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. 2024 Sep 9;16(9):1190.
doi: 10.3390/pharmaceutics16091190.

Binary and Ternary Inclusion Complexes of Niflumic Acid: Synthesis, Characterization, and Dissolution Profile

Zohra Bouchekhou  1 , Amel Hadj Ziane-Zafour  1 , Florentina Geanina Lupascu  2 , Bianca-Ștefania Profire  3 , Alina Nicolescu  4 , Denisse-Iulia Bostiog  4 , Florica Doroftei  4 , Ioan-Andrei Dascalu  4 , Cristian-Dragoș Varganici  4 , Mariana Pinteala  4 , Lenuta Profire  2 , Tudor Pinteala  5 , Bachir Bouzid  1
Affiliations

Binary and Ternary Inclusion Complexes of Niflumic Acid: Synthesis, Characterization, and Dissolution Profile

Zohra Bouchekhou et al. Pharmaceutics. .

Abstract

Although niflumic acid (NA) is one of the most used non-steroidal anti-inflammatory drugs, it suffers from poor solubility, low bioavailability, and significant adverse effects. To address these limitations, the complexation of NA with cyclodextrins (CDs) is a promising strategy. However, complexing CDs with low molecular weight drugs like NA can lead to low CE. This study explores the development of inclusion complexes of NA with 2-hydroxypropyl-β-cyclodextrin (2HP-β-CD), including the effect of converting NA to its sodium salt (NAs) and adding hydroxypropyl methylcellulose (HPMC) on complex formation. Inclusion complexes were prepared using co-evaporation solvent and freeze-drying methods, and their CE and Ks were determined through a phase solubility study. The complexes were characterized using physicochemical analyses, including FT-IR, DSC, SEM, XRD, DLS, UV-Vis, 1H-NMR, and 1H-ROESY. The dissolution profiles of the complexes were also evaluated. The analyses confirmed complex formation for all systems, demonstrating drug-cyclodextrin interactions, amorphous drug states, morphological changes, and improved solubility and dissolution profiles. The NAs-2HP-β-CD-HPMC complex exhibited the highest CE and Ks values, a 1:1 host-guest molar ratio, and the best dissolution profile. The results indicate that the NAs-2HP-β-CD-HPMC complex has potential for delivering NA, which might enhance its therapeutic effectiveness and minimize side effects.

Keywords: 2-hydroxypropyl-β-cyclodextrin; complexation efficiency; dissolution profile; drug delivery; inclusion complex; niflumic acid; solubility.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Phase solubility diagrams of the binary (NA/NAs-2HP-β-CD) and ternary (NA/NAs-2HP-β-CD-HPMC) systems. The lines represent the best-fit linear regression of the data points (n = 3, coefficient of variation < 3%, error bars not shown for clarity).
Figure 2
Figure 2
FT-IR spectra of NA, 2HP-β-CD, HPMC, binary (NA-2HP-β-CD), and ternary (NA/NAs-2HP-β-CD-HPMC) systems.
Figure 3
Figure 3
DSC curves of the studied structures: NA (a); NA-2HP-β-CD (b); HPMC (c) (first heating); 2HP-β-CD (d); NA-2HP-β-CD-HPMC (e); NAs-2HP-β-CD-HPMC (f); HPMC (g) (second heating); NA-2HP-β-CD-HPMC (h) (second heating); and NAs-2HP-β-CD-HPMC (i) (second heating).
Figure 4
Figure 4
SEM micrographs of NA (a), 2HP-β-CD (b), HPMC (c), NA-2HP-β-CD (d), NA-2HP-β-CD-HPMC (e), and NAs-2HP-β-CD-HPMC (f).
Figure 5
Figure 5
XRD patterns of NA, 2HP-β-CD, HPMC, NA-2HP-β-CD, NA-2HP-β-CD-HPMC, and NAs-2HP-β-CD-HPMC.
Figure 6
Figure 6
The hydrodynamic diameter (Dh) of 2HP-β-CD (a), NA-2HP-β-CD-HPMC (b), NA-2HP-β-CD (c), NAs-2HP-β-CD-HPMC (d), NA (e), and HPMC (f).
Figure 7
Figure 7
1H NMR spectra of NA (a), 2HP-β-CD (b), NA-2HP-β-CD (c), NA-2HP-β-CD-HPMC (d), and NAs-2HP-β-CD-HPMC (e).
Figure 7
Figure 7
1H NMR spectra of NA (a), 2HP-β-CD (b), NA-2HP-β-CD (c), NA-2HP-β-CD-HPMC (d), and NAs-2HP-β-CD-HPMC (e).
Figure 8
Figure 8
Two-dimensional ROSY spectra of NA-2HP-β-CD (a), NA-2HP-β-CD HPMC (b), and NAs-2HP-β-CD-HPMC (c).
Figure 8
Figure 8
Two-dimensional ROSY spectra of NA-2HP-β-CD (a), NA-2HP-β-CD HPMC (b), and NAs-2HP-β-CD-HPMC (c).
Figure 9
Figure 9
Dissolution profiles of NA, NAs, NA-2HP-β-CD, NA-2HP-β-CD-HPMC, and NAs-2HP-β-CD-HPMC (n = 3, coefficient of variation < 3%, error bars not shown for clarity).
Figure 10
Figure 10
Linear fitting of the mathematical models applied for the drug release: zero-order model (a); first-order model (b); Higuchi model (c); Hixson–Crowell model (d); and Korsmeyer–Peppas model (e).
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