Development of a batch process to produce ethylated fatty acid esters

Abstract

Pharmaceutical excipients account for the majority of the volume of administered drugs [1]. The problem with the manufacture of pharmaceutical excipients is that they were considered to be inert support material with no real contribution to the efficacy of drugs. Conversely, excipient formulation has proved to be a science on its own as it can significantly influence drug delivery in terms of stability, bioavailability and transfer of critical impurities and may even lead to adverse effects [1]. All manufacturers of pharmaceutical and complementary products have to be compliant with an extensive list of Good Manufacturing Practice (GMP) guidelines in order to be certified. However, the guidelines are only specified for the manufacturing process and not for each individual excipient [2]. Proper quality control has to be performed not only on the finished product, but on the raw material procurement process as well. A defined mixture of ethylated fatty acid esters used as a key component in the manufacture of the Pheroid® drug delivery system, is only available in South Africa on import. This project therefore aims to develop a sustainable batch process to produce the mixture of fatty acid ethyl esters locally, with the benefit of improving the economic feasibility of the drug delivery system. The product will be of pharmaceutical grade and the manufacturing facility will be GMP compliant. Transesterification reactions with pure ethanol and anhydrous sodium hydroxide are conducted in an attempt to optimize conversion of triglycerides to ethyl esters. Deuterated chloroform is used as solvent in NMR spectroscopy to determine the reaction conversion. The parameters to be optimized include reaction time, catalyst, concentration, reaction temperature, and molar ratio of alcohol to oil. With the optimized conditions, methods for effective separation of the product and by-products will be tested. This includes a dry method using a magnesium silicate to remove impurities and a water washing method followed by drying with anhydrous calcium chloride. In both cases, excess alcohol will be removed by distillation. The established method will be applied to larger batches in a stirred tank which will be designed as part of the study. The feedstock was characterized in terms of water and free fatty acid contents as these two parameters necessitates pretreatment of the feedstock if it is higher than 1% and 0.5%, respectively. The water content was found to be 0.03% and the free fatty acid content 1.20%. This indicates that pre-treatment of the feedstock will be necessary