NMR Study of the Association of Propofol with Nonionic Surfactants

Abstract

The general anesthetic 2,6-diisopropylphenol (propofol) is very poorly soluble in water and is normally administered in the form of an emulsion. We demonstrated that several commercially available nonionic surfactants (Tween 80, Cremophor EL, Poloxamer 188, Poloxamer 407, Solutol HS15, and Vitamin E TPGS) render propofol soluble with a specific solubilization capacity of at least 0.1 g/g. The room-temperature stability of the solutions appeared to be limited only by the chemical stability of the compounds involved. The association between propofol and the surfactants was investigated by various NMR approaches, including measurements of diffusion coefficients, 1 H longitudinal relaxation times, and the magnitude of intermolecular nuclear Overhauser effects. The results were consistent with the micellar solubilization mechanism of propofol by the surfactants (unimer solubilization in the case of Poloxamer 188). The 1 H longitudinal relaxation and diffusion behavior of propofol were monoexponential in each case. Solubilization caused a considerable shortening of propofol's proton T 1's. The values of the diffusion coefficient of propofol were several percent higher than those of surfactants. This was explained by the partitioning of propofol between swollen micelles and the aqueous solution. Diffusion measurements also revealed the presence of a rapidly diffusing ethylene oxide population in surfactant solutions, which is consistent with free poly(ethylene oxide) (PEO) known to be present in commercially produced surfactants. The free PEO blocks exhibited molecular association with the extramicellar propofol.

Structural and dynamic properties of polyoxyethylene sorbitan monooleate micelle in water dispersion studied by pulsed field gradient NMR

“…These R m values are typical for the nonionic surfactant aqueous solutions. The value of micelle sizes obtained in our investigation is close to the micelle sizes obtained by other technique [2,18,26]. These results show that it is possible to estimate the micellar size and to observe the micellar aggregation from the self-diffusion coefficient of molecules obtained by PFG NMR.…”

“…These values of the restriction size were much greater than the actual size of the surfactant micelle, which is about 10 nm [1,2,9,18]. This restriction size indicates the biological cell size with a permeable membrane [12,13].…”

“…3, curves 1-4). It may be concluded that the slow self-diffusion belongs mainly to POE-SMO micelles, which form micelles at the concentration range of 100-300 mM [18]. The ratio of self-diffusion coefficients Dsm in H20 and D:O are close to the ratio of their viscosity r/D_,o/r/H:o that is 1.23 [19].…”

Isotopic effect on tautomeric behavior of 5‐(2,6‐disubstituted‐aryloxy)‐tetrazoles

“…For instance, two isopropyl groups in 2,6-diisopropylphenol (propofol, is a short-acting, intravenously administered hypnotic agent) [58] are equivalent in chemical shifts [59] because of the low rotational barrier. Therefore, it seems that the appearance of approximately two doublets in 1 H NMR spectrum of 1c (before adding D 2 O) either attributed to the hindrance effect between two isopropyls and tetrazole groups upon phenyl ring and restricted rotation around ether linkage bonds in 1c or presumably to the equilibrium mixture of 1H-and 2H-tautomers that slightly have enough life time in NMR time scale.…”

Polymeric micelles: authoritative aspects for drug delivery

“…Higher solubility [245] Tanespimycin PEO-b-poly(D,L-lactide) 150-fold increase in solubility [246] Timolol maleate Pluronic F127 About 2.4-fold improved bioavailability [247] investigation about the effect of micelle shape (spherical and wormlike) on the aqueous solubility of three drugs: griseofulvin, spironolactone, and carbamazepine was conducted by Attwood and his research team. Griseofulvin and spironolactone were solubilized to a greater extent than the more water-soluble drug, carbamazepine.…”