Amoxicillin Production

The process under analysis comprises three major sections: (1) Dane Salt Synthesis; (2) Amoxycillin Production; and (3) Separation and Purification.

Dane Salt Synthesis. Initially, p-hydroxyphenylglycine is dissolved in a stirred tank reactor with anhydrous ethanol, ethylacetoacetate and potassium hydroxide. A salt is formed and precipitates in the reactor. The effluent from the reactor is cooled, what causes the crystallization of the Dane salt. The resulting slurry passes through a centrifuge for the separation of the salt from the ethanol solvent. The salt is washed with fresh ethanol and dried, while the liquor from the centrifuge is concentrated under vacuum.

Amoxycillin Production. The Dane salt is fed into a stirred reactor to be reacted with pivaloyl chloride, forming a mixed anhydride complex. The reaction occurs in the presence of methylene dichloride, as solvent, mixed with 2,6-Lutidine, N,N-Dimethylacetamide and 2,6-ethylhexanoic acid, as catalysts and pH balancing agents for improving the anhydride formation. The mixture is then sent to a condensation reactor, along with 6-APA raw material dissolved by triethylamine, yielding enamine protected Amoxicillin which in turn is fed to a hydrolysis reactor along with hydrochloric acid.

Separation and Purification. The product from hydrolysis is fed to a separation vessel, where the aqueous and organic layers are separated. The organic layer, containing the methylene chloride solvent, is purified by means of distillation and recycled. The aqueous layer, containing the Amoxicillin Trihydrate, is passed through crystallization and centrifugation steps, it is subsequently dried, ground and finally packed in bags.