**1. Introduction**

Pharmaceutical cocrystals have recently received a grea<sup>t</sup> deal of attention because of their therapeutic importance and remaining challenges [1–5]. The commercial success of rationally designed drugs which have been introduced into the market in last decade, such as Steglatro ® (a molecular cocrystal of ertugliflozin and L-pyroglutamic acid), Odomzol ® (a cocrystal of sonidegib and phosphoric acid), Suglat ® (a cocrystal of ipragliflozin and L-proline), and Entresto1 ® (a cocrystal of valsartan and sacubitril), has prompted "Big Pharma" companies to double their e fforts regarding testing the compositions of new solid systems fulfilling the conditions whereby they may be classified as cocrystals.

According to the generally accepted definition, cocrystals are homogenous (single phase) crystalline structures which are made up of two or more components in a definite stoichiometric ratio where the arrangemen<sup>t</sup> in the crystal lattice is not based on ionic bonds (as with salts) [6].

The remarkable advantage of pharmaceutical cocrystals is their significant improvement in terms of physicochemical properties without compromising on therapeutic benefit [7]. It is well known that many Active Pharmaceutical Ingredients (APIs) suffer from low solubility and/or poor permeability [8,9]. Notably, up to 90% of new drugs receive a BCS II (Biopharmaceutics Classification System) category rating, meaning that they demonstrate low solubility and high permeability [10]. In the case of cocrystals, these parameters are usually significantly enhanced.

For scientists dealing with solid state matter and the formulation of new crystalline materials, the preparation of cocrystals with desired properties is usually a challenging task. Progress in this field has been made possible due to grea<sup>t</sup> achievements in crystal engineering which allow researchers to predict supramolecular interactions, resulting in new solid forms [11]. Generally, therapeutic cocrystals consist of two components: a biologically active organic compound and a complementary molecular coformer. In the pharmaceutical sciences, the correct choice of a coformer for a desired API is essential [12]. The library of available coformers which fulfill structural prerequisites is significant; however, only selected compounds can be considered to belong to the group of "pharmaceutically useful" ones [13–15]. The basic requirement for a suitable coformer is to be pharmaceutically acceptable, i.e., generally regarded as safe (GRAS) substances. Furthermore, coformers should be relatively cheap, with rather low molecular weight, and possess multiple API-binding sites which can be involved in the formation of strong intermolecular interactions [16].

The intention of our work was to introduce a new compound containing the imidazole core to the group of useful pharmaceutical coformers. In the current project, we selected 1-Hydroxy-4,5- Dimethyl-Imidazole 3-Oxide (**1**) 1-Hydroxy-4,5-Dimethyl-Imidazole 3-Oxide (HIMO) [17] (see Figure 1), which has never been tested before in therapeutic applications. This compound, bearing appropriate functional groups, is capable of forming ordered solid structures. Moreover, a strong motivation for its selection was the fact that numerous imidazole derivatives play an important role in organic chemistry, medicinal chemistry as well as the pharmaceutical sciences. Imidazole derivatives with histidine are common in nature, as basic amino acids. Being a part of the structure of protein, histidine is an essential amino acid which is crucial for the catalytic activity of many enzymes. Moreover, imidazole-based drugs exhibit antiviral [18–20], antitumor [21–23], bacteriostatic [24], and antiprotozoal [25,26] activities. They were reported to act as hypotensive agents [27] and selective inhibitors for some kinases [28,29]. Such unique properties prompted us to prepare new cocrystals, which can be also considered as unknown drug–drug binary systems.

**Figure 1.** 1-Hydroxy-4,5-Dimethyl-Imidazole 3-Oxide (HIMO) (**1**), thiobarbituric acid (TBA) (**2**) and barbituric acid (BA) (**3**).

The compound 1-hydroxy-4,5-dimethyl-imidazole 3-oxide (**1**) exists in the equilibrium of tautomeric forms [30]. In solution and in gaseous phase, it forms a mixture of the –OH (i.e., 1-hydroxyimidazole) and N→O (i.e., imidazole 3-oxide) tautomers existing in comparable amounts; this fact has been demonstrated by theoretical and experimental studies. The observed equilibria depend not only on the solvent polarity, but also on the composition of substituents attached to the imidazole ring, and their ability to form the inter- or intra- molecular bonds [31–38]. On the other hand, knowledge about the structure of **1** in the solid state is limited, and this makes this compound even more intriguing.

In the present study, thiobarbituric acid (TBA) (**2**) and barbituric acid (BA) (**3**) (Figure 1) were chosen as potential APIs. Both compounds are well known and have been described in numerous crystallographic and physico-chemical reports [38–40].

As highlighted above, the imidazole *N*-oxide **1** has never been tested as a pharmaceutical coformer. Thus, in view of its potential use, we present also biological studies performed for HIMO and its cocrystals with TBA and BA, respectively. Compounds **1**, **2**, **3** and new cocrystals were analyzed using solid-state NMR spectroscopy (SS NMR), single-crystal and powder X-ray Di ffraction (XRD) techniques, as well as Di fferential Scanning Calorimetry (DSC).
