利用連續式超臨界反溶劑法處理原料藥：Sulfamerazine and Acetazolamide

Continuous Supercritical Anti-Solvent Treatments of Active Pharmaceutical Ingredients：Sulfamerazine and Acetazolamide

蔡豐年(Feng-Nien Tsai)

指導教授 ： 陳延平

國立臺灣大學/工學院/化學工程學研究所/碩士(2008年)

https://doi.org/10.6342/NTU.2008.02019

摘要

本研究以連續式超臨界反溶劑(SAS)法，針對原料:sulfamerazine and acetazolamide進行微粒化與再結晶之處理。主要目的為原料藥經由微粒化後，其溶離速率能提升，以及經由再結晶後，能得到藥物不同多晶型(Polymorph)。

本研究首先以sulfamerazine進行連續式SAS參數效應之探討，探討在不同的溶劑、壓力、溫度、溶液濃度及溶液流速下對粒徑大小與分布及晶貌(Crystal habit)與多晶型(Polymorph)之影響。研究結果顯示，在溶劑為丙酮、壓力為140 bar、溫度為35℃、溶液濃度為30%飽和濃度、溶液流率為0.5mL/min的情況下，可以得到sulfamerazine最小平均粒徑為0.61±0.38µm，其晶貌從不規則塊狀變為不規則片狀。在此最佳操作條件下經由連續式SAS操作得到的sulfamerazine藥物之溶離速率，較原始藥物提升了2.9倍。

本研究再來以acetazolamide進行連續式SAS參數效應之探討。研究結果顯示， 在溶劑為乙酸乙酯、壓力為100 bar、溫度為35℃、溶液濃度為90%飽和濃度、溶液流率為1mL/min的情況下，可以得到acetazolamide最小平均粒徑為0.36±0.12µm，其晶貌從不規則塊狀變為棒狀。在此最佳操作條件下經由連續式SAS操作得到的acetazolamide藥物之溶離速率，較原始藥物提升了4.4倍。原始藥物晶型為Form II，當溶劑為乙醇時，經連續式SAS法操作後，可得到晶型為Form I。

關鍵字

超臨界反溶劑法 ； 磺胺甲基嘧碇 ； 乙醯胺基硫唑嘧 ； 微粒化 ； 多晶型 ； 溶離速率

並列摘要

The purpose of this study was to apply the continuous supercritical anti-solvent (SAS) process to treat the active pharmaceutical ingredients (APIs)：sulfamerazine and acetazolamide. The aims are to increase dissolution rates of micronized APIs, and to obtain polymorphous APIs after the SAS processes.

In this research, the effects of the continuous SAS process parameters were discussed. The operating parameters resulted in various particle sizes, particle size distributions, crystal habits, and polymorphs of the APIs. These parameters included solvent, pressure, temperature, concentration of solution, and solution flow rate of solution. They were systematically studied and the optimum operating conditions were reported.

The smallest average particle of sulfamerazine was obtained as 0.61±0.38µm under the following operating conditions：solvent = acetone, P=140bar, T=35℃, solution concentration=30% sat., solution flow rate=0.5mL/min. The crystal habit changed from the original irregular lump to irregular flake. The dissolution rate of sulfamerazine
increased by 2.9 times after the SAS process.

The smallest average particle size of acetazolamide was obtained as 0.36±0.12µm under the following operating conditions：solvent = ethyl acetate, P=100bar, T=35℃, solution concentration=90% sat., solution flow rate=1mL/min. The crystal habit changed from the original irregular lump to bar shape. The dissolution rate of
acetazolamide increased by 4.4 times after the SAS process. The original acetazolamide was Form II while polymorph Form I was received from the SAS process using ethanol as the solvent.

並列關鍵字

Supercritical anti-solvent ； Sulfamerazine ； Acetazolamide ； Micronization ； Polymorph ； Dissolution rate

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