Applications Of Microextraction Technology Based On Deep Eutectic Solvents In The Analysis Of Non-steroidal Anti-inflammatory Drugs

Objective:In order to realize the efficient monitoring of non-steroidal anti-inflammatory drugs（NSAIDs）in complex samples,this study aims to develop novel microextraction technologies based on deep eutectic solvents（DESs）to enrich and determine the content of NSAIDs in environmental water and human plasma samples through combination with high performance liquid chromatography-ultraviolet detection（HPLC-UVD）.We intend to improve the detection sensitivity of NSAIDs in complex sample matrix,provide new methods for the detection of NSAIDs and new ideas for the development and application of novel DESs.Methods:The core-shell Fe₃O₄@MIL-101（Cr）was modified with menthol:lactic acid DES,which was used as the extraction phase together.After investigating and optimizing the parameters affecting the enrichment efficiency of the target analytes,DES-loaded magnetic solid phase extraction method（DES-L-MSPE）was established based on the combination of dispersive liquid-liquid microextraction and magnetic solid phase extraction.Methodological investigation was conducted under the optimal extraction conditions.Finally,this method was used for the extraction and concentration of ketoprofen,naproxen,flurbiprofen,diclofenac sodium,ibuprofen and mefenamic acid in environmental water samples.N,N-dimethylethanolamine:hexanoic acid DES,which was formed in situ,was used as the extractant.After investigating and optimizing the related factors affecting the enrichment of the target analytes,homogeneous liquid-liquid microextraction based on in-situ formation of switchable hydrophilic deep eutectic solvent（in-situ SHDES-HLLME）was established.The methodology was investigated under the optimal extraction conditions.Finally,the content of NSAIDs in environmental water and human plasma samples was determined with the established method.Results:The optimum extraction conditions of DES-L-MSPE were as follows:menthol:lactic acid（1:2,n:n）,18μL;Fe₃O₄@MIL-101（Cr）,15 mg;sample phase p H,5.0;salt concentration,10%;extraction time,90 s;desorption solvent,acetone;elution solvent volume,80μL;elution time,120 s.Under these conditions,the enrichment factors of the six target analytes ranged from 50 to 105.The linear ranges were 0.0050-1.0μg/m L for ketoprofen and ibuprofen,0.0015-0.60μg/m L for flubiprofen and mefenamic acid,0.0025-1.0μg/m L for naproxen,0.0030-0.60μg/m L for diclofenac sodium with the correlation coefficients between 0.9972 and 0.9993.Limit of detection（LOD）were 0.20×10^-3-1.1×10^-3μg/m L;limit of quantitation（LOQ）were 0.60×10^-3-3.4×10^-3μg/m L.The relative of standard deviations（RSDs）of intra-day and inter-day precision were in the range of 1.2%-7.8%and 3.3%-9.6%,respectively.The recoveries of Yingze Lake water were 89.2%-110.4%with RSDs≤8.3%,and the recoveries of Fenhe River water were83.8%-109.0%with RSDs≤9.0%.The optimum extraction conditions of in-situ SHDES-HLLME were as follows:extractant,N,N-dimethylethanolamine:hexanoic acid（1:1,n:n）;extractant volume,180μL;heating time,5 min;phase conversion solvent,HCl solution（5 mol/L,220μL）;extraction time,30 s.Under the optimal extraction conditions,the enrichment factors were132-221.Besides,flubiprofen in 0.0020-0.80μg/m L,diclofenac sodium and ibuprofen in0.0025-1.0μg/m L,mefenamic acid in 0.0015-0.60μg/m L showed good linear relationships.The correlation coefficients were between 0.9993 and 0.9997.LOD and LOQ were 0.50×10^-3-0.80×10^-3μg/m L and 1.5×10^-3-2.5×10^-3μg/m L,respectively.The RSDs for intra-day and intra-day precision were 1.0%-4.3%and 2.0%-5.3%,respectively.The recoveries in spiked of Fenhe River water were 85.8%-109.9%with RSDs in the range of0.5%-4.7%,and the recoveries in spiked Yingze Lake water were 87.4%-102.3%with RSDs in range of 2.1%-6.4%.The optimal conditions for the determination of NSAIDs in human plasma by in-situ SHDES-HLLME were as follows:extractant,N,N-dimethylethanolamine:hexanoic acid（1:1,n:n）;extractant volume,180μL;heating time,5 min;phase conversion solvent,HCl solution（5 mol/L,200μL）;extraction time,30 s;dilution ratio of plasma,25 times.Flubiprofen in the range of 0.0500-20.0μg/m L,diclofenac sodium and ibuprofen in the range of 0.0625-25.0μg/m L,mefenamic acid in the range of 0.0375-15.0μg/m L showed good linear relationships with the correlation coefficients between 0.9989 and 0.9999,LOD and LOQ were 1.1×10^-2-1.9×10^-2μg/m L and 3.75×10^-2-6.25×10^-2μg/m L,respectively.The enrichment factors ranged from 61 to 129.The RSDs of intra-day precision ranged from 0.94%to 4.8%with the relative error（REs）from-4.5%to 2.8%.The RSDs of inter-day precision ranged from 2.1%to 5.0%with the REs from-2.6%to2.3%.The RSDs for stability were 0.12%-6.6%with the REs range from-14%to 2.9%.Conclusions:In this paper,two kinds of microextraction methods based on DESs were established and successfully applied to the concentration and determination of NSAIDs in environmental water samples and human plasma samples.In DES-L-MSPE,DES was directly loaded into the pores of core-shell Fe₃O₄@MIL-101（Cr）nanoparticles,which was utilized as the extraction phase together for the enrichment and concentration of NSAIDs.In-situ SHDES-HLLME developed a simpler,integrating preparation and extraction liquid phase microextraction method based on DESs.These two methods broaden the application scope of DESs,achieve the target of simple operation and sensitive detection,and provide simple,efficient and green methods for complex sample pretreatment.