Enrichment And Enantioseparation Of Amlodipine From Wastewater By Coupling Of Membrane Extraction And Crystallization

Amlodipine is an effective calcium channel blocker,often used to treat angina pectoris and hypertension.As a chiral drug,the（S）-amlodipine shows excellent calcium antagonism,which is about 1000 times than that of the（R）-amlodipine.But the（R）-amlodipine also has a certain effect in the treatment or prevention of atherosclerosis.These liquid wastes,including wastewater and mother liquor,result in low yields and environmental pollution.The pollution by chiral drugs,such as amlodipine,has a potentially toxic effect on the natural environment and human.Therefore,it is of great practical significance to study the recovery of amlodipine from wastewater to increase the yield and to reduce the discharge of wastewater.This is not only beneficial for resource recovery,but also conducive to solving an environmental pollution problem.In this study,some new methods by coupling of membrane extraction and crystallization were used to enrich and enantioseparate amlodipine from the wastewater.The low-concentration amlodipine in the wastewater was enriched by membrane extraction,then separated and recovered by crystallization.These technologies realize the resource utilization of amlodipine,increase the total production yield,and greatly reduce the load of subsequent biochemical treatment.Thereby,the economic benefit of the enterprise is greatly improved,and the comprehensive cost of the treatment of pharmaceutical waste liquid is reduced.（1）Using PVDF hydrophobic hollow fiber membrane as the base membrane,a membrane extraction module was constructed to enrich the amlodipine from wastewater,then benzenesulfonic acid was used as the stripping agent,the amlodipine besylate crystal product was recovered by one-step.The influence of factors such as the concentration of the extractant P204,the concentration of amlodipine,the pH,and the concentration of benzenesulfonic acid on the enrichment and recovery of amlodipine was investigated.The optimal conditions were obtained:the concentration of P204 was 15 mmol/L,the initial concentration of amlodipine is 6mmol/L,the pH is 6,the concentration of benzenesulfonic acid is 0.1mol/L,and the flow rates of the raw material liquid and extraction phase are 100 mL/min and 30 mL/min,respectively.After running for 6 hours,E_AD and Y_ADcan reach to 96.17%and 77.65%,respectively.A new method by coupling of membrane extraction,benzene sulfonic acid stripping,and crystallization was developed with high recovery rate,simple steps,and continuous operation.（2）A new method for the enrichment and resolution of amlodipine by the combined use of supported liquid membrane-water/organic phase crystallization was further proposed.One-stage supported liquid membrane with strip dispersion（SLM-SD）recycled the amlodipine from wastewater into a stripping phase with a removal(E_AD)of 99.67%and a Y_1,AD of 87.91%.In the second step of water phase crystallization,a certain amount of NaOH and（L）-tartaric acid were added into the stripping phase of the first step to obtain amlodipine-1/2（L）-tartaric acid crystals.The results show that when the molar ratio of amlodipine to（L）-tartaric acid is greater than 0.5and the pH exceeds 6.68,the Y_2,AD of the water phase crystals can reach to more than 99%.Finally,using（L）-tartaric acid or（D）-tartaric acid as resolving agent and dimethylsulfoxide（DMSO）as solvent,high-value-added products（R）-amlodipine and（S）-amlodipine were obtained by two steps of organic phase crystallization.The ee of products was over 99%after optimizing the dosages of DMSO and resolving agent.To increase the total yield,the mother liquors were re-treated by SLM-SD with the recovery of over 99%for residual amlodipine.（3）In order to simplify the enrichment and resolution steps,a novel method was developed for the recovery and enantioseparation of the active pharmaceutical ingredient（S）-amlodipine from pharmaceutical wastewater:hollow fiber membrane extraction and in situ coupling of back-extraction with crystallization.Firstly,the amlodipine in the wastewater is extracted and transferred to the extraction phase by the extractant P507 through the hollow fiber membrane,and then back-extracted and enriched into the stripping phase.The stripping phase is a DMSO solution containing the resolving agent（D）-tartaric acid,in which（S）-amlodipine preferentially crystallizes with（D）-tartaric acid in situ in the stripping phase to form crystals:（S）-AD·1/2（D）-TA·DMSO.The simultaneous enrichment and resolution of amlodipine are realized,and the separation steps are simplified.The effects of the running time,amlodipine concentration,pH,P507 concentration,flow rate,（D）-tartaric acid concentration,DMSO dosage,number of fibers,and temperature were investigated.The best experimental conditions were obtained:the running time was 18 h,amlodipine concentration was 12 mmol/L,the pH is 6,the concentration of P507 is 0.17%,the flow rate is 30 mL/min,the concentration of（D）-tartaric acid is 0.065 mol/L,the dosage of DMSO is 24 mL,the number of fibers is 70,and the temperature is22℃.An ee_（S）-AD of 90.7±1.4%and a yield(Y_（S）-AD)of 48.8±2.4%for the crystal product were obtained under optimized conditions.The crystal products were characterized by high-performance liquid chromatography and scanning electron microscopy.These separation methods provide some new ideas for solving the problem of pharmaceutical wastewater generated in the production process of chiral drugs.It has certain research significance and application value.