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標題: | 利用超臨界溶液快速膨脹法進行藥物氯貝酸與百里酚之微粒化研究 Study of the RESS Process for Micronization of Clofibric acid and Thymol |
作者: | Hao-Chih Chien 簡豪志 |
指導教授: | 陳延平(Yan-Ping Chen) |
關鍵字: | 超臨界溶液快速膨脹法,實驗設計法,田口實驗方法,微粒化,溶離速率,氯貝酸,百里酚, RESS,Taguchi method,design of experiment,micronization,dissolution rate,clofibric acid,thymol, |
出版年 : | 2016 |
學位: | 碩士 |
摘要: | 本研究利用超臨界溶液快速膨脹法對兩種原料藥進行微粒化並探討微粒化前後之物理與化學性質差異,原料藥物分別為降血脂藥物氯貝酸(Clofibric acid)與抗菌藥物百里酚 (Thymol),微粒化之目的在於藉由縮小藥物顆粒尺寸,進而提高藥物總表面積、降低結晶度或改變結晶型態,增加其在生物體內之溶離速率,最終將提升藥物在生物體內之相容性與實用性。
本研究中,利用田口實驗方法 (Taguchi Method) 設計實驗操作表格,以超臨界二氧化碳為萃取溶劑,並改變四種不同的操作參數,如萃取溫度 (Text) 、 萃取壓力 (Pext) 、收集瓶溫度 (Tpost) 以及噴嘴內徑 (DN),進而分析這四種參數對藥物粒徑所造成的效應,利用實驗設計法操作實驗後,將能夠以最少的實驗次數快速找出實驗最佳操作條件,大幅提升了效率,而本研究後段將進行溶離速率實驗,以模擬人體腸液為溶離媒介,觀察藥物在微粒化前後,其溶離速率是否有提升。 首先在藥物Clofibric acid 的研究中,原始藥物經過微粒化程序後,藥物粒徑從97.41 μm 縮小為 1.01 μm 。在定性分析方面,從FTIR、DSC、TGA、XRD圖譜中皆可看出藥物沒有變質的情形產生,但卻因為藥物縮小而有結晶度降低的現象,有利於溶離速率之提升。接著比較藥物微粒化前後之溶離速率差異,可觀察到RESS 處理過後藥物之溶離速率高於原始藥物,代入Weibull model 進行迴歸後,原始藥物之kw值為0.033 min-1,微粒化後之藥物的kw值為0.061 min-1,溶離速率約提升1.85倍,溶離速率提升幅度不大,可能原因為進行溶離速率前,藥物先進行了壓錠的前處理,導致藥物緻密度提高,使得總表面積提升不大所致。 接著在藥物Thymol 的研究中,原始的藥物平均粒徑約為1385.21 μm,經過RESS 程序處理後,藥物平均粒徑為21.35 μm,最多可以縮小65 倍之多。而在定性分析方面,從FTIR、DSC、TGA、XRD 圖譜中皆可以觀察出藥物在RESS程序前後沒有變質的情形產生,但結晶度下降許多,有助於溶離速率的提升,進行Weibull model 的迴歸後,計算出原始藥物之kw 為0.027 min-1,而微粒化後藥物之kw 為0.12 min-1,溶離速率大幅提升了4.42 倍,本研究亦引用相似因子 (F1)與差異因子(F2),來探討微粒化前後溶離行為的差異性,實驗結果為溶離行為具有顯著之差異。 In this study, RESS process was applied for micronization and recrystallization of two active pharmaceutical ingredients (APIs) including clofibric acid and thymol. Also, Taguchi Method has been used to design for the experiment. Taguchi’s parameter design is an important tool for robust design. It offers a simple and systematic approach to optimize design for performance, quality and cost. After RESS processed, the submicron particles were precipitated in the expansion vessel with various effects of operating factors like extraction temperature (Text), extraction pressure (Pext), post temperature (Tpost), and the nozzle diameter (DN). Then, the original and micronized APIs were evaluated by SEM, FTIR, DSC, XRD and TGA analysis. Moreover, the comparison of the dissolution profile between original and RESS-processed APIs was also shown in this study. For clofibric acid, the particle size was dramatically reduced from 97.41 μm to 1.01 μm by RESS process. There was no change of the physical and chemical properties after the RESS process. Also, the decrease of crystallinity can be observed in the XRD result. Results from Taguchi method and analysis of variance (ANOVA) showed that nozzle diameter was the most significant factor. Then, the dissolution rate constant (kw) of original and RESS-processed particles can be calculated by optimally fitting the data points with Weibull model. As a result, the rate of dissolution only enhanced 1.85 times. Similar result can be discovered in the API thymol through RESS process. The mean particle size was significantly micronized from 1385.21 μm to 21.35 μm. Although no polymorphic transformation was found, the crystallinity of RESS-processed thymol diminished. Besides, the physical and chemical properties of the thymol remained the same. Results from Taguchi method and analysis of variance (ANOVA) showed that post-expansion temperature was the most important factor. Dissolution studies reported that the dissolution rate improved 4.42 times. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/50979 |
DOI: | 10.6342/NTU201600496 |
全文授權: | 有償授權 |
顯示於系所單位: | 化學工程學系 |
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