Maurice Le Blanc

Synergistic stabilization of perfluorocarbon-pluronic F-68 emulsion by perfluoroalkylated polyhydroxylated surfactants

One of the most serious limitations of the first generation of fluorocarbon emulsions destined to serve as injectable oxygen carriers (blood substitutes) is their insufficient, stability. Considerable stabilization of such emulsions has now been achieved by using a combination of Pluronic F-68, a polyoxyethylene polyoxypropylene block polymer, and of a perfluoroalkylated polyhydroxylated surfactant (PPFS) comprising a C6F13 or C8F17 fluorophilic tail and a hydrophilic head derived from maltose or xylitol. These new surfactants are either soluble in water or dispersible in an aqueous Pluronic F-68 solution. The tensions at the surface of these solutions and dispersions and at their interface with a typical fluorocarbon, F-decalin, are discussed. A strong stabilizing effect on F-decalin emulsions was obtained when small amounts of PPFS were incorporated, the total amount of surfactant used remaining constant. For 20% w/v emulsions, the maximum stabilizing effect was reached when 20–30% of PPFS were present, resulting after one year at 25°C in an up to 10 times smaller increase in particle size than for a reference emulsion prepared with Pluronic F-68 alone. The effect is even stronger with more concentrated 50% w/v emulsions, reaching a stabilizing ratio of 17 after one year for a one-to-one PPFS/Pluronic F-68 combination. None of the PPFS, when taken alone, permitted the preparation of stable emulsions. The characteristic U-shape taken after aging, by the particle size vs PPFS/Pluronic F-68 ratio curves demonstrates a strong synergistic effect of the two surfactants. They also permitted the selection of optimal formulations for the emulsions. The evolution of the particle sizes against time for such formulations was followed for 20% and 75% w/v concentrated F-decalin emulsions at 4°C, 25°C and 50°C. The best emulsion in terms of stability was obtained with the xylitol derivative C8F17CH=CHCH2OCH2(CHOH)4H; most significantly, temperature, from 4 to 50°C, had little or no effect on the aging of this emulsion over a two month period.

Reactions of perfluoroalkylcalcium derivatives with ketones and aldehydes

Abstract Perfluoroalkyl iodides, R F I, react in ethers with aldehydes and ketones in the presence of calcium to give the alcohols R F C(OH)R1R2. The best yields (20–70%) were obtained with Ca/Hg amalgam in THF as solvent at −20 to −40°C. The new alcohols were characterized by 1 H and 19 F NMR and mass spectrometry. The results are interpreted in terms of the intermediate formation of an organocalcium species.

The preparation of 1-hydroperfluorohexyne, octyne and decyne

Abstract 1-hydroperfluoroalkynes (RFCCH, RF  C4F9, C6F13, C8F17) were prepared from the corresponding alkenes by a multistep process involving bromination, dehydrobromination and debromination reactions. The influence of the perfluorinated chains length on chemical reactivity is illustrated by the important changes in experimental procedure, with respect to the lower terms, needed for the bromination and debromination steps. Physical data are reported for compounds RFCBr2CH2Br, RFCBrCHBr and RFCCH.

Deviation from molecular diffusion aging model in fluorocarbon emulsions stabilized by perfluoroalkylated surfactants

Abstract The adjunction of a perfluoroalkylated polyhydroxylated surfactant to F -decalin/Pluronic F -68 emulsions stabilizes these emulsions dramatically. Moreover, it is found that the increase in droplet volume over time is no longer linear as when Pluronic F -68 is used as the sole surfactant, the deviation being in the direction of a lower increase rate, i.e., in the direction of an increase of the stabilization effect over time. These observations could have a considerable impact on the development of fluorocarbon emulsions for therapeutic uses. They raise the question of the validity of existing theoretical treatments of molecular diffusion and also of whether molecular diffusion can still be invoked as being the principal cause of aging when such fluorinated surfactants are present.

Use of Lymphoblastoid Namalva Cell Cultures in a Toxicity Test. Application to the Monitoring of Detoxification Procedures for Fluorocarbons to be used as Intravascular Oxygen-Carriers

Cultures of lymphoblastoid Namalva cells have been used to check the absence of toxic impurities in fluorocarbons destined for biomedical applications. The test comprises the measurement of growth rate and viability in the presence of the fluorocarbon, and of growth after reseeding. It was used to establish a procedure for the detoxification of a family of fluorocarbons by evaluating the effect on toxicity of a series of individual or combined treatments. A convenient, rapid and industrially feasible procedure was developed which includes washing with 10 % aqueous KOH, shaking with charcoal and filtration over alumina.

Synthesis of Per(poly)fluoroalkyl aldehydes RF(CH2)nCHO

Abstract We report the preparation of polyfluoroalkyl aldehydes R F (CH 2 ) n CHO in high yields by direct oxidation of polyfluoroalkyl alcohols; the Swern oxidation, pyridinium chlorochromate and Dess-Martin periodinane are used and compared

19F NMR chemical shifts of n-F-alkyl compounds

Abstract The examination of 19F chemical shifts for ca. 650 F-alkylated compounds of general formula CF3(CF2)nCF2X led to the following conclusions: the CF2 groups α to X are very sensitive to the nature of X, and are spread over a range of 85 ppm. The effect of the length of the F-alkyl chain decreases rapidly, so that δCF2(α) can already be considered as characteristic of X for n = 1 or 2 for most practical purposes. Solvent effects (in 9 different solvents having e = 1.8 to 52.1) were found to be rather small except for the F-alkyl iodides. A chart which indicates the domain in which the CF2(α) resonance signal is to be expected is given for 42 different series of F-alkylated compounds; it is expected to provide the synthetic chemist with a useful tool for the identification and characterization of such compounds.

Asymmetric heterocyclocondensation of polyfluorinated aldehydes catalysed by a chiral titanium(IV) complex

Abstract The Binol/Ti(OiPr)4 chiral titanium complex catalyses the asymmetric cyclocondensation of polyfluoroalkylaldehydes with the Danishefsky’s diene leading to chiral polyfluoroalkyl dihydropyrenones with high enantiomeric excesses.

Nucleophilic ring opening of 3-F-alkyl 2,3-epoxypropanoates. Access to α,β-difunctional β-F-alkylpropanoates

Abstract Nucleophilic ring opening of 3-F-alkyl 2,3-epoxypropanoates 1 with primary amines or chloride ions leads regioselectively to 2-substituted 3-F-alkyl 3-hydroxypropanoates. Azidolysis is not so selective but 2-azido 3-F-alkyl 3-hydroxypropanoates 7 are still the major products. With NaBH4 in alcoholic media (EtOH, OcOH) 2-alkoxy 3-F-alkyl 1,3-propanediols ( 2 = Et , 3 = Oc ) are obtained.

Hetero Diels-Alder cyclocondensation of F-alkyl aldehydes with the Danishefsky diene

Abstract The heterocyclocondensation of F-alkylated aldehydes R F (CH 2 ) n CHO with Danishefskys diene depends on the mutual vicinity of the carbonyl and the F-alkyl chain: when n =4 it leads to 4-oxo pyr-2-ene 4 , but when n =0 the trimethylsilyloxypyrene 3 without methoxy elimination only results.