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

Abstract

Ciprofloxacin (CIP) can exist in two different forms: the zwitterion and the unionized form. While the crystal structure of each has been described independently, the ability of CIP to transform from one to the other in the solid state has not been described. The crystal structures of unionized and zwitterionic CIP were therefore compared using computational methods, including their packing arrangement, hydrogen bonding, packing energy, intermolecular potentials and HOMO/LUMO 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 PXRD, FTIR and DSC. 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 unionized form. The zwitterion was found to convert to the unionized form upon heating to its melting point, whereas the reverse transformation occurred when unionized 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. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 3 Abstract Ciprofloxacin (CIP) can exist in two different forms: the zwitterion and the unionized form.While the crystal structure of each has been described independently, the ability of CIP to transform from one to the other in the solid state has not been described. The crystal structures of unionized and zwitterionic CIP were therefore compared using computational methods, including their packing arrangement, hydrogen bonding, packing energy, intermolecular potentials and HOMO/LUMO energy gap. The pure amorphous form of this drug 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, and in particular ionization state, of these samples were examined by PXRD, FTIR and DSC. Analysis of the crystal packing of unionized and zwitterionic CIP revealed that the presence of ionic interactions between the charged groups of the latter results in a denser and more stable crystal lattice. A greater HOMO/LUMO energy gap was also calculated for this sample, confirming its lower reactivity. CIP proved to be very difficult to amo...

Generation of High Dose Inhalable Effervescent Dispersions against Pseudomonas aeruginosa Biofilms

“…As can be seen in Fig. 6, the results showed, in agreement with previous studies, stretching of the carboxyl group in CFX is missing in the region of 1710 cm −1 (23,24). It was suggested that a "betainelike structure" exists where electronic effects become more profound leading to the formation of a zwitterion, on the carboxyl (COOH).…”

Diversity of crystal structures and physicochemical properties of ciprofloxacin and norfloxacin salts with fumaric acid

“…8. as the critical water activity (a c w ). Since K h is known at a particular temperature, the standard free-energy change for the hydration reaction can be calculated using the following expression: (5) In order to establish the thermodynamic stability ranges of the different crystalline forms of ciprofloxacin and norfloxacin fumarates, solubility experiments in water/methanol mixtures of various compositions were performed. The details of the experimental procedure are provided in the Materials and methods section.…”

“…It was recently demonstrated that the solubility of pure CIP is determined by solid-state issues, since the zwitterionic molecules in their crystal form are held together by strong dipole-dipole interactions. 5 Salt formation changes the state of CIP molecules in their crystal form from zwitterionic to cationic, effectively reducing the lattice energy and improving aqueous solubility. 6 Therefore, a number of efforts have been made to extend the range of fluoroquinolone solid forms and to modify the poor solubility performance of CIP and NFX through salt preparation with different organic acids, including aliphatic [7][8][9][10][11][12] and aromatic carboxylic acids, [13][14][15][16] derivatives of sulfonic acids, and artificial sugars.…”

Polymer/Amorphous Salt Solid Dispersions of Ciprofloxacin

“…respectively. In addition to water loss, TGA analysis also showed that all of the samples undergo significant thermal degradation above ~200 o C. Similar levels of degradation were seen with binary polymeric CIP ASDs (12), and the pure drug is also known to decompose upon melting (2). The thermograms of each of the amorphous samples contained broad endotherms above 180 o C due to melting accompanied by decomposition (Figure 3).…”

“…These oppositely charged groups interact to form chains of molecules, resulting in a strong crystal lattice. CIP therefore exhibits solid-state limited solubility (2). CIP also largely exists in the zwitterionic form in neutral media, with an overall neutral charge, which contributes to its low solubility.…”