**1. Introduction**

A search for the different solid forms of an active pharmaceutical ingredient (API) is a crucial part of the drug development process. Solvate formation has many implications in the pharmaceutical industry, as it affects the physicochemical properties of materials, such as their melting point, density and dissolution rate, which in turn can influence their manufacturability and pharmacokinetic properties, without changing the pharmacology of the API through modification of covalent bonds [1–4]. The unexpected formation of undesired solvates can thus lead to unpredictable behavior of the drug and could prove costly. Organic solvents are constantly present in the pharmaceutical production processes, so many aspects of them have to be extremely controlled [5].

The rationalization of the solvate formation is one of the important topics in the current crystal engineering [6], and the discovery of solvates is important in several aspects: (1) formation of solvates can limit the selection of solvents for crystallization of the desired crystal form; (2) solvates can be used as intermediates for producing the necessary polymorphs, as specific polymorphs can sometimes be obtained only via desolvation of particular solvates; (3) solvates can serve to control the particle size distribution in the product in cases in which the nonsolvated forms are difficult to crystallize [6]; and (4) particularly stable solvates, typically but not exclusively hydrates (like diosgenin hydrate [7] for example), can be used as the marketed form [8]. Although the utilization of the most physically stable crystal form is typically desired as any change in the solid form may affect the bioavailability associated with the drug product, metastable modifications can be preferred when an improvement in the in vitro dissolution kinetics is achieved. Up to the present, there are some few solvates on the market such as trametinib dimethyl sulfoxide, dapaglifozin propanediol monohydrate, cabazitaxel, darunavir ethanolate, warfarin sodium, indinavir sulfate ethanolate and

atorvastatin calcium [9]. Limitations for the use of solvates in pharmaceutical industry are given by the toxicity of solvents they contain, and also, they may additionally accelerate decomposition of the final product. Permitted solvents and the limits of their content are provided by the regulatory authorities in the pharmacopeias [10].

The general prediction of solvate formation, similar to the prediction of other solid forms, is still largely an unresolved problem. Currently, in order to avoid unexpected structural transformations such as hydrate and solvate forms, in the pharmaceutical industry, high-throughput crystallization experiments are conducted to obtain all possible solid forms of a drug [11].

Two main structural driving forces responsible for incorporation of solvent molecules in the structure have been identified, on one hand, the ability of solvents to compensate unsatisfied potential intermolecular interactions between the molecules and, on the other hand, the ability to decrease the void space and/or lead to more efficient packing. Both the formation of an extensive hydrogen bond network established by the solvent molecules as well as an increase of the packing efficiency have been shown to be the main contributing factors for the solvate formation of pharmaceutical molecules. Most of the solvates, however, include contributions from both of these driving forces, and the solvate formation thus is due to a lowering of the crystal free energy [8].

Bilastine, 2-[4-[2-[4-[1-(2-ethoxyethyl)-1H-benzimidazol-2-yl]-1-piperidinyl]ethyl] phenyl]- 2-methylpropionic acid (Figure 1), is a well-tolerated, second generation antihistamine drug approved for the symptomatic treatment of allergic rhinoconjunctivitis and chronic urticaria [12]. It exerts its effect as a selective histamine H1 receptor antagonist and has an effectiveness similar to cetirizine, fexofenadine and desloratadine [13]. It was developed in Spain by FAES Farma, and it has been commercially available internationally since March 2011.

**Figure 1.** Chemical structure of Bilastine.

BL, its preparation and uses as H1 receptor antagonist were first described in the European patent EP0818454B1 [14]. Later, the patent WO03089425 reported three crystalline forms of BL: 1, 2 and 3, characterized by IR, and crystallographic parameters were provided only for form 1 [15]. It was said that forms 2 and 3 of BL easily converted into form 1. In the present study we have extended the knowledge about the solid forms landscape of BL by performing a polymorph screening starting from anhydrous forms I and III, whose crystal structures have been determined from single crystal and synchrotron powder X-ray diffraction, respectively. The thermodynamic relationship among the anhydrous forms has been established. In addition, during the screening three chloroform solvates (two heterosolvates (S3CHCl3-H2O and SCHCl3-H2O) and one monosolvate SCHCl3) have been obtained, being two of them transient solvates which transform into solvate SCHCl3-H2O immediately when exposed to ambient conditions. The crystal structures of the three solvates with different stoichiometries have been determined and will be discussed and compared with the anhydrous forms. Moreover, the different forms have been further characterized by differential scanning calorimetry (DSC), thermogravimetric analysis (TGA) and variable temperature powder X-ray diffraction (VT-PXRD). Finally, the phase transformations pathways among the different forms have been defined.
