Preparation Of Surface Molecularly Imprinted Materials For Chiral Separation Of Amlodipine Besylate

Pure enantiomorphism isomer used as raw medicine in recent years is one of the most important trend in the field of pharmaceutical.At present,more than half of the clinical used drugs are of chiral structures.Moreover,most of the best-selling drugs possess chiral activity.To date,the method for chiral drug separation are trace analysis in lab scale.However,a strategy which is suitalbe for large-scale separation of racemates and even industrialized production of racemates is difficult to establish.This paper was focused on the separation of a chiral antihypertensive drug of amlodipine besylate.By adopting the surface imprinting technology and membrane technology,several molecularly imprinted composite materials were prepared and demonstrated enantioseparation ability for amlodipine besylate.The methods used in the separation experiments could be amplified,and could provide a potential technology reference for large-scale enantioseparation of amlodipine besylate.The specific research work is as follows.1.molecularly imprinted hollow fiber composite membrane was prepared on the polyvinylidene hollow fiber membrane.The prepared imprinted composite membrane was in combination with homemade membrane module for cross-flow biphasic recognition extraction separation.Under the optimal extraction conditions,a good enantiomeric excess of 17.84% was achieved by cross-flow extraction separation with D-TA and SBE-?-CD as chiral additives.The triple recognition mechanism based on the selectivity of imprinted caves and the preferential recogniton capacity of D-TA and SBE-?-CD well explained the cross-flow biphasic recognition extraction separation system.This method combined the advantages of membrane science and molecular imprinting technology,and is expected to provide certain theory reference for industrial separation of amlodipine besylate.2.Surface imprinted microspheres were prepared by precipitation polymerization with the support of mesoporous silica microspheres,using methylacrylic acid and ethylene glycol dimethyl acrylic as the monomers and crosslinking agent,respectively.The prepared imprinted microspheres were characterized by thermogravimetric analysis and transmission electron microscopy,by which a thin imprinted layer of about 45 nm was found.The preparated surface molecularly imprinted microspheres showed rapid adsorption kinetics and good adsorption capacity,and the saturated adsorption time and maximum adsorption capacity were 20 min and 245 mg/g,respectively.This demonstrated that there are a large number of recognition sites on the surface of molecularly imprinted materials,which reduced the mass transfer resistance in rebinding step and was favorable for the combination between template molecules and molecularly imprinted materials.A separation column(3.0 cm)was packed by molecularly imprinted microspheres for dynamic separation of amlodipine besylate,and an enantiomeric excess of 11.3% was obtained.3.The mesoporous silica microspheres were modified with double bonds and carboxyl to generate carboxyl modified mesoporous silica microspheres.The template molecules(S)-amlodipine besylate were fixed on the modified microspheres in advanced,then the surface imprinted microspheres were obtained by hydrolysis condensation reaction with ethylene glycidyl ether.By comparing the adsorption kinetics and adsorption performance of surface imprinted materials and microspheres and carboxyl modified microspheres,it was found that the surface imprinted microspheres were saturated adsorbed within 20 min and the maximum adsorption capacity was 137 mg/g,which were slightly poor than that of carboxyl modified microspheres.This is because the decrease of the amount of surface carboxyl after hydrolytic condensation reaction.The imprinted material was used for dynamic separation of amlodipine besylate,the best enatioseparation ability with the enantiomeric excess of 13.8% was achieved by the imprinted comunm(2.3 cm)prepared from the optimal carboxyl modified silica microspheres.4.The thermosensitivity surface imprinted microspheres were prepared by precipitation polymerization,using N-isopropylacrylamide and N,N-methylenebis acrylamide as monomers and crosslinking agent,respectively.The material was tested by transmission electron microscopy and a thin surface imprinted layer of about 16 nm was found.The preparated surface molecularly imprinted microspheres showed rapid adsorption kinetics and excellent adsorption capacity,and the saturated adsorption time and maximum adsorption capacity were 5 min and 441 mg/g,respectively.The adsorption capacity of imprinted material in protic solvent decreased,but displayed sensitivity of adsorption performance to temperature changes and best adsorption performance was obtained at 35 ?.The imprinted material was used for dynamic separation of amlodipine besylate,and an enantiomeric excess of 10.2% was obtained.5.Surface imprinted silica microspheres were prepared by sol-gel polymerization,with Stober silica microspheres as the support core,3-ammonia propyl triethoxy silane and tetraethyl silicate as monomers and crosslinking agent,respectively.The imprinted microspheres reached saturated adsorption within 60 min,with the maximum adsorption capacity of about 94 mg/g and an imprinting factor of 1.52.The imprinted silica materials could keep the adsorption capacity almost invariant after seven cycles of adsorption-desorption test.The imprinted silica material was used for dynamic separation fo amlodipine besylate,and a certain enantioseparation ability was obtained.