臺灣博碩士論文加值系統

結晶方法在製藥工業中是十分重要且常見的分離技術，此方法不但直接從溶液獲取高純度的藥物，並且藉著結晶方法改進其微粒性質，以及提 高藥物的品質。由於多數藥物具有難溶於水或胃腸液的特性，為了增進療效，製藥工業中常以各種研磨加工方式來減低粒徑的大小，以加強藥物的溶解速率。然而細微的結晶粉末往往因為流動性、堆積性及壓縮性不佳，導致製程效率的降低，並且額外的研磨加工步驟也容易使藥物遭受污染而影響純度及療效。
本文研究的主要目的是利用球形結晶技術改善藥物結晶的微粒特性及溶解速率，藉此提高製程效率及藥物療效。藉由實驗分別探討高分子水溶液濃度、藥物溶液與水相溶液的溫度差、攪拌速率、藥物溶液與水相溶液的體積比、藥物溶液濃度，以及滴定速率對球形凝聚結晶的影響，進而尋求最佳的操作條件。此外，由於球形凝聚結晶表面附著水溶性高分子，使其有良好的潤濕性及滲透性。在微粒特性實驗方面，球形結晶因具有完整的圓球狀及平滑的表面，使其具有良好的堆積性和流動性。同時球形凝聚結晶具有多孔性結構，增加晶體的有效比表面積，將會改善藥物的溶解速率，進一步將各種球形結晶的藥物進行溶離動力實驗，證實球形結晶方法確實可以有效提高藥物的溶解速率

Crystallization is a significant separation technique which is often used in pharmaceutical industry. This method not only isolates drug substances with high purity directly from the solution, but improves the micromeritic characteristics and the quality of the drug products. Many of the drug substances are poorly soluble in water or gastrointestinal fluids. Considerable attention is therefore placed to reduce the particle size by milling steps to enhance the bioavailability. However, the fine crystals with poor flowability, packability and compressibility may result in lowering the efficiency of manufacturing processes. Moreover, the additional milling steps facilitate the drugs being polluted, affecting the purity and bioavailability of the products.
The aim of this study is to improve the micromeritic characteristics and the dissolution rate by spherical crystallization technique, so that the manufacturing processes are simplified and the bioavailability therefore is enhanced. The effects of various operating parameters on spherically agglomerated crystals such as the concentration of water-soluble polymers, the temperature difference（ΔT）between the drug solution and the aqueous solution, the rate of agitation, the volume ratio of drug solution and aqueous solution, the concentration of drug solution and the titration rate are extensively studied. In addition, the water-soluble polymers are incorporated into the spherically agglomerated crystals which may provide greater wettability and permeability of the drugs. On the experiment of micromeritic properties, it shows the good packability and flowability for spherical crystals due to the spherical shape and smooth surface. The porous structure of spherical agglomerated crystals also has a large specific surface area so as to increase the dissolution rate of the drug. Furthermore, the dissolution kinetics of drug substances produced from the spherical crystallization were carried out. It is validated that the spherical crystallization can effectively provides a better dissolution rate of the products.

摘 要 I
ABSTRACT III
誌 謝 V
目 錄 VI
表目錄 VIII
圖目錄 IX
第一章 序論 1
第二章 結晶原理與方法 3
2.1 前言 3
2.2 結晶基本原理 4
2.2.1 溶解度與超飽和度 4
2.2.2 純化程序 7
2.2.3 成核現象 8
2.2.4 晶體成長 11
2.3 傳統結晶方法 12
2.3.1 冷卻式結晶 13
2.3.2 鹽析式結晶 13
2.4 球形結晶 14
2.4.1 球形結晶製備技術 14
2.4.2 QESD法製備原理 17
2.4.2.1 乳化液滴的形成 17
2.4.2.2 溶劑與反溶劑的擴散行為 18
第三章 藥物溶解動力學 20
3-1 溶離理論 21
3-2 藥物吸收機制 23
3-3 影響藥物溶離之因素 24
第四章 實驗方法 26
4.1 實驗藥品與儀器 26
4.1.1 實驗藥品 26
4.1.2 實驗儀器 27
4.2 實驗規劃 28
4.3 溶劑與反溶劑的選擇 29
4.4 溶解度之測定 30
4.5 結晶實驗 31
4.5.1 冷卻式結晶 31
4.5.2 球形結晶 31
4.6 微粒特性分析 34
4.6.1 堆積性實驗 34
4.6.2 流動性實驗 34
4.7 溶離速率測定 34
4.7.1 模擬腸液之製備 34
4.7.2 檢量線之製作 34
4.7.3 溶離速率實驗 36
第五章 結果與討論 38
5.1 球形結晶技術對藥物結晶結構之影響 39
5.1.1 傅立葉轉換紅外光儀分析 39
5.1.2 示差熱分析儀分析 41
5.1.3 X光繞射儀分析 42
5.2 操作變數對球形凝聚結晶影響之探討 44
5.2.1 高分子添加物HPMC濃度 44
5.2.2 藥物溶液與水相溶液之溫度差 51
5.2.3 攪拌速率 56
5.2.4 藥物溶液和水相溶液的體積比 60
5.2.5 藥物溶液濃度 65
5.2.6 滴定速率 69
5.3 冷卻式結晶 73
5.4 微粒特性分析 74
5.4.1 堆積性 74
5.4.2 流動性 74
5.5 溶離試驗 75
5.5.1 高分子添加物對藥物溶離速率之影響 75
5.5.2 溶離速率之研究 79
第六章 結論 83
參考文獻 86
附錄
附錄A 93

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