Kim Jeong-Soo, Kim Min-Soo, Park Hee Jun, Jin Shun-Ji, Lee Sibeum, Hwang Sung-Joo
National Research Laboratory of Pharmaceutical Technology, College of Pharmacy, Chungnam National University, 220 Gung-dong, Yuseong-gu, Daejeon 305-764, Republic of Korea.
Int J Pharm. 2008 Jul 9;359(1-2):211-9. doi: 10.1016/j.ijpharm.2008.04.006. Epub 2008 Apr 12.
The objective of the study was to prepare amorphous atorvastatin hemi-calcium using spray-drying and supercritical antisolvent (SAS) process and evaluate its physicochemical properties and oral bioavailability. Atorvastatin hemi-calcium trihydrate was transformed to anhydrous amorphous form by spray-drying and SAS process. With the SAS process, the mean particle size and the specific surface area of amorphous atorvastatin were drastically changed to 68.7+/-15.8nm, 120.35+/-1.40m2/g and 95.7+/-12.2nm, 79.78+/-0.93m2/g from an acetone solution and a tetrahydrofuran solution, respectively and appeared to be associated with better performance in apparent solubility, dissolution and pharmacokinetic studies, compared with unprocessed crystalline atorvastatin. Oral AUC0-8h values in SD rats for crystalline and amorphous atorvastatin were as follow: 1121.4+/-212.0ngh/mL for crystalline atorvastatin, 3249.5+/-406.4ngh/mL and 3016.1+/-200.3ngh/mL for amorphous atorvastatin from an acetone solution and a tetrahydrofuran solution with SAS process, 2227.8+/-274.5 and 2099.9+/-339.2ngh/mL for amorphous atorvastatin from acetone and tetrahydrofuran with spray-drying. The AUCs of all amorphous atorvastatin significantly increased (P<0.05) compared with crystalline atorvastatin, suggesting that the enhanced bioavailability was attributed to amorphous nature and particle size reduction. In addition, the SAS process exhibits better bioavailability than spray-drying because of particle size reduction with narrow particle size distribution. It was concluded that physicochemical properties and bioavailability of crystalline atorvastatin could be improved by physical modification such as particle size reduction and generation of amorphous state using spray-drying and SAS process. Further, SAS process was a powerful methodology for improving the physicochemical properties and bioavailability of atorvastatin.
本研究的目的是采用喷雾干燥和超临界抗溶剂（SAS）工艺制备阿托伐他汀半钙无定形体，并评估其理化性质和口服生物利用度。通过喷雾干燥和SAS工艺将三水合阿托伐他汀半钙转化为无水无定形形式。采用SAS工艺时，从丙酮溶液和四氢呋喃溶液中得到的阿托伐他汀无定形体的平均粒径和比表面积分别急剧变化为68.7±15.8nm、120.35±1.40m²/g和95.7±12.2nm、79.78±0.93m²/g，与未处理的结晶阿托伐他汀相比，在表观溶解度、溶出度和药代动力学研究中表现出更好的性能。SD大鼠中结晶型和无定形阿托伐他汀的口服AUC0-8h值如下：结晶型阿托伐他汀为1121.4±212.0ng·h/mL，采用SAS工艺从丙酮溶液和四氢呋喃溶液中得到的无定形阿托伐他汀分别为3249.5±406.4ng·h/mL和3016.1±200.3ng·h/mL，采用喷雾干燥从丙酮和四氢呋喃中得到的无定形阿托伐他汀分别为2227.8±274.5和2099.9±339.2ng·h/mL。与结晶型阿托伐他汀相比，所有无定形阿托伐他汀的AUC均显著增加（P<0.05），这表明生物利用度的提高归因于无定形性质和粒径减小。此外，由于粒径减小且粒径分布窄，SAS工艺比喷雾干燥表现出更好的生物利用度。得出结论，通过喷雾干燥和SAS工艺等物理改性方法，如减小粒径和生成无定形状态，可以改善结晶型阿托伐他汀的理化性质和生物利用度。此外，SAS工艺是改善阿托伐他汀理化性质和生物利用度的有效方法。
