Micronization and Amorphization of Lapatinib and Nitrofurantoin Using Supercritical Anti-solvent Method

本研究利用超臨界反溶劑法針對水難溶性藥物進行微粒化及非晶型化之研究，以增加水難溶性藥物於人體中之溶離速率及生體可用性。所選用之目標藥物為抗乳癌標靶藥物拉帕替尼(lapatinib)及常用以治療泌尿道感染之抗生素硝基呋喃妥因(nitrofurantoin)，此兩種藥物於水中之溶解度皆非常低，幾乎不溶於水，不利藥物於人體之吸收。因此，本研究以超臨界反溶劑法對此兩項藥物進行微粒化，並評估此兩種藥物在微粒化之同時使其晶型轉變為非晶型之可能性，以提升其溶離速率，進而增加其生體可用性。而除了將藥物微粒化之外，本研究也以微粒化前後之藥物於模擬腸液中進行溶離速率測試，以觀察藥物經微粒化後是否有較高之溶離速率。此研究中所選用之反溶劑為超臨界二氧化碳，探討之實驗參數包括溶劑種類、操作溫度、壓力、溶液濃度、溶液流速及噴嘴內徑。 在拉帕替尼之微粒化研究中，於最佳操作條件時可將其由原始藥物粒徑之11.87 μm微粒化至0.32 μm。此外，XRD之分析結果顯示微粒化後之藥物已成為非晶型。關於溶離速率測試方面，實驗結果顯示拉帕替尼經微粒化後，與原始藥物相比具有較高之溶離速率，但由於此藥物本身為難溶性藥物之緣故，因此，無論是否經過微粒化程序處理，其溶離速率係數kw皆趨近於0。因此，推測此藥物可能不適合以溶離速率係數kw來進行溶離速率快慢之比較。 在硝基呋喃妥因之微粒化研究中，於最佳之操作條件可將其由原始藥物粒徑之202 μm微粒化至2.93 μm。經由XRD之分析，也確認了此藥物經過超臨界反溶劑法之處理後，其結晶性較原始藥物低。關於溶離速率測試方面，實驗結果顯示微粒化後之硝基呋喃妥因，與原始藥物相比具有較高之溶離速率，原始藥物之溶離速率係數kw為0.1712 min-1，微粒化後藥物之溶離速率係數kw為0.6441 min-1，較原始藥物提升約3.8倍。μThis study is focus on the micronization and amorphization of poorly water soluble pharmaceuticals using supercritical anti-solvent method to enhance the dissolution rate and bioavailability in human. The target pharmaceuticals used in this research include lapatinib ditosylate and nitrofurantoin. Lapatinib ditosylate is an orally active drug for breast cancer and nitrofurantoin is an antibiotic which is usually used in treating urinary tract infection. Both the drugs has poor water solubility and hence the low dissolution rate and low bioavailability in human. Therefore, the object of this study is to assess the possibility of micronization and amorphization of these two target drugs. The supercritical carbon dioxide was employed as the anti-solvent in this study. The effects of six process parameters were compared and discussed, including solvent, operation temperature, pressure, solution concentration, solution flow rate and nozzle diameter. About the micronization of lapatinib ditosylate, it could be successfully micronized from original 11.87 μm to 0.32 μm at the optimal operating conditions. From the results of XRD, the micronized lapatinib ditosylate was almost become amorphous since there were no characteristic peak in the XRD patterns. About the micronization of nitrofurantoin, it could also be successfully micronized from original 202 μm to 2.93 μm at the optimal operating conditions. And from the result of XRD, the micronized nitrofurantoin had lower crystallinity compared with the original drug since several characteristic peaks were weakended or disappeared in the XRD patterns. After the micronization process, the processed and unprocessed pharmaceuticals were tested using a dissolution tester. From the results of dissolution rate test, both the processed lapatinib ditosylate and nitrofurantoin has higher dissolution rate than the original drug