| Glycyl Glutamine, as a amino acid API, its production process including reactions of acylation and amination, one purification is conducted after amination process, and a final purification is done to obtain final purified Glycyl Glutamine. For the limit of some process parameters are relatively wide, and some large impurities are generated during production, although through final purification, the final Glycyl Glutamine meet specification, but the yield is not so high but with high cost, with the purpose to further improve quality of intermediates for Glycyl Glutamine, yield and competition advantage of the API, the thesis focuses on further study on production process of Glycyl Glutamine, and its critical process parameters are determinated with their ranges proposed by trial productions, and finally its process is optimized.For different process parameters in different steps, such as pH in acylation process, reaction temperature, temperature for crystallization, and influence of inorganic salt, reaction temperature in amination process and material formulation, volume of methanol used in first purification and crystallization temperature, amount of resin used in final purification and crystallization temperature, we have conducted study, and finally determine critical parameters are as listed: pH value, reaction temperature in acylation, reaction temperature and reaction time for amination process, crystallization temperature are critical for two-purification process, and specific limts are set for these parameters, and finally improve assay of acylated product with more than 2%, assay of amination intermediate are improved more than 2%, and yield of crude product and purified product is improved, and the manufacturing process is optimized.Lastly, by process valiation of thre consecutive batches of Glycyl Glutamine, accelerated stability study is done, and data shows that Glycyl Glutamine produced by our company are stable with aceptable reproducibility. |
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