*3.3. Structural Studies of Multi-Component Forms*

Single-crystal X-ray diffraction analysis (Table 1 and Figures S4 and S5) confirmed the cocrystal nature of FUR–ETZ and FUR–PRX obtained by LAG of the APIs in methanol.

Figure 1 shows a PXRD overlay of the ground and starting materials and the simulated pattern from the single crystal structure. This figure shows that the ground material matches the one from single crystal analysis, corresponding to FUR–ETZ cocrystal.

FUR–ETZ cocrystal crystallized in the monoclinic *P2*1/*c* space group. The asymmetric unit was composed of FUR and ETZ in a 1:1 stoichiometric ratio (Figure 2a). The cocrystal adopts a ribbon structure through the acid··· amide synthons which connect FUR catemer-like chains formed from SO2HN−H··· Ofuran weak hydrogen bonds between neighboring FUR molecules (Figure 2b). The ribbons stack 6-membered aromatic rings of FUR and ETZ (centroid–centroid distance: 3.7262(17) Å) to form columns running along the *b* axis (Figure 2c). These columns are reinforced by H-bonding interactions involving

the sulfonamide and amide moieties of the cocrystal. Finally, weak C−H··· Osulfonamide hydrogen bonds connect these columns to form the 3D structure.

**Figure 1.** PXRD patterns of the new phase FUR–ETZ obtained by liquid-assisted grinding (LAG) with methanol (MET) solvent, the simulated pattern from crystal structure and the corresponding reactants.

**Figure 2.** (**a**) Asymmetric unit of the FUR–ETZ cocrystal. (**b**) acid··· amide and sulfonamide··· furan synthons give a ribbon along the *b*-axis by H-bonding interactions (Table S1). (**c**) Left. Detail of the column structure in FUR–ETZ. Carbon bound H atoms omitted for clarity Right. π−π stacking interaction in the FUR–ETZ cocrystal.

Figure 3 shows a PXRD overlay of the ground and starting materials, as well as the simulated patterns from the single crystal structure and the reported acetone solvate [31]. As shown in this figure, the ground material matches a new single crystal phase, corresponding to the FUR–PRX solid form.

FUR–PRX cocrystal crystallizes in the monoclinic space group *P21/n*. The crystal structure contains one molecule each of FUR and PRX in the asymmetric unit that are associated by the heterosynthon acid··· pyridine (Figure 4a). PRX molecules exhibits a strong intramolecular H-bonding interaction O-H··· O=C (Table S3). FUR molecules form centrosymmetric dimers through H-bonding interactions involving sulfonamide groups (SO2HN−H··· O=S) and connect PRX molecules by additional H-bonds (SO2HN−H··· O=SPRX) to generate ribbons running along *a* axis. The ribbons have FUR dimers forming the backbone of the ribbon and PRX molecules in the periphery (Figure 4b). The structure is additionally stabilized by weak C−H··· O hydrogen bonds formed from sulfonamide oxygen atoms with methyl groups from PRX molecules to form the 3D structure.

**Figure 3.** PXRD patterns of the new phase FUR–PRX obtained by liquid-assisted grinding (LAG) with methanol (MET) solvent, the simulated patterns from crystal structure and reported acetone solvate structure and the corresponding reactants.

**Figure 4.** (**a**) Asymmetric unit of the FUR–PRX cocrystal. (**b**) Detail of the ribbon structure along the *a* axis.

All the reported polymorphs of FUR exhibit carboxylic dimer synthons; however, each polymorph has a variation in the hydrogen bonding of sulfonamide groups giving different synthons. In the stable FUR polymorph 1 [42], a robust dimeric centrosymmetric H-bonding interaction between sulfonamide groups is observed that further generate a linear tape structure. As expected, in both drug–drug FUR cocrystals, carboxylic dimer synthon is disrupted by the insertion of the amide or pyridine functional group for ETZ or PRX coformer, respectively. Moreover, in the case of FUR-ETZ, the sulfonamide synthon observed in the FUR polymorph 1 is replaced by two different synthons involving FUR and ETZ meanwhile in FUR-PRX, this synthon is partially maintained as sulfonamide dimer but the linear tape structure is blocked by PRX molecules. The resulting ribbon structures are different in both cocrystals and in principle would anticipate that both cocrystal will exhibit different physicochemical properties as will be discussed in the following sections.
