New Polymorphs of Fluconazole: Results from Cocrystallization Experiments

Fluconazole is known as an antifungal drug since 1983. Its propensity for the formation of new polymorphs and salts has been reported in the literature, mostly by powder X-ray diffraction and solid state Raman spectroscopy. In the present study, we are elucidating the structures of four polymorphs of fluconazole using single crystal X-ray diffraction. Raman spectra of the single crystals of these polymorphs also support our study. These polymorphs were grown in the presence of the cocrystal formers. This indicates that fluconazole interacts with the cocrystal former in the solution, and possibly these interactions result into the generation of new polymorphs of it. These polymorphs of fluconazole exhibit the conformational flexibility of the molecule, and hence we observed seven different conformers of the molecule in the reported polymorphs. Although these forms have strong O–H···N hydrogen bonds, the nature of the packing of the molecules is a cumulative effect of a number of weaker intermolecular forces such as C–H···O, C–H···N, and C–H···F and the strong hydrogen bond.

氟康唑（Fluconazole）自1983年起便被认定为抗真菌药物。已有文献报道其具备形成新型晶型与盐类的倾向，相关研究多采用粉末X射线衍射（powder X-ray diffraction）与固态拉曼光谱（solid state Raman spectroscopy）开展表征。本研究通过单晶X射线衍射（single crystal X-ray diffraction）解析了氟康唑的四种晶型的晶体结构，这些晶型单晶的拉曼光谱亦为本次研究提供了有力佐证。本次研究中的四种晶型均在共晶形成剂（cocrystal formers）存在的条件下培养得到，这表明氟康唑在溶液中可与共晶形成剂发生相互作用，此类相互作用或为该药物新型晶型的形成提供了关键诱因。该药物的这些晶型展现出显著的分子构象灵活性，因此在本次报道的晶型中我们共观测到七种不同的分子构象。尽管这些晶型中存在较强的O–H···N氢键，但分子的堆积模式实则是多种较弱分子间作用力（如C–H···O、C–H···N及C–H···F相互作用）与该强氢键共同作用的累积效应。