連續式旋轉盤反應器製備微粉之規模放大研究

Scale up of a Spinning Disk Reactor for Preparing Fine Powder in a Continuous Mode

王耀萱(Yao-Hsuan Wang)

指導教授 ： 戴怡德

國立臺灣大學/工學院/化學工程學研究所/博士(2011年)

https://doi.org/10.6342/NTU.2011.00208

摘要

微奈米粒子由於本身的尺寸與表面結構與一般塊材有非常大的差異，在物理化學性質方面都有很優異的表現，可廣泛應用於生醫、光電、化學等方面。而常見的製備方法有研磨法與沉澱法兩種。但是傳統研磨法在研磨過程中物質容易受汙染，晶格結構也有可能受到破壞。而沉澱法由於設備簡單、成本低且容易操作，極受到工業界的喜愛。不過工業上沉澱反應都是在批次攪拌槽中進行，由於屬於批次操作，在提升量產效能上會受到限制，且攪拌槽的微觀混合不佳，粒徑大小與產物外觀都難以控制。為克服上述問題，陳建峰等人在2000年利用旋轉填充床以循環式操作製備碳酸鈣等無機奈米顆粒，1公升的反應物溶液在旋轉填充床中的反應時間約為5-15分鐘，遠比一般靜止填充床約75-90分鐘來得短。雖然超重力循環式操作已大幅縮短反應時間，若能改為連續式操作的話則可大幅提升產能。
旋轉填充床與旋轉盤皆屬超重力設備。在製備微粉時，後者較不易引發粒子凝聚而較有利。故本實驗室則選用超重力旋轉盤以連續式操作製備出各種奈微米粉末，包括碳酸鈣、氫氧化鎂、銀粉、碘化銀、SMZ藥物等。無機銀粉的製備方法是將硝酸銀與PVP (Polyvinylpyrrolidone)溶在鹼性水溶液中再利用葡萄糖將銀粒子還原出來。藥物微粒的製備方法則是將藥物溶解在含保護劑的鹼性水溶液後再加入丙酸水溶液，改變溶液中的溶解度，將藥物再結晶析出。不過本實驗室未曾有系統地討論超重力反應器以連續式操作與規模放大後對於有機無機這兩種物系的影響。在無機銀粒子方面欲藉將超重力旋轉盤的規模放大，以增加反應物在盤面上的滯留時間，藉此提高產率。而在藥物方面希望盤面加大並改變噴嘴結構以得到更小的粒子。本研究選擇銀粉與有機藥物對-胺基水楊酸 (p-aminosalicylic acid)與格列本脲(glilbenclamide)作為超重力連續式實驗的目標產物。除討論不同操作變數對於產物粒徑與產率的影響外，也比較超重力旋轉盤盤面大小與進料管構造對於無機與有機物產物的影響。超重力設備包含旋轉盤(盤面直徑為12.0cm、19.5cm、與50cm)，與液體進料分散器(直管與環狀管) 。
在銀粉製程中，當在適當操作範圍下銀粉粒徑並不會受到旋轉盤大小以及噴嘴形狀的影響，可得到10nm左右的銀粒子。反應物流量在1-5L/min的範圍內並不會使粒子變大。在藥物微粒製程中，將盤面加大並使用環狀噴嘴可降低藥物尺寸，可得到微米甚至次微米等級的藥物微粒。當反應物流量增大時微觀混合效率就會變差，造成粒子變大，反應物最佳流量約在0.25L/min-0.50L/min之間。且經超重力再結晶後的藥物，結晶強度與粒徑皆小於原料藥，有助於促進溶解速率。以化學還原法可得到小於10nm的銀粒子，產率為40.1%，每日單位產能為31kg。利用酸鹼中和法可得到次微米級的PAS藥物粒子，產率為54.0%，每日單位產能為23kg。GBM藥物也同樣是以酸鹼中和法獲得，粒徑大約在1μm左右，產率為92.6%，每日單位產能為1.8kg。

關鍵字

超重力技術、旋轉盤反應器、沉澱法、連續式操作、奈米銀粉、難溶性藥物 、規模放大

並列摘要

Nano/micro particles, which have excellent physical and chemical properties, can widely applied to various industries, such as biological, electrical, and chemical, due to their small size and imperfect surface structure, which are different from that of bulk materials. The common methods for preparing particles include milling and precipitation. For the traditional milling method, the products are usually contaminated or the crystal lattice of products is disrupted. The precipitation method is most popular in industry for its simplicity, low cost, and ease of manipulation. But the reactive precipitation method using a batch stirred vessel is hard to improve the product quality and production capacity. The particle size and shape are difficult to control because of the poor mixing efficiency. To overcome these problems, an efficient method of rotation packed bed, which is one of the high-gravity equipment, has been applied by Chen et al. (2000) to synthesize CaCO3 nanoparticles in a recycle mode. The reaction time in a rotating packed bed is around 5- 15 min for 1 L reactant aqueous solution. At the same operating conditions, the reaction time in a conventional stirred reactor is eight times as large as that in a rotating packed bed. It is apparent that recycle operation in a high-gravity reactor has shortened the reaction time. If the recycle operation is replaced by the continuous operation, the production rate will be enhanced.
There are two types of high-gravity equipment, i.e. rotation packed bed and spinning disk. The latter is better for preparing particles due to less chance of particle collision to form agglomerates. In our laboratory, several compounds have been successfully synthesized using the SDR in a continuous mode, such as CaCO3, Mg(OH)2, Ag , AgI, and SMZ (drug). In the silver particle preparation, AgNO3 and PVP (protecting agent) were dissolved in an aqueous solution, and then the solution was mixed with an aqueous solution of glucose and NaOH to produce Ag particles through a reducing reaction. In the drug precipitation reaction, the drug and protecting agent were first dissolved in an alkaline solution, and an acidic solution was added and mixed to change the solubility of solution, and then drug particles were recrystallized. However, the scale up of the SDR for preparing organic and inorganic particles in a continuous mode has not been discussed and compared. In this study, the disk diameter was scaled up to 50cm to increase the retention time and to improve the yield of silver product. In the drug particle preparation, drugs were recrystallized with the larger SDR fitted with circular tube liquid distributors to obtain smaller particles. Drugs of p-aminosalicylic acid (PAS) and glilbenclamide (GBM) were chosen in this study of continuous operation. The main theme of this research was to discuss various operation conditions on particle size and yield, and to compare the performance of organic and inorganic systems. The equipment consists of a spinning disk of diameter being 12.0cm, 19.5cm, and 50.0cm, fitted with liquid distributors of straight or circular tubes.
In the process for preparing silver nanoparticles under the appropriate operating conditions, the effects of the disk size and liquid distributors were not observed on the silver particle size with the size, which was around 10nm. In addition, when the reactant flow rate varied from 0.3 to 5.0 L/min, the particle size remained quite constant. In the process for preparing drug particles, when increasing spinning disk diameter and using circular liquid distributors, the drug particles size could be reduced to micro or submicron level. On the other hand, the particle size of drug increased with increasing reactant flow rate due to the poor mixing efficiency. Therefore, the suitable reactant flow rate was between 0.25 L/min and 0.50 L/min. The size and crystalline intensity of the recrystallized drug were lower compared to that of the commercial drug, and thus the dissolution rate was enhanced. The silver particles synthetized by the chemical reaction method were smaller than 10nm and the production rate was 31kg with the yield of 40.1%. The PAS drug particles prepared by the neutralization method were reduced to submicron level and the production rate was 23kg with the yield of 54.0%. The GBM drug particles prepared by the neutralization method were around 1μm and the production rate was 1.8kg with the yield of 92.6%.

並列關鍵字

high-gravity technique, spinning disk reactor, precipitation method, continuous operation, silver nanoparticles, low solubility drugs, and scale up.

參考文獻

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