摘要
在本研究中，利用超臨界反溶劑法(SAS)，成功地將抗氧化劑異抗壞血酸、沒食子酸丙酯及食用色素薑黃素進行微粒化。藉由物質的微粒化，期望能提高抗氧化劑的抗氧化能力。本研究中也會探討操作的溫度、壓力、溶液流速、溶液濃度及噴嘴管徑等參數，對於微粒化結果所造成的影響。

在第一部份的研究中，以異抗壞血酸為標的藥物，進行超臨界反溶劑法微粒化的參數效應探討。在溶劑為丙酮、操作溫度為35 ℃、壓力為100 bar、溶液流速為1 mL/min、溶液濃度為5 mg/mL、毛細管噴嘴內徑為200 μm時，有最佳的微粒化效果，可將異抗壞血酸的顆粒尺寸由原始藥物的101 μm，微小化到3.30 μm的大小。在抗氧化能力方面，微粒化之後的產物其抗自由基效率，約為原始藥物的1.64倍，有明顯的提升。

第二部分的研究，則是以沒食子酸丙酯為目標藥物，進行超臨界反溶劑法微粒化的參數效應探討。在丙酮為溶劑、操作在溫度為35 ℃、壓力為140 bar、溶液流速為1 mL/min、溶液濃度為30 mg/mL、毛細管噴嘴內徑為100 μm時有最佳的微粒化效果。能將沒食子酸丙酯的顆粒尺寸由原始藥物的531 μm，微小化到7.70 μm的大小。在抗氧化能力方面，微粒化之後的產物其抗自由基效率約為原始藥物的1.93倍，也有明顯的增加。

第三部分的研究，是針對食用色素薑黃素，進行超臨界反溶劑法的微粒化及參數效應探討。在乙酸乙酯為溶劑、操作在溫度為35 ℃、壓力為100 bar、溶液流速為5 mL/min、溶液濃度為12 mg/mL、毛細管噴嘴內徑為200 μm時有最佳的微粒化效果。薑黃素的顆粒尺寸由原始藥物的17.74 μm，微小化到2.78 μm的大小。而當以乙酸乙酯為溶劑、操作在溫度為35 ℃、壓力為100 bar、溶液流速為5 mL/min、溶液濃度為10 mg/mL、毛細管噴嘴內徑為200 μm時，可得到外觀形貌多數為圓球狀的顆粒。

In this study, micronization of antioxidant, including D-isoascorbic acid, propyl gallate, and natural colorant curcumin has been successfully performed by using the Supercritical Antisolvent (SAS) method. The aim of this research was to increase the antioxidant activity of antioxidant after the SAS process. The parameters such as temperature, pressure, solution flow rate, solution concentration and nozzle diameter were discussed in order to find the optimal operating condition for micronization.

For D-isoascorbic acid, the optimal result was obtained under the following conditions: solvent = acetone, T = 35 ℃, P = 100 bar, solution flow rate = 1mL/min, concentration = 5 mg/mL, nozzle diameter = 200 μm. The mean particle size was decreased from 101 μm to 3.30 μm. In the antioxidant activity test, the antiradical efficiency was increased about 1.64 times.

In the second part, for propyl gallate, the optimal result was obtained under the following conditions: solvent = acetone, T = 35 ℃, P = 140 bar, solution flow rate = 1mL/min, concentration = 30 mg/mL, nozzle diameter = 100 μm. The mean particle size was decreased from 531.13 μm to 7.70 μm. In the antioxidant activity test, the antiradical efficiency was increased about 1.93 times.
For curcumin, the optimal result was obtained under the following conditions: solvent = ethyl acetate, T = 35 ℃, P = 100 bar, solution flow rate = 5 mL/min, concentration = 12 mg/mL, nozzle diameter = 200 μm. The mean particle size was decreased from 17.74 μm to 2.78 μm. When changing the concentration to 10 mg/mL and fixing other parameters, the spherical particles could be obtained.

總目錄
口試委員會審定書
致謝
摘要 I
Abstract III
總目錄 V
表目錄 VIII
圖目錄 IX
第一章 緒論 1
1-1 食品添加劑簡介 1
1-2 超臨界流體簡介 1
1-3 超臨界流體應用 2
1-4 微粒化的目的 4
1-5 常見的微粒化技術 4
1-6 超臨界流體微粒化技術簡介 6
1-6-1 超臨界溶液快速膨脹法 6
1-6-2 氣體飽和溶液沉積法 7
1-6-3 超臨界反溶劑法 8
1-7 抗氧化劑簡介 10
1-8 DPPH抗自由基測試法 11
1-9 研究動機 13
第二章 實驗方法 15
2-1 實驗裝置 15
2-2 實驗操作步驟 16
2-2-1 目標藥物的溶解度測試 16
2-2-2 超臨界反溶劑法實驗操作步驟 16
2-3 分析方法 17
2-3-1 顆粒外觀及粒徑大小 18
2-3-2 晶型特性分析 18
2-3-3 熱效應分析 19
2-3-4 定性分析 20
2-3-5 抗氧化試驗 20
第三章 結果與討論 22
3-1 異抗壞血酸D-isoascorbic acid微粒化研究 22
3-1-1 溶劑效應 22
3-1-2 溫度與壓力效應 23
3-1-3 溶液流速及噴嘴效應 24
3-1-4 微粒化前後的定性分析 25
3-1-5 抗自由基測試 26
3-2 沒食子酸丙酯Propyl gallate微粒化研究 27
3-2-1 溶劑效應 27
3-2-2 溫度與壓力效應 28
3-2-3 溶液流速與噴嘴效應 29
3-2-4 微粒化前後的定性分析 30
3-2-5 抗自由基測試 31
3-3 薑黃素Curcumin微粒化研究 32
3-3-1 溶劑效應 32
3-3-2 濃度效應 32
3-3-3 溫度效應 33
3-3-4 微粒化前後的定性分析 34
第四章 結論 35
第五章 參考文獻 80

Alfano, G., Saba, P. & Surracco, M. (1996). Development of a new jet mill for very fine mineral grinding. International Journal of Mineral Processing 44-5: 327-336.
Brandwilliams, W., Cuvelier, M. E. & Berset, C. (1995). Use of a free-radical method to evaluate antioxidant activity. Food Science and Technology-Lebensmittel- Wissenschaft & Technologie 28(1): 25-30.
Cardoso, M. A. T., Monteiro, G. A., Cardoso, J. P., Prazeres, T. J. V., Figueiredo, J. M. F., Martinho, J. M. G., Cabral, J. M. S. & Palavra, A. M. F. (2008). Supercritical antisolvent micronization of minocycline hydrochloride. Journal of Supercritical Fluids 44(2): 238-244.
Chang, Y. P., Tang, M. & Chen, Y. P. (2008). Micronization of sulfamethoxazole using the supercritical anti-solvent process. Journal of Materials Science 43(7): 2328-2335.
Chen, C. C. & Wagner, G. (2004). Vitamin E nanoparticle for beverage applications. Chemical Engineering Research & Design 82(A11): 1432-1437.
Choi, H., Lee, W., Kim, D. U., Kumar, S., Kim, S. S., Chung, H. S., Kim, J. H. & Ahn, Y. C. (2010). Effect of grinding aids on the grinding energy consumed during grinding of calcite in a stirred ball mill. Minerals Engineering 23(1): 54-57.
Espinoza, M., Olea-Azar, C., Speisky, H. & Rodriguez, J. (2009). Determination of reactions between free radicals and selected Chilean wines and transition metals by ESR and UV-vis technique. Spectrochimica Acta Part a-Molecular and Biomolecular Spectroscopy 71(5): 1638-1643.
Farrell, W. P., Aurigemma, C. M. & Masters-Moore, D. F. (2009). Advances in high throughput supercritical fluid chromatography. Journal of Liquid Chromatography & Related Technologies 32(11-12): 1689-1710.
Franceschi, E., De Cesaro, A. M., Feiten, M., Ferreira, S. R. S., Dariva, C., Kunita, M. H., Rubira, A. F., Muniz, E. C., Corazza, M. L. & Oliveira, J. V. (2008). Precipitation of beta-carotene and PHBV and co-precipitation from SEDS technique using supercritical CO2. Journal of Supercritical Fluids 47(2): 259-269.
Franceschi, E., De Cesaro, A. M., Ferreira, S. R. S. & Oliveira, J. V. (2009). Precipitation of beta-carotene microparticles from SEDS technique using supercritical CO2. Journal of Food Engineering 95(4): 656-663.
Halliwell, B., Aeschbach, R., Loliger, J. &Aruoma, O. I. (1995). The acaracterization of antioxidants. Food and Chemical Toxicology 33(7): 601-617.
Hezave, A. Z. & Esmaeilzadeh, F. (2010). Micronization of drug particles via RESS process. Journal of Supercritical Fluids 52(1): 84-98.
Hong, H. L., Suo, Q. L., Han, L. M. & Li, C. P. (2009). Study on precipitation of astaxanthin in supercritical fluid. Powder Technology 191(3): 294-298.
Jung, J. & Perrut, M. (2001). Particle design using supercritical fluids: Literature and patent survey. Journal of Supercritical Fluids 20(3): 179-219.
Kayrak, D., Akman, U. & Hortacsu, O. (2003). Micronization of ibuprofen by RESS. Journal of Supercritical Fluids 26(1): 17-31.
Kodama, D., Sugiyama, K., Ono, T. & Kato, M. (2008). Volumetric properties of carbon dioxide + isopropyl ethanoate mixtures at 308.15 and 313.15 K. The Journal of Supercritical Fluids 47(2): 128-134.
Lu, T., Blackburn, S., Dickinson, C., Rosseinsky, M. J., Hutchings, G., Axon, S. & Leeke, G. A. (2009). Production of titania nanoparticles by a green process route. Powder Technology 188(3): 264-271.
Mandzuka, Z. & Knez, Z. (2008). Influence of temperature and pressure during PGSS (TM) micronization and storage time on degree of crystallinity and crystal forms of monostearate and tristearate. Journal of Supercritical Fluids 45(1): 102-111.
Mattea, F., Martin, A. & Cocero, M. J. (2009). Carotenoid processing with supercritical fluids. Journal of Food Engineering 93(3): 255-265.
Miguel, F., Martin, A., Gamse, T. & Cocero, M. J. (2006). Supercritical anti solvent precipitation of lycopene - Effect of the operating parameters. Journal of Supercritical Fluids 36(3): 225-235.
Molyneux, P. (2004). the use of the stable free radical diphenylpicrylhydrazyl (DPPH) for estimating antioxidant activity. Sogklanakarin J. Sci. Technol. 26: 211-218.
Park, C. I., Shin, M. S. & Kim, H. (2008). Micronization of arbutine using supercritical anti-solvent. Korean Journal of Chemical Engineering 25(3): 581-584.
Ramsey, E., Sun, Q., Zhang, Z., Zhang, C. & Gou, W. (2009). Mini-Review: Green sustainable processes using supercritical fluid carbon dioxide. Journal of Environmental Sciences 21(6): 720-726.
Rasenack, N. &Muller, B. W. (2004). Micron-size drug particles: Common and novel micronization techniques. Pharmaceutical Development and Technology 9(1): 1-13.
Reverchon, E. (1999). Supercritical antisolvent precipitation of micro- and nano-particles. Journal of Supercritical Fluids 15(1): 1-21.
Reverchon, E. & De Marco, I. (2006). Supercritical antisolvent precipitation of Cephalosporins. Powder Technology 164(3): 139-146.
Sanchez-Moreno, C., Larrauri, J. A. & Saura-Calixto, F. (1998). A procedure to measure the antiradical efficiency of polyphenols. Journal of the Science of Food and Agriculture 76(2): 270-276.
Sharma, O. P. & Bhat, T. K. (2009). DPPH antioxidant assay revisited. Food Chemistry 113(4): 1202-1205.
Sihvonen, M., Jarvenpaa, E., Hietaniemi, V. & Huopalahti, R. (1999). Advances in supercritical carbon dioxide technologies. Trends in Food Science & Technology 10(6-7): 217-222.
Stievano, M. & Elvassore, N. (2005). High-pressure density and vapor-liquid equilibrium for the binary systems carbon dioxide-ethanol, carbon dioxide-acetone and carbon dioxide-dichloromethane. The Journal of Supercritical Fluids 33(1): 7-14.
Su, C. S. & Chen, Y. P. (2005). Recrystallization of salicylamide using a batch supercritical antisolvent process. Chemical Engineering & Technology 28(10): 1177-1181.
Weidner, E. (2009). High pressure micronization for food applications. Journal of Supercritical Fluids 47(3): 556-565.
Yamaguchi, T., Takamura, H., Matoba, T. & Terao, J. (1998). HPLC method for evaluation of the free radical-scavenging activity of foods by using 1,1-diphenyl-2-picrylhydrazyl. Bioscience Biotechnology and Biochemistry 62(6): 1201-1204.