The polymorphic and pseudopolymorphic behaviour of gatifloxacin crystal modifications / Zak Perold
Objective: Gatifloxacin is a broad-spectrum fluoroquinolone antibacterial agent that exhibits polymorphism. There was however little information available regarding the pbysico-chemical properties of the different forms. This study was conducted to classify the gatifloxacin crystal modifications, to identify possible new forms and to investigate the physico-chemical properties thereof. Methods: Various characterisation methods were used that included X-ray powder diffraction (XRPD), variable temperature X-ray powder diffraction (VT-XRPD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), infrared spectrometry, hot-stage microscopy (HSM), scanning electron microscopy (SEM) and Karl-Fischer moisture determination (KF). Solubility and dissolution studies were also conducted. Results: The results obtained made it possible to identify and characterise 5 possibly new forms of gatifloxacin: ZPO (mono-ethanol solvate), ZP1 (sesqui-butanol solvate), ZP2 (hemi-ethyl acetate solvate), ZP3 (sesquihydrate) and ZP4 (anhydrous form). Previously described crystal forms (form J, form I anhydrous and form CJ were identified and fully characterised in this study. Isomorphism was identified for form ZPO. Contrary to the literature form J (from THF recrystallisation) did not produce a THF solvate, but rather a sesquihydrated form. It was found that form Ω was the product from the desolvation/dehydration of either form ZP1 or ZP2. Since ZP1 and ZP2 arc new forms, the drying of these forms poses new methods to produce form ΩThe dehydration behaviour of the commercial sesquihydrate (form H4) revealed that the dehydration activation energy (E,) varied throughout the dehydration process. Solubility testing of the various crystal forms revealed that some forms (ZP3, I, nand an anhydrous form from gatifloxacin sesquihydrate) were more soluble than the commercial sesquihydrated form. Dissolution testing revealed that ZP1, ZP3 and 0 have similar dissolution profiles to that of the commercial sesquihydrate. Using different water:ethanol mixtures, it was possible to investigate the influence of water on the recrystallisation outcome using ethanol. It was observed that ethanol (99- 100%) produced a mono-ethanol solvate, ethanol (95%) produced a mono-ethanolhemihydrate, ethano1:water (75:25) produced a hemi-ethanol-sesquihydrate and ethanol in concentrations 50% vlv produced sesquihydrated forms. This made it possible to state that water content, however small, influences the product when present in so-called water-free solvents. Conclusion: Gatifloxacin crystallises in a variety of crystal modifications that differ in physico-chemical properties. Five new forms were identified and characterised.
- ETD@PUK