Two Faces of Ciprofloxacin: Investigation of Proton Transfer in Solid State Transformations

Ciprofloxacin (CIP) can exist in two different forms: the zwitterion and the un-ionized form. While the crystal structure of each has been described independently, the ability of CIP to transform from one form to the other in the solid state has not been described. The crystal structures of un-ionized and zwitterionic CIP were therefore compared using computational methods, including their packing arrangement, hydrogen bonding, packing energy, intermolecular potentials, and highest occupied molecular orbital/lowest occupied molecular orbital energy gap. The pure amorphous form of CIP has also never been prepared or studied. Ball milling, cryomilling, and spray drying were used in this study to prepare partially and fully amorphous CIP for the first time. The physical characteristics were examined by powder X-ray diffraction, Fourier transform infrared spectroscopy, and differential scanning calorimetry. CIP proved to be very difficult to amorphize, and only spray drying in pure water resulted in a fully amorphous product. It was discovered that while most processing methods resulted in the more stable zwitterionic form of the drug, spray drying in an ethanol/water mixture produced the un-ionized form. The zwitterion was found to convert to the un-ionized form upon heating to its melting point, whereas the reverse transformation occurred when un-ionized CIP was exposed to high humidity. This study thus provides insight into the proton transfer which can occur in a zwitterionic drug in the solid state and the resultant changes to its crystal structure.