CN102718984A - 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 invention has 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-Theelin,dihydro-bimodulus plate molecular imprinting complex microsphere.
Background technology
Microbiotic is medically having important use; But their meta-bolites has substantial connection with some human disease; Can get into environment through the metabolism of life entity; Or get into environment with trade refuse as the parent compound of synthetic other new antibiotics, all can cause direct or indirect harm to the health of people and other biological, ecological living environment.Sanderson is once to open in the risk assessment of medicine, is arranged in order according to be detrimental to health degree with environment to be microbiotic>female hormone>cardiovascular agent>antitumor drug.Ofloxacine USP 23 is third generation quinolones (FQs) Broad spectrum antibiotics; Oestrogenic hormon is one type and disturbs toxic organic pollutants human and other animal endocrine systems; The 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 are used in the aquaculture, if long-term edible animal property food; Wherein residual antibiotic medicine may deposit in human body through food chain, thereby the eater is produced effects such as certain toxicity and potential carcinogenic, teratogenesis, mutagenesis; Therefore, the safety-problems 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 common multiple microbiotic is present in food or the environment with trace or ultra-trace simultaneously, and this their content of correct analysis and risk assessment have brought certain degree of difficulty.Utilize the high recognition capability of molecularly imprinted polymer (MIP), MIP is applied to the separation and the enrichment of drug residue, can solve present drug residue analysis speed, sensitivity and the low problem of the recovery, can also reduce analysis cost simultaneously.
The single template molecule of the most employings of synthetic molecularly imprinted polymer (MIP) at present; When multiple drug residue, it only can detect wherein a kind of, can not detect the medicine of other coexistences simultaneously; Like this, cause omission taking place in testing process or detecting loaded down with trivial details problem.Also there is the people that the multiple medicine in the similar medicine is done template; Be template perhaps, utilize the substance law Synthesis of Molecular Imprinting Polymers, still with two kinds of isomer; It remains similar medicine; Only can detect similar medicine, and its technology in the 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 is the preparation method of the bimodulus plate molecular imprinting complex microsphere of template with Ofloxacine USP 23 and 17 beta estradiols.
The technical scheme that technical solution problem of the present invention is adopted 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, Vinylpyrrolidone polymer are added in the absolute ethyl alcohol; The mass ratio of vinylbenzene and Diisopropyl azodicarboxylate, Vinylpyrrolidone polymer, absolute ethyl alcohol is 1:0.01～0.04:0.1～0.3:7.5～9; Ultra-sonic dispersion, logical nitrogen deoxygenation is stirred; 70 ℃ were reacted 24 hours, and were prepared into PS; It is 0.2% lauryl sodium sulfate aqueous solution ultra-sonic dispersion that PS is used massfraction, obtains the monodisperse polystyrene dispersion liquid;
2) the monodisperse cross-linked GMA microballoon of preparation
Lucidol and GMA, ethylene glycol dimethacrylate, dispersant solution are added in the mixed solvent of hexalin and toluene, and the mass ratio of toluene and hexalin, Lucidol, GMA, ethylene glycol dimethacrylate, dispersant solution is 1:2:0.15:2:3:60, and using the cytoclasis appearance is ultrasonic under 300～500W at power; Every interval 10～20 seconds ultrasonic 1 time; Each ultrasonic 10～20 seconds, ultrasonic emulsification to upper strata did not have oil droplet, joins in the monodisperse polystyrene dispersion liquid of step 1); The mass ratio of PS is 1:0.1 in GMA and the monodisperse polystyrene dispersion liquid; 30 ℃ were stirred swelling 10 hours, logical nitrogen deoxygenation, 70 ℃ of polyreactions 24 hours; Filter; Use methyl alcohol, washing with acetone successively, 60 ℃ of vacuum-drying 4 hours is prepared into monodisperse cross-linked GMA microballoon;
3) the monodisperse cross-linked GMA microballoon of extracting
With step 2) the monodisperse cross-linked GMA microballoon of preparation is with toluene 140 ℃ of extractings 48 hours in cable type extractor according, uses absolute ethyl alcohol, washing with acetone successively, and drying obtains the sour epoxy propyl ester of monodisperse porous crosslinked methacrylic 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 Rocryl 400 and 1, the mass ratio of 4-dioxane, BFEE is the mixed solution of 1:2～5:4～6, and the mass ratio of monodisperse porous crosslinked methacrylic acid epoxy propyl ester microballoon and Rocryl 400 is 1:0.1～2; 30～60 ℃ were stirred 8～15 hours; Filter, product uses 1 successively, 4-dioxane, methyl alcohol, zero(ppm) water, washing with acetone; Vacuum-drying obtains the monodisperse cross-linked GMA microballoon of surface bond vinyl;
5) preparation Ofloxacine USP 23 and 17 beta estradiol bimodulus plate molecular imprinting complex microspheres
Is that the amount of 1:2.5～15:250～563 is mixed with 17 beta estradiols and methylacrylic acid, acetonitrile according to mass ratio, ultra-sonic dispersion, and prepolymerization at room temperature 4～12 hours, rotating speed is 30～150 rev/mins;
Is that the amount of 1:2～12:200～400 is mixed ultra-sonic dispersion, prepolymerization at room temperature 4～12 hours, 30～150 rev/mins of rotating speeds with Ofloxacine USP 23 and methylacrylic acid, acetonitrile according to mass ratio;
The mixed solution of 17 beta estradiols, methylacrylic acid, acetonitrile is mixed with the mixed solution of Ofloxacine USP 23, methylacrylic acid, acetonitrile; In the monodisperse cross-linked GMA microballoon of the surface bond vinyl of adding step 4); Add ethylene glycol dimethacrylate and Diisopropyl azodicarboxylate; The monodisperse cross-linked GMA microballoon of 17 beta estradiols and Ofloxacine USP 23, surface bond vinyl, ethylene glycol dimethacrylate, Diisopropyl azodicarboxylate mass ratio are 1:1.25:20～120:8～20:1～2; Logical nitrogen deoxygenation, 60～70 ℃ were reacted 16～48 hours, and removed Ofloxacine USP 23 and 17 beta estradiols with the mixed solution wash-out of methyl alcohol and acetate; The volume ratio of acetate 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 Vinylpyrrolidone polymer 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% polyvinyl alcohol solution is the mixed of 1:1 with the volume ratio, and the polymerization degree of Z 150PH is 1700, and alcoholysis degree is 88%.
Above-mentioned steps 5) monodisperse cross-linked GMA 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 a solvent; The monodisperse cross-linked GMA microballoon of preparation surface bond vinyl; Monodisperse cross-linked GMA microballoon with the surface bond vinyl is a carrier, and Ofloxacine USP 23 and two kinds of microbiotic of 17 beta estradiols are template, adopts surface imprinted technology to be prepared into Ofloxacine USP 23 and 17 beta estradiol bimodulus plate molecular imprinting complex microspheres; Preparing method's reaction conditions of the present invention is gentle; Can prepare all has recognition performance preferably, the bimodulus plate molecular imprinting complex microsphere of adsorption and desorption and good stability fast to Ofloxacine USP 23 and 17 beta estradiols, purification enrichment when having realized to two types or multiclass trace components heng, in the food multiple medicine the time rapid detection reference is provided.
Description of drawings
Fig. 1 is the color atlas that Ofloxacine USP 23 keeps on trace post and non-trace post.
Fig. 2 is the color atlas that 17 beta estradiols keep on trace post and non-trace post.
Fig. 3 is the color atlas that template molecule and comparison thereof keep on the trace post.
Fig. 4 is bimodulus plate molecular imprinting complex microsphere of the present invention (MIP) and non-molecular imprinting complex microsphere (NIP) adsorption isothermal curve to 17 beta estradiols.
Fig. 5 is bimodulus plate molecular imprinting complex microsphere of the present invention (MIP) and non-molecular imprinting complex microsphere (NIP) adsorption isothermal curve to Ofloxacine USP 23.
Fig. 6 is the 3 kinds of quinolones materials and the 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 handled.
Embodiment
To further explain of the present invention, but the invention is not restricted to these embodiment below in conjunction with accompanying drawing and embodiment.
The preparation method of 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
With 10.908g vinylbenzene, 0.218g Diisopropyl azodicarboxylate, 1.528g number-average molecular weight is that 40000 Vinylpyrrolidone polymer k-30 (dimension chemical industry ltd in Jiaozhuo) adds and fills in the 250mL single port flask of 96g absolute ethyl alcohol; The mass ratio of vinylbenzene and Diisopropyl azodicarboxylate, Vinylpyrrolidone polymer, absolute ethyl alcohol is 1:0.02:0.14:8.8; Use ultrasonic cleaner to be ultra-sonic dispersion under the 80W 20 minutes at power, logical nitrogen deoxygenation in 15 minutes is stirred; 70 ℃ were reacted 24 hours; Absolute ethanol washing is used in spinning, is prepared into PS; Is 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 PS at power;
Step 2: prepare monodisperse cross-linked GMA microballoon
With Lucidol 0.1559g, GMA 1.92g, ethylene glycol dimethacrylate 3.118g and by massfraction is that 0.4% sodium lauryl sulphate and massfraction are that (polymerization degree is 1700 for 4% Z 150PH; Alcoholysis degree is 88%) be that dispersant solution 62.35g that the mixed of 1:1 is processed adds and fills in the 250mL beaker of 1.92g hexalin and 1.0392g toluene according to volume ratio, the mass ratio of toluene and hexalin, Lucidol, GMA, ethylene glycol dimethacrylate, dispersant solution is 1:2:0.15:2:3:60, use the cytoclasis appearance at power as ultrasonic under the 400W; Every interval 15 seconds ultrasonic 1 time; Each ultrasonic 15 seconds, ultrasonic emulsification to upper strata did not have oil droplet, joined in the monodisperse polystyrene dispersion liquid that step 1 obtains; The mass ratio of PS is 1:0.1 in GMA 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,, use methyl alcohol, washing with acetone more successively with 70 ℃ of distilled water washs; 60 ℃ of vacuum-drying 4 hours is prepared into monodisperse cross-linked GMA microballoon.
Step 3: the monodisperse cross-linked GMA microballoon of extracting
The monodisperse cross-linked GMA microballoon of step 2 preparation is placed cable type extractor according; Add 50mL toluene; 140 ℃ of extractings 48 hours; Using absolute ethyl alcohol, washing with acetone successively, is 60 ℃ of dryings 3 hours under the 0.06MPa in vacuum tightness, obtains monodisperse porous crosslinked methacrylic acid epoxy propyl ester microballoon.
Step 4: monodisperse cross-linked GMA 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 adds 2.0g Rocryl 400,5.2g 1; The mixed solution of 4-dioxane, 10.0g BFEE, Rocryl 400 and 1, the mass ratio of 4-dioxane, BFEE are 1:2.6:5; The mass ratio of monodisperse porous crosslinked methacrylic acid epoxy propyl ester microballoon and Rocryl 400 is 1:1, and 45 ℃ were stirred 12 hours, filtered; Product uses 1 successively; 4-dioxane, methyl alcohol, zero(ppm) water, washing with acetone, 30 ℃ of vacuum-drying 2 hours obtains the monodisperse cross-linked GMA 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 methylacrylic acid 126mg are dissolved in the 5.4g acetonitrile; The mass ratio of Ofloxacine USP 23 and methylacrylic acid, acetonitrile is 1:7:300; Use ultrasonic cleaner to be ultra-sonic dispersion under the 80W 5 minutes at power; 50 rev/mins of stirrings, room temperature prepolymerization 8 hours is prepared into mixed solution (I);
17 beta estradiol 14mg and methylacrylic acid 126mg are dissolved in the 5300g acetonitrile; 17 beta estradiols and methylacrylic acid, acetonitrile mass ratio are 1:9:380; Use ultrasonic cleaner to be ultra-sonic dispersion under the 80W 5 minutes 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 GMA microballoon 0.98g of the surface bond vinyl that adding step 4 obtains; As initiator, the monodisperse cross-linked GMA microballoon of 17 beta estradiols and Ofloxacine USP 23, surface bond vinyl, ethylene glycol dimethacrylate, Diisopropyl azodicarboxylate mass ratio are 1:1.25:70:14:1.5 to adding ethylene glycol dimethacrylate 56mg as linking agent, Diisopropyl azodicarboxylate 21mg, logical nitrogen deoxygenation in 20 minutes; 65 ℃ of polyreactions 24 hours; Product is earlier used zero(ppm) water, methanol wash successively, and the volume ratio of using methyl alcohol and acetate again is the elutriant wash-out of 4:1 24 hours, removes Ofloxacine USP 23,17 beta estradiols; Product is washed till neutrality with zero(ppm) water; Use methanol wash again, 30 ℃ of vacuum-drying 2 hours is prepared into Ofloxacine USP 23,17 beta estradiol bimodulus plate molecular imprinting complex microspheres.
With preparation Ofloxacine USP 23 and 17 beta estradiol bimodulus plate molecular imprinting complex microspheres is example, and its preparation method may further comprise the steps:
Step 1: synthetic monodisperse polystyrene dispersion liquid
With 10.908g vinylbenzene, 0.11 Diisopropyl azodicarboxylate, 1.09g molecular-weight average is that 40000 Vinylpyrrolidone polymer k-30 adds and fills in the 250mL single port flask of 82g absolute ethyl alcohol; The mass ratio of vinylbenzene and Diisopropyl azodicarboxylate, Vinylpyrrolidone polymer, absolute ethyl alcohol is 1:0.01:0.1:7.5; Use ultrasonic cleaner to be ultra-sonic dispersion under the 80W 20 minutes 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 GMA microballoon.
Step 3: identical with embodiment 1 obtains monodisperse porous crosslinked methacrylic acid epoxy propyl ester microballoon.
Step 4: monodisperse cross-linked GMA 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 0.2g Rocryl 400,0.4g 1, the mixed solution of 4-dioxane, 0.8g BFEE, Rocryl 400 and 1 in the mixed solution; The mass ratio of 4-dioxane, BFEE is 1:2:4; The mass ratio of monodisperse porous crosslinked methacrylic acid epoxy propyl ester microballoon and Rocryl 400 is 1:0.1, and other operations are identical with embodiment 1, obtain the monodisperse cross-linked GMA microballoon of surface bond vinyl.
Step 5: synthetic Ofloxacine USP 23,17 beta estradiol bimodulus plate molecular imprinting complex microspheres
17 beta estradiol 14mg (0.05mmol) and methylacrylic acid 35mg are dissolved in the 3.5g acetonitrile; 17 beta estradiols and methylacrylic acid, acetonitrile mass ratio are 1:2.5:250; Use ultrasonic cleaner to be ultra-sonic dispersion under the 80W 5 minutes at power; 50 rev/mins of stirrings, room temperature prepolymerization 4 hours is prepared into mixed solution (II);
Ofloxacine USP 23 18mg (0.05mmol) and methylacrylic acid 36mg are dissolved in the 3.6g acetonitrile; The mass ratio of Ofloxacine USP 23 and methylacrylic acid, acetonitrile is 1:2:200; Use ultrasonic cleaner to be ultra-sonic dispersion under the 80W 5 minutes 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 GMA microballoon 0.28g of the surface bond vinyl that adding step 4 obtains; Add ethylene glycol dimethacrylate 112mg as linking agent, Diisopropyl azodicarboxylate 14mg as initiator; The monodisperse cross-linked GMA microballoon of 17 beta estradiols and Ofloxacine USP 23, surface bond vinyl, ethylene glycol dimethacrylate, Diisopropyl azodicarboxylate mass ratio are 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 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
With 10.908g vinylbenzene, 0.4363g Diisopropyl azodicarboxylate, 3.2724g molecular-weight average is that 40000 k-30 Vinylpyrrolidone polymer adds and fills in the 250mL single port flask of 98g absolute ethyl alcohol; The mass ratio of vinylbenzene and Diisopropyl azodicarboxylate, Vinylpyrrolidone polymer, absolute ethyl 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 GMA microballoon.
Step 3: identical with embodiment 1, obtain monodisperse porous crosslinked methacrylic acid epoxy propyl ester microballoon.
Step 4: monodisperse cross-linked GMA 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 2.0g Rocryl 400,10.0g 1, the mixed solution of 4-dioxane, 12.0g BFEE, Rocryl 400 and 1; The mass ratio of 4-dioxane, BFEE is 1:5:6; The mass ratio of monodisperse porous crosslinked methacrylic acid epoxy propyl ester microballoon and Rocryl 400 is 1:2, and other operation is identical with embodiment 1, obtains the monodisperse cross-linked GMA microballoon of surface bond vinyl.
Step 5: synthetic Ofloxacine USP 23,17 beta estradiol integration templates molecular imprinting complex microspheres
17 beta estradiol 14mg (0.05mmol) and methylacrylic acid 210mg are dissolved in the 7.88g acetonitrile; 17 beta estradiols and methylacrylic acid, acetonitrile mass ratio are 1:15:563; Use ultrasonic cleaner to be ultra-sonic dispersion under the 80W 5 minutes at power; 50 rev/mins of stirrings, room temperature prepolymerization 4 hours is prepared into mixed solution (II);
Ofloxacine USP 23 18mg (0.05mmol) and methylacrylic acid 216mg are dissolved in the 7.20g acetonitrile; The mass ratio of Ofloxacine USP 23 and methylacrylic acid, acetonitrile is 1:12:400; Use ultrasonic cleaner to be ultra-sonic dispersion under the 80W 5 minutes 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 GMA microballoon 1.68g of the surface bond vinyl that adding step 4 obtains; Add ethylene glycol dimethacrylate 280mg as linking agent, Diisopropyl azodicarboxylate 28mg as initiator; The monodisperse cross-linked GMA microballoon of 17 beta estradiols and Ofloxacine USP 23, surface bond vinyl, ethylene glycol dimethacrylate, Diisopropyl azodicarboxylate mass ratio are 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 the foregoing description 1 ~ 3; Mixed solution (I) is mixed with mixed solution (II); The monodisperse cross-linked GMA microballoon 0.56g of the surface bond vinyl that adding step 4 obtains; Add ethylene glycol dimethacrylate 168mg as linking agent, Diisopropyl azodicarboxylate 14mg as initiator; The monodisperse cross-linked GMA microballoon of 17 beta estradiols and Ofloxacine USP 23, surface bond vinyl, ethylene glycol dimethacrylate, Diisopropyl azodicarboxylate mass ratio are 1:1.25:40:12:1, and other operations are identical with respective embodiments in this step.
Other step is identical with respective embodiments, is prepared into Ofloxacine USP 23,17 beta estradiol bimodulus plate molecular imprinting complex microspheres.
In the step 5 of the foregoing description 1 ~ 3; Mixed solution (I) is mixed with mixed solution (II); The monodisperse cross-linked GMA microballoon 1.12g of the surface bond vinyl that adding step 4 obtains; Add ethylene glycol dimethacrylate 252mg as linking agent, Diisopropyl azodicarboxylate 28mg as initiator; The monodisperse cross-linked GMA microballoon of 17 beta estradiols and Ofloxacine USP 23, surface bond vinyl, ethylene glycol dimethacrylate, Diisopropyl azodicarboxylate mass ratio are 1:1.25:80:18:2, and other operations are identical with respective embodiments in this step.
Other step is identical with respective embodiments, is prepared into Ofloxacine USP 23,17 beta estradiol bimodulus plate molecular imprinting complex microspheres.
In the foregoing description 1 ~ 5; Mixture aqueous solution adding with Lucidol, GMA, ethylene glycol dimethacrylate, sodium lauryl sulphate and Z 150PH in step 2 fills in the 250mL beaker of hexalin and toluene; Use the cytoclasis appearance at power as ultrasonic under the 300W, every interval 10 seconds ultrasonic 1 time, each ultrasonic 10 seconds; Ultrasonic emulsification to upper strata does not have oil droplet; Join in the monodisperse polystyrene dispersion liquid that step 1 obtains, in this step other operation identical with respective embodiments, be prepared into monodisperse cross-linked GMA microballoon.
In step 4, 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 with monodisperse porous crosslinked methacrylic acid epoxy propyl ester microballoon; In the 4-dioxane, 200 rev/mins of stirrings, room temperature swelling 4 hours; Logical nitrogen deoxygenation in 20 minutes; Add Rocryl 400,1, the mixed solution of 4-dioxane, BFEE, 60 ℃ were stirred 8 hours; Other operation is identical with respective embodiments in this step, obtains the monodisperse cross-linked GMA microballoon of surface bond vinyl.
In step 5, Ofloxacine USP 23 and methylacrylic acid are dissolved in the acetonitrile, use ultrasonic cleaner to be ultra-sonic dispersion under the 80W 5 minutes at power, 30 rev/mins of stirrings, room temperature prepolymerization 12 hours is prepared into mixed solution (I); 17 beta estradiols and methylacrylic acid are dissolved in the acetonitrile, use ultrasonic cleaner to be ultra-sonic dispersion under the 80W 5 minutes at power, 30 rev/mins of stirrings, room temperature prepolymerization 12 hours is prepared into mixed solution (II); Mixed solution (I) is mixed with mixed solution (II); The monodisperse cross-linked GMA 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 respective embodiments in this step.
Other step is identical with respective embodiments, is prepared into Ofloxacine USP 23,17 beta estradiol bimodulus plate molecular imprinting complex microspheres.
Embodiment 7
In the foregoing description 1 ~ 5; Mixture aqueous solution adding with Lucidol, GMA, ethylene glycol dimethacrylate, sodium lauryl sulphate and Z 150PH in step 2 fills in the 250mL beaker of hexalin and toluene; Use the cytoclasis appearance at power as ultrasonic under the 500W, every interval 20 seconds ultrasonic 1 time, each ultrasonic 20 seconds; Ultrasonic emulsification to upper strata does not have oil droplet; Join in the monodisperse polystyrene dispersion liquid that step 1 obtains, in this step other operation identical with respective embodiments, be prepared into monodisperse cross-linked GMA microballoon.
In step 4, 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 with monodisperse porous crosslinked methacrylic acid epoxy propyl ester microballoon; In the 4-dioxane, 200 rev/mins of stirrings, room temperature swelling 12 hours; Logical nitrogen deoxygenation in 20 minutes; Add Rocryl 400,1, the mixed solution of 4-dioxane, BFEE, 30 ℃ were stirred 15 hours; Other operation is identical with respective embodiments in this step, obtains the monodisperse cross-linked GMA microballoon of surface bond vinyl.
In step 5, Ofloxacine USP 23 and methylacrylic acid are dissolved in the acetonitrile, use ultrasonic cleaner to be ultra-sonic dispersion under the 80W 5 minutes at power, 150 rev/mins of stirrings, room temperature prepolymerization 4 hours is prepared into mixed solution (I); 17 beta estradiols and methylacrylic acid are dissolved in the acetonitrile, use ultrasonic cleaner to be ultra-sonic dispersion under the 80W 5 minutes at power, 150 rev/mins of stirrings, room temperature prepolymerization 4 hours is prepared into mixed solution (II); Mixed solution (I) is mixed with mixed solution (II); The monodisperse cross-linked GMA 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 respective embodiments in this step.
Other step is identical with respective embodiments, 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 following:
The preparation method of the non-molecular imprinting complex microsphere of bimodulus plate of Comparative Examples 1 is the monodisperse cross-linked GMA microballoon for preparing the surface bond vinyl 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 methylacrylic acid 70 μ L (0.8mmol) are dissolved in the 15mL acetonitrile, use ultrasonic cleaner to be ultra-sonic dispersion under the 80W 5 minutes, 50 rev/mins of stirrings, stirring at room 4 hours at power.The monodisperse cross-linked GMA microballoon that adds 0.8g surface bond vinyl; Add 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 zero(ppm) water, methanol wash successively; 30 ℃ of vacuum-drying 2 hours is prepared into non-molecular imprinting complex microsphere.
Experiment reagent: Lucidol (BPO, A.R. Tianjin good fortune chemical reagent in morning factory); GMA (GMA, Sigma-Aldrich); Ethylene glycol dimethacrylate (EDMA, Sigma-Aldrich); Methylacrylic acid (MAA, Sigma-Aldrich); Rocryl 400 (HEMA, Sigma-Aldrich); 1,4-dioxane (A.R. Tianjin good fortune chemical reagent in morning factory); N, dinethylformamide (DMF, Tianjin good fortune chemical reagent in morning factory); 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 the food and medicine check institute in Shaanxi Province; 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); With the acetonitrile is moving phase, up to obtaining 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, the non-trace post reservation situation to 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
Can find out 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 to the reservation of five kinds of materials all very a little less than; 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 materials all be nonspecific.
Can know by Fig. 1; Methanol-water solution 40% is under the condition of moving phase; The Ofloxacine USP 23 of one of template is not all eluted within last 50 minute at the trace post; Demonstrate very strong retention behavior, and it keeps not almost on non-trace post, this explanation bimodulus plate molecular imprinting complex microsphere has specific adsorption performance preferably to Ofloxacine USP 23.
Can know that by Fig. 2 under identical separation condition, another template 17 beta estradiols reservation on the trace post is stronger than non-trace post, show that bimodulus plate molecular imprinting complex microsphere has very strong specific adsorption to template molecule 17 beta estradiols.
As can beappreciated from fig. 3; On the trace post; The template molecule Ofloxacine USP 23 was not eluted at 50 minutes; Possess 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.
Can find out from Fig. 4 and Fig. 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 to wait amount of substance, explain 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, be settled to scale with the mixed solution of V (acetonitrile): V (water)=85%:15%; The ultrasonic 30min mixing of 80W moves 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 and do methanol constant volume;, millipore filtration (0.22 μ m) supply HPLC-UV to analyze the recovery such as Fig. 6 after filtering.
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 through octadecyl silane (C18), silica gel (silica) and Magnesium Silicate q-agent (Florisil) and bimodulus plate molecular imprinting complex microsphere (MIP) handles after the filtering with microporous membrane of 0.22 μ m supplies HPLC-UV to analyze.
Fig. 6 is that the mark-on milk (2 μ g/mL) of 6 kinds of microbiotic (Ofloxacine USP 23, CIPROFLOXACIN USP 24, norfloxicin, 17 beta estradiols, trihydroxy-oestrin and oestrone) is after octadecyl silane (C18), silica gel (silica), Magnesium Silicate q-agent (Florisil) and bimodulus plate molecular imprinting complex microsphere (MIP) are handled; The recovery under optimum separately extraction conditions; Can find out by figure; Through MIP the recovery of Ofloxacine USP 23, CIPROFLOXACIN USP 24, norfloxicin is respectively: 90%, 89% and 98%; To 17 beta estradiols, trihydroxy-oestrin and three kinds of estrogenic recovery of oestrone 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 purification enrichment when SPE sorbing material that bimodulus plate molecular imprinting complex microsphere can be used as highly selective is realized quinolones material and estrogenic chemicals trace components heng, in the food multiple medicine the time rapid detection reference is provided.
Claims (4)
1. 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, Vinylpyrrolidone polymer are added in the absolute ethyl alcohol; The mass ratio of vinylbenzene and Diisopropyl azodicarboxylate, Vinylpyrrolidone polymer, absolute ethyl alcohol is 1:0.01～0.04:0.1～0.3:7.5～9; Ultra-sonic dispersion, logical nitrogen deoxygenation is stirred; 70 ℃ were reacted 24 hours, and were prepared into PS; It is 0.2% lauryl sodium sulfate aqueous solution ultra-sonic dispersion that PS is used massfraction, obtains the monodisperse polystyrene dispersion liquid;
2) the monodisperse cross-linked GMA microballoon of preparation
Lucidol and GMA, ethylene glycol dimethacrylate, dispersant solution are added in the mixed solvent of hexalin and toluene, and the mass ratio of toluene and hexalin, Lucidol, GMA, ethylene glycol dimethacrylate, dispersant solution is 1:2:0.15:2:3:60, and using the cytoclasis appearance is ultrasonic under 300～500W at power; Every interval 10～20 seconds ultrasonic 1 time; Each ultrasonic 10～20 seconds, ultrasonic emulsification to upper strata did not have oil droplet, joins in the monodisperse polystyrene dispersion liquid of step 1); The mass ratio of PS is 1:0.1 in GMA and the monodisperse polystyrene dispersion liquid; 30 ℃ were stirred swelling 10 hours, logical nitrogen deoxygenation, 70 ℃ of polyreactions 24 hours; Filter; Use methyl alcohol, washing with acetone successively, 60 ℃ of vacuum-drying 4 hours is prepared into monodisperse cross-linked GMA microballoon;
3) the monodisperse cross-linked GMA microballoon of extracting
With step 2) the monodisperse cross-linked GMA microballoon of preparation is with toluene 140 ℃ of extractings 48 hours in cable type extractor according, uses absolute ethyl alcohol, washing with acetone successively, and drying obtains the sour epoxy propyl ester of monodisperse porous crosslinked methacrylic 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 Rocryl 400 and 1, the mass ratio of 4-dioxane, BFEE is the mixed solution of 1:2～5:4～6, and the mass ratio of monodisperse porous crosslinked methacrylic acid epoxy propyl ester microballoon and Rocryl 400 is 1:0.1～2; 30～60 ℃ were stirred 8～15 hours; Filter, product uses 1 successively, 4-dioxane, methyl alcohol, zero(ppm) water, washing with acetone; Vacuum-drying obtains the monodisperse cross-linked GMA microballoon of surface bond vinyl;
5) preparation Ofloxacine USP 23 and 17 beta estradiol bimodulus plate molecular imprinting complex microspheres
Is that the amount of 1:2.5～15:250～563 is mixed with 17 beta estradiols and methylacrylic acid, acetonitrile according to mass ratio, ultra-sonic dispersion, and prepolymerization at room temperature 4～12 hours, rotating speed is 30～150 rev/mins;
Is that the amount of 1:2～12:200～400 is mixed ultra-sonic dispersion, prepolymerization at room temperature 4～12 hours, 30～150 rev/mins of rotating speeds with Ofloxacine USP 23 and methylacrylic acid, acetonitrile according to mass ratio;
The mixed solution of 17 beta estradiols, methylacrylic acid, acetonitrile is mixed with the mixed solution of Ofloxacine USP 23, methylacrylic acid, acetonitrile; In the monodisperse cross-linked GMA microballoon of the surface bond vinyl of adding step 4); Add ethylene glycol dimethacrylate and Diisopropyl azodicarboxylate; The monodisperse cross-linked GMA microballoon of 17 beta estradiols and Ofloxacine USP 23, surface bond vinyl, ethylene glycol dimethacrylate, Diisopropyl azodicarboxylate mass ratio are 1:1.25:20～120:8～20:1～2; Logical nitrogen deoxygenation, 60～70 ℃ were reacted 16～48 hours, and removed Ofloxacine USP 23 and 17 beta estradiols with the mixed solution wash-out of methyl alcohol and acetate; The volume ratio of acetate 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.
2. the preparation method of Ofloxacine USP 23 according to claim 1 and 17 beta estradiol bimodulus plate molecular imprinting complex microspheres, it is characterized in that: the specification of Vinylpyrrolidone polymer is k-30 in the said step 1), number-average molecular weight is 40000.
3. the preparation method of Ofloxacine USP 23 according to claim 1 and 17 beta estradiol bimodulus plate molecular imprinting complex microspheres; It is characterized in that: said step 2) dispersion agent is that massfraction is that 0.4% sodium lauryl sulphate and massfraction are that 4% Z 150PH is the mixed of 1:1 with the volume ratio; The polymerization degree of Z 150PH is 1700, and alcoholysis degree is 88%.
4. the preparation method of Ofloxacine USP 23 according to claim 1 and 17 beta estradiol bimodulus plate molecular imprinting complex microspheres is characterized in that: monodisperse cross-linked GMA 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 step 5).
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