- 學位論文
應用超臨界溶液快速膨脹法進行藥物 Pyrazinamide 與 Metronidazole 之微粒化研究
Study of the RESS Process for Micronization of Pyrazinamide and Metronidazole
摘要
本研究利用超臨界溶液快速膨脹法對兩種藥物進行微粒化探討，分別為抗結 核病藥物吡井羧胺 (Pyrazinamide) 與抗生素甲硝唑(Metronidazole) 兩種原料藥 進行微粒化，目的在於藉由縮小藥物顆粒尺寸以及控制結晶特性，以增加其溶離 速率或增加藥物進入生物體內之途徑，最終提升藥物在人體的生物相容性與可用 率。這兩種藥物之原始顆粒相當大，本研究將利用超臨界溶液快速膨脹法進行藥 物微粒化，以縮小顆粒尺寸以及控制結晶型態，來達到上述的目的。 本研究中，使用二氧化碳作為超臨界流體，利用調控不同實驗參數，有如萃 取溫度、萃取壓力、藥物收集瓶溫度以及噴嘴內徑等參數，分析微粒化後的結果， 探討不同實驗參數對藥物顆粒形成的效應，了解各種參數之影響程度，最後可得 知如何達到最佳化操作條件，進而提升微粒化效果。本研究後段將進行溶離速率 實驗，並且參照2013 年美國藥典 [USP 36th, 2013] 規範的設備條件，觀察經過超 臨界溶液快速膨脹法進行微粒化後的藥物，其溶離速率是否提升。 首先在藥物Pyrazinamide 的研究中，原始藥物經過微粒化程序後，藥物粒徑 由80.98 μm 縮小為0.53 μm。在定性分析方面，由FTIR、DSC 與XRD 等儀器觀 察到藥物經由微粒化處理後，藥物並無變質現象發生，但藥物產生晶型轉變且結 晶度下降，在各種實驗條件下可得到不同晶型混合共存。接著比較藥物處理前後 之溶離速率差異，發現RESS 處理過後藥物之溶離速率只有略快於原始藥物，代入 Weibull model 進行回歸後，處理後藥物之溶離速率係數kw 為0.2774 min-1，而原始 藥物物之溶離速率係數kw 為0.2406 min-1，溶離速率約略提升1.153 倍，溶離速率 提升不明顯，造成兩者差異不大的原因可能為壓錠所造成。在進行溶離實驗前， 藥物會進行壓錠，此將影響溶離速率的表現。 在第二個藥物Metronidazole 的研究中，原始藥物之粒徑為76.81 μm，進行微 粒化處理後最小可降為0.47μm。在藥物定性方面，經由FTIR、DSC 與XRD 分析 III 後，發現藥物並無變質現象，晶型也尚未轉變，且藥物結晶度降低許多。在溶離 速率實驗中發現，原始藥物之溶離速率略快於微粒化處理過後之藥物，而經過 Weibull model 回歸後，原始藥物之溶離速率係數kw 為0.5463 min-1，微粒化後藥物 之 kw 為0.4372 min-1，此結果同樣推測可能為壓錠過程所導致，因為相同重量下， 較小藥物顆粒可形成較緻密之藥錠，使得錠劑之表面積可能較小，如此可能影響 溶離速率的表現。
並列摘要
Microniztion of pharmaceutical substances plays a role in the pharmaceutical industry for enhancing the dissolution rate of the active pharmaceutical ingredients (APIs) since near 40% of APIs are almost insoluble or slightly soluble in water or aqueous solution. As a result, the efficiency of oral or injectable drug is limited due to the low bioavailability. In this study, the rapid expansion of supercritical solution (RESS) process is applied to improve the dissolution rate of pharmaceutical agents so as to increase the bioavailability in human body. In the RESS process, the solid solute was extracted by CO2 which was the supercritical solvent, and submicron particles were precipitated in the expansion chamber. The effects of operation parameters, inclusive of extraction temperature (Text), extraction pressure (Pext), post temperature (Tpost) and the nozzle diameter (DN) were investigated by the analysis results. The dissolution profile of RESS-processed drugs will be compared to the originals. Pyrazinamide particles were formed with a mean particle size of 0.53 μm which was much smaller than the originals, 80.98 μm. Through RESS process, the polymorph transformation was found from the FTIR, DSC and XRD results. Also, the crystallinity of micronized particles decreased. The dissolution rate constants (kw) of original and RESS-processed drug are 0.2406 and 0.2774, respectively. It was shown that the RESS-processed pyrazinamide showed a better dissolution behavior than the originals, but not significant. The metronidazole particles were micronized from the original mean size of 76.81 μm to a much smaller average size of 0.47μm after the RESS process. Although no polymorph transformation was found, the crystallinity of RESS-processed metronidazole diminished. But, the dissolution rate of micronized metronidazole V decreased compared to the original agent. This can be explained that the drug before conducting dissolution rate experiments will be compressed into a tablet, and the smaller particles formed the dense tablet whose surface area was smaller than the original drug. Therefore, the micronized metronidazole had a lower dissolution rate compared to the unprocessed.