Synthesis And Separation Of RRR-α-mono- Tocopheryl Polyethylene Glycol Succinate

RRR-α-tocopheryl polyethylene glycol succinate (TPGS), as a water-soluble derivative of natural vitamin E, is a nutrient component and a medicine, and is also a new type of nonionic surfactant that can be applied as a solubilizer, emulsifier, absorption enhancer and penetrant in the drug delivery systems. Crude TPGS synthesized by the esterifiction of RRR-α-tocopheryl acid succinate (TAS) and polyethylene glycol (PEG) is composed of mono- and di-TPGS, in which mono-TPGS is the effective component since it has higher surface activity and water solubility than di-TPGS. The selectivities of mono-TPGS in the reported esterification methods were poor. Due to the polymer feature and the structural similarity of mono- and di-TPGS, the separation of mono- and di-TPGS was difficult. Chromatographic method was the main separation method in the literature, which existed problems of low capacity, high organic solvent consumption and large equipment investment. In this dissertation, heterogeneous solid acid catalysts were tried to increase the selectivity of the esterification to mono-TPGS, and the extraction systems based on ionic liquids (ILs) were established for the separation of mono- and di-TPGS.Firstly, the standards of mono- and di-TPGS were prepared by the simulated moving bed (SMB) chromatography system. The purity and the molecular weight information of these standards were characterized by the matrix assisted laser desorption ionization time of flight mass spectrometry (MALDI-TOF MS). Then a simple and direct reversed-phase high performance liquid chromatography (RP-HPLC) method was developed for the quantification of mono- and di-TPGS with UV detector at 284 nm, C30 column as the stationary phase, and acetonitrile/isopropyl alcohol as the mobile phase at gradient elution mode. The validation experiments confirmed the accuracy and precision of the analytical method. It could be applied to the quantification of TPGS samples which have similar average degrees of polymerization and similar average molecular weights to the standards, but not completely the same molecular weight distribution as the standards. The quantification of mono- and di-TPGS was much simplified.Taking advantage of the flexibility of the heterogeneous catalysts to modify the important parameters such as acidity, pore size and surface area, heterogeneous acidic zeolites, heteropolyacid, and polyoxometalates were used to catalyze the reaction of TAS and PEG for the first time. It was found that the catalytic activity of phosphotungstic acid was lower than the homogeneous catalyst -p-toluene sulphonic acid (PTSA), but the selectivity of mono-TPGS was higher. When the molar ratio of TAS/PEG was 1:1, the addition amount of phosphotungstic acid was 1 wt% of the reaction material, the reaction temperature was 120℃, and the reaction time was 12 hours, the selectivity of mono-TPGS was 91.4%, the yield of esters were 75.5% with the hydrolytic lost 1.6%.The adsorption technique was used to remove the unreacted TAS. The difference between TAS and TPGS lied in the carboxyl group in TAS. The single-component equilibrium experiments revealed that TAS was strongly adsorbed onto the weakly basic anion exchange resins, while TPGS was scarcely adsorbed. The adsorption amount of TAS on HZD-9 decreased with the increase of the temperature, the adsorption isotherm accorded with the Langmuir isotherm, with the monolayer saturation capacity of TAS as high as 1068.38 mg/g at 273 K. The adsorption process of TAS onto HZD-9 was spontaneous (ΔG0< 0), exothermic (ΔH9<0), and no obvious entropy change was discovered (ΔS0≈0). The kinetic of TAS adsorbed onto HZD-9 fitted well with the pseudo-second-order equation.Due to the unique structures of ILs composed of asymmetric organic cations and organic or inorganic anions, ILs have high cohesive energy, and could readily form immiscible liquid-liquid biphasic systems with various solvents. The ternary biphasic systems consisted of long-chain ILs+water+organic solvents were constructed to separate mono-and di-TPGS. High selectivities and large distribution coefficients were achieved as well as the emulsification was eliminated. The interaction between the long-chain ILs and mono-TPGS was the main reason for the high distribution coefficients. Take [CnPy]Br as an example, when n increased from 6 to 8 and 12, the solution of the extraction phase turned from no aggregation structure in it to the aggregation structures of micelle and liquid crystal, the distribution coefficients of mono-TPGS increased from 1.91 to 7.75 and 15.09, while the selectivity decreased from 795.6 to 22.8 and 8.5, respectively. With the aqueous solution of [C6Py]Br at the initial concentration of 4 mol% as the extractant, simple two stage cross current extraction could increase the relative content of mono-TPGS to 99.9 wt% from 80.0 wt%, with the recovery of 82.0% at the same time. These ternary biphasic systems could extend to the separation of other PEG fatty acid ester mixtures, the selectivities obtained were larger than 10. Thus the extraction technology based on these systems was expected to be the general efficient separation method for this type of surface-active mixtures.FT-IR,1H NMR, MALDI-TOF MS, TGA and DSC were carried out to characterize the molecular structures, the molecular weight information and the thermal properties of mono-and di-TPGS. The calculated hydrophilic-lipophilic balance (HLB) number of mono-TPGS was about 13, the HLB number of di-TPGS was about 9. The solubility of mono-TPGS in water was good. The surface activity of mono-TPGS was excellent. The critical micellar concentration (CMC) of mono-TPGS was 0.029 mM at 22.℃. di-TPGS was almost not soluble in water.