Three Polymorphic Forms of Ciprofloxacin Maleate: Formation Pathways, Crystal Structures, Calculations, and Thermodynamic Stability Aspects

Polymorphism of the pharmaceutical salt of ciprofloxacin with maleic acid has been investigated. Ciprofloxacin maleate was found to exist in three polymorphic forms and one hydrate. The formation pathways of the salt polymorphs were elucidated by using solvent screening of the mechanochemical synthesis. It has been found that the mechanochemical reaction of the salt formation consists of two steps, including the formation of a kinetic polymorph as a transitional stage and its conversion into a thermodynamically favorable form. The thermodynamic relationships between the polymorphs were rationalized based on solubility and solution calorimetry measurements. The pattern of intermolecular interactions and crystal lattice energies of the polymorphs were quantified by solid-state density functional theory followed by Bader analysis of periodic electron density.