本研究先探討四個氟化非固醇類抗發炎藥物(氟芬那酸(flufenamic acid)、來氟米特(Leflunomid)、尼氟密酸(niflumic acid)、希樂葆(celecoxib))在超臨界二氧化碳隨著接觸時間的長短的溶解情形，接著在足夠長的接觸時間下，利用一套半流動式的高壓相平衡的裝置，量測這四種非固醇類抗發炎藥物在超臨界二氧化碳中的平衡溶解度，量測溫度的範圍從313.2 K 到353.2 K，壓力最高到31 MPa。本研究也利用Peng-Robinson狀態方程式配合含二個參數的凡得瓦單一流體混合律來關聯飽和溶解度的數據，另外也分別用Chrastil與Mendez-Santiago Teja半經驗模式來關聯這些藥物的飽和溶解度作數據。本階段之研究目的在於量取這些非固醇類抗發炎藥物在超臨界二氧化碳中的溶解度，提供以超臨界流體快速膨脹法製備藥物微細化的製程開發所需之基本數據。
由於在四個非固醇類抗發炎藥標的物中，氟芬那酸具有最高的溶解度(高至莫耳分率為2.13×10-4)，因此我們選擇氟芬那酸來進行以超臨界流體快速膨脹法製備此藥物微粒的研究，探討一些重要操作變數對氟芬那酸微粒的外觀形態，以及平均粒徑的影響，這些操作變數包括萃取溫度(Text)和壓力(Pext)、超臨界流體膨脹前的溫度(Tpre)、結晶槽溫度(Tcry)、毛細管內徑(Dnozzle)和長度(Lnozzle)，以及粒子樣品收集板與毛細管出口之間的距離(Z)。實驗結果顯示藉由調控以上這些實驗的變數，我們可以成功製得超微粒的氟芬那酸粒子，其粒徑分佈範也很窄小。另外也發現經由臨界流體快速膨脹法所製得的氟芬那酸微粒，其結晶的型態由原來的晶型I 轉變為晶型III。
本研究也探討以超臨界流體快速膨脹法製備來氟米特藥物微粒之多晶型，有系統地觀察操作變數：萃取的溫度(Text)和壓力(Pext)、超臨界流體膨脹之前的溫度(Tpre)以及結晶槽的溫度(Tcry)對來氟米特微粒的結晶型態、粒子的外觀形態，以及粒子大小等的影響。實驗結果顯示調控超臨界流體快速膨脹法的操作條件，可分別製備出結晶型態I、結晶型態II和一種新發現的結晶型態IV的藥物微粒，所得到的結晶同時擁有奈米尺寸(小至約60 nm)且粒徑分佈狹窄。

In the present study, dissolution of four fluorinated and non-steroidal anti-inflammatory drugs (flufenamic acid (FFA), leflunomid (LEF), niflumic acid (NFA), and celecoxib (CCB)) with supercritical carbon dioxide was investigated over a wide range of contact time. After that, the saturated solubility data of these four non-steroidal anti-inflammatory drugs in supercritical carbon dioxide were measured under sufficient contact time with a semi-flow type phase equilibrium apparatus at temperatures ranging from 313.2 K to 353.2 K and pressures up to 31 MPa. The Peng-Robinson equation of state (PR EOS) with van der Waals one-fluid two parameters (vdW2) mixing rule was applied to correlate the solid-gas phase equilibria data of these four non-steroidal anti-inflammatory drugs in supercritical carbon dioxide. The new solubility data were also correlated with the Chrastil equation and the Mendez-Santiago and Teja model over the entire experimental conditions. The main objective of this study is to obtain the fundamental solubility data and developing the micronization process of the pharmaceutical compounds with rapid expansion of supercritical solutions (RESS) technique.Because FFA has the highest solubility among the four investigated drugs in supercritical carbon dioxide (up to 2.13×10-4 in mole fraction), micronization of FFA by the RESS method was studied. The influences of various process variables on the morphology and the mean size of the resultant particles were explored experimentally. These process variables include extraction temperature (Text), extraction pressure (Pext), pre-expansion temperature (Tpre), crystallization temperature (Tcry), inside diameter of capillary tube (Dnozzle), length of capillary tube (Lnozzle), and spraying distance (Z). As evidence form the experimental results, by manipulation of these process conditions, ultra-fine particles with a narrow particle size distribution of FFA are successfully prepared through the RESS technique. Additionally, the polymorphism of FFA particles converted from the original Form I into Form III after the RESS processing.
Studying the polymorphs preparation of LEF particles through the RESS crystallization process was also made. The effects of various process variables, including extraction temperature (Text) and pressure (Pext), pre-expansion temperature (Tpre), and crystallization temperature (Tcry), on the polymorphism, the morphology, and the mean size of the resultant particles were observed systematically. As evidence from experimental results, polymorphs I, II and a new form IV of LEF can be generated from the RESS processing by manipulation of the operating conditions. Additionally, the produced LEF particles are in nano scale (around 60 nm) with narrow size distribution.

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