3.3.2. **(lid/res)** Systems

**(lid)2(res)** crystallises in the triclinic P-1 space group. As in the **(lid)2(hq)** cocrystal, the coformer is sitting on an inversion centre; however, in this compound, the **(res)** coformer molecular symmetry does not exhibit inversion. Therefore, a disorder of the molecule about this particular special position is observed. The **(res)** adopts a syn–syn conformation, pointing the –OH groups through the –C=O group of **(lid)** (*D*<sup>1</sup> <sup>1</sup>(2) graph set) and establishing a 2:1 stoichiometric ratio (Figure 8). These discrete units are connected in a similar way than in **(lid)2(hq)** through shorter –C–H···π (2.864 Å) and –N–H···π (3.216 Å) interactions between **(lid)** molecules, generating chains. Again, hydrophobic interactions involving methyl groups associate chains to build up the 3D structure. Crystal structure similarities in the **(lid)** cocrystals [20] with **(hq)** and **(res)** coformers could explain the template effect of **(lid)2(hq)** solid when used as hetero-seeds during the synthesis of crystals of **(lid)2(res)** (see Section 2.3). The results obtained from crystal packing similarity calculations of one of the alternative positions of the disordered **(lid)2(res)** structure and **(lid)2(hq)** structure using Mercury [21] showed that 14 out of 20 molecules were matched in the pairs of 2:1 cocrystals with a PXRD similarity index of 0.96745 and RMSD of 0.268 (Figure 9). These results suggest that these pairs possess identical intermolecular interactions and lead to the same crystal packing [22].

**Figure 8.** (**a**) Asymmetric unit of **(lid)2(res)** cocrystal. Only one of the two alternative positions in the disordered structure is shown for clarity. (**b**) Detailed view of the –C–H···π and –N–H···π interactions that connect discrete **(lid)(res)** units to form a chain structure.

**Figure 9.** Crystal packing similarity plot comparing the **(lid)2(hq)** and **(lid)2(res)** crystal structures. Green and red: **lid-hq** molecules.

The **(lidhcl)2(res)** ionic cocrystal [20] contains one **(lidhcl)** salt and half a **(res)** molecule located in an inversion centre, giving a 2:1:1 stoichiometric ratio (Figure 10a). As observed in the ionic cocrystal of **(lidhcl)** with **(hq)**, protonation of **(lid)** imposes a conformational change resulting in a chain structure build-up by electrostatic hydrogen bonds involving protonated lidocaine donor and acceptor groups, as well as chloride ions. Disordered **(res)** molecules connect chains to generate the supramolecular 3D crystal structure. Similarly, as in the ionic cocrystal **(lidhcl)2(hq)**, **(res)** coformer molecules are protected with **(lid+)** cations, preventing them from oxidation (Figure 10b).

**Figure 10.** (**a**) Asymmetric unit of **(lidhcl)2(res)** ionic cocrystal. Only one of the two alternative positions in the disordered structure is shown for clarity. (**b**) Detailed view of the crystal packing of **(lidhcl)2(res)** ionic cocrystal (view along the a axis). Blue: **(lid+)** ion, green: Cl<sup>−</sup> ion, red: **(res)** molecules.
