*3.3. Structural Analysis of Multicomponent Forms*

DIC–ADE cocrystal crystallized in the triclinic P-1 space group. The asymmetric unit is composed of DIC and ADE in a 1:1 stoichiometric ratio, where ADE adopts its most stable and expected 9H tautomeric form. DIC exhibits its aromatic ring twisted out (dihedral angle: 71.92◦) and is stabilized by an intramolecular N–H(amine)··· O(carbonyl) hydrogen bond (Figure 2a). Centrosymmetric H-bonded adenine dimers (N29-H29···N23#2 2.00 Å, 166.6◦; #2: -x + 3,-y + 2,-z) aggregate through the Hoogsteen edge (N26-H26B···N27#1: 2.10 Å, 162.7◦; #1:-x + 2,-y + 1,-z), creating infinite zig-zag chains. DIC molecules connect to the chain structure by H-bonding interactions through the Watson–Crick edge (O2-H2···N21: 1.84 Å, 169◦; N26-H26A···O1: 2.10 Å, 169◦), resulting in an infinite tape structure (Figure 2b). C–H···F hydrogen bonds reinforce this structure and also connect adjacent tapes. Finally, the 3D structure is accomplished by piling these tapes through C=O···π and C-H···π interactions among DIC and aromatic rings from the adenine (Figure 2c).

DIC–CYT crystallized as a molecular salt in the orthorhombic Pca21 spacegroup. The asymmetric unit consisted of two symmetry-independent molecules of diclofenac anion and two symmetry-independent molecules of cytosinium cation in a 1:1 stoichiometric ratio (Figure 3a). Cytosinium over hemicytosinium duplex formation was observed in agreement with the cutoff pKa value for acids reported by Sun et al. [44] (pKa value for DIC: 4.15). The analysis of the C–O bond distances of the carboxylate group of DIC supports the salt formation [45]. In the DIC–CYT system, C–O distances were indicative of a deprotonated acid, as expected for a salt with ΔDC–O values of 0.001 Å and 0.002 Å for both DIC anions, respectively, according to the ΔDC–O values observed in salts (typically less than 0.03 Å). As in DIC–ADE, the two aromatic rings of diclofenac are bent out of plane, with dihedral angles of 81.78 and 84.06◦. In the crystal, DIC<sup>−</sup> and CYT–H+ form an alternating layered structure where cytosinium molecules are associated through single-point N–H···O bonds, graph set *C*1 <sup>1</sup> (6), generating CYT–H+···CYT–H<sup>+</sup> chains running along the a-axis [Figure 3b]. DIC<sup>−</sup> layers are reinforced by C–H···F hydrogen bonds. The two-point 2-amino-pyridinium– carboxylate synthon (N4A–H4AA···O1A, 1.85 Å, 178◦, N2A–H2A+···O2A, 1.92 Å, 176.3◦, and N4B–H4BA···O1B, 1.84 Å, 178.4◦, N2B–H2B+···O2B, 1.92 Å, 176.5◦) associates the DIC<sup>−</sup> and CYT–H+ layers, generating the supramolecular 3D structure.

**Figure 2.** (**a**) Asymmetric unit of the DIC–ADE cocrystal. (**b**) Fragment of the tape structure generated by H-bonding interactions. (**c**) Detailed view of the crystal packing of the DIC–ADE cocrystal. Orange: DIC molecules, green: ADE molecules. (**d**) C=O···π and C-H···π interactions in the DIC–ADE cocrystal.

**Figure 3.** (**a**) Asymmetric unit of the DIC–CYT molecular salt. (**b**) Detailed view of the packing arrangement of DIC<sup>−</sup> anions (blue and green) and CYT–H<sup>+</sup> cations (red and yellow) in the DIC–CYT crystal structure (viewed along the b and a axes), showing an alternating layered structure.

DIC–ICT crystallized in the triclinic P1 spacegroup. Both diclofenac and isocytosine components are present in their neutral and ionic forms, resulting in a hybrid solid with a cocrystal and a salt in the asymmetric unit (Figure 4a). In the DIC–ICT system, C– O distances confirmed the presence of carboxylate and carboxylic groups, as expected for ΔDC–O values observed for the two symmetry-independent diclofenac molecules (0.080 Å and 0.006 Å for neutral diclofenac and diclofenac anion, respectively). Isocytosine and isocytosinium molecules formed a dimeric structure through H-bonds involving the 2-amino-pyridinium–carbonyl synthon (graph set motif *D*<sup>1</sup> <sup>1</sup>(2)). These dimers connect with adjacent dimers using the amine-carbonyl synthon (graph set motif *D*<sup>1</sup> <sup>1</sup>(2)), generating a chain structure. The two-point 2-amino-pyridine–carboxylic (N4B–H4BA···O1B, 2.02 Å, 166.5◦, and O2B–H2B···N2B#1, 1.80 Å, 171.7◦; #1: x + 1, y, z) and 2-amino-pyridinium– carboxylate (N4A–H4AB···O1A, 1.82 Å, 158.1◦, and N2A–H2A+···O2A, 1.99 Å, 174.0◦) synthons connect components to build up a ribbon structure (Figure 4b). C–H···π interactions (C13B-H13D···Cg; H···Cg distance: 2.97 Å; C-H···Cg angle: 118◦; Cg = C7B-C8B-C9B-C10B-C11B-C12B) associate these ribbons to form a layered structure. Finally, weak C–H···F hydrogen bonds connect these layers to create the 3D structure.

**Figure 4.** (**a**) Asymmetric unit of the DIC–ICT multicomponent form. (**b**) Fragment of the ribbon structure generated by H-bonding interactions between DIC components and a chain of –ICT–H+···ICT– dimmers. (**c**) Detailed view of the packing arrangement of ribbons structures containing DIC (blue), DIC<sup>−</sup> (green), ICT (yellow), and ICT–H+ (red), building up a layered structure. (**d**) Detailed view of the C–H···π interaction between DIC molecules.
