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. 2022 May 4;22(5):3060-3071.
doi: 10.1021/acs.cgd.1c01509. Epub 2022 Apr 11.

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

Ciaran O'Malley  1 , Patrick McArdle  1 , Andrea Erxleben  1   2
Affiliations

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

Ciaran O'Malley et al. Cryst Growth Des. .

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-, A2 +B2-, A2 +B2-B, and A+B-A. Depending on the solvent, different stoichiomorphs, solvates, or polymorphs were obtained. All salts and cocrystals contain the robust R2NH2 +...-OOC or R3NH+...-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.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Structures of the fluoroquinolone antibiotics and dicarboxylic acids used in this study.
Figure 2
Figure 2
(a) R2NH2+...–OOC, (b) R2NH2+...O=C(OH)R, and (c) R2NH...O=C(OH)R synthons in the supramolecular salts of nor, cip, and enro described in this study.
Figure 3
Figure 3
Hydrogen-bonding motifs in (a) (cip+)(glu–), (b) (cip+)(az–)·CH3CN, (c) (enro+)(az–), and (d) (enro+)(pim–)·H2O. Solvent molecules of crystallization in (cip+)(az–)·CH3CN is omitted for clarity.
Figure 4
Figure 4
Hydrogen-bonding motifs in (a) (nor+)(pim–), (b) (nor+)(pim–)·CH3OH, (c) (nor+)(sub–), and (d) (nor+)(sub–)·3H2O. The colors in panels (a) and (b) indicate crystallographically independent cations and anions.
Figure 5
Figure 5
Hydrogen-bonding motif in (enro+)(pim–)·3H2O.
Figure 6
Figure 6
Hydrogen-bonding motifs in (a) (cip+)2(pim2–)·H2O, (b) (nor+)2(pim2–)·C2H5OH, (c) (cip+)2(sub2–)·H2O, and (d) (nor+)2(sub2–)·CH3OH. For clarity, only one component of the disordered pim– in (nor+)2(pim–)·C2H5OH and only components A and B of (nor+)2(sub2–)·CH3OH are shown. The water of crystallization is omitted in panel (a).
Figure 7
Figure 7
Hydrogen-bonding motifs in (a) (nor+)2(glu2–)·H2O·CH3OH, (b) (nor+)2(glu2–)·H2O·0.75CH3CN, (c) (nor+)2(adi2–)·2H2O form I, and (d) (nor+)2(adi2–)·2H2O form II. For clarity, only one component of the disordered glu2– in (nor+)2(glu2–)·H2O·CH3OH and only two of the four crystallographically independent nor+ ions and one of two crystallographically independent glu2– ions of (nor+)2(glu2–)·H2O·0.75CH3CN are shown. Water and solvent molecules of crystallization are not shown in panels (a) and (b).
Figure 8
Figure 8
Hydrogen-bonding motifs in (a) (enro+)2(adi2–)·adi·CH3CN, (b) (nor+)2(az2–)·az·4H2O: red, nor+ A; blue, nor+ B; green, az2–; and purple, az; and (c) (nor+)(seb–)·nor·H2O: red, nor+; blue, nor. Solvent molecules of crystallization are not shown in panel (a).
Figure 9
Figure 9
(a) Gel formation of nor/az/propylene glycol. (b) Plot of Tgel (°C) vs gelator concentration (wt %) for cip/sub/propylene glycol (solid squares), nor/az/propylene glycol (solid diamonds), enro/sub/propylene glycol (solid triangles) and enro/sub/H2O (open triangles).
Figure 10
Figure 10
(a) Scanning electron microscopic image of the enro/sub/propylene glycol xerogel. (b) Single crystal of (enro+)(sub–)·H2O indexed on the diffractometer. (c) Unit cell diagram of (enro+)(sub–)·H2O.
See this image and copyright information in PMC

References

    1. Prabodh Chander S.; Ankit J.; Sander J. Fluoroquinolone antibacterials: a review on chemistry, microbiology and therapeutic prospects. Acta Pol. Pharm. 2009, 66, 587–604. - PubMed
    1. Van Bambeke F.; Michot J. M.; Van Eldere J.; Tulkens P. M. Quinolones in 2005: an update. Clin. Microbiol. Infect. 2005, 11, 256–280. 10.1111/j.1469-0691.2005.01131.x. - DOI - PubMed
    1. Escribano E.; Calpena A. C.; Garrigues T. M.; Freixas J.; Domenech J.; Moreno J. Structure-absorption relationships of a series of 6-fluoroquinolones. Antimicrob. Agents Chemother. 1997, 41, 1996–2000. 10.1128/AAC.41.9.1996. - DOI - PMC - PubMed
    1. Pudipeddi M.; Serajuddin A. T. M.; Grant D. J. W.; Stahl P. H.. Handbook of Pharmaceutical Salts, Properties, Selection and Use; Stahl P. H.; Wermuth C. G., Eds.; Wiley-VCH: Weinheim, 2002; pp 19–40.
    1. Romañuk C. B.; Manzo R. H.; Linck Y. G.; Chattah A. K.; Monti G. A.; Olivera M. E. Characterization of the solubility and solid-state properties of saccharin salts of fluoroquinolones. J. Pharm. Sci. 2009, 98, 3788–3801. 10.1002/jps.21688. - DOI - PubMed