Formation of Salts and Molecular Ionic Cocrystals of Fluoroquinolones and α,ω-Dicarboxylic Acids

Abstract

The cocrystallization of the fluoroquinolones ciprofloxacin (cip), norfloxacin (nor), and enrofloxacin (enro) with the α,ω-dicarboxylic acids glutaric acid (glu), adipic acid (adi), pimelic acid (pim), suberic acid (sub), azeliac acid (az), and sebacic acid (seb) resulted in 27 new molecular salts and ternary molecular ionic cocrystals of compositions A + B − , A 2 + B 2− , A 2 + B 2− B, and A + B − A. Depending on the solvent, different stoichiomorphs, solvates, or polymorphs were obtained. All salts and cocrystals contain the robust R 2 NH 2 +...− OOC or R 3 NH +...− OOC synthon but have different supramolecular ring motifs. Moderate solubility enhancements over the parent fluoroquinolones were observed. Salts in the ratio of 1:1 and 2:1 were also prepared by ball-milling. The milled sample nor/az (1:1) was shown to gel the GRAS (generally recognized as safe) solvent propylene glycol, and enro/sub (1:1) was shown to gel both propylene glycol and water. Dynamic rheology measurements confirmed that nor/az and enro/sub behave like viscoelastic materials and supramolecular gels.

The Benefits and Challenges of Antibiotics–Non-Steroidal Anti-Inflammatory Drugs Non-Covalent Reaction

“…Both ionic and non-ionic reactions of the fluoroquinolone group, i.e., ciprofloxacin and levofloxacin, with some substituents increase the solubility of these compounds [6,9], as well as showing increased stability towards humidity and light, which is the main advantage of these systems. For example, the combination of levofloxacin-citric acid [6] and levofloxacin-dihydroxybenzoic acid [7], and ciprofloxacin with cyclodextrin and cucurbit (7)-uril (CB7) improves photostability up to three-fold [27].…”

“…The first and crucial step in creating multi-component structures is determining the coformer or stoichiometric ratio. Once this is established, appropriate methods can be used to react with the components, including slow evaporation, fast evaporation, neat grinding, liquid-assisted grinding, slurry, and co-precipitation [9][10][11]. Additionally, greener methods are currently available, such as hot melt extrusion (HME) [12], supercritical carbon dioxide [13], sonication slurry technique [14], sublimation [15], and microwaving [16,17].…”

Pharmaceutical cocrystal of antibiotic drugs: A comprehensive review

“…Recently, two ternary molecular ionic cocrystals (salt cocrystals) have been reported by O'Malley et al. [ 35 ] the detailed structure is shown in Figure 3 (2 and 3). Using azeliac acid (az) and sebacic acid (seb) as coformers yielded (nor + ) 2 (az 2− )·az·4H 2 O and (nor + ) (seb − )·nor·H 2 O.…”

“…(2) (nor + ) 2 (az 2− )·az·4H 2 O: red, nor + A; blue, nor + B; green, az 2− ; and purple, az; and (3) (nor + ) (seb − )·nor·H 2 O: red, nor + ; blue, nor; green, H 2 O. Adapted from [ 35 ]. …”

Multicomponent solid forms of antibiotic cephalexin towards improved chemical stability

“…10 Although multicomponent solids like cocrystals are in high trend in tuning the solubility/permeability of zwitterionic drugs (e.g. norfloxacin, ciprofloxacin, sparfloxacin), 11,12 their application towards chemical stability in aqueous medium is comparatively less studied in the literature. Chemically stable drug molecules in the biological pH medium generally maintain a long shelf life and bioavailability.…”