Polyethylene glycol fatty acid esters are an important class of amphiphilic compounds with high biocompatibility and low toxicity, enabling broad application. In pharmaceuticals, they act as nonionic surfactants, emulsifiers, and stabilizers that enhance the solubility of poorly soluble active ingredients, prevent protein aggregation and denaturation, and reduce protein adsorption to surfaces. These properties make them indispensable in modern parenteral formulations, particularly biological drugs. Their long-standing use and favourable safety profile further underscore their significance.
This master’s thesis focuses on the synthesis and physicochemical evaluation of polyethylene glycol esters of selected fatty acids, with the aim of gaining an in-depth understanding of their structure, synthetic pathways, and degradation mechanisms. Since polyethylene glycol esters of fatty acids constitute integral components of polysorbates, which are complex mixtures, one of the key objectives of the thesis is the preparation of pure polyethylene glycol esters that could serve as reference standards in the analytical characterization of polysorbates.
In the experimental part, sixteen esterification reactions were performed between various polyethylene glycol chains and four acid chlorides: lauroyl, myristoyl, nonadecanoyl, and oleoyl chloride. We investigated the effects of polyethylene glycol chain length, fatty acid type, reagent ratio, and base choice on yield, selectivity, and product purity. Shorter polyethylene glycol chains and saturated fatty acids gave higher yields and simpler purification, while oleoyl chloride showed a strong tendency toward oxidation during synthesis. Pyridine proved more effective than triethylamine, enhancing selectivity for monoester products. Characterization by nuclear magnetic resonance, high-resolution mass spectrometry, and ultra-high-performance liquid chromatography coupled with high-resolution mass spectrometry confirmed the structure and purity of the products and enabled the identification of oxidized species. Optimized conditions were crucial for achieving high yields with minimal degradation of esters derived from saturated fatty acids. In the case of esters containing unsaturated oleic acid, oxidation with triplet oxygen occurred, making it impossible to separate the desired products from the undesired oxidation products.
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