*3.4. Crystallographic Analysis*

Single crystal X-ray diffraction (SC-XRD) showed that the cocrystal had a triclinic unit cell composed of four molecules (Z = 4) in a P1 space group (Table S1). The asymmetric unit crystal was formed by two ITR molecules and two halves of a TER molecule. The stoichiometry of the cocrystal was determined as 2 moles of ITR per 1 mole of TER. In this arrangement, the ITR molecules are in an antiparallel orientation with a TER molecule, which is sandwiched in the formed space by the drug molecules (Figure 7). SC-XRD also identified H-bonds formed by the hydroxyl of the carboxyl acid and the nitrogen of the azole ring of ITR (Figure 7 and Table S2), in agreemen<sup>t</sup> with the results of vibrational spectroscopy (Figure 6). This interaction was also observed in other cocrystals of ITR [14,35], however, in the ITR–TER cocrystal, another H-bond, of the C–H ... O type, was also identified (Figure 7 and Table S2).

**Figure 7.** Crystal structure of the ITR–TER cocrystal (symmetry transformations used to generate equivalent atoms: (i) −x, 2-y, 1-z; (ii) 1-x, 1-y, 1-z) showing the major disorder in the ITR moiety only.

As the only single crystal X-ray data for ITR cocrystals available in the Cambridge Structural Database (CSD) are for ITR–succinic acid (ITR–SUC), record REWTUK [33], a more detailed comparison of the two cocrystals was made. Although both cocrystals have their crystal lattice formed by four molecules, the ITR–SUC cocrystal was described as a monoclinic system with a P21/c space group [32].

The 2D fingerprint plots, based on the 3D Hirshfeld surfaces of the ITR molecules in ITR–TER and ITR–SUC cocrystals, were generated to investigate the differences in interactions (Figure 8). It can be seen that the H ... H interactions are dominant and represent the most significant contribution (44.6% and 49.4%, in ITR–TER and ITR–SUC cocrystal, respectively) to the total Hirshfeld surfaces. In the ITR–TER cocrystal, the contribution of the C ... H contacts is greater (18.2%) in comparison to the ITR–SUC system (14.2%), most likely due to the additional weak C–H ... O H-bond. The dominant N–H ... O interaction is visible in both systems, showing as a well-defined "horn" when looking at the N ... H interactions only (Figure 8). What can be concluded is that the degree of interactions including C ... H, N ... H and O..H contacts in the ITR–TER systems is higher than that in the TER–SUC cocrystal.

**Figure 8.** Two-dimensional Hirshfeld fingerprints for ITR–TER (top) and ITR–SUC (bottom) cocrystals.
