以超臨界反溶劑沉積法進行Probenecid、 Allopurinol與Sulfasalazine之再結晶研究

本研究利用超臨界反溶劑沉積法對三種原料藥:丙磺舒(Probenecid)、柳氮磺吡啶(Sulfasalazine)與異嘌呤醇(Allopurinol)，進行再結晶與微微粒化之研究，以二氧化碳當反溶劑，選定17種具有較低毒性，ICH Q3C中所列Class 2與Class 3之溶劑系統；先以不同溶劑，固定操作溫度、操作壓力、溶液濃度、噴嘴孔徑、溶液流速與二氧化碳流率各別進行實驗，經過溶劑效應實驗後，由於丙磺舒及異嘌呤醇於各個溶劑實驗所得之微粒化效果均不明顯，故僅選定柳氮磺吡啶，以四氫呋喃(Tetrahydrofuran ,THF)當溶劑進行後續參數效應之實驗；並以SEM、XRD、DSC、TGA、FTIR、NMR等儀器分析處理前後藥物之物性。在柳氮磺吡啶的研究方面，不同條件可得到Form II或 Form I＋Form II之晶型結果，而結晶外觀(Crystal habit)也因條件不同而有所不同，包含針狀、球狀、長條狀、短棒狀之藥物粉體，部分條件會同時存在2種結晶外觀；在本研究中，以溫度55℃、壓力100bar、二氧化碳流率4L/min、溶液流率1mL/min、噴嘴孔徑100μm下所得之全部球型外觀，平均粒徑約1微米為最佳條件。

關鍵字

超臨界反溶劑；微粒化；再結晶

並列摘要

In this study, recrystallization and micronization of three active pharmaceutical ingredients (APIs), probenecid, sulfasalazine and allopurinol, are studied using the supercritical anti-solvent (SAS) process. Supercritical carbon dioxide is used as anti-solvent. 17 organic solvents listed in ICH Q3C as Class 2 and Class 3 are used as solvent candidates. At fixed temperature, pressure, solution concentration, nozzle diameter, solution flow rate and carbon dioxide flow rate, effects of different solvents on recrystallization and micronization are investigated firstly. In solvents effect, probenecid and allopurinol do not have obvious micronization result. Thus sulfasalazine is selected to study the effect of operating parameters in SAS process using Tetrahydrofuran as solvent. In the recrystallization of probenecid, under the solvent Acetone, the mean size can be reduced from 40μm~200μm to 5μm ~30μm. In the recrystallization of allopurinol, under the solvent NMP, the mean size can be reduced from 10μm~50μm to 2μm. In addition, the crystal habits are modified from irregular to rod-loke. In the recrystallization of sulfasalazine, under the optimizing conditions, the mean size can be reduced from 6μm to 1μm. In addition, the crystal habits are modified from irregular to spherical. Furthermore, the dissolution rate study of original and SAS-process sulfasalazine is also investigated.

並列關鍵字

supercritical anti-solvent ； micronization ； recrystallization

參考文獻

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以超臨界反溶劑沉積法進行Probenecid、 Allopurinol與Sulfasalazine之再結晶研究

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