Reactive crystallization of β-lactam antibiotics: strategies to enhance productivity and purity of ampicillin

Abstract

Seeded reactive crystallization in the manufacture of semi-synthetic β-lactam antibiotics is described and the beneficial effects on yield are discussed. Conventional enzymatic synthesis of β-lactam is limited by secondary hydrolysis reactions that consume the desired product as it is being produced. Recent work in this area has pointed to the potential advantage of performing reactions at conditions that allow product crystallization to reduce the rate of secondary hydrolysis by protecting ampicillin in the solid phase. However, these approaches led to crystallization of both D-phenylglycine and ampicillin, which will greatly increase downstream processing. In the work described here, seeded crystallization is used to promote secondary nucleation of the desired ampicillin while it is being produced by the synthesis reaction, thereby selectively crystallizing ampicillin. Quantification of the solid phase confirmed selective crystallization of ampicillin with purities greater than 95% wt in all runs.React. Chem. Eng. This journal is

Application of In Situ Product Crystallization and Related Techniques in Biocatalytic Processes

“…To solve this issue, Encarnación‐Gómez et al. developed a seeding protocol within this ISPC, which improved the crystal purity, by the careful addition of pure seeds of 23 , to >95 wt %; this was sufficient for further DSP …”

Multiobjective Dynamic Optimization of Ampicillin Batch Crystallization: Sensitivity Analysis of Attainable Performance vs Product Quality Constraints

“…13 One method of circumventing impurity accumulation and solvent occlusion in the crystalline produce is reactive crystallization, a form of process intensification which has been implemented in the literature for β-lactam antibiotic molecules and other pharmaceutical compounds. [37][38][39] Reactive crystallization requires that the ratios of reaction to mass transfer and crystallization be ensured such that the mixture supersaturation is not so high as to result in excessive nucleation and thus wide size distributions. 27 Figure 8: 3D Pareto front of the multiobjective optimisation problem for all cases.…”

Efficient enzymatic synthesis of cephalexin in suspension aqueous solution system

“…In contrast, the latter is preferred because reactants’ conversion is not restrained by reaction equilibrium and higher yield could be achieved [5]. The kinetically controlled synthesis of β‐lactam antibiotics is a complex process, where PGA can act either as a transferase or as a hydrolase, catalyzing two undesired side reactions: the hydrolysis of the acyl side‐chain precursor (an ester or amide, a parallel reaction) and the hydrolysis of the antibiotic itself (a consecutive reaction) [6]. For example, when CEX is enzymatically synthesized from d ‐phenylglycine methyl ester (PGME) and 7‐amino 3‐desacetoxy cephalosporanic acid (7‐ADCA), PGA does not only transfer the acyl group of PGME to 7‐ADCA to generate CEX, but also hydrolyze PGME into d ‐phenylglycine (PG) and CEX into 7‐ADCA and PG (Fig.…”