Shiraki Koji, Takata Noriyuki, Takano Ryusuke, Hayashi Yoshiki, Terada Katsuhide
Discovery Platform Technology Department, Chugai Pharmaceutical Co. Ltd., 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan.
Pharm Res. 2008 Nov;25(11):2581-92. doi: 10.1007/s11095-008-9676-2. Epub 2008 Jul 24.
To demonstrate improvement in the dissolution of exemestane and megestrol acetate from cocrystallization using various particle sizes and to investigate the mechanism of the improved dissolution.
Cocrystal screening was performed by slurry crystallization. The cocrystals were identified and characterized by powder X-ray diffraction, thermal analysis, and single crystal X-ray diffraction. Different particle sizes of each cocrystal were prepared from organic solutions. Solubility and dissolution rates were evaluated using dissolution tests. Transformation behavior of the cocrystals in suspension was analyzed by PXRD and polarization microscopy.
Two novel cocrystals were obtained: exemestane (EX)/maleic acid (MAL) (cocrystal 1) and megestrol acetate (MA)/saccharin (SA) (cocrystal 2). Cocrystal 1 showed a high dissolution rate even with large particles. Cocrystal 2 showed supersaturation with fine particles. The transformation from cocrystal 1 to EX was observed within 1 min in suspension. Cocrystal 2 was transformed to MA within 2-4 h.
Cocrystallizations of EX and MA improved initial dissolution rates compared to the respective original crystals. The mechanism of dissolution enhancement varied. With cocrystal 1, fine particle formation resulted in enhancement, whereas with cocrystal 2, enhancement was due to the maintenance of the cocrystal form and rapid dissolution before transformation to the original crystal.
通过使用不同粒径的共结晶来证明依西美坦和醋酸甲地孕酮的溶出度提高，并研究溶出度提高的机制。
通过淤浆结晶进行共晶筛选。通过粉末X射线衍射、热分析和单晶X射线衍射对共晶进行鉴定和表征。从有机溶液中制备每种共晶的不同粒径。使用溶出度试验评估溶解度和溶出速率。通过粉末X射线衍射和偏光显微镜分析共晶在悬浮液中的转变行为。
获得了两种新型共晶：依西美坦（EX）/马来酸（MAL）（共晶1）和醋酸甲地孕酮（MA）/糖精（SA）（共晶2）。即使是大颗粒，共晶1也显示出高溶出速率。共晶2对细颗粒显示出过饱和现象。在悬浮液中观察到共晶1在1分钟内转变为依西美坦。共晶2在2 - 4小时内转变为醋酸甲地孕酮。
与各自的原始晶体相比，依西美坦和醋酸甲地孕酮的共结晶提高了初始溶出速率。溶出增强的机制各不相同。对于共晶1，细颗粒的形成导致溶出增强，而对于共晶2，增强是由于共晶形式的维持以及在转变为原始晶体之前的快速溶解。
