Structural Landscape of Pure Enrofloxacin and Its Novel Salts: Enhanced Solubility for Better Pharmaceutical Applicability

The
crystal structures of anhydrous enrofloxacin (EFC) (1), enrofloxacin hexahydrate (EFC·6H2O) (2), enrofloxacin maleate (EFC-M) (3), enrofloxacin hemifumarate
(EFC-F) (4), enrofloxacin hemisuccinate (EFC-S) (5), enrofloxacin hemioxalate (EFC-O) (6), enrofloxacin
acetate (EFC-A) (7) and ammonium salt of enrofloxacin
(Am-EFC) (8) have been determined by using single crystal
X-ray diffraction (SCXRD). The crystals of 1 were grown
from a dilute solution of EFC in dilute ammonium hydroxide. The crystals
of 2 were grown from a solution of EFC with nicotinic
acid. Solvent drop grinding experiments on enrofloxacin with various
dicarboxylic acids resulted in four new salts (3–6). When a solution of EFC in glacial acetic acid evaporated
to dryness over a period of time, crystals of 7 were
grown. Crystals of 8 were found to grow when EFC was
dissolved in liquid ammonia and solution was slowly evaporated at
room temperature (RT). All these products (1–8) were characterized by 1H and 13C
NMR spectroscopy, Fourier transform infrared (FTIR) spectroscopy,
differential scanning calorimetry (DSC) and powder X-ray diffraction
(PXRD). Single crystal X-ray diffraction study has indicated that
the products 3–6 had a cation of
enrofloxacin and an anion of the acid in common. Four of these eight
products have been found to contain water of crystallization. Three
of these salts were found to have one neutral acid molecule. The proton
transfer and hydrate stoichiometry were confirmed from single crystal
X-ray diffraction. Solubility of 1 and 3–6 was determined in water (pH = 6.8) using UV–vis
spectroscopy at RT. The alteration between the neutral, zwitterionic,
anionic and cationic forms EFC has led to very interesting structures
of these salt/cocrystals and also the pure forms (1 and 2).