Solid–liquid equilibrium of substrates and products of the enzymatic synthesis of ampicillin

Abstract

The solid-liquid equilibrium of precursors and products of the enzymatic synthesis of ampicillin (AMP) [6-aminopencillanic acid (6-APA) and D(À)phenylglycine (PG)] was investigated at different temperatures (283-298 K) and pHs (5.5-7.5). Solubility data were obtained using an analytical methodology. Equilibrium dissociation constants were experimentally measured at several temperatures for AMP, 6-APA, PG, and D(À)phenylglycine methyl ester. A model based on the simplified perturbed hard sphere theory proposed by Khoshkbarchi and Vera (Ind Eng Chem Res. 1996;35:4319-4327) was fitted against solubility data. The model could describe the water solubility behavior for AMP and PG as function of pH and temperature, but a bias was observed when fitting the model to the solubility of 6-APA. V

A new approach for the thermodynamic modeling of the solubility of amino acids and β-lactam compounds as a function of pH

“…They modeled amino acids as Lennard-Jones spheres with dipole-dipole interactions. Santana et al [22] showed that this model fails to quantitatively predict the solubility of ampicillin, d-phenylglycine and 6-aminopenicillanic acid as a function of pH even adjusting five parameters. Pradhan and Vera [6], using an equation similar to that proposed by Gupta and Heidemann [9] with the NRTL equation, correlated the dlalanine solubility as a function of pH, with good agreement with the experimental data in the vicinity of the isoelectric point.…”

“…Fig. 9 shows the chemical structures of two ␤-lactam compounds: the antibiotic ampicillin and its precursor 6-aminopenicillanic acid, for which solubility data as a function of pH and temperature are available [22]. In this case, one can apply Eq.…”

Solid-liquid equilibrium data of amoxicillin and hydroxyphenylglycine in aqueous media

“…In the enzymatic synthesis of amoxicillin from hydroxyphenylglycine methyl ester (HPGM) and 6-APA, as indicated in Figure 1, the Penicillin G Acylase (PGA) catalyzes both the synthesis of the antibiotic by coupling (Reaction 1) and the undesired hydrolysis of the substrate (Reaction 2) and its product (Reaction 3), generating hydroxyphenylglycine (HPG) and alcohol. Therefore, the yield of the process depends on the kinetic rates of these three reactions, where the antibiotic acts as the intermediate component within a set of series-parallel reactions (Santana et al, 2010). Thus, the concentration curve of antibiotic reaches a maximum value, beyond which the hydrolytic reactions prevail.…”

“…Literature measurements concerning the solidliquid equilibrium of β-lactam antibiotics are scarce (Santana et al, 2010). Diender et al (1998) determined the solubility of HPG, 6-APA and AMOX in water as function of pH at 298.15 K according to the analytical method proposed by Gude et al (1996).…”

“…The optimal conditions according to these data were found to be in the range of pH between 6 and 7, the precipitation of ampicillin being effective only at pH below 7.5. Santana et al (2010) determined the solubility for a series of the components involved in the enzymatic synthesis of ampicillin at different values of temperature and pH, using the saturation method proposed by Gude et al (1996) and modified by Vieira (2003). In order to describe the measured solubilities, the model of Khoshkbarchi and Vera (1996) was applied.…”