The asymmetric unit of the tetragonal polymorph contains one molecule of the title compound. The planar molecular conformation is supported with the intramolecular O-H...O bonding between hydroxide and amide groups. Additionally, each molecule takes part in intermolecular H-bonding with four neighboring molecules. Hydrogen atoms of the amide group interact with oxygen atoms of the amide group, and N(4) atoms of the pyrazine cycle. In both polymorphs, the local environment is similar. For three of the four neighbors, the average deviation of non-hydrogen atoms is less than 0.1 Å, and only the disposition of the acceptor of H-bonding towards the oxygen atom of the amide group differs for the two polymorphs (Figure 3
a). Comparison of two crystal structures using the ”Crystal Packing Similarity” tool [25
] indicates clusters of seven molecules with an average deviation of non-hydrogen atoms of 0.08 Å only (Figure 3
b) connected through H-bonds, C-H...O and C-H...F interactions. The H-bonded chains formed by N-H...N interactions are packed parallel to the distance between their meanplanes equal to 3.17–3.31 Å (Figure 3
c). Thus, molecular conformations of favipiravir in the two polymorphs are similar, and in both solids, the molecule can be considered as a four-connected node of a network formed by hydrogen bonds. Note that in accord with the Etter rules [27
], the molecule should tend to form all the possible hydrogen bonds. As the molecule realizes the intramolecular O-H...O bond, we expect that a pure favipiravir will be involved in four strong hydrogen bonds (through two donor hydrogen atoms of the amide group, and any two of the four remaining acceptor atoms, N2, N3, O1 or O2). However, possible competition between various functional groups arouses the question as to whether the experimentally observed local H-bonded environment corresponds to the most likely H-bonds, and if the OH group can also form intermolecular interactions.
Recently, a convenient tool for analysis of the competition of H-bonding donors and acceptors in crystals of polyfunctional molecules was suggested [29
]. The tool is based on occurrences of various H-bonded synthons in the Cambridge Structural Database containing more than 1,000,000 crystal structures of small organic and organometallic compounds [30
]. The tool was previously applied for analysis of H-bonding systems in some drug molecules [31
]. The results of ranking synthons by propensity for the favipiravir molecule are listed in Table 2
. The favipiravir molecule contains four functional groups (amide, two aromatic nitrogens and hydroxide) that contain, in total, three donor hydrogen atoms (from amide and hydroxide) and four acceptors (oxygen atoms of amide and hydroxide, two aromatic nitrogen atoms) of H-bonding. Thus, the solvent-free form of favipiravir can theoretically realize eleven different types of hydrogen bonds. These bonds are ranked using the H-bonding propensity tool implemented within the Mercury package [39
] as listed in Table 1
. Among them, the amide…pyrazine NH…N and amide…amide NH…O hydrogen bond are the most likely intermolecular interactions to occur. The hydroxide group is more likely to take part in intramolecular H-bonding with the oxygen atom of the amide group. Experimentally observed H-bonds in both polymorphs are in accord with the results of this calculation, indicating that other theoretically possible polymorphs with another H-bonding environment would be less stable than experimentally observed ones. This conclusion is visualized in Figure 4
, where a possible H-bonded polymorphism is depicted as a set of green and blue triangles. Green and blue denote the overall number of H-bond pairs of a molecule (3 and 2, respectively), so that the higher the overall number of H-bonds and of H-bond pairs, the lower a point is situated on the putative structure landscape. For each set of H-bond pairs, their mean H-bond propensities were also calculated based on values in Table 2
. Thus, the higher the mean propensity is, the more a point is shifted to the right. Thus, the points that correspond to a molecule that realizes the maximal number of H-bonds with the highest propensities are situated in the bottom right corner of Figure 4
and are expected to correspond to the most stable polymorph. Despite variations in the overall packing, positions of H-bonding environments for both polymorphs of favipiravir correspond to the most stable bonding. Thus, additional calculations of crystal packing energy are required to reveal which of the two polymorphs is more stable.