A Twist in Cocrystals of Salts: Changes in Packing
and Chloride Coordination Lead to Opposite Trends in the Biopharmaceutical
Performance of Fluoroquinolone Hydrochloride Cocrystals
posted on 2014-06-04, 00:00authored byJuan M. Martínez-Alejo, Jorge G. Domínguez-Chávez, Jesús Rivera-Islas, Dea Herrera-Ruiz, Herbert Höpfl, Hugo Morales-Rojas, Juan P. Senosiain
Fluoroquinolones are extensively
used antibiotics that are generally
prescribed as hydrochloride salts because the neutral forms display
low solubility due to their zwitterionic character. Starting from
the hydrochloride salts of ciprofloxacin (CiHCl) or (S,S)-moxifloxacin (MoHCl) and 4-hydroxybenzoic acid
(4HBA) as a cocrystal former, two cocrystalline solids, CiHCl–4HBA
and MoHCl–4HBA, were obtained in a salt/coformer stoichiometric
ratio of 1:1. The cocrystalline phases were identified by X-ray powder
diffraction analysis and further characterized by IR spectroscopy,
thermogravimetric analysis-differential scanning calorimetry, and
single crystal X-ray diffraction analysis. The novel solid phases
could be formed using different methodologies, namely, solution-mediated
phase transformation, solvent drop grinding, crystallization by solvent
evaporation, and reaction crystallization. Pharmaceutically relevant
properties such as phase stability, thermodynamic solubility, and
dissolution rate were examined. All cocrystalline phases remained
stable when suspended in acidic aqueous solutions and did not transform
upon accelerated temperature/relative humidity exposition for 30 days.
Interestingly, opposite trends in the thermal stability, solubility,
and dissolution rate of the cocrystals were exhibited by the different
fluoroquinolones in comparison to the parent starting salts. Upon
heating, the CiHCl–4HBA cocrystal releases first the coformer
before decomposing and displayed a lower solubility and dissolution
rate in comparison to CiHCl·1.34H2O. By contrast,
the MoHCl–4HBA cocrystal melts in a single-phase transition
process and showed enhanced solubility and dissolution rate when compared
to the parent moxifloxacin salt. The similar composition of the cocrystals
and the structural resemblance of the fluoroquinolones examined herein
allowed for a detailed vis-à-vis comparison between the supramolecular
structures in the solid-state and the physicochemical properties.
The incorporation of 4HBA in the crystal lattice caused changes in
the number, type, and strength of the intermolecular interactions
between the ionic components (chloride and fluoroquinolinium cations),
which could be related to the solubility and dissolution rate properties.
While the cocrystal CiHCl–4HBA retained essential features
of the supramolecular assembly found also for the starting hydrochloride
and gave an overall three-dimensional hydrogen bonded network with
the cocrystal former, MoHCl–4HBA showed a singular two-dimensional
assembly, with linear chains formed between the 4HBA molecules and
chloride ions through O–H···Cl–···H–O hydrogen bonds in place of the usual
charged-assisted N+–H···Cl– interactions.