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. 2023 Feb 7;24(4):3305.
doi: 10.3390/ijms24043305.

Enhanced NSAIDs Solubility in Drug-Drug Formulations with Ciprofloxacin

Francisco Javier Acebedo-Martínez  1 , Alicia Domínguez-Martín  2 , Carolina Alarcón-Payer  3 , Alejandro Sevillano-Páez  1   2 , Cristóbal Verdugo-Escamilla  1 , Josefa María González-Pérez  2 , Fernando Martínez-Checa  4   5 , Duane Choquesillo-Lazarte  1
Affiliations

Enhanced NSAIDs Solubility in Drug-Drug Formulations with Ciprofloxacin

Francisco Javier Acebedo-Martínez et al. Int J Mol Sci. .

Abstract

Drug-drug salts are a kind of pharmaceutical multicomponent solid in which the two co-existing components are active pharmaceutical ingredients (APIs) in their ionized forms. This novel approach has attracted great interest in the pharmaceutical industry since it not only allows concomitant formulations but also has proved potential to improve the pharmacokinetics of the involved APIs. This is especially interesting for those APIs that have relevant dose-dependent secondary effects, such as non-steroidal anti-inflammatory drugs (NSAIDs). In this work, six multidrug salts involving six different NSAIDs and the antibiotic ciprofloxacin are reported. The novel solids were synthesized using mechanochemical methods and comprehensively characterized in the solid state. Moreover, solubility and stability studies, as well as bacterial inhibition assays, were performed. Our results suggest that our drug-drug formulations enhanced the solubility of NSAIDs without affecting the antibiotic efficacy.

Keywords: NSAIDs; ciprofloxacin; crystal engineering; mechanochemistry; molecular salts.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Scheme 1
Scheme 1
Chemical formulas for mefenamic acid (MEF), tolfenamic acid (TLF), dexketoprofen (DKT), ketoprofen (KET), diclofenac (DIC), sulindac (SLD), and ciprofloxacin (CIP).
Figure 1
Figure 1
Powder X-ray diffraction (PXRD) patterns for CIP and the new solid forms reported in this work.
Figure 2
Figure 2
(a) Fragment of the infinite CIP column built from π–π stacking interactions. (b) A pair of stacked CIP–CIP cations surrounded by NSAID (KET) cations.
Figure 3
Figure 3
Detailed view of the packing arrangement of CIP cations (green) and MEF anions (blue) in the crystal structure of CIP–MEF.
Figure 4
Figure 4
Channels in the crystal structure of CIP–MEF·H2O along the b-axis (a) and a-axis (b) directions mapped with the Voids tool in Mercury [48].
Figure 5
Figure 5
Detailed view of the packing arrangements for (a) CIP–MEF·H2O and (b) CIP–TLF. Green, CIP cations; blue, MEF and TLF anions; red, water molecules.
Figure 6
Figure 6
(a) Detailed view of the ribbon structure in the molecular salt CIP–SLD. (b) Packing arrangement of CIP cations (blue) and SLD anions (green) in the crystal structure of CIP–SLD.
Figure 7
Figure 7
Detailed view of the packing arrangement of CIP cations (red) and DIC anions (blue), forming a grid in the crystal structure of CIP–DIC (neutral DIC molecules in green).
Figure 8
Figure 8
Detailed view of the packing arrangements for (a) CIP–KET (CIP cations in green, KET anions in blue) and (b) CIP–DKT (CIP cations in green and blue, DKT anions in red and yellow).
Figure 9
Figure 9
DSC traces for the pure molecular salts and the melting point of the CIP drug [51] (black dotted line).
Figure 10
Figure 10
Antibiogram of CIP and the reported molecular salts tested against S. Aureus and E. Coli.
See this image and copyright information in PMC

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