Dissolution improvement and the mechanism of the improvement from cocrystallization of poorly water-soluble compounds.
OBJECTIVE
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Shiraki
Koji
K
Discovery Platform Technology Department, Chugai Pharmaceutical Co. Ltd., 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan. shirakikj@chugai-pharm.co.jp
Takata
Noriyuki
N
Takano
Ryusuke
R
Hayashi
Yoshiki
Y
Terada
Katsuhide
K
D000730:Androstadienes / Q000737:chemistry; D003460:Crystallization; D008298:Maleates / Q000737:chemistry; D019290:Megestrol Acetate / Q000737:chemistry; D012439:Saccharin / Q000737:chemistry; D012995:Solubility; D014961:X-Ray Diffraction
D000730:Androstadienes; D008298:Maleates; C030272:maleic acid; D012439:Saccharin; C056516:exemestane; D019290:Megestrol Acetate