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    Please use this identifier to cite or link to this item: http://ir.lib.ncu.edu.tw/handle/987654321/3966


    Title: 外消旋(R/S)-(+/-)伊普的初始溶劑篩選及伊普鈉鹽結晶動力學;Initial Solvent-screening of Racemic (R/S)(±)-Ibuprofen and Crystallization Kinetics of Ibuprofen Sodium Salt
    Authors: 陳映秀;Ying-Hsiu Chen
    Contributors: 化學工程與材料工程研究所
    Keywords: 成核;晶體成長;結晶動力學;溶劑篩選;同質異相;外消旋;nucleation;polymorph;solvent screening;racemic;crystal growth;kinetics
    Date: 2007-01-05
    Issue Date: 2009-09-21 12:27:14 (UTC+8)
    Publisher: 國立中央大學圖書館
    Abstract: 外消旋物質包含外消旋聚集物、外消旋混合物或者擬消旋體(固體溶液)。市面上大部分(90-95%)的外消旋藥都是外消旋混合物。在這篇論文中,我們集中在包含伊普以及伊普鹽二水化合物的外消旋混合物藥的結晶,並且嘗試提供對增進藥物發展效率的一系列工程技術資料。這篇論文完成了兩個重要的研究。 首先,我們是第一個使用23種溶液(水、甲醇、乙醇、異丙醇、正丁醇、苯甲醇、丙酮、乙睛、硝基苯、二甲基甲醯胺、二甲基亞楓、丁酮、乙酸乙酯、甲基第三丁基醚、正庚烷、N,N-二甲基苯胺、二甲苯、間二甲苯、甲苯、苯、1,4,-二氧陸圜、四氫呋喃以及氯仿)利用初始溶液篩選法來徹底以及同時收集依普的外消旋混合物包含溶解度、同質異相、結晶度以及結晶形貌的工程技術資料。在這個部份,我們是伊普外消旋混合物的溶劑同質異相表的發明者。溶劑同質異相表是材料的特性。研究的結果如下:(1)伊普外消旋混合物幾乎不溶於水,(2)粉末X光繞射以及微分熱插掃描分析儀的研究顯示伊普為同型物質,(3)伊普外消旋混合物從二甲基甲醯胺溶液中成長的結晶比起其他容易有最高的結晶度,最後(4)不同的溶液(從極性溶劑到非極性溶劑)可以修改伊普外消旋混合物的結晶體長寬比。對於伊普而言,在晶體中是以二聚物的鍵結方式形成羧酸,且羧酸族群相對地比較喜歡溶解於極性的溶劑中。因此伊普的晶體長寬比,在極性溶劑中會比非極性溶劑小。 第二,我們集中在伊普外消旋混合物的結晶動力學。在這個部份,我們是第一個使用0.02公克的純對應結構體的 (S)-(-)-伊普鈉鹽二水化合物以及單對掌性的酸性 (S)-(+)-伊普作為添加物。另外,我們使用電導度計來執行原位監控整個結晶程序並且整合熱力學與動力學的資訊。利用電導度計我們可以獲得結晶過程的時間點從成核的誘發期到晶體成長終點,然後評估基礎地成核與結晶成長因子。這個研究的結果非常的重要,因為不同的添加劑被加入的出現會改變結晶的路徑來製造:(1)伊普鈉鹽二水外消旋混合物,(2)伊普鈉鹽二水外消旋聚集物,(3)伊普鈉鹽的擬外消旋體。 Racemic species involve racemic conglomerate, racemic compound, or pseudoracemate (solid solution). On the market, most racemic drugs are racemic compound (90-95%). In this thesis, we focused on the crystallization of the racemic compound drug including ibuprofen ((R/S)(±)-2-[4-isobutylphenyl)propionic acid, C13H18O2) and sodium ibuprofen dihydrate ((R/S)(±)-sodium 2-(4-isobutylphenyl) propanoate, C13H17NaO2·2H2O), and attempted to provide a series of effective engineering technology data to improve the efficiency for drug development. Two important studies in this thesis were performed. Firstly, we were the first to use 23 solvents (water, methanol, ethanol, isopropyl alcohol (IPA), n-butyl alcohol, benzyl alcohol, acetone, acetonitrile, nitrobenzene, N,N-Dimethylformamide (DMF), dimethy sulfoxide (DMSO), methyl ethyl ketone (MEK), ethyl acetate, methyl-t- butyl ester (MTBE), n-heptane, N,N-dimethylaniline(DMA), xylene, p-xylene, toluene, benzene, 1,4 dioxane, tetrahydrofurn (THF), and chloroform.) by initial solvent-screening to collect engineering technology data including solubility, polymorphism, crystallinity, and crystal habit of racemic compound of ibuprofen, simultaneously. In this section, we are the inventors for the “form space” of the racemic compound of ibuprofen. “Form space” is the material’s characteristics. Results of this investigation were shown as the following: (1) the racemic compound of ibuprofen was practically insoluble in water, (2) the powder x-ray diffraction (PXRD) and differential scanning calorimetry (DSC) studies showed that ibuprofen was isomorphic, (3) the degree of crystallinity of racemic ibuprofen in DMF was higher than the ones given from other solvents, finally, (4) the different type of solvents (from polar to non-polar) can modify the aspect ratio of racemic compound of ibuprofen. Because the racemic compound of ibuprofen packing was formed by dimer formation in solution before the incorporation into the crystal. Hence, racemic compound of ibuprofen have a carboxylic acid group are likely to dissolve in polar solvents. Secondly, we focused on the crystallization kinetics of racemic compound of ibuprofen. In this section, we were the first to use 0.02g of the pure enantiomer of S(-)-sodium ibuprofen dihydrate and the homochiral parent acid (S)-(+)-ibuprofen as additives. In addition, we employed electrical conductance in situ monitor the entire crystallization process and to gather thermodynamics (solubility, Gibbs free energy) and kinetics (nucleation and crystal growth) information. The fundamental nucleation and crystal growth parameters were then estimated. This investigational results were very important. Because the presence of different additives could alter the crystallization pathways to produce (1) racemic compound of sodium ibuprofen dihydrate, (2) racemic conglomerate of sodium ibuprofen dehydrate, and (3) pseudoracemic of sodium ibuprofen.
    Appears in Collections:[化學工程與材料工程研究所] 博碩士論文

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