Goloveshkin Alexander S, Korlyukov Alexander A, Vologzhanina Anna V
A. N. Nesmeyanov Institute of Organoelement Compounds of the Russian Academy of Sciences, 28 Vavilova str, 119991 Moscow, Russia.
Higher Chemical College of the Russian Academy of Sciences, D.M. Mendeleev University of Chemical Technology of Russia, Miusskaya sq. 9, 125047 Moscow, Russia.
Pharmaceutics. 2021 Jan 21;13(2):139. doi: 10.3390/pharmaceutics13020139.
Various solid forms of pharmaceutically important compounds exhibit different physical properties and bioactivity; thus, knowledge of the structural landscape and prediction of spontaneous polymorph transformations for an active pharmaceutical ingredient is of practical value for the pharmaceutical industry. By recrystallization from ethyl acetate, a novel polymorph of 6-fluoro-3-hydroxypyrazine-2-carboxamide (trademark favipiravir, RNA polymerase inhibitor) was obtained and characterized using differential scanning calorimetry (DSC), infra-red spectroscopy and powder X-ray diffraction (XRD) analysis. The favipiravir molecule in two polymorphs realizes similar H-bonding motifs, but the overall H-bonded networks differ. Based on periodic density functional theory calculations, the novel tetragonal polymorph with two interpenetrated H-bonded networks is slightly less stable than the orthorhombic one with the topology of the underlying H-bonded net that is in accord with experimentally observed powder XRD patterns of slow conversion of the tetragonal phase to the orthorhombic one. However, topological analysis of net relations revealed that no transformations can be applied to convert H-bonded networks in the experimental unit cells, and DSC data indicate no solid-state reactions at heating.
多种具有药学重要性的化合物的固态形式表现出不同的物理性质和生物活性；因此，了解活性药物成分的结构特征并预测其自发多晶型转变对制药行业具有实际价值。通过从乙酸乙酯中重结晶，获得了6-氟-3-羟基吡嗪-2-甲酰胺（商标名法匹拉韦，RNA聚合酶抑制剂）的一种新型多晶型物，并使用差示扫描量热法（DSC）、红外光谱和粉末X射线衍射（XRD）分析对其进行了表征。两种多晶型物中的法匹拉韦分子实现了相似的氢键基序，但整体氢键网络不同。基于周期性密度泛函理论计算，具有两个相互贯穿的氢键网络的新型四方多晶型物比具有符合实验观察到的四方相缓慢转变为正交相的粉末XRD图谱的氢键网络拓扑结构的正交晶型略不稳定。然而，网络关系的拓扑分析表明，实验晶胞中的氢键网络无法通过任何转变来转换，并且DSC数据表明加热时没有固态反应。
