Development of a new method and device for chiral drug enrichment and enantioseparation: Multiple-phase extraction and in situ coupling of crystallization

Abstract

This work developed a new method of multiple-phase extraction and in situ coupling of crystallization (MPE-CC) for the enrichment and enantioseparation of amlodipine (AD) from pharmaceutical wastewater. Liquid-liquid extraction (LLE) experiments were utilized to estabilish a suitable extraction system. An n-heptane solution containing P507 (2-ethylhexyl phosphonic acid mono-2-ethylhexyl ester) as extractant and a dimethylsulfoxide solution containing (D)-tartaric acid or (L)-tartaric acid as chiral resolving agent were used as the extraction phase and stripping phase (also as crystallization mother liquor), respectively. The optimized LLE conditions were: P507 concentration of 4.44 mmol/L, pH of 6.0, and amlodipine concentration of 10 mmol/L. However, the enrichment performance of single stage extraction and back-extraction was insufficient to crystallize amlodipine in the stripping phase with an extraction percentage of 34.0%, so repetitive LLE was used to increase the extraction percentage (86.3%, repeat six times) and subsequently (S)-amlodipine crystal was in situ generated with (D)-tartaric acid. The operation of repetitive LLE was intermittent and tedious. To simplify the operation, an equivalent method of three-phase extraction and in situ coupling of crystallization (TPE-CC) were developed. After optimizing the parameters of TPE-CC, an enantiomeric excess (ee(S)-AD) of 85.8% for the (S)-amlodipine crystal was obtained under the flow rate of 30 mL/min and molar ratio of 0.25 for (D)-tartaric acid to amlodipine. Finally, MPE-CC was established by adding a secondary back-extraction and crystallization column based on TPE-CC. The racemic amlodipine from wastewater was recycled and enantioseparated into high-value-added products of two amlodipine enantiomers with an ee(S)-AD of 92.2% for (S)-amlodipine crystal and an ee(R)-AD of 94.3% for (R)-amlodipine crystal. The crystal products were characterized by HPLC and SEM. MPE-CC exhibits better enantioseparation performance than TPE-CC due to the additional effect of impurity removal in MPE-CC.