Phase transition and solubility of levofloxacin crystal forms: anhydrates versus hydrates

Levofloxacin (LF), a pure levo-isomer of ofloxacin, is a quinolone-class antibiotic marketed in its hemihydrate (LF-½H) crystal form. Another LF hydrate is known as monohydrate (LF-1H), and LF-½H and LF-1H dehydration results in a pair of anhydrous polymorphs: LF- γ (from LF-½H) and LF- α (from LF-1H). Herein, a pure crystalline material of each of these four LF crystal forms has been successfully produced and systematically characterized by X-ray powder diffraction (PXRD), infrared attenuated total reflectance spectroscopy, differential scanning calorimetry (DSC) and thermogravimetric analyses. Coupling cyclic DSC and ex-situ PXRD analyses allowed probing dehydration, melting, crystallization and polymorphic phase transitions involving LF-½H, LF-1H, LF- α , LF- γ , and LF- δ (an enantiotropic polymorph of LF- γ ). Furthermore, for the first time, the LF-½H, LF-1H, LF- γ and LF- α equilibrium solubilities were individually measured in five different aqueous media (pH from 1.0 to 7.2). The general solubility order is: LF- γ > LF-½H = LF- α > LF-1H. The crystal phases identified in the residual solid materials separated from equilibrium solutions show that LF-½H and LF- α forms in converted to LF-1H. The information provided herein about stability and solubility of known LF crystal forms proved to be essential to control the hydration/dehydration/rehydration process between the LF crystalline phases and ensure safe drugs with low toxicity or design LF solids with properties improved physical chemistry. Graphical Abstract