CN102718984B - Preparation method of ofloxacin and 17beta-estradiol double-template molecularly-imprinted composite microsphere - Google Patents
Preparation method of ofloxacin and 17beta-estradiol double-template molecularly-imprinted composite microsphere Download PDFInfo
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Abstract
The invention relates to a preparation method of ofloxacin and 17beta-estradiol double-template molecularly-imprinted composite microspheres, which comprises the following steps of: preparing monodisperse cross-linked epoxypropyl methacrylate microspheres with vinyl bonded on surfaces by using 1, 4-dioxane as a solvent, and preparing the ofloxacin and 17beta-estradiol double-template molecularly-imprinted composite microspheres by using two antibiotics ofloxacin and 17beta-estradiol as templates and by adopting a surface-imprinting technology. The preparation method disclosed by the inventionhas mild reaction conditions and can be used for preparing the double-template molecularly-imprinted composite microspheres which have better identifying performance for the ofloxacin and the 17beta-estradiol, can be rapidly adsorbed and desorbed and have good stability, so that the simultaneous purification and enrichment of two or more trace components are realized, and references are provided for the simultaneous and rapid detection of multiple medicaments in foods.
Description
Technical field
The invention belongs to the synthesis technical field of molecular imprinting complex microsphere, particularly relate to the preparation method of a kind of Ofloxacine USP 23 and 17-estradiol bimodulus plate molecular imprinting complex microsphere.
Background technology
Microbiotic is medically having important application, but some disease close relation of their meta-bolites and the mankind, can be by the metabolism entered environment of life entity, or the parent compound of synthetic other new antibiotics of conduct all can cause direct or indirect harm with the industrial waste entered environment to the health of people and other biological, ecological living environment.Sanderson is once to open in the risk assessment of medicine, according to be detrimental to health and the degree of environment be arranged in order be microbiotic female hormone cardiovascular agent antitumor drug.Ofloxacine USP 23 is third generation quinolones (FQs) Broad spectrum antibiotics, oestrogenic hormon is the toxic organic pollutant that a class is disturbed human and other animal endocrine systems, stability and the regulating and controlling effect of body are got muddled, 17 beta estradiols in the oestrogenic hormon can improve and can compare and output by zoophagous lean meat, also often be used in the aquaculture, if long-term edible animal food, wherein residual antibiotic medicine may deposit in human body by food chain, thereby the eater is produced the effects such as certain toxicity and potential carcinogenic, teratogenesis, mutagenesis; Therefore, the safety problem that residual microbiotic and oestrogenic hormon cause can not be ignored, and especially the analyzing and testing of such drug residue should give attention highly in agricultural-food and the food.But Multiple Classes of Antibiotics is present in food or the environment with trace or ultra-trace simultaneously usually, and this has brought certain difficulty to their content of Correct Analysis and risk assessment.Utilize the high recognition capability of molecularly imprinted polymer (MIP), MIP is applied to separation and the enrichment of drug residue, can solve present drug residue analysis speed, sensitivity and the low problem of the rate of recovery, can also reduce analysis cost simultaneously.
The single template molecule of the at present most employings of synthetic molecularly imprinted polymer (MIP), when multi-medicament was residual, it only can detect wherein a kind of, can not detect simultaneously the medicine of other coexistences, like this, cause in testing process occuring undetected or detect loaded down with trivial details problem.Also there is the people that the multi-medicament in the similar drugs is done template, perhaps take two kinds of isomer as template, utilize the substance law Synthesis of Molecular Imprinting Polymers, but, it remains similar drugs, only can detect similar medicine, and its technique in preparation process is loaded down with trivial details, the particle diameter scope wider distribution that wastes time and energy and select by sieving, can cause loading second-rate.
Summary of the invention
For existing deficiency in the building-up process that solves molecularly imprinted polymer in the prior art, the invention provides a kind of preparation method take Ofloxacine USP 23 and 17 beta estradiols as the bimodulus plate molecular imprinting complex microsphere of template.
The technical scheme that technical solution problem of the present invention adopts is: the preparation method of Ofloxacine USP 23 and 17 beta estradiol bimodulus plate molecular imprinting complex microspheres may further comprise the steps:
1) synthetic monodisperse polystyrene dispersion liquid
Vinylbenzene and Diisopropyl azodicarboxylate, polyvinylpyrrolidone are added in the dehydrated alcohol, the mass ratio of vinylbenzene and Diisopropyl azodicarboxylate, polyvinylpyrrolidone, dehydrated alcohol is 1:0.01～0.04:0.1～0.3:7.5～9, ultra-sonic dispersion, logical nitrogen deoxygenation, stir, 70 ℃ were reacted 24 hours, and were prepared into polystyrene; Be 0.2% lauryl sodium sulfate aqueous solution ultra-sonic dispersion with the polystyrene massfraction, obtain the monodisperse polystyrene dispersion liquid;
2) the monodisperse cross-linked glytidyl methacrylate microballoon of preparation
With benzoyl peroxide and glytidyl methacrylate, ethylene glycol dimethacrylate, dispersant solution adds in the mixed solvent of hexalin and toluene, toluene and hexalin, benzoyl peroxide, glytidyl methacrylate, ethylene glycol dimethacrylate, the mass ratio of dispersant solution is 1:2:0.15:2:3:60, be ultrasonic under 300～500W with cell crushing instrument at power, every interval 10～20 seconds ultrasonic 1 time, each ultrasonic 10～20 seconds, ultrasonic emulsification to the upper strata without oil droplet, join in the monodisperse polystyrene dispersion liquid of step 1), the mass ratio of polystyrene is 1:0.1 in glytidyl methacrylate and the monodisperse polystyrene dispersion liquid, 30 ℃ were stirred swelling 10 hours, logical nitrogen deoxygenation, 70 ℃ of polyreactions 24 hours, filter, use successively methyl alcohol, washing with acetone, 60 ℃ of vacuum-drying 4 hours is prepared into monodisperse cross-linked glytidyl methacrylate microballoon;
3) the monodisperse cross-linked glytidyl methacrylate microballoon of extracting
With step 2) the monodisperse cross-linked glytidyl methacrylate microballoon of preparation is with toluene 140 ℃ of extractings 48 hours in cable type extractor according, uses successively dehydrated alcohol, washing with acetone, and drying obtains monodisperse porous crosslinked methacrylic acid epoxy propyl ester microballoon;
4) monodisperse porous crosslinked methacrylic acid epoxy propyl ester microsphere surface bonding ethylene base
The monodisperse porous crosslinked methacrylic acid epoxy propyl ester microballoon of step 3) preparation is added 1, in the 4-dioxane, every 100mL 1, add the monodisperse porous crosslinked methacrylic acid of 3～10g epoxy propyl ester microballoon in the 4-dioxane, stirring at room swelling 4～12 hours, logical nitrogen deoxygenation, add hydroxyethyl methylacrylate and 1, the 4-dioxane, the mass ratio of boron trifluoride diethyl etherate is the mixed solution of 1:2～5:4～6, the mass ratio of monodisperse porous crosslinked methacrylic acid epoxy propyl ester microballoon and hydroxyethyl methylacrylate is 1:0.1～2,30～60 ℃ were stirred 8～15 hours, filter, product is used Isosorbide-5-Nitrae-dioxane successively, methyl alcohol, distilled water, washing with acetone, vacuum-drying obtains the monodisperse cross-linked glytidyl methacrylate microballoon of surface bond vinyl;
5) preparation Ofloxacine USP 23 and 17 beta estradiol bimodulus plate molecular imprinting complex microspheres
Be that the amount of 1:2.5～15:250～563 is mixed with 17 beta estradiols and methacrylic acid, acetonitrile according to mass ratio, ultra-sonic dispersion, at room temperature prepolymerization 4～12 hours, rotating speed is 30～150 rev/mins;
Be that the amount of 1:2～12:200～400 is mixed ultra-sonic dispersion, at room temperature prepolymerization 4～12 hours, 30～150 rev/mins of rotating speeds with Ofloxacine USP 23 and methacrylic acid, acetonitrile according to mass ratio;
With 17 beta estradiols, methacrylic acid, the mixed solution of acetonitrile and Ofloxacine USP 23, methacrylic acid, the mixed solution of acetonitrile mixes, in the monodisperse cross-linked glytidyl methacrylate microballoon of the surface bond vinyl of adding step 4), add ethylene glycol dimethacrylate and Diisopropyl azodicarboxylate, 17 beta estradiols and Ofloxacine USP 23, the monodisperse cross-linked glytidyl methacrylate microballoon of surface bond vinyl, ethylene glycol dimethacrylate, the Diisopropyl azodicarboxylate mass ratio is 1:1.25:20～120:8～20:1～2, logical nitrogen deoxygenation, 60～70 ℃ were reacted 16～48 hours, remove Ofloxacine USP 23 and 17 beta estradiols with the mixed solution wash-out of methyl alcohol and acetic acid, the volume ratio of acetic acid and methyl alcohol is 1:4, be neutral with methyl alcohol and water washing to product surface, drying is prepared into Ofloxacine USP 23 and 17 beta estradiol bimodulus plate molecular imprinting complex microspheres.
Above-mentioned steps 1) the polyvinylpyrrolidone specification is k-30 in, and number-average molecular weight is 40000.
Above-mentioned steps 2) dispersion agent is that massfraction is that 0.4% sodium dodecyl sulfate solution and massfraction are that 4% the ratio of polyvinyl alcohol solution take volume ratio as 1:1 mixed, and the polymerization degree of polyvinyl alcohol is 1700, and alcoholysis degree is 88%.
Above-mentioned steps 5) monodisperse cross-linked glytidyl methacrylate microballoon, ethylene glycol dimethacrylate, the Diisopropyl azodicarboxylate mass ratio of 17 beta estradiols and Ofloxacine USP 23 and surface bond vinyl is 1:1.25:40～80:12～18:1～2 in.
The present invention is with 1, the 4-dioxane is solvent, the monodisperse cross-linked glytidyl methacrylate microballoon for preparing surperficial bonding ethylene base, take the monodisperse cross-linked glytidyl methacrylate microballoon of surface bond vinyl as carrier, Ofloxacine USP 23 and two kinds of microbiotic of 17 beta estradiols are template, adopt surface imprinted technology to be prepared into Ofloxacine USP 23 and 17 beta estradiol bimodulus plate molecular imprinting complex microspheres, preparation method's reaction conditions of the present invention is gentle, can prepare has preferably recognition performance to Ofloxacine USP 23 and 17 beta estradiols, can quick adsorption and the bimodulus plate molecular imprinting complex microsphere of desorb and good stability, realized the Simultaneous purification enrichment to two classes or multiclass trace components, in the food when multi-medicament rapid detection reference is provided.
Description of drawings
Fig. 1 color atlas that to be Ofloxacine USP 23 keep at trace post and non-trace post.
Fig. 2 color atlas that to be 17 beta estradiols keep at trace post and non-trace post.
Fig. 3 is the color atlas that template molecule and comparison thereof keep at the trace post.
Fig. 4 is that bimodulus plate molecular imprinting complex microsphere of the present invention (MIP) and non-molecular imprinting complex microsphere (NIP) are to the adsorption isothermal curve of 17 beta estradiols.
Fig. 5 is that bimodulus plate molecular imprinting complex microsphere of the present invention (MIP) and non-molecular imprinting complex microsphere (NIP) are to the adsorption isothermal curve of Ofloxacine USP 23.
Fig. 6 is 3 kinds of quinolones materials and the rate of recovery of 3 kinds of estrogenic chemicalses after bimodulus plate molecular imprinting complex microsphere (MIP), silica gel (Silica), Magnesium Silicate q-agent (Florisil) and octadecyl silane (C18) are processed.
Embodiment
The present invention is described in more detail below in conjunction with drawings and Examples, but the invention is not restricted to these embodiment.
The preparation method of the present embodiment Ofloxacine USP 23 and 17 beta estradiol bimodulus plate molecular imprinting complex microspheres may further comprise the steps:
Step 1: synthetic monodisperse polystyrene dispersion liquid
Be dimension chemical industry company limited in polyvinylpyrrolidone k-30(Jiaozhuo of 40000 with 10.908g vinylbenzene, 0.218g Diisopropyl azodicarboxylate, 1.528g number-average molecular weight) add and fill in the 250mL single port flask of 96g dehydrated alcohol, the mass ratio of vinylbenzene and Diisopropyl azodicarboxylate, polyvinylpyrrolidone, dehydrated alcohol is 1:0.02:0.14:8.8, be ultra-sonic dispersion 20 minutes under the 80W with ultrasonic cleaner at power, logical nitrogen deoxygenation in 15 minutes, stir, 70 ℃ were reacted 24 hours, centrifugation, use absolute ethanol washing, be prepared into polystyrene; Be that ultra-sonic dispersion obtains the monodisperse polystyrene dispersion liquid under the 80W in the 10mL massfraction is 0.2% lauryl sodium sulfate aqueous solution with the 0.2g polystyrene at power;
Step 2: prepare monodisperse cross-linked glytidyl methacrylate microballoon
With benzoyl peroxide 0.1559g, glytidyl methacrylate 1.92g, ethylene glycol dimethacrylate 3.118g and be that 0.4% sodium lauryl sulphate and massfraction are that (polymerization degree is 1700 for 4% polyvinyl alcohol by massfraction, alcoholysis degree is 88%) be that dispersant solution 62.35g that the ratio of 1:1 is mixed adds and fills in the 250mL beaker of 1.92g hexalin and 1.0392g toluene according to volume ratio, toluene and hexalin, benzoyl peroxide, glytidyl methacrylate, ethylene glycol dimethacrylate, the mass ratio of dispersant solution is 1:2:0.15:2:3:60, be ultrasonic under the 400W with cell crushing instrument at power, every interval 15 seconds ultrasonic 1 time, each ultrasonic 15 seconds, ultrasonic emulsification to the upper strata without oil droplet, join in the monodisperse polystyrene dispersion liquid that step 1 obtains, the mass ratio of polystyrene is 1:0.1 in glytidyl methacrylate and the monodisperse polystyrene dispersion liquid, 120 rev/mins of stirrings, 30 ℃ of swellings 10 hours, logical nitrogen deoxygenation in 20 minutes, 70 ℃ of polyreactions 24 hours, use the glass sand hourglass suction filtration, with 70 ℃ of distilled water washs, use successively again methyl alcohol, washing with acetone, 60 ℃ of vacuum-drying 4 hours is prepared into monodisperse cross-linked glytidyl methacrylate microballoon.
Step 3: the monodisperse cross-linked glytidyl methacrylate microballoon of extracting
The monodisperse cross-linked glytidyl methacrylate microballoon of step 2 preparation is placed cable type extractor according, add 50mL toluene, 140 ℃ of extractings 48 hours, use successively dehydrated alcohol, washing with acetone, be 60 ℃ of dryings 3 hours under the 0.06MPa in vacuum tightness, obtain monodisperse porous crosslinked methacrylic acid epoxy propyl ester microballoon.
Step 4: monodisperse cross-linked glytidyl methacrylate microsphere surface bonding ethylene base
The monodisperse porous crosslinked methacrylic acid epoxy propyl ester microballoon 2.0g of step 3 preparation is added 50mL1, in the 4-dioxane, 200 rev/mins of stirrings, room temperature swelling 6 hours, logical nitrogen deoxygenation in 20 minutes, add the 2.0g hydroxyethyl methylacrylate, 5.2g 1, the 4-dioxane, 10.0g the mixed solution of boron trifluoride diethyl etherate, hydroxyethyl methylacrylate and 1, the 4-dioxane, the mass ratio of boron trifluoride diethyl etherate is 1:2.6:5, the mass ratio of monodisperse porous crosslinked methacrylic acid epoxy propyl ester microballoon and hydroxyethyl methylacrylate is 1:1, and 45 ℃ were stirred 12 hours, filtered, product uses 1 successively, the 4-dioxane, methyl alcohol, distilled water, washing with acetone, 30 ℃ of vacuum-drying 2 hours obtains the monodisperse cross-linked glytidyl methacrylate microballoon of surface bond vinyl.
Step 5: preparation Ofloxacine USP 23,17 beta estradiol integration templates molecular imprinting complex microspheres
Ofloxacine USP 23 18mg and methacrylic acid 126mg are dissolved in the 5.4g acetonitrile, the mass ratio of Ofloxacine USP 23 and methacrylic acid, acetonitrile is 1:7:300, be ultra-sonic dispersion 5 minutes under the 80W with ultrasonic cleaner at power, 50 rev/mins of stirrings, room temperature prepolymerization 8 hours is prepared into mixed solution (I);
17 beta estradiol 14mg and methacrylic acid 126mg are dissolved in the 5300g acetonitrile, 17 beta estradiols and methacrylic acid, acetonitrile mass ratio are 1:9:380, be ultra-sonic dispersion 5 minutes under the 80W with ultrasonic cleaner at power, 50 rev/mins of stirrings, room temperature prepolymerization 8 hours is prepared into mixed solution (II);
Mixed solution (I) is mixed with mixed solution (II), the monodisperse cross-linked glytidyl methacrylate microballoon 0.98g of the surface bond vinyl that adding step 4 obtains, add ethylene glycol dimethacrylate 56mg as linking agent, Diisopropyl azodicarboxylate 21mg is as initiator, 17 beta estradiols and Ofloxacine USP 23, the monodisperse cross-linked glytidyl methacrylate microballoon of surface bond vinyl, ethylene glycol dimethacrylate, the Diisopropyl azodicarboxylate mass ratio is 1:1.25:70:14:1.5, logical nitrogen deoxygenation in 20 minutes, 65 ℃ of polyreactions 24 hours, product is used first distilled water successively, methanol wash, be the elutriant wash-out 24 hours of 4:1 again with the volume ratio of methyl alcohol and acetic acid, remove Ofloxacine USP 23,17 beta estradiols, product is washed till neutrality with distilled water, use again methanol wash, 30 ℃ of vacuum-drying 2 hours is prepared into Ofloxacine USP 23,17 beta estradiol bimodulus plate molecular imprinting complex microspheres.
To prepare Ofloxacine USP 23 and 17 beta estradiol bimodulus plate molecular imprinting complex microspheres as example, its preparation method may further comprise the steps:
Step 1: synthetic monodisperse polystyrene dispersion liquid
Be that 40000 polyvinylpyrrolidone k-30 adds and fills in the 250mL single port flask of 82g dehydrated alcohol with 10.908g vinylbenzene, 0.11 Diisopropyl azodicarboxylate, 1.09g molecular-weight average, the mass ratio of vinylbenzene and Diisopropyl azodicarboxylate, polyvinylpyrrolidone, dehydrated alcohol is 1:0.01:0.1:7.5, be ultra-sonic dispersion 20 minutes under the 80W with ultrasonic cleaner at power, logical nitrogen deoxygenation in 15 minutes, other operation is identical with embodiment 1, obtains the monodisperse polystyrene dispersion liquid;
Step 2: identical with embodiment 1, be prepared into monodisperse cross-linked glytidyl methacrylate microballoon.
Step 3: identical with embodiment 1 obtains monodisperse porous crosslinked methacrylic acid epoxy propyl ester microballoon.
Step 4: monodisperse cross-linked glytidyl methacrylate microsphere surface bonding ethylene base
The monodisperse porous crosslinked methacrylic acid epoxy propyl ester microballoon 2g of step 3 preparation is added 50mL1, in the 4-dioxane, 200 rev/mins of stirrings, room temperature swelling 6 hours, logical nitrogen deoxygenation in 20 minutes, add the 0.2g hydroxyethyl methylacrylate, 0.4g 1, the 4-dioxane, 0.8g the mixed solution of boron trifluoride diethyl etherate, hydroxyethyl methylacrylate and 1 in the mixed solution, the 4-dioxane, the mass ratio of boron trifluoride diethyl etherate is 1:2:4, the mass ratio of monodisperse porous crosslinked methacrylic acid epoxy propyl ester microballoon and hydroxyethyl methylacrylate is 1:0.1, other operations are identical with embodiment 1, obtain the monodisperse cross-linked glytidyl methacrylate microballoon of surface bond vinyl.
Step 5: synthetic Ofloxacine USP 23,17 beta estradiol bimodulus plate molecular imprinting complex microspheres
With 17 beta estradiol 14mg(0.05mmol) be dissolved in the 3.5g acetonitrile with methacrylic acid 35mg, 17 beta estradiols and methacrylic acid, acetonitrile mass ratio are 1:2.5:250, be ultra-sonic dispersion 5 minutes under the 80W with ultrasonic cleaner at power, 50 rev/mins of stirrings, room temperature prepolymerization 4 hours is prepared into mixed solution (II);
With Ofloxacine USP 23 18mg(0.05mmol) be dissolved in the 3.6g acetonitrile with methacrylic acid 36mg, the mass ratio of Ofloxacine USP 23 and methacrylic acid, acetonitrile is 1:2:200, be ultra-sonic dispersion 5 minutes under the 80W with ultrasonic cleaner at power, 50 rev/mins of stirrings, room temperature prepolymerization 4 hours is prepared into mixed solution (I);
Mixed solution (I) is mixed with mixed solution (II), the monodisperse cross-linked glytidyl methacrylate microballoon 0.28g of the surface bond vinyl that adding step 4 obtains, add ethylene glycol dimethacrylate 112mg as linking agent, Diisopropyl azodicarboxylate 14mg is as initiator, 17 beta estradiols and Ofloxacine USP 23, the monodisperse cross-linked glytidyl methacrylate microballoon of surface bond vinyl, ethylene glycol dimethacrylate, the Diisopropyl azodicarboxylate mass ratio is 1:1.25:20:8:1, other operations are identical with embodiment 1, are prepared into Ofloxacine USP 23,17 beta estradiol bimodulus plate molecular imprinting complex microspheres.
The preparation method of the present embodiment Ofloxacine USP 23 and 17 beta estradiol bimodulus plate molecular imprinting complex microspheres may further comprise the steps:
Step 1: synthetic monodisperse polystyrene dispersion liquid
Be that 40000 k-30 polyvinylpyrrolidone adds and fills in the 250mL single port flask of 98g dehydrated alcohol with 10.908g vinylbenzene, 0.4363g Diisopropyl azodicarboxylate, 3.2724g molecular-weight average, the mass ratio of vinylbenzene and Diisopropyl azodicarboxylate, polyvinylpyrrolidone, dehydrated alcohol is 1:0.04:0.3:9, other operation is identical with embodiment 1, obtains the monodisperse polystyrene dispersion liquid;
Step 2: identical with embodiment 1, be prepared into monodisperse cross-linked glytidyl methacrylate microballoon.
Step 3: identical with embodiment 1, obtain monodisperse porous crosslinked methacrylic acid epoxy propyl ester microballoon.
Step 4: monodisperse cross-linked glytidyl methacrylate microsphere surface bonding ethylene base
The monodisperse porous crosslinked methacrylic acid epoxy propyl ester microballoon 1.0g of step 3 preparation is added 50mL1, in the 4-dioxane, 200 rev/mins of stirrings, room temperature swelling 6 hours, logical nitrogen deoxygenation in 20 minutes, add the 2.0g hydroxyethyl methylacrylate, 10.0g 1, the 4-dioxane, 12.0g the mixed solution of boron trifluoride diethyl etherate, hydroxyethyl methylacrylate and 1, the 4-dioxane, the mass ratio of boron trifluoride diethyl etherate is 1:5:6, the mass ratio of monodisperse porous crosslinked methacrylic acid epoxy propyl ester microballoon and hydroxyethyl methylacrylate is 1:2, other operation is identical with embodiment 1, obtains the monodisperse cross-linked glytidyl methacrylate microballoon of surface bond vinyl.
Step 5: synthetic Ofloxacine USP 23,17 beta estradiol integration templates molecular imprinting complex microspheres
With 17 beta estradiol 14mg(0.05mmol) be dissolved in the 7.88g acetonitrile with methacrylic acid 210mg, 17 beta estradiols and methacrylic acid, acetonitrile mass ratio are 1:15:563, be ultra-sonic dispersion 5 minutes under the 80W with ultrasonic cleaner at power, 50 rev/mins of stirrings, room temperature prepolymerization 4 hours is prepared into mixed solution (II);
With Ofloxacine USP 23 18mg(0.05mmol) be dissolved in the 7.20g acetonitrile with methacrylic acid 216mg, the mass ratio of Ofloxacine USP 23 and methacrylic acid, acetonitrile is 1:12:400, be ultra-sonic dispersion 5 minutes under the 80W with ultrasonic cleaner at power, 50 rev/mins of stirrings, room temperature prepolymerization 4 hours is prepared into mixed solution (I);
Mixed solution (I) is mixed with mixed solution (II), the monodisperse cross-linked glytidyl methacrylate microballoon 1.68g of the surface bond vinyl that adding step 4 obtains, add ethylene glycol dimethacrylate 280mg as linking agent, Diisopropyl azodicarboxylate 28mg is as initiator, 17 beta estradiols and Ofloxacine USP 23, the monodisperse cross-linked glytidyl methacrylate microballoon of surface bond vinyl, ethylene glycol dimethacrylate, the Diisopropyl azodicarboxylate mass ratio is 1:1.25:120:20:2, other operations are identical with embodiment 1, are prepared into Ofloxacine USP 23,17 beta estradiol bimodulus plate molecular imprinting complex microspheres.
In the step 5 of above-described embodiment 1 ~ 3, mixed solution (I) is mixed with mixed solution (II), the monodisperse cross-linked glytidyl methacrylate microballoon 0.56g of the surface bond vinyl that adding step 4 obtains, add ethylene glycol dimethacrylate 168mg as linking agent, Diisopropyl azodicarboxylate 14mg is as initiator, 17 beta estradiols and Ofloxacine USP 23, the monodisperse cross-linked glytidyl methacrylate microballoon of surface bond vinyl, ethylene glycol dimethacrylate, the Diisopropyl azodicarboxylate mass ratio is 1:1.25:40:12:1, and other operations are identical with corresponding embodiment in this step.
Other step is identical with corresponding embodiment, is prepared into Ofloxacine USP 23,17 beta estradiol bimodulus plate molecular imprinting complex microspheres.
In the step 5 of above-described embodiment 1 ~ 3, mixed solution (I) is mixed with mixed solution (II), the monodisperse cross-linked glytidyl methacrylate microballoon 1.12g of the surface bond vinyl that adding step 4 obtains, add ethylene glycol dimethacrylate 252mg as linking agent, Diisopropyl azodicarboxylate 28mg is as initiator, 17 beta estradiols and Ofloxacine USP 23, the monodisperse cross-linked glytidyl methacrylate microballoon of surface bond vinyl, ethylene glycol dimethacrylate, the Diisopropyl azodicarboxylate mass ratio is 1:1.25:80:18:2, and other operations are identical with corresponding embodiment in this step.
Other step is identical with corresponding embodiment, is prepared into Ofloxacine USP 23,17 beta estradiol bimodulus plate molecular imprinting complex microspheres.
Embodiment 6
In above-described embodiment 1 ~ 5, in step 2 with benzoyl peroxide, glytidyl methacrylate, ethylene glycol dimethacrylate, the mixture aqueous solution adding of sodium lauryl sulphate and polyvinyl alcohol fills in the 250mL beaker of hexalin and toluene, be ultrasonic under the 300W with cell crushing instrument at power, every interval 10 seconds ultrasonic 1 time, each ultrasonic 10 seconds, ultrasonic emulsification to the upper strata without oil droplet, join in the monodisperse polystyrene dispersion liquid that step 1 obtains, other operation is prepared into monodisperse cross-linked glytidyl methacrylate microballoon with embodiment is identical accordingly in this step.
In step 4, with monodisperse porous crosslinked methacrylic acid epoxy propyl ester microballoon according to every 100mL1, the amount that adds the monodisperse porous crosslinked methacrylic acid of 3g epoxy propyl ester microballoon in the 4-dioxane adds 1, in the 4-dioxane, 200 rev/mins of stirrings, room temperature swelling 4 hours, logical nitrogen deoxygenation in 20 minutes, add hydroxyethyl methylacrylate, 1, the 4-dioxane, the mixed solution of boron trifluoride diethyl etherate, 60 ℃ were stirred 8 hours, and other operation obtains the monodisperse cross-linked glytidyl methacrylate microballoon of surface bond vinyl with embodiment is identical accordingly in this step.
In step 5, Ofloxacine USP 23 and methacrylic acid are dissolved in the acetonitrile, be ultra-sonic dispersion 5 minutes under the 80W with ultrasonic cleaner at power, 30 rev/mins of stirrings, room temperature prepolymerization 12 hours is prepared into mixed solution (I); 17 beta estradiols and methacrylic acid are dissolved in the acetonitrile, are ultra-sonic dispersion 5 minutes under the 80W with ultrasonic cleaner at power, 30 rev/mins of stirrings, and room temperature prepolymerization 12 hours is prepared into mixed solution (II); Mixed solution (I) is mixed with mixed solution (II), the monodisperse cross-linked glytidyl methacrylate microballoon of the surface bond vinyl that adding step 4 obtains, add ethylene glycol dimethacrylate, Diisopropyl azodicarboxylate, logical nitrogen deoxygenation in 20 minutes, 60 ℃ of polyreactions 48 hours, other operation is identical with corresponding embodiment in this step.
Other step is identical with corresponding embodiment, is prepared into Ofloxacine USP 23,17 beta estradiol bimodulus plate molecular imprinting complex microspheres.
Embodiment 7
In above-described embodiment 1 ~ 5, in step 2 with benzoyl peroxide, glytidyl methacrylate, ethylene glycol dimethacrylate, the mixture aqueous solution adding of sodium lauryl sulphate and polyvinyl alcohol fills in the 250mL beaker of hexalin and toluene, be ultrasonic under the 500W with cell crushing instrument at power, every interval 20 seconds ultrasonic 1 time, each ultrasonic 20 seconds, ultrasonic emulsification to the upper strata without oil droplet, join in the monodisperse polystyrene dispersion liquid that step 1 obtains, other operation is prepared into monodisperse cross-linked glytidyl methacrylate microballoon with embodiment is identical accordingly in this step.
In step 4, with monodisperse porous crosslinked methacrylic acid epoxy propyl ester microballoon according to every 100mL1, the amount that adds the monodisperse porous crosslinked methacrylic acid of 10g epoxy propyl ester microballoon in the 4-dioxane adds 1, in the 4-dioxane, 200 rev/mins of stirrings, room temperature swelling 12 hours, logical nitrogen deoxygenation in 20 minutes, add hydroxyethyl methylacrylate, 1, the 4-dioxane, the mixed solution of boron trifluoride diethyl etherate, 30 ℃ were stirred 15 hours, and other operation obtains the monodisperse cross-linked glytidyl methacrylate microballoon of surface bond vinyl with embodiment is identical accordingly in this step.
In step 5, Ofloxacine USP 23 and methacrylic acid are dissolved in the acetonitrile, be ultra-sonic dispersion 5 minutes under the 80W with ultrasonic cleaner at power, 150 rev/mins of stirrings, room temperature prepolymerization 4 hours is prepared into mixed solution (I); 17 beta estradiols and methacrylic acid are dissolved in the acetonitrile, are ultra-sonic dispersion 5 minutes under the 80W with ultrasonic cleaner at power, 150 rev/mins of stirrings, and room temperature prepolymerization 4 hours is prepared into mixed solution (II); Mixed solution (I) is mixed with mixed solution (II), the monodisperse cross-linked glytidyl methacrylate microballoon of the surface bond vinyl that adding step 4 obtains, add ethylene glycol dimethacrylate, Diisopropyl azodicarboxylate, logical nitrogen deoxygenation in 20 minutes, 70 ℃ of polyreactions 16 hours, other operation is identical with corresponding embodiment in this step.
Other step is identical with corresponding embodiment, is prepared into Ofloxacine USP 23,17 beta estradiol bimodulus plate molecular imprinting complex microspheres.
In order to verify beneficial effect of the present invention, the contriver adopts the Ofloxacine USP 23 of the embodiment of the invention 1 preparation and the non-molecular imprinting complex microsphere of 17 beta estradiol bimodulus plate molecular imprinting complex microspheres and Comparative Examples 1 preparation to carry out various tests, and concrete test situation is as follows:
The preparation method of the non-molecular imprinting complex microsphere of bimodulus plate of Comparative Examples 1 is the monodisperse cross-linked glytidyl methacrylate microballoon for preparing surperficial bonding ethylene base according to the method for the step 1 in the embodiment of the invention 1～4.Do not add template molecule Ofloxacine USP 23,17 beta estradiols, directly with methacrylic acid 70 μ L(0.8mmol) be dissolved in the 15mL acetonitrile, be ultra-sonic dispersion 5 minutes under the 80W with ultrasonic cleaner at power, 50 rev/mins of stirrings, stirring at room 4 hours.The monodisperse cross-linked glytidyl methacrylate microballoon that adds 0.8g surface bond vinyl, adding ethylene glycol dimethacrylate 300 μ L(3mmol), Diisopropyl azodicarboxylate 20mg(0.12mmol), logical nitrogen deoxygenation in 20 minutes, 70 ℃ of polyreactions 24 hours, product is used distilled water, methanol wash successively, 30 ℃ of vacuum-drying 2 hours is prepared into non-molecular imprinting complex microsphere.
Experiment reagent: benzoyl peroxide (BPO, A.R. Tianjin good fortune chemical reagent factory in morning); Glytidyl methacrylate (GMA, Sigma-Aldrich); Ethylene glycol dimethacrylate (EDMA, Sigma-Aldrich); Methacrylic acid (MAA, Sigma-Aldrich); Hydroxyethyl methylacrylate (HEMA, Sigma-Aldrich); Isosorbide-5-Nitrae-dioxane (A.R. Tianjin good fortune chemical reagent factory in morning); DMF (DMF, Tianjin good fortune chemical reagent factory in morning); 17 beta estradiols, trihydroxy-oestrin and oestrone are all purchased the brilliant pure Industrial Co., Ltd. from Shanghai; Ofloxacine USP 23, norfloxicin and paraxin are all bought in the foods in Shaanxi province institute for drug control; Quercetin.
1, chromatography experiment
Take by weighing Ofloxacine USP 23 and 17 beta estradiol bimodulus plate molecular imprinting complex microspheres (MIP), each 0.8g of non-molecular imprinting complex microsphere (NIP) places the 30mL Virahol, ultrasonic homogenate 10 minutes, under 20MPa pressure, with acetonitrile as displacing liquid, wet method dress post (50mm * 4.6mm), take acetonitrile as moving phase, until obtain stable baseline.The chromatographic column of filling with bimodulus plate molecular imprinting complex microsphere is called the trace post, and the chromatographic column of filling with non-molecular imprinting complex microsphere is called non-trace post.With methanol-water solution (80/20, v/v) be moving phase, flow velocity is 0.8mL/ minute, sample size is 10.0 μ L, sample: Ofloxacine USP 23 20 μ g/mL, the acetonitrile solution of 17 beta estradiols, 20 μ g/mL; The detection wavelength is 280nm, has investigated trace post, non-trace post to the reservation situation of template molecule, and is referring to the specific selectivity of table 1 and trace post, referring to Fig. 1 ~ 5, specific as follows:
Two kinds of template molecules of table 1 and comparison thereof the reservation situation on trace post, non-trace post
As can be seen from Table 1, the trace post not only has specific selectivity to two kinds of template molecule Ofloxacine USP 23s and 17 beta estradiols, and the analog norfloxicin of Ofloxacine USP 23, the analog trihydroxy-oestrin of 17 beta estradiols also there is certain specific selectivity, but not the trace post is all very weak to the reservation of five kinds of materials, do not possess specific selectivity, further specify and do not have the trace hole that is complementary with formwork structure in the non-imprinted polymer, with the keying action of all substances all be nonspecific.
As shown in Figure 1, methanol-water solution 40% is under the condition of moving phase, the Ofloxacine USP 23 of one of template all is not eluted within upper 50 minute at the trace post, present very strong retention behavior, and it does not almost keep on non-trace post, and this explanation bimodulus plate molecular imprinting complex microsphere has preferably specific adsorption performance to Ofloxacine USP 23.
As shown in Figure 2, under identical separation condition, another template 17 beta estradiols reservation on the trace post is stronger than non-trace post, shows that bimodulus plate molecular imprinting complex microsphere has very strong specific adsorption to template molecule 17 beta estradiols.
As can be seen from Figure 3, on the trace post, the template molecule Ofloxacine USP 23 was not eluted at 50 minutes, possesses very strong retention behavior, much larger than the reservation of comparison Quercetin, bimodulus plate molecular imprinting complex microsphere does not possess recognition capability to it yet in the reservation of another template molecule 17 beta estradiols.
As can be seen from Figure 4 and Figure 5, all greater than both loading capacities at the non-molecularly imprinted polymer of bimodulus plate (NIP), and bimodulus plate molecularly imprinted polymer (MIP) is basic identical to the loading capacity of two kinds of templates in the loading capacity of bimodulus plate molecularly imprinted polymer (MIP) for two template molecule Ofloxacine USP 23s and 17 beta estradiols.Two kinds of templates that add in the building-up process are Isoequivalent weights, illustrate that the trace effect is of equal value to two kinds of templates, and are not different because of both nature difference selective adsorptions.
2, sample analysis
Milk: take by weighing sample 2.0g (being accurate to 0.001g), place the 25ml volumetric flask, mixed solution with V (acetonitrile): V (water)=85%:15% is settled to scale, the ultrasonic 30min mixing of 80W, move in the centrifuge tube, the centrifugal 10min of 10000rpm/min, get supernatant liquid and add certain density determinand, cross homemade trace post and the homemade solid phase extraction column of other commercialization solid phase extraction fillers, with nitrogen elutriant is blown near dried, methanol constant volume is analyzed the rate of recovery such as Fig. 6 for HPLC-UV after millipore filtration (0.22 μ m) filters.
Mobile phase A: methyl alcohol, Mobile phase B: 0.2% aqueous formic acid; Gradient: 0-15min, A:28%; 15-35min, A:28%-70%.Flow velocity 0.8mL/min detects wavelength: 280nm.The mark-on milk of 6 kinds of materials (2 μ g/mL) is processed filtering with microporous membrane by 0.22 μ m through octadecyl silane (C18), silica gel (silica) and Magnesium Silicate q-agent (Florisil) and bimodulus plate molecular imprinting complex microsphere (MIP), analyzes for HPLC-UV.
Fig. 6 is 6 kinds of microbiotic (Ofloxacine USP 23s, Ciprofloxacin, norfloxicin, 17 beta estradiols, trihydroxy-oestrin and oestrone) mark-on milk (2 μ g/mL) through octadecyl silane (C18), silica gel (silica), after Magnesium Silicate q-agent (Florisil) and bimodulus plate molecular imprinting complex microsphere (MIP) are processed, the rate of recovery under optimum separately extraction conditions, as can be seen from Figure, through MIP to Ofloxacine USP 23, Ciprofloxacin, the rate of recovery of norfloxicin is respectively: 90%, 89% and 98%, to 17 beta estradiols, three kinds of estrogenic rate of recovery of trihydroxy-oestrin and oestrone are all more than 80%, and all be higher than commercial solid phase extraction adsorbents octadecyl silane (C18), silica gel (silica) and Magnesium Silicate q-agent (Florisil), this shows that Solid-Phase Extraction sorbing material that bimodulus plate molecular imprinting complex microsphere can be used as highly selective realizes the Simultaneous purification enrichment to quinolones material and estrogenic chemicals trace components, in the food when multi-medicament rapid detection reference is provided.
Claims (1)
1. the preparation method of an Ofloxacine USP 23 and 17 beta estradiol bimodulus plate molecular imprinting complex microspheres may further comprise the steps:
1) synthetic monodisperse polystyrene dispersion liquid
Vinylbenzene and Diisopropyl azodicarboxylate, polyvinylpyrrolidone are added in the dehydrated alcohol, the mass ratio of vinylbenzene and Diisopropyl azodicarboxylate, polyvinylpyrrolidone, dehydrated alcohol is 1:0.01～0.04:0.1～0.3:7.5～9, ultra-sonic dispersion, logical nitrogen deoxygenation, stir, 70 ℃ were reacted 24 hours, and were prepared into polystyrene; Be 0.2% lauryl sodium sulfate aqueous solution ultra-sonic dispersion with the polystyrene massfraction, obtain the monodisperse polystyrene dispersion liquid;
2) the monodisperse cross-linked glytidyl methacrylate microballoon of preparation
With benzoyl peroxide and glytidyl methacrylate, ethylene glycol dimethacrylate, dispersant solution adds in the mixed solvent of hexalin and toluene, toluene and hexalin, benzoyl peroxide, glytidyl methacrylate, ethylene glycol dimethacrylate, the mass ratio of dispersant solution is 1:2:0.15:2:3:60, be ultrasonic under 300～500W with cell crushing instrument at power, every interval 10～20 seconds ultrasonic 1 time, each ultrasonic 10～20 seconds, ultrasonic emulsification to the upper strata without oil droplet, join in the monodisperse polystyrene dispersion liquid of step 1), the mass ratio of polystyrene is 1:0.1 in glytidyl methacrylate and the monodisperse polystyrene dispersion liquid, 30 ℃ were stirred swelling 10 hours, logical nitrogen deoxygenation, 70 ℃ of polyreactions 24 hours, filter, use successively methyl alcohol, washing with acetone, 60 ℃ of vacuum-drying 4 hours is prepared into monodisperse cross-linked glytidyl methacrylate microballoon;
3) the monodisperse cross-linked glytidyl methacrylate microballoon of extracting
With step 2) the monodisperse cross-linked glytidyl methacrylate microballoon of preparation is with toluene 140 ℃ of extractings 48 hours in cable type extractor according, uses successively dehydrated alcohol, washing with acetone, and drying obtains monodisperse porous crosslinked methacrylic acid epoxy propyl ester microballoon;
4) monodisperse porous crosslinked methacrylic acid epoxy propyl ester microsphere surface bonding ethylene base
The monodisperse porous crosslinked methacrylic acid epoxy propyl ester microballoon of step 3) preparation is added 1, in the 4-dioxane, every 100mL1, add the monodisperse porous crosslinked methacrylic acid of 3～10g epoxy propyl ester microballoon in the 4-dioxane, stirring at room swelling 4～12 hours, logical nitrogen deoxygenation, add hydroxyethyl methylacrylate and 1, the 4-dioxane, the mass ratio of boron trifluoride diethyl etherate is the mixed solution of 1:2～5:4～6, the mass ratio of monodisperse porous crosslinked methacrylic acid epoxy propyl ester microballoon and hydroxyethyl methylacrylate is 1:0.1～2,30～60 ℃ were stirred 8～15 hours, filter, product is used Isosorbide-5-Nitrae-dioxane successively, methyl alcohol, distilled water, washing with acetone, vacuum-drying obtains the monodisperse cross-linked glytidyl methacrylate microballoon of surface bond vinyl;
5) preparation Ofloxacine USP 23 and 17 beta estradiol bimodulus plate molecular imprinting complex microspheres
Be that the amount of 1:2.5～15:250～563 is mixed with 17 beta estradiols and methacrylic acid, acetonitrile according to mass ratio, ultra-sonic dispersion, at room temperature prepolymerization 4～12 hours, rotating speed is 30～150 rev/mins;
Be that the amount of 1:2～12:200～400 is mixed ultra-sonic dispersion, at room temperature prepolymerization 4～12 hours, 30～150 rev/mins of rotating speeds with Ofloxacine USP 23 and methacrylic acid, acetonitrile according to mass ratio;
With 17 beta estradiols, methacrylic acid, the mixed solution of acetonitrile and Ofloxacine USP 23, methacrylic acid, the mixed solution of acetonitrile mixes, in the monodisperse cross-linked glytidyl methacrylate microballoon of the surface bond vinyl of adding step 4), add ethylene glycol dimethacrylate and Diisopropyl azodicarboxylate, 17 beta estradiols and Ofloxacine USP 23, the monodisperse cross-linked glytidyl methacrylate microballoon of surface bond vinyl, ethylene glycol dimethacrylate, the Diisopropyl azodicarboxylate mass ratio is 1:1.25:40～80:12～18:1～2, logical nitrogen deoxygenation, 60～70 ℃ were reacted 16～48 hours, remove Ofloxacine USP 23 and 17 beta estradiols with the mixed solution wash-out of methyl alcohol and acetic acid, the volume ratio of acetic acid and methyl alcohol is 1:4, be neutral with methyl alcohol and water washing to product surface, drying is prepared into Ofloxacine USP 23 and 17 beta estradiol bimodulus plate molecular imprinting complex microspheres;
Above-mentioned steps 1) specification of polyvinylpyrrolidone is k-30 in, and number-average molecular weight is 40000;
Above-mentioned steps 2) dispersion agent is that massfraction is that 0.4% sodium lauryl sulphate and massfraction are that 4% the ratio of polyvinyl alcohol take volume ratio as 1:1 mixed, and the polymerization degree of polyvinyl alcohol is 1700, and alcoholysis degree is 88%.
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