Norfloxacin salts with benzenedicarboxylic acids: charge-assisted hydrogen-bonding recognition and solubility regulation

Abstract

The crystallization of norfloxacin, an antibacterial fluoroquinolone compound, with different benzenedicarboxylic acids yields five novel pharmaceutical salts via molecular recognition. X-ray single-crystal diffraction analyses reveal that these pharmaceutical agents present uniform charge-assistant hydrogen-bonding networks, which are in 1 : 1 stoichiometry of norfloxacin and dicarboxylate therein (with the exception of that with terephthalate). Unsubstituted benzenedicarboxylates (phthalate in 1, isophthalate in 2, and terephthalate in 3, respectively) are likely to crystallize with norfloxacin without lattice solvents, while the substituted isophthalate moieties (2-aminoisophthalate in 4 and 5-aminoisophthalate in 5) tend to form supramolecular adducts with the inclusion of water. Aromatic stacking interactions are present in all these structures, occurring between the fluoroquinolone and carboxylate phenyl rings (in 1–4) as well as between the fluoroquinolone planes (in 5). Thermal stability and solubility of all crystalline binary adducts have been determined. The effect of carboxylate counterions, substituents, and hydration states on the solubility and dissolution profile of drug salts 1–5 are investigated in pure water and 0.1 M HCl. After the formation of salts, the solubility increases at near neutral pH in almost all cases (except 3), but the order is changed in acidic medium. Phthalic acid shows evidence of a good candidate to enhance the solubility of fluoroquinolone drugs for the solubility of 1 is approximately 39 times as large as that of norfloxacin in pure water and also larger than that of norfloxacin in acidic system. For the isophthalates series, 2 has very poor solubility in 0.1 M HCl (only 0.06 times as that of Nf), while amino substituted isophthalates result in the enhancement of the solubility. Remarkably, crystal packing analyses of these pharmaceutical salts allow a possible correlation between the H-bonding prototypes and the solubility to be established.