Thermodynamics and molecular insight in guest–host complexes of fluoroquinolones with β-cyclodextrin derivatives, as revealed by ATR-FTIR spectroscopy and molecular modeling experiments

Abstract

β-Сyclodextrin (CD) is a perspective class of excipients used in pharmaceutical formulations to enhance solubility, bioavailability, and pharmacokinetics of various poorly soluble drugs, forming a non-covalent guest-host complex. However, the development of such formulations is usually a very laborious and time-consuming process due to lack of appropriate analytical tools to directly track and study the detailed molecular mechanism of such complex formation. Here, using guest-host complexes of fluoroquinolones (FQ) with CDs, as an example, we demonstrate the utility of ATR-FTIR to determine the thermodynamic stability, as well as structural features associated with complex formation, including involvement of certain functional groups. Furthermore, varying the CD's side groups, we were able to tailor the CD's geometry and binding surface to make FQ-CD interactions strong enough to potentially affect its pharmacokinetics and justify development of a new sustained-release drug formulation (dissociation constant decreased from 5 * 10 M to 10 M). 3D molecular modeling with energy optimization supports the findings and conclusions made on the basis of ATR-FTIR data analysis and explains the observed difference in dissociation constants.

Spectroscopy Approach for Highly-Efficient Screening of Lectin-Ligand Interactions in Application for Mannose Receptor and Molecular Containers for Antibacterial Drugs

“…The studied conjugates are also able to effectively incorporate drugs. The dissociation constants of Lev –HPCD-spermine-Man- 2 are about 320 μM (three times better than a simple HPCD [ 70 ]) with the simultaneous increased capacity of the drug. The cyclodextrin conjugate with a heavy PEI of 35 kDa ( Figure S3 ) retains up to 40–50 levofloxacin molecules ( K d ≈ 21 μM—more affine than spermine’s conjugate) presumably to a greater extent due to their interaction with polymer chains.…”

“…The shift of this peak to the region of low wave numbers corresponds to the interaction of Lev with spermine ( Figure S18 ). An increase in intensity of the peak of aromatic C-N bonds at 1398 cm −1 is due to the effects of the polymer chains , because formation of “guest-host” complexes Lev with monomeric CD, in contrast, resulted in decreasing of intensity ( Figure S19 ) [ 70 , 71 ].…”

“…At the same time, the maximum in the spectra of Lev shifts less—up to 1619 cm −1 . It is known that Lev is included in the CD’s cavity from the side of the carboxyl group [ 43 , 70 ], but only in a protonated form, which is accompanied by the disappearance of a peak at 1580 cm −1 corresponding to COO – due to protonation and immersion in the top of the CD [ 43 , 70 ]. We have discovered the fact that the aromatic peak (C–C 1474 cm −1 ) in solid-phase spectra is very sensitive to the microenvironment of levofloxacin, with a separation into two components.…”

Effect of Methyl-β-Cyclodextrin on the Interaction of Fluoroquinolones with Human Serum Albumin

“…CDs and their derivatives are of great interest to the pharmaceutical industry. They help to increase the solubility [6,7], bioavailability and stability of drugs, reduce toxicity, and allow varying the pharmacokinetic properties of biologically active molecules [1,8]. Despite the widespread use of drug formulations based on CDs, the interaction of complexes with biological substances requires more detailed consideration.…”

Molecular Assembly between Weak Crosslinking Cyclodextrin Polymer and trans-Cinnamaldehyde for Corrosion Inhibition towards Mild Steel in 3.5% NaCl Solution: Experimental and Theoretical Studies

“…For instance, the characteristic peak (3385 cm −1 ) belonging to β-CD is found in Figure 3c; whilst the characteristic peaks of CA (3028, 1678 and 1495 cm −1 ) are also observed in this spectrum. The spectrum of SCDP/CA assembly denoted in Figure 3d is akin to that of β-CD due to its higher molecular weight compared with CA [32,33]. It is worth further attention that the peak (1651 cm −1 , Figure 3a) assigned to bound water in the interior of the β-CD cavity vanishes in the spectrum of SCDP/CA assembly.…”