藥物固體於超臨界二氧化碳中溶解度與微粒化之研究

Investigation on solubility and micronization of pharmaceutical solids in supercritical carbon dioxide

蘇至善(Chie-Shaan Su)

指導教授 ： 陳延平

國立臺灣大學/工學院/化學工程學研究所/博士(2007年)

https://doi.org/10.6342/NTU.2007.00189

摘要

中文摘要
在本研究中，主要針對藥物固體於超臨界二氧化碳中，溶解度量測、迴歸以及微粒化，進行研究。在溶解度實驗量測方面，本研究選定三種非類固醇抗發炎藥物， 即萘丁美酮(nabumetone) 、苯丁唑酮(phenylbutazone) 與水楊酸胺(salicylamide)，進行其於超臨界二氧化碳中之溶解度量測。量測溫度為308 K、318 K 與328 K，而量測壓力範圍則介於10 MPa 至22 MPa 間。經量測發現，熔點較低的nabumetone 與phenylbutazone，擁有較高的固體溶解度，其溶解度莫耳分率介於10-3 至10-4 之間。而熔點較高的salicylamide，其溶解度莫耳分率則介於10-4 至10-5。除了實驗量測外，本研究亦利用兩文獻中常使用之半經驗式，Chrastil equation 與Mendez-Santiago and Teja equation，進行溶解度數據迴歸，發現兩方程式皆能合理描述固體溶解度行為。

在溶解度迴歸計算方面，本研究利用一溶液模式，即規則溶液模式(regular solution model)配合Flory-Huggins equation，描述藥物溶質的無限稀薄活性係數，進而進行固體溶解度計算。藉由模式中，參數簡化與關連，本研究提出一參數關連式，用以關連模式參數與藥物物性間之關係，進而預測藥物固體於超臨界二氧化碳中的溶解度行為。此外，為提升溶解度預測效能，本研究嘗試藉由藥物系統分類，針對酚環類固體溶解度數據，進行迴歸、參數簡化與關連。並提出適用於該類化合物之參數關連式。經分類後，的確能改善固體溶解度預測結果。且針對預測結果較差之系統，僅需利用單一實驗點調整，即可明顯改善溶解度行為的描述。此外，本研究亦利用溶液模式針對所量測的三種抗發炎藥物與文獻搜尋得到的抗發炎藥物固體溶解度數據，進行數據迴歸、參數簡化與參數關連。提出針對非類固醇抗發炎藥物此一系統，其溶液模式中，參數與藥物物性間的關連式，進而達到溶解度預測目的。且亦針對預測結果較差之系統，驗證利用單一實驗點調整，確實能改善固體溶解度行為的描述。

在最後一部份研究中，選擇上一階段固體溶解度量測中，具有較高溶解度之nabumetone 與phenylbutazone 為藥物對象，利用快速膨脹法進行藥物微粒化與再結晶研究。經快速膨脹法處理後，phenylbutazone 外觀有明顯改變，由原始長條型外觀變為不規則形。此外，其多晶型性質亦有所轉變，由原始的form δ 轉變為form β。此部分研究結果則與文獻中發現相同。而對nabumetone 而言，本研究首先藉由實驗設計法之應用，探討快速膨脹法中，萃取溫度、萃取壓力、膨脹前溫度與膨脹後溫度四操作參數效應。經變異數分析結果可知，各參數中，以膨脹後溫度的效應最為顯著，且低膨脹後溫度有利小顆粒生成，而萃取壓力與膨脹後溫度間，存在一交互作用效應。此外，亦以微粒化為目標，藉由其他操作參數的改變，探討可能得到的最小粒徑。在本研究中，可得到平均粒徑為3.3 微米的nabumetone 藥物微粒，並經由溶離試驗分析可知，經快速膨脹法處理後的nabumetone 藥物微粒，其溶離速率有顯著的提升。

關鍵字

超臨界技術 ； 固體溶解度 ； 快速膨脹法 ； 藥物微粒化 ； 溶液模式

並列摘要

In this study, measurement and correlation of solid solubility for pharmaceutical compounds in supercritical carbon dioxide was investigated. Measurement of solid solubility for non-steroidal anti-inflammatory drug (NSAID) was accomplished. The solubilities for three NSAIDs of nabumetone, phenylbutazone, and salicylamide in supercritical carbon dioxide were measured using a semi-flow type apparatus. The experimental data were taken at 308, 318 and 328 K, over the pressure range from 10 to 22 MPa. The measured results were then correlated using semi-empirical equations presented by Chrastil, and that presented by Mendez-Santiago and Teja. With optimally fitted parameters, these two equations yielded satisfactory results.

Besides the solubility measurement, correlation of solubility data for sixty pharmaceutical systems was attempted using solution model approach. The infinite dilution activity coefficient for pharmaceutical compound is described by regular solution model coupled with Flory-Huggins equation. Data correlation, parameters simplification and generalization were investigated in our research. A revised generalized equation between model parameter and physical properties of pharmaceutical compounds was proposed. Prediction of solid solubility for
pharmaceutical compounds in supercritical carbon dioxide was demonstrated. In addition, in order to improve the ability for solubility prediction using the generalized correlation equation. Further classification for pharmaceutical systems was suggested.Correlation of solubility data for phenolic compounds was attempted. Similar procedure for parameter generalization was employed. A new generalized correlation equation for phenolic compounds was proposed in this study. Solubility prediction for phenolic compounds was improved by applying the new generalized correlation equation. Furthermore, prediction of solid solubility using only one data point was attempted. Reasonable prediction for solid solubility using solution model was observed when only single data point was available. Finally, the solid solubilities of three NSAIDs measured in this study and seven other NSAIDs in supercritical carbon dioxide were correlated by applying the solution model. The parameters in the solution model could be generalized for the specific drug of NSAIDs. Predicted solubilities of ten NSAIDs in supercritical carbon dioxide were demonstrated to be reliable.

In our research, micronization of two pharmaceutical compounds with higher solid solubility in supercritical carbon dioxide, nabumetone and phenylbutazone, using the rapid expansion of supercritical solution process (RESS) was investigated. For the phenylbutazone, the crystal habit and polymorphism behavior were modified after the RESS process. Irregular particle with polymorph conversion from δ-form to β-form was obtained. For the nabumetone, effect of process parameters was discussed by design of experiment (DOE) for extraction temperature, extraction pressure, pre-expansion temperature and post-expansion temperature. Results from analysis of variance (ANOVA) showed that the effect of post-expansion temperature is most significant. Lower post-expansion temperature favor the production of small particle. In addition, interaction effect between extraction pressure and post-expansion temperature was confirmed from the results of analysis of variance. Further investigation for micronization of nabumetone was demonstrated. The smallest particle obtained from the RESS process is 3.3 μm in this study. Further study on dissolution profile for original and processed nabumetone was investigated. After the RESS process, dissolution rate of nabumetone was improved significantly.

並列關鍵字

supercritical fluid technology ； solid solubility ； RESS ； micronization of pharmaceutical ； solution model

參考文獻

Ahlers, J., Yamaguchi, T. and Gmehling, J., Development of a universal group contribution equation of state. 5. prediction of the solubility of high-boiling compounds in supercritical gases with the group contribution equation of state volume-translated Peng-Robinson, Ind. Eng. Chem. Res., 43 (2004) 6569-6576

Alessi, P., Cortesi, A., Kikic, I., Foster, N. R., Macnaughton, S. J. and Colombo, I., Particle production of steroid using supercritical fluid processing, Ind. Eng. Chem. Res., 35 (1996) 4718-4726

Ashour, I., Almehaideb, R., Fateen, S. E. and Aly, G., Representation of solid-supercritical fluid phase equilibria using cubic equation of state, Fluid Phase Equilib., 167 (2000) 41-61

Aymonier, C., Loppinet-Serani, A., Reveron, H., Garrabos, Y. and Cansell, F., Review of supercritical fluids in inorganic materials science, J. Supercrit. Fluids, 38 (2006) 242-251

Bahrami, M., Ranjbarian, S., Production of micro- and nano-composite particles by supercritical carbon dioxide, J. Supercrit. Fluids, 40 (2007) 263-283