臺灣博碩士論文加值系統

本文以噴射結晶技術針對難溶性藥物進行結晶研究，並藉由添加物的加入，以改善難溶性藥物的溶離速率，進而提高藥物的療效。文中採用tolbutamide（TBM）及phenylbutazone（PBZ）為模式藥物，四種添加物分別為hydroxypropylcellulose（HPC）、polyvinylpyrrolidone（PVP）、sodium lauryl sulfate（SDS）以及D-mannitol（D-M）進行實驗。以丙酮為藥物的溶劑，水為反溶劑，針對不同的過飽和度以及添加物濃度等操作變數進行探討。由觀察得知，不同的添加物會使藥物晶體獲得不同的晶貌如片狀、針狀或是棒狀等。由TBM藥物的研究結果顯示，當溶液的過飽和度愈高，所析出的晶體粒徑愈小且分佈愈集中，其中以流量比T1：3.57W獲得的最為細小及均勻。由噴射後的藥物晶體發現，經噴射後所獲得的PBZ藥物晶體將會發生多晶型相轉變，同時由DSC以及XRD鑑別加入添加物後，將會引起另一種多晶型的出現。再進一步將藥物粉體進行體外溶離試驗發現，噴射結晶中加入添加物將會改善TBM藥物溶離速率。至於加入添加物的改善效果依序為添加HPC＞SDS＞PVP＞D-M＞未添加。另一方面，PBZ藥物溶離速率快慢依序則是添加SDS＞HPC＞PVP＞D-M＞未添加。因此證實添加物的加入確實可以提升藥物粉體的潤濕效果，進而使溶離速率大幅上升，有助於提升藥物的療效。

The research conducts the study of impinging-jets crystallization for poorly water-soluble drugs by adding additives to improve dissolution rate, thus enhancing the therapeutic effect of drugs. Tolbutamide and phenylbutazone were used as model drugs while hydroxyproplcellulose（HPC）, polyvinylpyrrolidone（PVP）, sodium lauryl sulfate（SDS） and D-mannitol（D-M） were additives used in this work. Also, acetone was the solvent for the drugs, while water was the anti-solvent. In the experiments, different operating variables such as supersaturation as well as the ratios of additive to drug were studied.
According to the observations of crystal shapes, different additives would lead to different crystal morphologies, such as tabular, needle or rod. The results of tolbutamide showed that as the supersaturation of solution increases, the crystal size becomes smaller and the particle distribution becomes narrower. Furthermore, for a mixed solution of acetone and water with a volume ratio of 1:3.57, the most uniform and smallest size of crystals was found. A polymorphism phase shift for phenylbutazone from the rod-like crystals to the needle-like crystals was observed through impinging-jet crystallization. In addition, adding additives were shown to cause another phase transformation, which was characterized by DSC and XRD. Furthermore, a dissolution test in vitro was performed for the drug products. The test illustrated that the impinging-jets crystallization with the additives will improve the dissolution rate of tolbutamide. The effect of improvement for the additives is in the order of adding HPC> SDS> PVP> D-M> non-added. On the other hand, the improvement in the dissolution rate for phenylbutazone takes the order of adding SDS> HPC> PVP> D-M > non-added. The results show that the additives may enhance the wetting effect of particles, which will result in greatly improving the dissolution rate of poorly water-soluble drugs, thus raising the therapeutic effect of drugs.

目 錄

中文摘要.........................................................................................................................Ⅰ
英文摘要.........................................................................................................................Ⅱ
誌謝.................................................................................................................................Ⅳ
目錄.................................................................................................................................Ⅴ
表目錄............................................................................................................................Ⅶ
圖目錄.....................................................................................................................Ⅷ
第一章 緒論...................................................................................................................1
第二章 結晶理論...........................................................................................................3
2.1 前言.................................................................................................................3
2.2 結晶基本理論.................................................................................................4
2.2.1 晶體結構與特性..................................................................................4
2.2.2 溶解度.................................................................................................5
2.2.3 過飽和度與介穩區.............................................................................7
2.2.4晶體成核動力學............................................................................9
2.2.5晶體成長動力學….....................................................................10
2.3 傳統的結晶方法...........................................................................................11
2.3.1冷卻式結晶................................................................................11
2.3.2 鹽析式或溶析式結晶..................................................................11
2.3.3 反應式結晶..................................................................................12
2.3.4其他結晶方法.......................................................................13
第三章 噴射結晶技術….............................................................................................14
3.1 微混合效應.......................................................................................15
3.2 動量相等原理.............................................................................................16
3.3 溫度效應...............................................................................................17
第四章 添加物對結晶程序的影響..........................................................................21
4.1 添加物進入晶體之機制...............................................................21
4.2添加物對晶體成核速率的影響..................................................22
4.3添加物對晶體成長速率的影響..................................................23
第五章 藥物溶解動力學.............................................................................................29
5.1藥物吸收與吸收機制...................................................................................29
5.2 溶離理論..............................................................................31
5.3 影響藥物溶離之因素.................................................................33
第六章 實驗方法.........................................................................................................35
6.1 實驗藥品與儀器......................................................................35
6.1.1 實驗藥品…......................................................................................35
6.1.2 實驗儀器.........................................................................................36
6.2 實驗規劃.....................................................................................................36
6.3 鹽析式結晶................................................................................................37
6.4 噴射結晶....................................................................................................39
6.5 溶離速率測定..................................................................................41
6.5.1 模擬腸液之製備...........................................................................41
6.5.2 檢量線之製作.........................................................................41
6.5.3 溶離速率實驗.....................................................................43
第七章 結果與討論....................................................................................................44
7.1 噴射結晶技術對藥物晶體之影響..........................................................44
7.1.1噴射結晶改變藥物濃度與鹽析結晶之探討..................................45
7.1.2噴射結晶改變流量比例之探討....................................................54
7.1.3以模式藥物PBZ進行噴射結晶之探討...................................62
7.2添加物對藥物晶體之影響…..................................................70
7.2.1噴射結晶改變藥物濃度以及添加物種類之探討..........................70
7.2.2加入添加物改變噴射結晶的流量比之探討.................................84
7.2.3添加物不同加入相之探討.............................................................92
7.2.4改變添加物加入濃度之探討.........................................................99
7.2.5不同添加物與PBZ藥物進行噴射結晶之探討........................107
7.3 溶離速率之探討..............................................................117
7.3.1噴射結晶技術對溶離速率之影響...........................................117
7.3.2添加物對於溶離速率之影響..................................................121
第八章 結論.......................................................................................................127
參考文獻......................................................................................................129
附錄
附錄A…………………………………………………………………………………138

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