Structural and Solubility Studies of Novel Salts and Cocrystals of the Antihistamine Drug Bilastine with Carboxylic Acid Derivatives

Bilastine (BLS) is a second-generation antihistamine drug molecule used for the treatment of allergic rhinoconjunctivitis and chronic urticaria. The main disadvantage of BLS is its low aqueous solubility. In the present work, six molecular salts and three cocrystals of BLS with coformers, namely, saccharin (SAC), oxalic acid (OXA), fumaric acid (FUM), maleic acid (MEA), 3-hydroxybenzoic acid (3HBA), 3,5-dihydroxybenzoic acid (35HBA), 4-hydroxyphenylacetic acid (4HPA), and 2,6-dihydroxybenzoic acid (26HBA), are reported, and their crystal structures were determined by single-crystal X-ray diffraction techniques. All the salts and cocrystals were crystallized as hydrates except BLS+-SAC–(1:1) and BLS+-26HBA–(1:1). Salt formation with OXA resulted in two ratios of crystalline hydrate forms such as 1:0.5:3 and 1:1:1 ratios of BLS:OXA:H2O in the asymmetric unit. Along with salts and cocrystals, the crystal structure of BLS·5H2O was determined and is reported in the present work. In all the salts, proton transfer from the coformer to piperidine nitrogen was observed, and the primary interactions involved were N–H···O and O–H···O hydrogen bonds between BLS and coformer molecules. Furthermore, all the crystalline structures were characterized by the thermal method (DSC/TGA) and powder X-ray diffraction techniques. The equilibrium solubility at 37 °C in purified water demonstrates that the BLS solubility increased by about 8- and 5.5-fold in BLS+-OXA2–-H2O­(1:1:1) and BLS+-MEA–-H2O­(1:1:1) salts, respectively. The solubility in water (pH = 6.5) follows the order BLS+-OXA2–-H2O­(1:1:1) > BLS+-OXA1–-H2O­(1:0.5:3) > BLS+-MEA–-H2O­(1:1:1) > BLS+-26HBA– > BLS-3HBA-H2O­(2:1:1) > BLS-4HPA-H2O­(2:1:4) > BLS > BLS-35HBA-H2O­(1:1:1) > BLS+-FUM–-H2O­(1:0.5:2) > BLS+-SAC–(1:1). About 2-fold increment in solubility was observed in 0.1 N HCl (pH = 1.2) for BLS+-OXA2–-H2O­(1:1:1) and BLS+-MEA–-H2O­(1:1:1), and the solubility follows the order BLS+-OXA2–-H2O­(1:1:1) > BLS+-MEA–-H2O­(1:1:1) > BLS+-FUM–-H2O­(1:0.5:2) > BLS-3HBA-H2O­(2:1:1) > BLS-35HBA-H2O­(1:1:1) > BLS+-OXA1–-H2O­(1:0.5:3) > BLS-4HPA-H2O­(2:1:4) > BLS > BLS+-SAC–(1:1) > BLS+-26HBA–(1:1) in 0.1 N HCl (pH = 1.2). Furthermore, all salts and cocrystals were found to be stable for 45 days under accelerated stability conditions (40 ± 2 °C, 75 ± 5% RH).