The dissertation is devoted to the optimization of industrial technology for the synthesis of sympathomimetic active pharmaceutical ingredients (АРІ), taking into account the principles of "green chemistry". Adherence to these principles allows you to avoid the negative impact of toxic waste from pharmaceutical industries on the environment and human health and condition.
The optimization consisted in the introduction of the solvent – 1,2,4-trichlorobenzene into the synthesis scheme to minimize the generation of waste and improve the quality and final yield of the substance in comparison with the traditional production technology. According to the traditional synthesis technology, at the first stage of condensation, a large amount of resins were formed as a result of the reaction with hydrochloric acid at high temperatures. Hydrochloric acid was removed from the synthesis scheme and ethylenediamine hydrochloride was introduced to avoid the use of precursors during API production. To obtain naphazoline base instead of 40% sodium hydroxide solution, ethanolamine was used, which increased the yield of technical naphazoline nitrate, and subsequently pharmacopoeial naphazoline nitrate due to the lack of water, which led to the precipitation of naphazoline base. To obtain pharmacopoeial naphazoline hydrochloride, a solvent for crystallization of privin was selected, namely water in a product-water ratio of 1:2. This made it possible to obtain a proper yield of the product and clean it of impurities that are well soluble in water.
For 1,2,4-trichlorobenzene, a regeneration technique has been developed and introduced into production. During regeneration, the amount of waste per 1 kg of product was reduced, namely 5 kg of regenerated solvent was obtained. In the future, the regenerated solvent is used to obtain API. The influence of the regenerated solvent on the quality of naphazoline nitrate, its crystal structure and impurity profile was investigated. The use of a regenerated solvent has no negative effect on the quality of the target API. A method for determining residual solvents (1,2,4-TCB, ethanolamine and 2-propanol) in naphazoline nitrate was developed and validated. The final scheme for obtaining API was formed, the necessary quantities of raw materials and synthesis materials were calculated, and the final production recipe for obtaining naphazoline nitrate was described.
It has been proven that the optimized technology provides a higher yield of naphazoline nitrate, its purity and a lower content of impurities. The amount of waste has decreased compared to traditional technology, which is confirmed by a 7-fold decrease in the E-factor.
Considering the introduction of changes in the traditional synthesis technology, the validation of the technological process was carried out for both naphazoline salts, during which the control of critical indicators of the quality of intermediate products was carried out. The obtained results confirm the acceptability of the proposed synthesis technology.
Having analyzed the market of preparations with xylometazoline, it is important to obtain the basis of xylometazoline, which is soluble in essential oils and is suitable for the development of preparations based on them.
A method of obtaining xylometazoline base by reacting xylometazoline hydrochloride with a 2% sodium hydroxide solution was developed. The optimal ratio was chosen: 4.5 mol of sodium hydroxide is taken for 4.6 mol of the starting substance. After washing with water, the paste is dried for 7-8 hours at a temperature 25-30 °C to prevent the formation of degradation products. The yield of xylometazoline base is about 89%. The structure of the obtained xylometazoline base was proved using the methods of 1H and 13C NMR spectroscopy, mass- spectrometry, and elemental analysis. Developed methods of quality control of the obtained xylometazoline base. Since xylometazoline is not described in the European monograph, for the development of methods based on the monograph on xylometazoline hydrochloride – Ph. Eur. 01/2008:1162 "Xylometazoline hydrochloride". For the xylometazoline base, new indicators such as "chlorides" and "melting point" were added. Appropriate solvents are selected for other quality indicators. The validation of the quality control methods of the obtained xylometazoline base was carried out according to the quality indicators "related substances" and "assay". Based on the results, an internal specification was developed. It has been proven that the developed technology ensures the proper quality of the substance in accordance with the requirements of the internal specification. The stability of API for 1 year was proven and extrapolation was carried out for a shelf-life of 2 years.
