Solid Forms of Ciprofloxacin Salicylate: Polymorphism, Formation Pathways, and Thermodynamic Stability

Abstract

The crystallization of ciprofloxacinan antibacterial fluoroquinolone compoundwith salicylic acid resulted in the isolation of five distinct solid forms of the drug, namely, an anhydrous salt, two polymorphic forms of the salt monohydrate, methanol and acetonitrile solvates, and the salt-cocrystal hydrate. The salicylate salts were investigated by different analytical techniques ranging from powder and single crystal X-ray diffractometry, differential scanning calorimetry, thermogravimetric analysis, variable temperature powder X-ray diffraction, dynamic vapor sorption analysis, dissolution, and solubility investigations. Real-time in situ Raman spectroscopy was used to investigate the mechanochemical formation pathways of the different solid polymorphs of ciprofloxacin salicylate. The mechanism of the phase transformation between the crystalline forms was evaluated under mechanochemical conditions. It was found that the formation pathway and kinetics of the grinding process depend on the form of the starting material and reaction conditions. The analysis of the solid-state thermal evolution of the hydrated salts revealed the two-step mechanism of dehydration process, which proceeds through a formation of the distinct intermediate crystalline products.

Ciprofloxacin salt and salt co-crystal with dihydroxybenzoic acids

“…Several crystal structures of ciprofloxacin salts with benzoic acid derivatives have been reported, including salts with salicylic acid (Surov et al, 2019;Nagalapalli & Yaga Bheem, 2014; CSD refcode family DOFWUT), 4-hydroxybenzoic acid (Surov et al, 2020; CSD refcode PUNMUJ), 4-aminobenzoic acid (Surov et al, 2020; CSD refcode PUNMIX) and gallic acid (Surov et al, 2020;CSD refcode PUNMOD). A search for salt co-crystals of ciprofloxacin hydrochloride yielded one reported crystal structure, a co-crystal of ciprofloxacin hydrochloride with 4-hydroxybenzoic acid (Martı ´nez-Alejo et al, 2014; CSD refcode XOHTUL).…”

Antimicrobial Activities of Highly Bioavailable Organic Salts and Ionic Liquids from Fluoroquinolones

“…The formation of organic salts based on cationic fluoroquinolones (mostly comprising ciprofloxacin (Cip), but also norfloxacin (Nor)) has been widely explored by the academic community by protonation of the drugs' amine group(s). More precisely, these fluoroquinolones have been combined with dicarboxylic acids (malonic and tartaric [31], adipic, fumaric [32] and maleic [33,34], succinic [35]), citric acid [32], saccharine [36,37] and acesulfame [36], as well as with other drugs (diflunisal and ibuprofen [38], salicylic [39] and barbituric acids [40]). Some works involve the combination of ciprofloxacin or enrofloxacin as cations and/or as anions with amino acids [41] and ionic polymers [42,43].…”

Fluoroquinolone-Based Organic Salts and Ionic Liquids as Highly Bioavailable Broad-Spectrum Antimicrobials

“…The formation of organic salts based on cationic fluoroquinolones (mostly comprising ciprofloxacin (Cip), but also norfloxacin (Nor)) has been widely explored by the academic community by protonation of drugs' amine group(s). More precisely, these fluoroquinolones have been combined with several dicarboxylic acids [17][18][19][20][21], citric acid [17], as well as with other drugs [22][23][24] in order to assess bioavailability, crystallinity/amorphous profiles and thermodynamic stability. Some works involve the combination of ciprofloxacin or enrofloxacin as cations and/or as anions, by combination with amino acids [25] and ionic polymers [26,27] have indeed presented for the first time enhanced antimicrobial activity of the salts in comparison with the parent drugs, in particular against Gramnegative bacteria strains.…”