Co-Crystal Polymorphs from a Solvent-Mediated Transformation

co-crystals of carbamazepine and isonicotinamide can form through a solvent-mediated transformation process when a dry mixture of the pure crystalline components is suspended in ethanol. First, needle-like crystals (form II) grow while the pure crystalline components dissolve. Eventually plate-like crystals (form I) grow at the expense of the needle-like crystals. Single crystal structure determination showed that form I consists of chains of alternating dimers of carbamazepine and dimers of isonicotinamide. The powder diffraction pattern and the needle-like shape of form II show that it most probably is isostructural to the known 1:1 co-crystal structure of carbamazepine and nicotinamide, consisting of dimers of carbamazepine linked to chains of nicotinamide through hydrogen bonding. In both form I and form II, the pyridine heteronitrogen of isonicotinamide does not participate in hydrogen bonding. Both co-crystal structures have 1:1 stoichiometry, and they are therefore polymorphs. The solvent-mediated transformation showed that form I is the stable form at room temperature. The phase diagram for carbamazepine-isonicotinamide in ethanol shows that an excess of isonicotinamide is optimum to form co-crystals, and that solutions with 1:1 stoichiometry result in carbamazepine crystals or at best mixtures of carbamazepine and co-crystals. Under optimal conditions, determined by the pure component solubilities, the solvent-mediated transformation method is a simple and effective way of searching for co-crystal polymorphs.

卡马西平（carbamazepine）与异烟酰胺（isonicotinamide）的共晶可通过溶剂介导转化过程制备：将纯结晶组分的干燥混合物悬浮于乙醇中，即可触发该过程。初始阶段，针状晶体（晶型II，form II）随纯结晶组分的溶解而生长；后续阶段，片状晶体（晶型I，form I）将以针状晶体为代价逐步长大。单晶结构解析结果表明，晶型I由卡马西平二聚体与异烟酰胺二聚体交替构成的链状结构所组成。晶型II的粉末衍射图谱与针状形貌特征显示，其极有可能与已知的卡马西平-烟酰胺1:1共晶结构同构——该结构通过氢键将卡马西平二聚体与烟酰胺链连接为整体。在晶型I与晶型II中，异烟酰胺的吡啶杂环氮原子均不参与氢键作用。两种共晶结构均遵循1:1化学计量比，因此二者互为多晶型物。溶剂介导转化实验证实，室温下晶型I为稳定晶型。乙醇体系中卡马西平-异烟酰胺的相图显示，过量的异烟酰胺最利于共晶的生成；而采用1:1化学计量比的溶液体系，仅能得到卡马西平晶体，至多仅能获得卡马西平与共晶的混合物。在由纯组分溶解度确定的最优条件下，溶剂介导转化法是一种简便高效的共晶多晶型筛选方法。