*3.7. Solubility Studies*

As observed in the previous section, only the DIC–ADE cocrystal was thermodynamically stable in a water solution at room temperature. Initial attempts to determine solubility by the shake-flask method [49] were not possible due to the overlap of UV absorption maxima of both the API and coformer (Figure S8). Evaluation of solubility was then performed by a polythermal method using the Crystal16 equipment. Results showed an improvement in the solubility of DIC–ADE (0.993 mg/mL, Figure 9) compared with the reported solubility of DIC (0.9 μg/mL) [5]. Although the difference in solubility between DIC and the DIC–ADE cocrystal was significant, the amount of solubility improvement is not significant compared with the solubility of the sodium salt (16.18 mg/mL) [50]. The layered structure observed in the DIC–ADE cocrystal directly impacts the solubility improvement of DIC. Different studies have reported the effect of a layer structure consisting of high-solubility molecules on the solubility of multicomponent solid forms [51–53]. Although the dimeric DIC structure is disrupted and a better solubility is obtained in DIC–ADE, the intercalated layers composed of low water-soluble ADE molecules do not confer enough solubility improvement themselves in comparison with other multicomponent DIC solids.

A potential risk observed in the use of multicomponent systems is their tendency to experience unexpected dissociation in contact with water or with high relative humidity (RH), which leads to a return to the respective free API and coformer [54,55] and denies the solubility advantage achieved by multicomponent solid formation. To rationalize the dissociation observed for DIC–CYT and DIC–ICT solids, crystal morphologies of the three reported multicomponent DIC forms were computed using the Bravais– Friedel–Donnay–Harker (BFDH) method included in the visualization software package Mercury [27]. As described previously, all the crystal structures consist of alternate layers of type DIC···coformer···DIC··· and these supramolecular arrangements seem responsible for the enhanced properties. Figure 10 shows the predicted morphologies for the reported multicomponent solids. Notably, the facets with the largest surface, following the order: DIC–ICT (57.2%) > DIC–CYT (50%) > DIC–ADE (24.2%), contain hydrogen bond donor and acceptor groups that potentially could interact with water during the dissolution process. Water solubility depends not only on the groups exposed on the surface of a crystal but on other different factors, including density, coformer solubility, or lattice energy [56]. We cannot argue that the high polarity of the crystal surfaces could impact the solubility performance by itself, but it does affect the dissolution of the reported solids as evidenced by the rapid dissociation observed for DIC–CYT and DIC–ICT during the slurry experiments in water. Dissolution is carried out at higher rate in the DIC–CYT and DIC–ICT species. As expected, dissolution in these species is favored by extensive surface exposure. On the other hand, dissolution of the DIC–ADE phase occurs at a slower rate, evidenced by the apparent stability at 24 h.

**Figure 9.** Solubility curve for DIC–ADE in water as a function of concentration and temperature.

**Figure 10.** BFDH-predicted morphologies of (**a**) DIC–ADE I (green: DIC, blue: ADE); (**b**) DIC–CYT (blue and green: DIC, yellow and red: CYT), and (**c**) DIC–ICT (DIC: blue and green: ICT: red and yellow), showing the largest faces.
