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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 陳延平 | |
| dc.contributor.author | Chen-An Lee | en |
| dc.contributor.author | 李振安 | zh_TW |
| dc.date.accessioned | 2021-06-07T23:45:11Z | - |
| dc.date.copyright | 2014-07-11 | |
| dc.date.issued | 2014 | |
| dc.date.submitted | 2014-07-01 | |
| dc.identifier.citation | 參考文獻
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/16754 | - |
| dc.description.abstract | 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。 | zh_TW |
| dc.description.abstract | 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. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-07T23:45:11Z (GMT). No. of bitstreams: 1 ntu-103-D98524019-1.pdf: 9413084 bytes, checksum: bde4179baa98114cfdc64ef2f36facc0 (MD5) Previous issue date: 2014 | en |
| dc.description.tableofcontents | 目錄
摘要 I Abstract III 目錄 V 表目錄 VII 圖目錄 IX 第一章 緒論 1 1-1 超臨界流體之簡介與發展趨勢 1 1-2 熱力學性質研究之重要性 3 1-3 藥物微粒化與多晶型之重要性 5 1-4 超臨界流體微粒製備技術介紹 7 1-5 研究規劃 11 第二章 藥物固體於超臨界二氧化碳中之溶解度實驗量測 15 2-1 研究背景與動機 15 2-2 實驗方法 19 2-3 應用熱力學模式計算固體溶解度 25 2-4 實驗用藥品 27 2-5 實驗結果與討論 27 2-6 結論 30 第三章 利用超臨界溶液快速膨脹法進行藥物Fampridine再結晶與微粒化研究 72 3-1 研究背景與動機 72 3-2 實驗用藥品 74 3-3 實驗方法 75 3-4 分析方法 77 3-5藥物溶離行為分析 81 3-6實驗結果與討論 83 3-7 結論 89 第四章 利用超臨界反溶劑法進行藥物Chlorothiazide再結晶與微粒化研究 108 4-1 研究背景與動機 108 4-2 實驗用藥品 111 4-3 實驗方法 111 4-4 分析方法 115 4-5藥物溶離行為分析 116 4-6晶體成核與成長模式分析 117 4-7 實驗結果與討論 125 4-8 結論 135 第五章 結論 170 符號說明 173 參考文獻 177 附錄 185 作者簡介 192 | |
| dc.language.iso | zh-TW | |
| dc.subject | 溶解度 | zh_TW |
| dc.subject | 擬態多晶型 | zh_TW |
| dc.subject | 微粒化 | zh_TW |
| dc.subject | 關連 | zh_TW |
| dc.subject | 超臨界二氧化碳 | zh_TW |
| dc.subject | 原料藥 | zh_TW |
| dc.subject | Micronization | en |
| dc.subject | Active pharmaceutical ingredient | en |
| dc.subject | Pseudopolymorph | en |
| dc.subject | Solubility | en |
| dc.subject | Correlation | en |
| dc.subject | Supercritical carbon dioxide | en |
| dc.title | 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 | zh_TW |
| dc.title | Investigation on Solubility and Micronization of Nitrogen-Containing Drugs Using Supercritical Carbon Dioxide Process | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 102-2 | |
| dc.description.degree | 博士 | |
| dc.contributor.oralexamcommittee | 林威宇,陳立仁,林祥泰,蘇至善 | |
| dc.subject.keyword | 溶解度,原料藥,超臨界二氧化碳,關連,微粒化,擬態多晶型, | zh_TW |
| dc.subject.keyword | Solubility,Active pharmaceutical ingredient,Supercritical carbon dioxide,Correlation,Micronization,Pseudopolymorph, | en |
| dc.relation.page | 193 | |
| dc.rights.note | 未授權 | |
| dc.date.accepted | 2014-07-01 | |
| dc.contributor.author-college | 工學院 | zh_TW |
| dc.contributor.author-dept | 化學工程學研究所 | zh_TW |
| 顯示於系所單位： | 化學工程學系 | |
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