Course of pH during the formation of amoxicillin by a suspension-to-suspension reaction

Amoxicillin can be produced in an enzymatic suspension-to-suspension reaction in which the substrate(s) and product(s) are mainly present as solid particles, while the reaction takes place in the liquid phase. During these suspension-to-suspension reactions different subprocesses take place, such as dissolution/crystallization of substrates and products, enzymatic synthesis of the product(s), and undesired enzymatic hydrolysis of substrates and/or products. All these subprocesses are influenced by pH and also influence the pH because the reactants are weak electrolytes. This paper describes a quantitative model for predicting pH and concentrations of reactants during suspension-to-suspension reactions. The model is based on mass and charge balances, pH-dependent solubilities of the reactants, and enzyme kinetics. For the validation of this model, the kinetically controlled synthesis of amoxicillin from 6-aminopenicillanic acid and d-(p)hydroxyphenylglycine methyl ester was studied. The pH and the dissolved concentrations took a very different course at different initial substrate amounts. This was described quite reasonably by the model. Therefore, the model can be used as a tool to optimize suspension-to-suspension reactions of weak electrolytes.