Cost-Effective Isolation of a Process Impurity of Pregabalin

Abstract

Cost-effective isolation methods were developed on preparative HPLC, flash LC, and simulated moving bed (SMB) to prepare the process impurity, 3-(aminomethyl)-5-methylhex-4-enoic acid (4-ene impurity), of pregabalin. By a thorough experimental study on the different isolation techniques available, it was concluded that SMB was the most cost-effective. Hence, it was a continuous chromatography that utilized the advantage of SMB so that a high quantity of the impurity was generated in a short period of time. SMB was equipped with eight reversed-phased columns and was used to separate the process impurity of pregabalin. The effects of flow rate in zone 2 (Q2) and 3 (Q3), as well as switching time, on the operating performance parameters like purity, productivity, and desorbent consumption were studied. Operating conditions leading to more than 90% purity in the raffinate outlet stream were identified, together with those achieving optimal performance. All of these developed methods are novel, cost-effective, and can be applied to the isolation of other process- and stability-related impurities of pregabalin.

Keywords: Flash chromatography; Impurity; Isolation; Pregabalin; Preparative HPLC; Simulating moving bed.

Fig. 1

Synthesis of pregabalin

Fig. 2

Synthetic enhancement of the impurity

Fig. 3

HPLC chromatogram of crude pregabalin

Fig. 4

Prep HPLC and flash LC impurity isolation chromatograms

Fig. 5

Purity chromatograms of the 4-ene impurity isolated by prep HPLC, flash LC, and SMB

Fig. 6

Effect of zone 2 flow rates on purity

Fig. 7

Effect of zone 3 flow rates on purity

Fig. 8

Effect of switching time on purity