Solvents in the industrial synthesis of naphazoline nitrate: implementation of the principles of “Green chemistry” and analysis

Abstract

The aim: implementation of the principles of green chemistry by regenerating the synthesis solvent 1,2,4-trichlorobenzene and reusing it during the synthesis of the Naphazoline nitrate substance. Study of the influence of the regenerated solvent on the quality of the final product by controlling analytical quality parameters. Development of a method for the quantitative determination and validation of synthesis solvents in a substance. Materials and methods: samples of the substance were synthesized according to the optimized proprietary technology of Farmak JSC. The obtained batches of fresh and regenerated 1,2,4-trichlorobenzene were analyzed according to the monograph of the European Pharmacopoeia on Naphazoline nitrate 0147. Results: the possibility of using regenerated 1,2,4-trichlorobenzene for the synthesis of the substance Naphazoline nitrate has been proven. It is shown that the regenerated solvent does not have a negative effect on the profile of impurities and the polymorphic form of the substance. Analytical quality parameters met the requirements of the internal specification and the requirements of the European Pharmacopoeia monograph. The developed and validated method of quantitative determination of synthesis solvents makes it possible to determine them at the required level. Conclusions: the introduction of regenerated 1,2,4-trichlorobenzene into the synthesis scheme made it possible to significantly reduce the amount of waste per 1 kg of product, which in turn significantly reduced the negative impact on the environment. Analytical quality parameters for regenerated 1,2,4-trichlorobenzene meet the requirements of the internal specification. Industrial series obtained on the regenerated solvent meet the requirements of the monograph of the European Pharmacopoeia. The polymorphic form of the substance batches manufactured on regenerated 1,2,4-trichlorobenzene corresponds to the polymorphic form of the substance batches manufactured on the fresh solvent. The obtained results on the influence of the regenerated solvent on the profile of impurities in the finished substance show the similarity of the profile of the series manufactured on both solvents. According to the requirements of ICH Q3C Impurities: Guideline for residual solvents, a method for quantitative determination of the residual content of 1,2,4-trichlorobenzene in the final product by gas chromatography was developed and validated. The absence of synthesis solvents at the limit of detection is shown