大學化學工程學研究所碩士論文,2008
Sathe D.G., Sawant K.D., Naik T.A., Omray A., Agashe Y.M., Patade P.T., Jog S.S., Chlorothiazide, chlorothiazide salts and pharmaceutical compositions thereof, US 2011/0263579 A1
Alam M.A., Al-Jenoobi F.I., Al-mohizea AM, Commercially bioavailable proprietary technologies and their marketed products, Drug Discov. Today, 18 (2013) 936-949.
Bahrami M., Ranjbarian S., Production of micro- and nano-composite particles by supercritical carbon dioxide. J. Supercrit. Fluids, 40 (2007) 263-283
Bartle K.D., Clifford A.A., Jafar S.A., Shilstone G.F., Solubilities of solids and liquids of low volatility in supercritical carbon dioxide, J. Phys. Chem. Ref. Data, 20 (1991) 713-756

被引用紀錄


方鈞顥(2015)。利用超臨界溶液快速膨脹法進行藥物Monobenzone、Ethylparaben、Edaravone與Kojic acid之微粒化研究〔碩士論文,國立臺灣大學〕。華藝線上圖書館。https://doi.org/10.6342%2fNTU.2015.01054

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