On Complex Formation between 5-Fluorouracil and β-Cyclodextrin in Solution and in the Solid State: IR Markers and Detection of Short-Lived Complexes by Diffusion NMR

Abstract

In this work, the nuclear magnetic resonance (NMR) and IR spectroscopic markers of the complexation between 5-fluorouracil (5-FU) and β-cyclodextrin (β-CD) in solid state and in aqueous solution are investigated. In the attenuated total reflectance(ATR) spectra of 5-FU/β-CD products obtained by physical mixing, kneading and co-precipitation, we have identified the two most promising marker bands that could be used to detect complex formations: the C=O and C-F stretching bands of 5-FU that experience a blue shift by ca. 8 and 2 cm–1 upon complexation. The aqueous solutions were studied by NMR spectroscopy. As routine NMR spectra did not show any signs of complexation, we have analyzed the diffusion attenuation of spin–echo signals and the dependence of the population factor of slowly diffusing components on the diffusion time (diffusion NMR of pulsed-field gradient (PFG) NMR). The analysis has revealed that, at each moment, ~60% of 5-FU molecules form a complex with β-CD and its lifetime is ca. 13.5 ms. It is likely to be an inclusion complex, judging from the independence of the diffusion coefficient of β-CD on complexation. The obtained results could be important for future attempts of finding better methods of targeted anticancer drug delivery.

Weak complexation of 5-fluorouracil with β-cyclodextrin, carbonate, and dianhydride crosslinked β-cyclodextrin: in vitro and in silico studies

“…Except for the DPC-NS4, all the recorded NMR spectra did not show any significant chemical shift changes from that of 5-FU indicating no complexation with 5-FU. In a recently published study by Melnikova et al, no evidence of complexation was observed between 5-FU and β-cyclodextrin using 1H NMR data ( 29 ).…”

“…The formulated complexes enhanced the therapeutic efficacy of 5-FU by inhibiting the cell growth of different cell lines ( 31 ). In contrast, a recent study has shown the development of a 5-FU complex with cyclodextrin polymer in an aqueous solution and suggested the formation of an unstable inclusion complex ( 29 ). Moreover, a recent study suggested that cyclodextrin-based nanosponge formulations may be a promising technique for the delivery of 5-FU ( 32 ).…”

“…The drug release experiments results did not show significant changes in 5-FU release between the prepared nanosponges, 5-FU-β-cyclodextrin, and raw 5-FU. This can be attributed to the low stability of the 5-FU formed a complex with β-cyclodextrin polymer and the recently reported short lifetime of the formed complex (13.5 ms) ( 29 ). The initial rate of 5-FU release calculated in the first 30 min was 1.79 ± 0.13, compared to 2.21 ± 0.087, 1.84 ± 0.15, 2.23 ± 0.1, and 2.49 ± 0.2 for 5-FU-β-cyclodextrin complex, NS4, DPC-NS8, and EDTA-NS8, respectively.…”

“…Such instability was observed by Melnikova et al . who reported short-term stability of the formed complex with a lifetime of 13.5 ms ( 29 ).…”

Solid State NMR for Nonexperts: An Overview of Simple but General Practical Methods

“…Many of these techniques are easy to implement as well. When done correctly, NMR can provide truly unique information [2][3][4][5]. The same is with solid state NMR.…”