**1. Introduction**

Crystal engineering through multicomponent crystals has attracted substantial attention in the pharmaceutical field in recent years [1,2] because of the possibility of improved solubility and bioavailability of newly designed drug compounds (polymorphs, salt and cocrystals) [3,4]. The formation of the salt/cocrystal is based on the crystal engineering concepts [5]. The salt/cocrystal formation provides an enormous scope for the manipulation and modification of crucial pharmaceutical physical properties such as the dissolution rate, solubility, thermodynamic stability and bioavailability [6,7]. Proton transfer is a decisive factor that distinguishes salts from cocrystals: In salt formation, proton transfer and ionization occur, while these do not occur in the formation of cocrystals [8]. Salts and cocrystals have been employed in the pharmaceutical industry because of their excellent solubility [9]. Although cocrystallization has many exciting advantages, salt formation still represents a widely accepted method to obtain higher solubility of the drug [10].

Most of the active pharmaceutical ingredients (APIs) available in the current market cause formulation difficulties because of poor water solubility, which may lead to poor oral bioavailability [11,12]. Hence, improving the solubility and bioavailability of APIs without changing their stability and other characteristics has become a challenging task. Notably, every crystal structure is the result of mutual balance between numerous noncovalent interactions, but the hydrogen bond remains an important factor in supramolecular assembly [13]. The design of supramolecular heterosynthons derived from organic salts was hypothesized on the basis of the supramolecular synthon strategy in the context of crystal engineering [14,15]. Recently, this strategy has been effectively adopted in the field of pharmaceutical crystallization [16].

Enrofloxacin (1-cyclopropyl-7-(4-ethylpiperazin-1-yl)-6-fluoro-4-oxo-1,4-dihydroquinoline-3 carboxylate) shows a wide spectrum of antibacterial activity, and it belongs to the class of fluoroquinolone antibiotics [17]. As an important synthetic bacteriostatic drug, it has been widely used in stock raising. In good clinical trials, its effectiveness in treating uncomplicated and complicated urinary tract infections, urethral and cervical gonococcal infections, respiratory tract infections, and skin and tissue infections has been proven [18]. It exhibits concentration-dependent antibacterial activity [19]. Enrofloxacin exists in a zwitterionic form within a neutral aqueous solution due to the acid/base interaction between the basic nitrogen of the piperazine and the carboxylic acid group [20,21]. Therefore, in water at pH ≈ 7, enrofloxacin exhibits a low solubility (0.45 mg/mL) [21]. In addition, low solubility of enrofloxacin is one of the unfavourable properties in formulation [22]. Therefore, a method to improve its solubility without compromising performance has been sought. A weak organic acid can be used as an organic counterionic component for salt formation [23,24]. These acids can potentially present the formation of salts with multiple stoichiometries due to the containment of carboxylic group. This approach is widely used in pharmaceutical industries to enhance solubility, bioavailability and controlled release of drugs [25]. Therefore, we adopted crystal engineering concepts to select pharmaceutically acceptable organic counterions to form salts with enrofloxacin.

In this study, we prepared enrofloxacin anhydrate and salt trihydrate with tartaric acid and salt solvate with nicotinic acid and suberic acid, and we analysed the crystal structures of these compounds. The obtained crystal compounds were characterized by field-emission scanning electron microscopy (FESEM), Fourier transform infrared spectroscopy (FT-IR), powder X-ray diffraction (PXRD) and differential scanning calorimetry (DSC). All the crystal structure data were successfully resolved by single-crystal X-ray diffraction (SCXRD), and the crystal conformations and packing arrangements were studied in detail. Finally, the solubility of the new phases in water was also determined by high-performance liquid chromatography (HPLC). The new salts were found to exhibit significantly improved solubility and were therefore suitable for use in drug formulation.
