本論文之目的在開發醫療用微球之生產設備及研發相關微球製程，以因應成大醫學院林錫璋醫師臨床醫學研究以及各種醫療微球應用之需要。透過跨領域研究所開發的醫療用微球配方，為了達成某種特殊的醫療目標，必須混合數種藥物及高分子聚合物，其霧化製程比傳統單純物質之霧化困難度高很多，非傳統製程設備可達成，故必須自己發展市場上尚未有的新製程設備。本研究所研發的製程技術為醫療用複合式霧化技術，即統合外部激擾法、靜電噴霧技術，建構複合式單粒徑微球產生機制，進行複合式單粒徑產生裝置之參數研究，主要目的在建立醫療用微球核心技術機台，並進行醫療用微球生產，目標為製造單粒徑範圍 50 μm ~ 300 μm 之微球，以因應各種醫療需求。本研究之霧化器，係利用注射泵浦將工作流體注入霧化器內，在固定流體流率下調整噴嘴電壓使生醫材料流體受電場影響形成液柱後，再施以外部激擾，外部激擾是由波形產生器產生正弦波，訊號經功率放大器放大以推動壓電致動元件，壓電致動元件所產生之外部激擾使液柱在擾動下形成單粒徑醫療微球。本研究使用之實驗流體為聚已內酯混合溶液。研究內容包含噴嘴性能測試及噴霧造粒參數研究，參數包含噴嘴電壓、流體流率、外部激擾頻率、與噴嘴孔徑。實驗結果顯示，施
加靜電力可以控制噴流之液柱直徑，噴嘴電壓與生醫材料流體流率可直接控制醫療微球粒徑大小，噴嘴孔徑與醫療微球粒徑大小無明顯影響。在固定流體流率下微球平均粒徑隨噴嘴電壓增加而縮小。結果亦顯示，微球平均粒徑隨流體流率增加而遞增，當噴嘴電壓提高時，靜電噴霧單粒徑微球生產頻率區間有往高頻方向移動的趨勢。醫療微球生產製程實驗結果顯示，所產生之單粒徑微球粒徑介於 52 μm ~ 358 μm 之間，可應用於各種醫療微球粒徑之需求。

This paper aims at the production of microspheres to meet the requirements for medical applications. The droplet formation of non-Newtonian fluid is rather difficult to produce by traditional atomization processes, especially for the fluid containing many species of the pharmaceutical excipients and medicines. Hence a hybrid atomization process combining the techniques of external excitation and electrostatic spraying was developed to produce the monodisperse microspheres for medical applications The goal of this research is to produce the monodisperse microsphere with diameters ranging from 50 μm to 350 μm to meet the required specifications of the medical applications. Results show that the particle size can be controlled by voltage applied on capillary, flow rate and excitation frequency, etc. It is found that the size of particle can be determined by the jet diameter which is controlled by the voltage applied on capillary and flow rate. The monodispersed droplets can only be produced within certain excitation frequency range while non-uniform droplets would be produced as the excitation frequency was out of this range. It is also found that the particle diameter became smaller as the voltage applied on capillary is increased. However, the boundaries of the typical frequency domain were moved towards higher frequency as the voltage applied on capillary was increased. Typical frequencies under electrostatic spraying still to be realized strongly depend on the size of the drops (i.e., on the jet diameter D j ), and on the velocity V j of the jet. They are proportional to V j /D j and may range well in the higher kHz regime, so that the excitation frequency must be able to perform excitation at such frequencies. It is concluded that our microspheres satisfy the requirements of microspheres in various medical applications.

[1] MCCUAN, John. Retardation of Plateau-Rayleigh instability: a distinguishing characteristic among perfectly wetting fluids. arXiv preprint math/9701214, 1997.
[2] RAYLEIGH, Lord. On the instability of jets. Proceedings of the London mathematical society, 1.1: 4-13, 1878.
[3] RAYLEIGH, Lord. On the capillary phenomena of jets. In: Proc. R. Soc. London. p. 71-97, 1879.
[4] ASHGRIZ, Nasser (ed.). Handbook of atomization and sprays: theory and applications. Springer Science & Business Media, p. 8-12, p. 603-606, 2011.
[5] WEBER, Constantin. Zum zerfall eines flüssigkeitsstrahles. ZAMM‐Journal of Applied Mathematics and Mechanics/Zeitschrift für Angewandte Mathematik und Mechanik, 11.2: 136-154, 1931.
[6] Haenlein, A., “Disintegration of a Liquid Jet,” NACA TN 659, 1932.
[7] Ohnesorge, W., “Formation of Drop by Nozzles and the Breakup of Liquid Jet,” Z. Angew.Math. Mech., Vol. 16, pp. 355-358, 1936.
[8] SAVART, Félix. Mémoire sur la constitution des veines liquides lancées par des orifices circulaires en mince paroi. Ann. Chim. Phys, 1833, 53.337, 1833.
[9] BERGLUND, Richard N.; LIU, Benjamin YH. Generation of monodisperse aerosol standards. Environmental Science & Technology, 7.2: 147-153, 1973.
[10] BRENN, G.; LACKERMEIER, U. Drop formation from a vibrating orifice generator driven by modulated electrical signals. Physics of Fluids (1994-present), 9.12: 3658-3669, 1997.
[11] ROTH, Ing Norbert, et al. Droplet Generation. In: Dynamics of Droplets. Springer Berlin Heidelberg. p. 63-84 , 2000.
[12] KEBARLE, Paul; TANG, Liang. From ions in solution to ions in the gas phase-the mechanism of electrospray mass spectrometry. Analytical chemistry, 1993, 65.22: 972A-986A.
[13] BAILEY, Adrian G. Electrostatic spraying of liquids. New York etc: Wiley, 1988.
[14] CASTELLANOS, A.; PEREZ, A. Electrohydrodynamics. CISM courses and lectures No 380, International Centre for Mechanical Sciences. 1998.
[15] TAYLOR, Geoffrey. Disintegration of water drops in an electric field. In: Proceedings of the Royal Society of London A: Mathematical, Physical and Engineering Sciences. The Royal Society, 1964. p. 383-397.
[16] Smith, David P. H., “The Electrohydrodynamic Atomization of Liquids,” Industry Applications, IEEE Transactions on, Vol. IA-22, pp.527-535, 1986.
[17] Cloupeau, M., Prunet-Foch, B., “Electrostatic spraying of liquids in cone-jet mode,”Journal of Electrostatics, Vol. 22(2), pp.135-159, 1989.
[18] Cloupeau, Michel; Prunet-Foch, Bernard. Electrohydrodynamic spraying functioning modes: a critical review. Journal of Aerosol Science, 1994, 25.6: 1021-1036.
[19] Huebner, A. L., “ Disintegration of charged liquid jets. Results with isopropyl alcohol,” Science, Vol. 168, pp. 118-119, 1970.
[20] ] Rosell-Llompart, J., De La Mora, J. F., “Generation of monodisperse droplets 0.3 to 4 μm in diameter from electrified cone-jets of highly conducting and viscous liquids,” Journal of Aerosol Science, Vol. 25, pp. 1093-1119, 1994.
[21] GRACE, J. M.; MARIJNISSEN, J. C. M. A review of liquid atomization by electrical means. Journal of aerosol science, 1994, 25.6: 1005-1019.
[22] Brandenberger, H., Nüssli, D., Piëch, V., Widmer, F., “Monodisperse particle production: A method to prevent drop coalescence using electrostatic forces,” Journal of Electrostatics, Vol. 45, pp. 227-238, 1999.
[23] ] Hartman, R. P. A., Brunner, D. J., Camelot, D. M. A., Marijnissen, J. C. M., Scarlett, B., “Electrohydrodynamic atomization in the cone–jet mode physical modeling of the liquid cone and jet,” Journal of Aerosol Science, Vol. 30, pp. 823-849, 1999.
[24] Hartman, R. P. A., Brunner, D. J., Camelot, D. M. A., Marijnissen, J. C. M., Scarlett, B., “Jet break-up in electrohydrodynamic atomization in the cone-jet mode,” Journal of Aerosol Science, Vol. 31, pp. 65-95, 2000.
[25] V. T. Tran, J. P. Benoit, M. C. Venier-Julienne, “Why and how to prepare biodegradable, monodispersed, polymericmicroparticles in the field of pharmacy ”, International Journal of Pharmaceutics, Vol. 407, no.1, pp.1-11, 2011.
[26] Almería, B., Gomez, A., “Electrospray synthesis of monodisperse polymer particles in a broad (60nm–2μm) diameter range: guiding principles and formulation recipes,” Journal of Colloid and Interface Science, Vol. 417, pp. 121-130, 2014
[27] DE LA MORA, J. Fernandez; LOSCERTALES, Ignacio González. The current emitted by highly conducting Taylor cones. Journal of Fluid Mechanics, 260: 155-184, 1994.
[28] GAÑAN-CALVO, Alfonso M. 20. O. 05 The size and charge of droplets in the electrospraying of polar liquids in cone-jet mode, and the minimum droplet size. Journal of Aerosol Science, 25: 309-310, 1994.
[29] Gañan-Calvo, A. M., Davila, J., Barrero, A.,“The emitted current and droplet size laws in steady cone-jet electrosprays of polar and non-polar liquids,”in: 4th International Aerosol Conference, Los Angeles, 1994.
[30] REZVANPOUR, Alireza; LIM, Eldin Wee Chuan; WANG, Chi‐Hwa. Computational and experimental studies of electrohydrodynamic atomization for pharmaceutical particle fabrication. AIChE Journal, 58.11: 3329-3340, 2012.
[31] HEINZEN, Christoph; BERGER, Andreas; MARISON, Ian. Use of vibration technology for jet break-up for encapsulation of cells and liquids in monodisperse microcapsules. In: Fundamentals of cell immobilisation biotechnology. Springer Netherlands, p. 257-275, 2004.
[32]楊國明,“藥物釋放之親疏水性乙基纖維素/羥丙基纖維素摻合微粒的製備與其藥物釋放之研究.”國立成功大學博士論文, 2006.
[33]李昱翰,“單粒徑噴霧造粒技術及其在栓塞微球製程之研究.”國立成功大學碩士論文, 2012.