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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 陳延平 | |
dc.contributor.author | Li-Shiuan Lin | en |
dc.contributor.author | 林立軒 | zh_TW |
dc.date.accessioned | 2021-07-11T14:34:53Z | - |
dc.date.available | 2023-07-18 | |
dc.date.copyright | 2018-07-18 | |
dc.date.issued | 2018 | |
dc.date.submitted | 2018-07-16 | |
dc.identifier.citation | Adeli, E. (2016). The use of supercritical anti-solvent (SAS) technique for preparation of Irbesartan-Pluronic® F-127 nanoparticles to improve the drug dissolution. Powder Technology, 298, 65-72.
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/77789 | - |
dc.description.abstract | 本研究利用超臨界反溶劑法對兩種低水溶性原料藥進行藥物微粒化之研究並探討藥物微粒化前後在晶型以及熔點等是否有變化,本實驗中使用的目標藥物分別為治療泌尿道感染的藥物甲氧苄啶 (trimethoprim)以及用作利尿劑和抗高血壓藥物氯噻嗪 (chlorothiazide),此實驗目的在於增加藥物的溶離速度,進而增加目標藥物的總表面積、降低結晶強度,增加其在人體內的溶離速率,進而提升藥物在生物體內之溶解度以及可吸收率。
因此,實驗以超臨界二氧化碳當作反溶劑,並選用較安全的溶劑乙醇以及丙酮當作藥物甲氧苄啶 (trimethoprim)以及氯噻嗪 (chlorothiazide)的溶劑,接著利用田口實驗法 (Taguchi Method)探討不同參數,如操作溫度、壓力、溶液濃度及溶液流速等,對於微粒化結果的影響,並利用實驗設計表格操作實驗後的結果加以分析可探討這四個參數對於藥物微粒化的效應,並且能夠經由田口法的數學計算得到最佳化操作條件,進而提升其溶離速率。此外,本研究也將微粒化前後之藥物加入模擬人體腸液後進行溶離速率測試,觀察藥物經由微粒化後,是否有較高的溶離速率。 首先在藥物Trimethoprim的微粒化研究中,最佳化操作條件下可將原始藥物的平均粒徑從51.31μm 縮小為 1.26 μm,縮小了41倍左右。且由分析儀器XRD、DSC及FTIR可知,藥物並沒有發生晶型的轉變也沒有發生變質或是溶劑殘留的情況發生,但因為藥物縮小而且結晶強度降低導致熱含量下降的現象。溶離速率實驗方面,經過SAS處理過後的藥物溶離速率高於原始藥物,且經過Weibull model回歸後,原始藥物溶離速率係數kw為0.0418 min-1,經微粒化後藥物之溶離速率係數kw為0.182 min-1,溶離速率提升約3.99倍,本研究引用相似因子(F1)和相似因子(F2)來探討溶離前後的速率差異性,結果為有顯著之差異。 最後,在藥物chlorothiazide的研究中,最佳化條件是可將原始的藥物平均粒徑從24.64 μm 縮小為0.23 μm,縮小了107倍之多。且由分析儀器XRD、DSC、TGA及FTIR可知,藥物也並沒有發生晶型的轉變也沒有發生變質或是溶劑殘留的情況發生,但跟上一隻藥物一樣因為藥物縮小而且結晶強度降低導致熱含量下降的現象,而且在DSC上也可以發現原始藥物和經微粒化後處理的藥物都有熱裂解的情況發生,溶離速率實驗方面,經過SAS處理過後的藥物溶離速率高於原始藥物,經過Weibull model的迴歸後,計算出原始藥物溶離速率係數kw為0.1869 min-1,經微粒化後藥物之溶離速率係數kw為2.6634 min-1,溶離速率提升約14.25倍,本研究引用相似因子(f1)和相似因子(f2)來探討溶離前後的速率差異性,結果為有顯著之差異。 | zh_TW |
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dc.description.tableofcontents | 摘要 I
Abstract III 表目錄 VII 圖目錄 VIII 第一章 超臨界流體 1 1-1 超臨界流體簡介 1 1-2 超臨界流體技術與應用 2 1-3 藥物微粒化之目的 4 1-4 超臨界流體微粒化技術 5 1-4-1 超臨界溶液快速膨脹法 (Rapid Expansion of Supercritical Solution,RESS) 6 1-4-2 氣體飽和溶液沉積法 (Particles from Gas Saturated Solution,PGSS) 7 1-4-3 超臨界反溶劑法 (Supercritical Anti-Solvent,SAS) 8 1-4-4 超臨界流體輔助霧化法 (Supercritical Assisted Atomization,SAA) 9 1-5 研究動機 10 第二章 實驗設計法 15 2-1 實驗設計法 15 2-2 田口法摘要 16 2-3 田口法原理 17 2-4 變異數分析 20 2-5 田口方法應用實例 21 第三章 實驗方法 32 3-1 實驗藥品 32 3-1-1 目標藥品 32 3-1-2 其它藥品 32 3-2 實驗裝置 33 3-3 實驗步驟 35 3-4 實驗分析 37 第四章 結果與討論 51 4-1 甲氧苄啶 (Trimethoprim) 51 4-1-1 實驗設計法 51 4-1-2 變異數分析 52 4-1-3 各參數的因子效應 54 4-1-4 定性分析 56 4-1-5 溶離速率測試 57 4-2 氯噻嗪 (Chlorothiazide) 58 4-2-1 實驗設計法 58 4-2-2 變異數分析 59 4-2-3 各參數的因子效應 61 4-2-4 定性分析 63 4-2-5 溶離速率測試 64 第五章 結論 102 第六章 參考文獻 103 第七章 附錄 110 7-1 藥物甲氧苄啶之S/N值計算 110 7-2 藥物氯噻嗪之S/N值計算 110 Table 1-1. Characteristics of supercritical fluid. 10 Table 1-2. Critical conditions of fluids. 11 Table 1-3. Micronization of pharmaceuticals by using SAS process in 2014-2017. 12 Table 2-1. One-factor-at-a-time. 26 Table 2-2. L4 orthogonal array. 26 Table 2-3. Analysis of variance. 26 Table 2-4. Factors and their levels affecting the weld strength of the plastic product. 26 Table 2-5. L9 orthogonal array. 27 Table 2-6. Experimental data. 27 Table 2-7. The effects of operating factors and their contribution. 28 Table 2-8. ANOVA of the example. 28 Table 3-1. Components of SAS apparatus in this study. 44 Table 3-2. List of the physical properties of SAS pharmaceuticals in this study. 47 Table 4-1. L9(34) Orthogonal Array 66 Table 4-2. Parameters and their levels of the orthogonal array design for trimethoprim. 66 Table 4-3. Orthogonal array design matrix L9 and experimental results for trimethoprim. 67 Table 4-4. ANOVA analysis result of four parameters for SAS micronization of trimethoprim. 68 Table 4-5. The effects of operating temperature on particle size. 69 Table 4-6. The effects of operating pressure on particle size. 70 Table 4-7. The effects of concentration on particle size. 71 Table 4-8. The effects of solution flow rate on particle size. 71 Table 4-9. The optimally fitted Weibull model parameters, dissolution rate constants, and the rate enhancement for APIs. 72 Table 4-10. Parameters and their levels of the orthogonal array design for chlorothiazide. 73 Table 4-11. Orthogonal array design matrix L9 and experimental results for chlorothiazide. 74 Table 4-12. ANOVA analysis result of four parameters for SAS micronization of chlorothiazide. 75 Figure 1-1. Pure compound pressure-temperature phase diagram. 14 Figure 2-1. Quality Loss Function 29 Figure 2-2. The difference between high S/N and low S/N 29 Figure 2-3. The comparison of variance 30 Figure 2-4. Response graph. 30 Figure 2-5. Schematic diagram of 95% confidence interval. 31 Figure 3-1. SEM image of unprocessed Trimethoprim. 48 Figure 3-2. SEM image of unprocessed Chlorothiazide. 48 Figure 3-3. Semi-continuous type experimental apparatus of the SAS process. 49 Figure 3-4. Schematic diagram of the coaxial nozzle in this study. 50 Figure 4-1. Comparison of the SEM images of the (a) original and (b) SAS processed trimethoprim with a magnification of 1000 times. 76 Figure 4-2. Comparison of the SEM images of the (a) original and (b) SAS processed trimethoprim with a magnification of 1500 times. 77 Figure 4-3. Comparison of the SEM images of the (a) original and (b) SAS processed trimethoprim. 78 Figure 4-4. Comparison of the mean particle size and particle size distribution for the original and SAS processed trimethoprim. 79 Figure 4-5. SEM images of trimethoprim after SAS processed at 35oC. Pressure, concentration, and solution flow rate effect: (a)100bar,5mg/ml,0.5ml/min(b)130bar,10mg/ml,1.0ml/min(c) 160bar,12mg/ml,1.5ml/min. 80 Figure 4-6. SEM images of trimethoprim after SAS processed at 45oC. Pressure, concentration, and solution flow rate effect: (a)100bar,10mg/ml,1.5ml/min(b)130bar,12mg/ml,0.5ml/min(c) 160bar,5mg/ml,1.0ml/min. 81 Figure 4-7. SEM images of trimethoprim after SAS processed at 55oC. Pressure, concentration, and solution flow rate effect: (a)100bar,12mg/ml,1.0ml/min(b)130bar,5mg/ml,1.5ml/min(c) 160bar,10mg/ml,0.5ml/min. 82 Figure 4-8. Effects of different operating parameters on S/N ratio. 83 Figure 4-9. Effect of different operating parameters on mean particle size. 83 Figure 4-10. Comparison of the FTIR spectra for the original and SAS processed trimethoprim. 84 Figure 4-11. Comparison of the DSC result for the original and SAS processed trimethoprim. 85 Figure 4-12. Comparison of the XRD result for the original and SAS processed trimethoprim. 86 Figure 4-13. UV-VIS spectrum of trimethoprim in simulated intestinal fluid. 87 Figure 4-14. Calibration curve for trimethoprim in simulated intestinal fluid (pH=6.8) from UV measurement. 87 Figure 4-15. Comparison of the dissolution profiles for the original and SAS processed trimethoprim. 88 Figure 4-16. Comparison of the SEM images of the (a) original and (b) SAS processed chlorothiazide with a magnification of 3000 times . 89 Figure 4-17. Comparison of the SEM images of the (a) original and (b) SAS processed chlorothiazide. 90 Figure 4-18. Comparison of the mean particle size and particle size distribution for the original and SAS processed chlorothiazide. 91 Figure 4-19. SEM images of chlorothiazide after SAS processed at 35oC. Pressure, concentration, and solution flow rate effect: (a)100bar,2.5mg/ml,0.5ml/min(b)140bar,5mg/ml,1.0ml/min(c) 180bar,8mg/ml,2.0ml/min. 92 Figure 4-20. SEM images of chlorothiazide after SAS processed at 45oC. Pressure, concentration, and solution flow rate effect: (a)100bar,5mg/ml,2.0ml/min(b)140bar,8mg/ml,0.5ml/min(c) 180bar,2.5mg/ml,1.0ml/min. 93 Figure 4-21. SEM images of chlorothiazide after SAS processed at 55oC. Pressure, concentration, and solution flow rate effect: (a)100bar,8mg/ml,1.0ml/min(b)140bar,2.5mg/ml,2.0ml/min(c) 180bar,5mg/ml,0.5ml/min. 94 Figure 4-22. Effect of different operating parameters on S/N ratio. 95 Figure 4-23. Effect of different operating parameters on mean particle size. 95 Figure 4-24. Comparison of the FTIR spectra for the original and SAS processed chlorothiazide. 96 Figure 4-25. Comparison of the DSC result for the original and SAS processed chlorothiazide. 97 Figure 4-26. Comparison of the XRD result for the original and SAS processed chlorothiazide. 98 Figure 4-27. Comparison of the TGA result for the original and SAS processed chlorothiazide. 99 Figure 4-28. UV-VIS spectrum of chlorothiazide in simulated intestinal fluid. 100 Figure 4-29. Calibration curve for chlorothiazide in simulated intestinal fluid (pH=6.8) from UV measurement. 100 Figure 4-30. Comparison of the dissolution profiles for the original and SAS processed chlorothiazide. 101 | |
dc.language.iso | zh-TW | |
dc.title | 利用超臨界反溶劑法進行藥物甲氧苄啶及氯噻嗪
之微粒化研究 | zh_TW |
dc.title | Micronization of Trimethoprim and Chlorothiazide by Using Supercritical Anti-solvent Method | en |
dc.type | Thesis | |
dc.date.schoolyear | 106-2 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 蘇至善,吳喬松,蔡榮進 | |
dc.subject.keyword | 超臨界反溶劑法,實驗設計法,田口實驗方法,微粒化,溶離速率,甲氧?啶,氯??, | zh_TW |
dc.subject.keyword | SAS,Taguchi method,design of experiment,micronization,dissolution rate,trimethoprim,chlorothiazide, | en |
dc.relation.page | 112 | |
dc.identifier.doi | 10.6342/NTU201801424 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2018-07-16 | |
dc.contributor.author-college | 工學院 | zh_TW |
dc.contributor.author-dept | 化學工程學研究所 | zh_TW |
dc.date.embargo-lift | 2023-07-18 | - |
顯示於系所單位: | 化學工程學系 |
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