**1. Introduction**

A pharmaceutical cocrystal can be defined as a multicomponent crystal wherein at least one component is the active pharmaceutical ingredient (API) and is in a well-defined stoichiometric ratio and bonded by non-covalent interactions with the other component(s), i.e., the coformer(s) [1,2]. These interactions are mainly intermolecular hydrogen bonds between functional groups forming supramolecular synthons, and moreover, additional weaker interactions such as van der Waals forces, π-stacking or halogen bonds may also help to stabilize the cocrystal structure [3,4]. The purpose of synthesizing pharmaceutical cocrystals is to improve the characteristics of APIs, such as the aqueous solubility, dissolution rates and stability [5].

Itraconazole (ITR) is an API with a broad-spectrum antifungal activity used for the treatment of topical and systemic mycoses as well as for prophylaxis in immunosuppressed patients [6,7]. ITR, due to a low aqueous solubility but a high systemic absorption, is considered a class II drug according to the biopharmaceutics classification system (BCS) [8]. Indeed, ITR has a very low solubility in water (around 1 ng/mL), which increases in an acidic medium (4 μg/mL) [9], thus the poor solubility is the limiting factor for ITR absorption. To improve the poor physicochemical properties, ITR can be converted into disordered forms such as liquid crystalline [10–12] and amorphous structures, as well as polymer-based solid dispersions [12]. The commercial solid dosage formulation of ITR, Sporanox ®, is available as pellets enclosed in oral capsules [13]. The pellets are manufactured by spray-layering a solution of ITR and hydroxypropyl methylcellulose (HPMC) on sucrose beads. Then, the drug-coated beads are treated with a seal coating polymer layer (polyethylene glycol (PEG) 20,000 Da) to prevent the sticking of the beads. The API in these pellets is in the amorphous state [13]. Since the physical stability of drug in an amorphous phase can be short-lived, a crystalline, but a better soluble form of ITR would be preferred.

The development of ITR cocrystals was first achieved combining this API with aliphatic dicarboxylic acids used as coformers, including fumaric acid, succinic acid, l-malic acid, l-tartaric acid, d-tartaric acid and <sup>d</sup>,<sup>l</sup>-tartaric acid [14]. Remenar's work reported a remarkable improvement of the ITR dissolution with an approximately 20-fold enhancement of the cocrystals prepared with l-malic and l-tartaric acids, which had dissolution profiles comparable to the commercial form of ITR, Sporanox ® capsules. In another work, Shevchenko et al. [15] produced ITR cocrystals with coformers of di fferent carbon chain lengths and determined that linear aliphatic dicarboxylic acids should have no more than seven carbon atoms in their chains to successfully form a cocrystal with ITR. That work also demonstrated that cocrystallisation is an e fficient approach to improve the dissolution rates of ITR. However, a recent study presented that an ITR cocrystal with an aliphatic dicarboxylic acid comprising more than seven carbon atoms, suberic acid, can be prepared by rapid solvent evaporation and spray drying, resulting in the material being able to dissolve rapidly. This cocrystal had a 39 times faster intrinsic dissolution rate than the crystalline ITR [16].

Little is published on the structural analysis of ITR cocrystals, nevertheless, such studies on the ITR and succinic acid (SUC) cocrystal revealed that this form has a trimeric building block, where two molecules of the API are oriented antiparallel to one another and bridged by the coformer. The main interactions found to be responsible for the intermolecular arrangemen<sup>t</sup> of this structure were H-bonds formed by the hydroxyl moiety located on both sides of the acid and one of the nitrogen atoms of the 1,2,4-triazole ring of each ITR molecule (Figure 1) [14].

**Figure 1.** Molecular structures of (**a**) itraconazole (ITR) and (**b**) terephthalic acid (TER).

Terephthalic acid (TER) is a benzenedicarboxylic acid with the carboxylic groups attached in positions one and four (Figure 1). TER has very low toxicity and has been employed in the cocrystallization of a few APIs, such as apovincamine [17], betulin [18], isoniazid [19] and gabapentin [20]. Considering that most investigations on the identification of ITR cocrystals are limited

to aliphatic dicarboxylic acids [14–16,21], coformers with other architecture appears to be unexplored. Therefore, this work carried out an experimental screening aiming to identify a possible new cocrystal of ITR combining this API with TER to ascertain the relevant molecular elements in the coformers that enable the formation of new cocrystal phases of ITR. This new cocrystalline form was extensively evaluated regarding its solid-state characteristics, as was the impact ITR cocrystallisation had on a range of pharmaceutical properties. Finally, the cocrystal dissolution was studied including an intrinsic dissolution study, a simple mixture with lactose as well as a mixture comprising excipients used in the commercial ITR formulation, comparing the performance of the new cocrystal with those based on aliphatic dicarboxylic acids.
