A triclinic polymorph of miconazole

A second polymorphic form of solvent-free miconazole, a triclinic form (MIC-tri), is reported, and compared with the anhydrous monoclinic form of miconazole (MIC-mono).

In this article a second polymorphic form of pure solventfree miconazole, a triclinic form (MIC-tri), is reported, and compared with the anhydrous monoclinic form of miconazole (MIC-mono) (Kaspiaruk & Che ˛cin ´ska, 2022;Panini et al., 2022).
To make a comparison between the triclinic and monoclinic polymorphic forms of miconazole, the superposition of the three miconazole skeletons is shown in Fig. 2, considering separately two disorder components A and B of MIC-tri (MIC-tri-A and MIC-tri-B).One can see the difference in the orientation of the dichlorophenyl ring (ring 3) in the two polymorphic forms: they are approximately perpendicular to each other.Interestingly, such an orientation of the arene ring (ring 3) as observed in the MIC-tri form seems to be preferable for hydrated/solvated forms of miconazole (Kaspiaruk & Che ˛cin ´ska, 2022).Additionally, the compared polymorphs also differ from each other with regard to the position of the N2 atom of the imidazole ring in that they are related by a rotation of about 180 � .The mutual arrangement of the aromatic rings in the analysed miconazole molecules can be described by the dihedral angles between their best planes, calculated by the least-squares method (Table 1).

Supramolecular features
In the crystal structure of the title miconazole polymorph (MIC-tri), there are no typical hydrogen bonds.In contrast to the monoclinic form (MIC-mono), where two C-H� � �X (X = N, Cl) interactions were observed, here only a weak C7-Cl1� � �Cl1(À x, À y, 1 À z) halogen interaction is found

Figure 1
The molecular structure of MIC-tri showing the atom-labelling scheme.The disorder components A and B have equal site-occupancies (1/2).Labels 1A, 1B, 2 and 3 refer to the best planes of the aromatic rings.Displacement ellipsoids are drawn at the 50% probability level.

Hirshfeld surface analysis
Hirshfeld surface analysis (Spackman & Jayatilaka, 2009) complements the comparison of the two polymorphic forms of the miconazole drug.Hirshfeld surfaces and fingerprint plots (Spackman & McKinnon, 2002;Spackman & Jayatilaka, 2009) were generated using CrystalExplorer software (Turner et al., 2017).Fig. 4 presents the 2D fingerprint plots of all close contacts characteristic of the MIC-tri and MIC-mono structures; among them, additionally, C� � �H/H� � �C interactions are highlighted as their contributions to the Hirshfeld surface differ the most between polymorphs.An increase in the number of such interactions is observed for MIC-tri.As shown in breakdown diagrams (Fig. 5), in contrast to the C� � �H interactions, the contribution of C� � �C close contacts, mainly representing aromatic �-� interactions, decreased quite significantly for the triclinic form (2.0%) compared to the monoclinic one (9.8%).Other close contacts remain essentially comparable; the H� � �Cl/Cl� � �H and H� � �H contacts have the largest share of the Hirshfeld surface of both analysed polymorphs.

Pairwise model energies and their energy frameworks
The similarities and differences between two polymorphic forms of miconazole can also be analysed by comparison of the interaction energies calculated between molecules within a representative cluster of 3.8 A ˚from the crystal lattices and their visualization as energy frameworks.All interaction energies for MIC-tri are listed in Table 2. Similarly to the analysis presented previously for MIC-mono (Kaspiaruk & Che ˛cin ´ska, 2022), only one molecular pair has a relatively high total energy value over 50 kJ mol À 1 with the highest calculated contribution of dispersive and repulsive forces resulting from C-H� � ��(arene) interactions (Fig. 3).Unfortunately, it is quite difficult to assign the remaining energies from the table to specific interactions in the crystal of MIC-tri because of the limited number of contacts that met the geometrical criteria of hydrogen bonds.For example, the total energy value of the molecular pair connected by the Cl1� � �Cl1 halogen bond is only À 6.6 kJ mol À 1 while much higher total energies (45.0, 35.4, 25.5, 23.4, in kJ mol À 1 ) seem to result from the specific mutual arrangement of molecules supported by the weaker aromatic �-� interactions.

Table 2
Interaction energies (kJ mol À 1 ) for the cluster of molecules with a radius of 3.8 A ˚for MIC-tri.
N is the number of molecular pairs.R is the distance (A ˚) between molecular centroids.E tot is the total energy and E ele is the electrostatic (k = 1.057),E pol is the polarization (k = 0.740), E dis is the dispersion (k = 0.871) and E rep is the repulsion (k = 0.618) component.Generally, for MIC-tri, the contribution of dispersive forces predominates over electrostatic ones.The relationship between these two forces can be expressed by the proportions of electrostatic (�kE ele ) and dispersion (�kE dis ) energies (both scaled), given as percentages, that contribute to their sums for all molecular pairs in the cluster of molecules �kE ele / (�kE ele +�kE dis ); [�kE dis /(�kE dis +�kE ele )].The percentages showing the proportion of the electrostatic component to the dispersion component are: 20%:80% for MIC-tri, which is comparable to MIC-mono (26%:74%).

N
Fig. 6 shows the representative energy frameworks for the analysed structure of MIC-tri.Energies between two molecules are represented as cylinders connecting these molecular pairs, with the radius of the cylinder proportional to the contribution of the corresponding energy.Red individual cylinders correspond to electrostatic energy (E ele ), green to dispersive energy (E dis ), and blue to total energy (E tot ).Views along all crystallographic axes demonstrate that the MIC-tri structure exhibits a tri-periodic energy pattern; the total energy framework reflects the framework of its dominant dispersion component.Pairwise model energies (Turner et al., 2014) were estimated and visualized (Turner et al., 2015;Mackenzie et al., 2017) between molecules within a cluster with a radius of 3.8 A ˚, using CrystalExplorer software (Turner et al., 2017).The computational approach uses a B3LYP/6-31G(d,p) molecular wave function calculated for the respective molecular arrangement in the crystal.The total interaction energy between any nearest-neighbour molecular pairs was estimated in terms of four components: electrostatic, polarization, dispersion and exchange-repulsion, with scale factors (k) of 1.057, 0.740, 0.871 and 0.618, respectively.

Synthesis and crystallization
A second polymorphic form of solvent-free miconazole (MICtri) was found after a couple of months, probably as an effect of decomposition of miconazole co-crystals with small aromatic carboxylic acids or any other hydrated/solvated forms of miconazole.The MIC-tri crystals are dull and yellow in colour; they are distinctly different from the co-crystals (Fig. S1 in the supporting information).

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 3.During the refinement of the title compound MIC-tri, the imidazole ring was found to be disordered over two orientations (ring 1A: N1A, C3A, N2A, C4A, C5A and ring 1B: N1B, C3B, N2B, C4B, C5B); site occupancies of two components were fixed at 0.5.Component B of the disordered imidazole ring was restrained using RIGU and SADI commands in SHELXL.Furthermore, the C2 methylene atom was also split; constraints (EXYZ and EADP) were used to fix the overlapping atoms C2A and C2B.It was difficult to determine the position of the nitrogen N2 atom in the disordered imidazole ring, mainly due to the poor quality of the crystals for which the single-crystal diffraction pattern was disturbed by powder diffraction effects.All hydrogen atoms bonded to carbon atoms were placed geometrically and refined as riding, with U iso (H) = 1.2U eq (C) for the methylene, methine and aromatic groups.

Special details
Geometry.All esds (except the esd in the dihedral angle between two l.s.planes) are estimated using the full covariance matrix.The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry.An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s.planes.

Figure 2
Figure 2 An overlay of three miconazole molecules, showing the best fit for atoms C1, C2 and N1: the colour code is blue = MIC-mono, red = MIC-tri-A, green = MIC-tri-B.N2* is the position of the N2 atom in molecule MICmono.

Figure 3 A
Figure 3 A part of the crystal structure of MIC-tri (only disorder component A is shown) showing the formation of C7-Cl1� � �Cl1(À x, À y, 1 À z) halogen bonds and C-H� � ��(arene) interactions between adjacent molecules.Red balls represent the centroids of the phenyl rings (Cg1A and Cg3).Interactions are shown as dashed lines (blue and red), and for the sake of clarity, H atoms not involved in these interactions have been omitted.

Figure 4
Figure 4 Comparison of two-dimensional fingerprint plots for the two miconazole polymorphic forms, MIC-tri (disorder component A only) and MICmono, showing all close contacts, and delineated into C� � �H/H� � �C interactions.The d i and d e values are the closest internal and external distances (in A ˚) from given points on the Hirshfeld surface.

Figure 5
Figure 5 Diagram showing the percentage contributions of different close contacts to the Hirshfeld surface area of miconazole molecules in the two polymorphic forms, MIC-tri (disorder component A only) and MIC-mono.

Figure 6
Figure 6Representative energy framework diagrams for separate electrostatic (red) and dispersion (green) components, and the total interaction energy (blue) for MIC-tri (disorder component A only).All diagrams use the same energy tube scale factor of 80 and an energy threshold of 20 kJ mol À 1 to be compatible with Fig.6(Kaspiaruk & Che ˛cin ´ska, 2022).

Table 3
Experimental details.