Remenar Julius F, Morissette Sherry L, Peterson Matthew L, Moulton Brian, MacPhee J Michael, Guzmán Héctor R, Almarsson Orn
Transform Pharmaceuticals, Inc., 29 Hartwell Avenue, Lexington, Massachusetts 02421-3102, USA.
J Am Chem Soc. 2003 Jul 16;125(28):8456-7. doi: 10.1021/ja035776p.
Cocrystals of the poorly soluble antifungal drug cis-itraconazole (1) with 1,4-dicarboxylic acids have been prepared. The crystal structure of the succinic acid cocrystal with 1 was determined to be a trimer by single-crystal X-ray. The trimer is comprised of two molecules of 1 oriented in antiparallel fashion to form a pocket with a triazole at either end. The extended succinic acid molecule fills the pocket, bridging the triazole groups through hydrogen-bonding interactions rather than interacting with the more basic piperazine nitrogens. The solubility and dissolution rate of some of the cocrystals are approximately the same as those of the amorphous drug in the commercial formulation and are much higher than those for the crystalline free base. The results suggest that cocrystals of drug molecules have the possibility of achieving the higher oral bioavailability common for amorphous forms of water-insoluble drugs while maintaining the long-term chemical and physical stability that crystal forms provide.
已制备出难溶性抗真菌药物顺式伊曲康唑（1）与1,4 - 二羧酸的共晶体。通过单晶X射线确定了1与琥珀酸共晶体的晶体结构为三聚体。该三聚体由两个以反平行方式排列的1分子组成，在两端形成一个带有三唑的口袋。延伸的琥珀酸分子填充该口袋，通过氢键相互作用桥连三唑基团，而不是与碱性更强的哌嗪氮原子相互作用。一些共晶体的溶解度和溶解速率与市售制剂中无定形药物的溶解度和溶解速率大致相同，且远高于结晶游离碱的溶解度和溶解速率。结果表明，药物分子共晶体有可能实现水不溶性药物无定形形式常见的较高口服生物利用度，同时保持晶体形式所提供的长期化学和物理稳定性。
