Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd., 2-17-85 Jusohonmachi, Yodogawa-ku, Osaka 532-8686, Japan.
Int J Pharm. 2011 Dec 15;421(2):230-6. doi: 10.1016/j.ijpharm.2011.09.034. Epub 2011 Oct 1.
Miconazole salts and cocrystals were studied to improve the physicochemical properties of miconazole. Maleate, hemifumarate, and hemisuccinate were prepared and characterized by powder X-ray diffractometry, differential scanning calorimetry, and single crystal X-ray diffractometry. The intrinsic dissolution rate and stability of each miconazole crystal form were compared to those of freebase and nitrate to evaluate the optimal crystal form. Crystal structure analysis indicated that maleate was a salt formed by proton transfer from the acid to the imidazole group of miconazole. Hemifumarate and hemisuccinate were determined to be cocrystals formed by hydrogen bonding between the acids and the base in their crystal lattices. Intrinsic dissolution tests showed that the formation of salts and cocrystals improved the dissolution rate of miconazole. Stability tests of preliminary formulations prepared with each crystal form indicated that maleate and hemifumarate were unstable at 80°C and generated a specific degraded product, i.e., a Michael adduct, between miconazole and the acids. Hemisuccinate had a superior intrinsic dissolution rate and stability, and is thus considered a promising crystal form of miconazole.
咪康唑盐和共晶被研究以改善咪康唑的物理化学性质。马来酸盐、富马酸盐和琥珀酸盐通过粉末 X 射线衍射、差示扫描量热法和单晶 X 射线衍射进行了制备和表征。每种咪康唑晶型的固有溶解速率和稳定性与游离碱和硝酸盐进行了比较，以评估最佳晶型。晶体结构分析表明，马来酸盐是通过酸向咪康唑的咪唑基团质子转移形成的盐。富马酸盐和琥珀酸盐被确定为在其晶格中通过酸和碱之间的氢键形成的共晶。固有溶解试验表明，盐和共晶的形成提高了咪康唑的溶解速率。用每种晶型制备的初步配方的稳定性试验表明，马来酸盐和富马酸盐在 80°C 下不稳定，并在咪康唑和酸之间生成特定的降解产物，即迈克尔加成物。琥珀酸盐具有优越的固有溶解速率和稳定性，因此被认为是一种有前途的咪康唑晶型。
