*3.1. Coformer Selection*

Before the experimental trials, we performed virtual cocrystal screening to improve the success rate. A survey on the Cambridge Structural Database (CSD version 5.42, update 2 from May 2021) based on FUR resulted in 70 hits. After excluding datasets corresponding to FUR polymorphs, the remaining dataset corresponded to multi-component crystals (cocrystals, salts, and solvates), 60 hits. Several authors have reported pharmaceutical salts and cocrystals of FUR. A search of this dataset for drug–drug multi-component crystals revealed a total of 11 systems [8,10–13,29–31]. A common structural feature observed is the key role of the carboxylic group in the interaction with the coformer or counterion and the formation of other synthons involving the sulfonamide group that participates in stabilizing the crystal structure packing. Hence, the abundance of heterosynthons observed in the survey involving carboxylic group follows the order: carboxylic-pyridine (54%) > carboxylic-amide (20%) > carboxylic-imidazole (8%) > carboxylate··· piperazinium/carboxylate··· ammonium/ carboxylate··· pyridinium (6%). According to the abovementioned, the main prerequisite for the coformer selection was having the above-referred groups and being a drug. From our library of coformers, two molecules fulfil these criteria: ETZ and PRX. COSMOQuick software was used to validate our selection, predicting the tendency of cocrystal formation based on thermodynamics calculations. This tool calculates the excess enthalpy of formation (Hex) between FUR and the corresponding coformer/drug relative to the pure components in a supercooled liquid phase [32]. It requires the simplified molecular input line entry specification or SMILES of a molecule as input data. Table 2 shows COSMOQuick calculations for a list of candidates to form multi-component crystals with FUR. The list includes our two selected drugs and other coformer molecules involved in the formation of cocrystals/salts reported in the survey. Compounds with negative Hex values show an increased probability of forming cocrystals since Hex is a rough approximation of the free energy of cocrystal formation ΔGcocrystal. The results obtained by COSMOQuick confirm FUR preference to form cocrystals with coformers that exhibit the functional groups observed in the CSD survey, including our drug coformer candidates.


**Table 2.** Ranking positions for FUR coformers reported at CSD, including the two drugs used in this study (in bold) based on COSMOQuick calculations. Non-drug molecules marked with \*.
