Obtaining the substance enoxaparin sodium equivalent to the original Clexane® and Lovenox®. Selection of technological parameters of the key stage of the synthesis

Abstract

The aim: to carry out the key stage of synthesis to obtain a substance equivalent to the original drugs Clexane® and Lovenox® by determining the technological parameters of the synthesis that are critical from the point of view of the formation of the molecule and studying the correlation between the structural characteristics of Enoxaparin samples and the experimental conditions of the technological process. Materials and methods: samples of the Enoxaparin sodium substance were synthesized according to the method described in the patent, as well as with a variation of the selected critical technological parameters. The obtained samples of Enoxaparin sodium were analyzed according to pharmacopoeial requirements, as well as by non-pharmacopoeial methods, such as two-dimensional NMR spectroscopy and size exclusion chromatography for detailed structural characterization of the molecule. Results: determination and variation of technological parameters critical for the formation of the molecule, such as temperature, the amount of alkali for the depolymerization reaction, and the reaction time of the reaction mass, were determined and varied. Enoxaparin sodium samples were developed according to the selected parameters and a detailed analysis of the structure of the obtained samples was carried out, followed by a comparison with the original Clexane® and Lovenox®. It was established that with an increase in the temperature of the reaction mass, the amount of alkali and the holding time individually and in combination, the degree of depolymerization increases, which makes the composition of the molecule unbalanced in comparison with the original drugs Clexane® and Lovenox®. Conclusions: As a result of the experiments, the technological parameters of the synthesis of a sample of Enoxaparin sodium were evaluated and determined, allowing to obtain a substance comparable to the originator in terms of chemical structure (alkali/ heparin benzyl ester ratio 0.06; temperature – 57 °C, reaction mixture holding time - 1.5 hours)