CN101507916B - Preparation method of macrolide antibiotics molecular engram polymer microsphere - Google Patents
Preparation method of macrolide antibiotics molecular engram polymer microsphere Download PDFInfo
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Abstract
The invention discloses a method for preparing macrolide antibiotics molecular engram polymer microspheres, which is characterized by comprising the following steps: dissolving a dispersant, namely polyvinyl alcohol or hydroxyethyl cellulose into secondary distilled water to prepare a water-phase dispersion liquid; dissolving engram molecules and functional monomers into an organic solvent to prepare an oil-phase mixture; adding the oil-phase mixture into the water-phase dispersion liquid under the action of stirring, adding an initiator, namely azo-bis-iso-butyrynitrile into the mixture, performing thermal initiation polymerization on the mixture in water bath, and obtaining polymer microspheres; and adopting an ultrasonic extraction method to elute the engram molecules in a butyl acetate aqueous solution or a methanol solution of acetic acid, using distilled water to wash the engram molecules, and performing vacuum drying on the engram molecules to obtain the macrolide antibiotics molecular engram polymer microspheres. Through the method, the macrolide antibiotics molecular engram polymer microspheres are prepared in water phases and are recognized in the water phases; the reorganization result is close to that obtained by a natural biological molecular recognition system; and the invention provides a method for recognizing, separating and analyzing hydrophilic medicaments .
Description
Technical field
The present invention relates to a kind of preparation method's of molecular blotting polymer microsphere, particularly macrolide antibiotics molecular engram polymer microsphere preparation method.
Background technology
Macrolide antibiotics is to use in the more alkalescence to compose antibiotic, all is to be parent with 12～16 membered macrolides on chemical constitution, a class polyoxy macrolide antibiotic that connects mutually with the sugar of glycosidic bond and 1～3 molecule.Erythromycin (erythromycin is called for short EM) and ROX (roxithromycin) are 14 the most frequently used membered macrolide class antibiotic.Azithromycin (azithromycin) is the 15 yuan of semisynthetic C-9 tertiary amines derived of lactonic ring things, and medecamycin (midecamycin), acetyl spiramycin (spiramycin) are antibiotic semisynthetic medecamycin of semisynthetic 16 membered macrolides and spiramvcin derivative.Erythromycin is the biofermentation antibiotic, and all the other are semisynthetic macrolide antibiotics.
In above-mentioned antibiotic fermentation system and the synthetic system, exist the very similar multicomponent of structure, its antibacterial activity difference, toxicity differs.Obtain highly purified antimicrobial, refine with building-up process in must carry out component and separate, very similar as the structure of Erythromycin A and Erythromycin C, but the Erythromycin C antibacterial activity is more much lower than Erythromycin A, and its toxicity is high more a lot of than Erythromycin A, is impurity in medicine.As medicine, Erythromycin C must be separated with Erythromycin A, with antibacterial activity and the reduction toxicity that improves medicine.Because its structure is very similar, refine with building-up process in be difficult to separate.
The macrolide antibiotics molecular engram polymer that adopts molecular imprinting to prepare can utilize its distinctive space structure effect property and specific recognition, come the molecular configuration of " memory " macrolide antibiotic, thereby possess identification selection ability specific isomers.
The preparation research of molecularly imprinted polymer mainly concentrates in the non-aqueous solvent system for many years, hydrone is considered to weaken the intensive polar solvent of hydrogen bond action between microsphere and the function monomer, easily the combination between microsphere and the functional group is damaged, if the condition of trace is selected the improper failure that just probably causes trace.And the Recognition of Biomolecular system carries out in aqueous environment mostly, the effect of molecularly imprinted polymer in aqueous environment of non-aqueous system preparation is relatively poor, trace in the organic solvent can't be simulated the aqueous environment in the practical application as a rule again, can not satisfy the diversified requirement of environment for use.
Document " number of patent application is 200610023903.7 patent of invention " discloses a kind of preparation method of chloramphenicol molecularly imprinted polymeric microspheres, its preparation be to be used for the chloramphenicol molecularly imprinted polymeric microspheres that food chloramphenicol detect to separate, chloramphenicol belongs to benzene hydrocarbon base amine antibiotic.By literature search, do not find as yet to adopt molecular imprinting to prepare the relevant report of macrolide antibiotics molecular engram polymer microsphere at aqueous phase.
Summary of the invention
Adopt molecular imprinting can not prepare the deficiency of macrolide antibiotics molecular engram polymer microsphere at aqueous phase in order to overcome prior art, the invention provides a kind of preparation method of macrolide antibiotics molecular engram polymer microsphere, prepare macrolide antibiotics molecular engram polymer microsphere at aqueous phase.
The technical solution adopted for the present invention to solve the technical problems: a kind of preparation method of macrolide antibiotics molecular engram polymer microsphere is characterized in may further comprise the steps:
(a) polyethylene of dispersing agent alcohol or hydroxyethylcellulose are dissolved in 50～90 ℃ the redistilled water, are stirred to whole dissolvings, become aqueous dispersion liquid, dispersant dosage is 0.8%～1.5% of a function monomer consumption;
(b) microsphere and function monomer are dissolved in the organic solvent, behind ultrasonication 30～60min, add crosslinking agent under 20～30 ℃ of conditions, ultrasonication 10～20min becomes the oil phase mixed liquor; Microsphere: function monomer: crosslinking agent=1: 2～6: 5～40 (mol ratio);
(c) under 400～500r/min stirring action, the oil phase mixed liquor that step (b) is prepared slowly is added drop-wise in the aqueous dispersion liquid of step (a) preparation, and the volume ratio of oil phase mixed liquor and aqueous dispersion liquid is 1: 6～14; Rate of addition is controlled at 2～3ml/min; Feed N
215～30min, N
2Flow 0.5～1ml/min;
(d) under 400～500r/min stirring action, in the mixed liquor of step (c) preparation, add the initator azodiisobutyronitrile, adopt heat to cause and carry out suspension polymerization, initiator amount is 0.5～1.5% of a function monomer consumption, thermal-initiated polymerization 10～24h in 50～70 ℃ of water-baths, be cooled to room temperature, suction filtration is handled, and obtains polymer microballoon;
(e) polymer microballoon that step (d) is obtained is in the methanol solution of 20～30 ℃, 10～15% butyl acetate aqueous solution or 10～15% acetate, adopt the method wash-out microsphere of ultrasonic extraction, ultrasonic elution time is 30～60min, till can not detecting antibiotic;
(f) use the distilled water cyclic washing, remove residual butyl acetate, methyl alcohol and acetate;
(g) with the molecular blotting polymer microsphere behind the wash-out 50～60 ℃ of following vacuum drying, obtain macrolide antibiotics molecular engram polymer microsphere;
Described microsphere is erythromycin, ROX, azithromycin, 9,3 "-any of diacetyl medecamycin or acetyl spiramycin; Described function monomer is any of α-Jia Jibingxisuan, acrylic acid or acrylamide; Described crosslinking agent is ethylene glycol dimethyl double methacrylate, trimethylolpropane triacrylate or N ', any of N '-dimethyl bisacrylamide ethylene glycol dimethacrylate; Described organic solvent is any of chloroform, second eyeball, toluene, butyl acetate, acetate or methyl alcohol.
The invention has the beneficial effects as follows: the present invention has prepared macrolide antibiotics molecular engram polymer microsphere at aqueous phase, can carry out molecular recognition at aqueous phase, more approach natural biomolecule recognition system, for hydrophilic medicament provides method in aqueous phase identification, separation and analysis.
Below in conjunction with embodiment the present invention is elaborated.
The specific embodiment
Embodiment 1: the polyvinyl alcohol that takes by weighing 0.622g joins in the 100ml redistilled water, stirs down and is warming up to 80 ℃ with its dissolving, and the one-tenth aqueous dispersion liquid changes in the 250ml reactor after being cooled to room temperature.Take by weighing 0.734g erythromycin and be dissolved in the 10ml toluene, add 0.4ml acrylic acid, ultrasonication 40min under 30 ℃ of conditions, make erythromycin and acrylic acid fully act on the formation compound, add 4.655g ethylene glycol dimethyl double methacrylate again, ultrasonic 10min becomes the oil phase mixed liquor.1 part oil phase mixed liquor slowly is added drop-wise under the stirring of 450r/min in 6 parts the aqueous dispersion liquid, rate of addition is controlled at 2ml/min, makes it form milky little suspension emulsion.Feed N
215min, N
2Flow 0.5ml/min.Then the 0.0760g azobisisobutyronitrile is added and stirring, stirring condition 400r/min, thermal-initiated polymerization is 24 hours in 50 ℃ of water-baths.After being cooled to room temperature, filter processing, obtain polymer microballoon.
Above-mentioned polymer microballoon under 20 ℃ of conditions, in 10% the butyl acetate aqueous solution, is adopted the method wash-out microsphere of ultrasonic extraction, and ultrasonic elution time is 30min, till can not detecting the erythromycin molecule at the 492nm place.Remove residual methanol, acetic acid solution with the distilled water cyclic washing again.60 ℃ of vacuum drying of resulting polymers microballoon obtain the erythromycin molecular engram polymer microballoon.
After testing, prepared erythromycin molecular engram polymer microsphere average grain diameter is 60 μ m.The competition substrate is sieve mycin, and separation factor is 1.87.
Embodiment 2: the hydroxyethylcellulose that takes by weighing 0.0451g joins in the 90ml redistilled water, stirs down and is warming up to 50 ℃ with its dissolving, and the one-tenth aqueous dispersion liquid changes in the 250ml reactor after being cooled to room temperature.Taking by weighing 0.734g erythromycin is dissolved in the 7.5ml acetonitrile, add the 0.4ml α-Jia Jibingxisuan, ultrasonication 30min under 25 ℃ of conditions, make erythromycin and methacrylic acid fully act on the formation compound, add 3.960g ethylene glycol dimethyl double methacrylate again, ultrasonic 20min becomes the oil phase mixed liquor.1 part oil phase mixed liquor slowly is added drop-wise under the stirring of 400r/min in 14 parts the aqueous dispersion liquid, rate of addition is controlled at 3ml/min, makes it form milky little suspension emulsion.Feed N
230min, N
2Flow 1ml/min.Then the 0.0760g azobisisobutyronitrile is added and stirring, stirring condition 500r/min, thermal-initiated polymerization is 20 hours in 70 ℃ of water-baths.After being cooled to room temperature, filter processing, obtain polymer microballoon.
With above-mentioned polymer microballoon under 30 ℃ of conditions, in 15% the butyl acetate aqueous solution, adopt the method wash-out microsphere of ultrasonic extraction, ultrasonic elution time is 60min, till can not detecting the erythromycin molecule, remove residual methanol, acetic acid solution with the distilled water cyclic washing again at the 492nm place.50 ℃ of vacuum drying of resulting polymers microballoon.Obtain the erythromycin molecular engram polymer microballoon.
After testing, prepared erythromycin molecular engram polymer microsphere average grain diameter is 45 μ m.The competition substrate is sieve mycin, separation factor 2.25.
Embodiment 3: the hydroxyethylcellulose that takes by weighing 0.055g joins in the 10ml redistilled water, stirs down and is warming up to 80 ℃ with its dissolving, and the one-tenth aqueous dispersion liquid changes in the 250ml reactor after being cooled to room temperature.Taking by weighing 0.734g erythromycin is dissolved in the 7.5ml acetonitrile, add the 0.4ml α-Jia Jibingxisuan, ultrasonication 50min under 20 ℃ of conditions, make erythromycin and α-Jia Jibingxisuan fully act on the formation compound, add 3.960g ethylene glycol dimethyl double methacrylate again, ultrasonic 10min becomes the oil phase mixed liquor.1 part oil phase mixed liquor slowly is added drop-wise under the stirring of 500r/min in 7 parts the aqueous dispersion liquid, rate of addition is controlled at 2ml/min, makes it form milky little suspension emulsion.Feed N
220min, N
2Flow 0.6ml/min.Then the 0.0760g azobisisobutyronitrile is added and stirring, stirring condition 450r/min, thermal-initiated polymerization is 20 hours in 65 ℃ of water-baths.After being cooled to room temperature, filter processing, obtain polymer microballoon.
With above-mentioned polymer microballoon under 25 ℃ of conditions, in 13% the butyl acetate aqueous solution, adopt the method wash-out microsphere of ultrasonic extraction, ultrasonic elution time is 40min, till can not detecting the erythromycin molecule, remove residual methanol, acetic acid solution with the distilled water cyclic washing again at the 492nm place.55 ℃ of vacuum drying of resulting polymers microballoon.Obtain the erythromycin molecular engram polymer microballoon.
After testing, prepared erythromycin molecular engram polymer microsphere average grain diameter is 40 μ m.The competition substrate is sieve mycin, and separation factor is 2.18.
Embodiment 4: take by weighing the 0.622g polyvinyl alcohol and join in the 120ml redistilled water, stir down and be warming up to 90 ℃ with its dissolving, the one-tenth aqueous dispersion liquid changes in the 250ml reactor after being cooled to room temperature.Take by weighing the 0.825g ROX and be dissolved in the 9ml chloroform, add 0.5ml acrylic acid, ultrasonication 40min under 20 ℃ of conditions, make ROX and acrylic acid fully act on the formation compound, add the 2.90g trimethylolpropane triacrylate again, ultrasonic 15min becomes the oil phase mixed liquor.1 part oil phase mixed liquor slowly is added drop-wise under the stirring of 410r/min in 8 parts the aqueous dispersion liquid, rate of addition is controlled at 3ml/min, makes it form milky little suspension emulsion.Feed N
218min, N
2Flow 0.7ml/min.Then the 0.0760g azobisisobutyronitrile is added and stirring, stirring condition 410r/min, thermal-initiated polymerization is 18 hours in 65 ℃ of water-baths.After being cooled to room temperature, filter processing, obtain polymer microballoon.
With above-mentioned polymer microballoon under 22 ℃ of conditions, in 11% the butyl acetate aqueous solution, adopt the method wash-out microsphere of ultrasonic extraction, ultrasonic elution time is 50min, till can not detecting the erythromycin molecule at the 492nm place, remove residual methanol, acetic acid solution with the distilled water cyclic washing again, 54 ℃ of vacuum drying of resulting polymers microballoon.Obtain the ROX molecular blotting polymer microsphere.
After testing, prepared ROX molecular blotting polymer microsphere average grain diameter is 50 μ m.The competition substrate is an azithromycin, and separation factor is 1.62.
Embodiment 5: the hydroxyethylcellulose that takes by weighing 0.0521g joins in the 100ml redistilled water, stirs down and is warming up to 60 ℃ with its dissolving, and the one-tenth aqueous dispersion liquid changes in the 250ml reactor after being cooled to room temperature.Take by weighing the 0.825g ROX and be dissolved in the 9ml chloroform, add 0.5ml acrylic acid, ultrasonication 40min under 30 ℃ of conditions, make ROX and acrylic acid fully act on the formation compound, add the 2.90g trimethylolpropane triacrylate again, ultrasonic 15min becomes the oil phase mixed liquor.1 part oil phase mixed liquor slowly is added drop-wise under the stirring of 420r/min in 9 parts the aqueous dispersion liquid, rate of addition is controlled at 2ml/min, makes it form milky little suspension emulsion.Feed N
216min, N
2Flow 0.8ml/min.Then the 0.0760g azobisisobutyronitrile is added and stirring, stirring condition 430r/min, thermal-initiated polymerization is 18 hours in 55 ℃ of water-baths.After being cooled to room temperature, filter processing, obtain polymer microballoon.
With above-mentioned polymer microballoon under 26 ℃ of conditions, in 14% the butyl acetate aqueous solution, adopt the method wash-out microsphere of ultrasonic extraction, ultrasonic elution time is 35min, till can not detecting the erythromycin molecule at the 492nm place, remove residual methanol, acetic acid solution with the distilled water cyclic washing again, 53 ℃ of vacuum drying of resulting polymers microballoon obtain the ROX molecular blotting polymer microsphere.
After testing, prepared ROX molecular blotting polymer microsphere average grain diameter is 40 μ m.The competition substrate is an azithromycin, and separation factor is 1.93.
Embodiment 6: take by weighing the 0.622g polyvinyl alcohol and add in the 120ml redistilled water, stir and be warming up to 80 ℃ with its dissolving, become aqueous dispersion liquid, change in the 250ml reactor after being cooled to room temperature.Take by weighing the 0.880g azithromycin and be dissolved in the 7.5ml acetonitrile, add the 0.3g acrylamide, ultrasonication 60min under 25 ℃ of conditions, make azithromycin and acrylamide fully act on the formation compound, add 4.655g ethylene glycol dimethyl double methacrylate again, ultrasonic 10min becomes the oil phase mixed liquor.1 part oil phase mixed liquor slowly is added drop-wise under the stirring of 430r/min in 10 parts the aqueous dispersion liquid, rate of addition is controlled at 3ml/min, makes it form milky little suspension emulsion.Feed N
217min, N
2Flow 0.9ml/min.Then the 0.0760g azobisisobutyronitrile is added and stirs, stirring condition 440r/min, thermal-initiated polymerization is 16 hours in 60 ℃ of water-baths, be cooled to room temperature after, filter processing, obtain polymer microballoon.
With above-mentioned polymer microballoon under 28 ℃ of conditions, in 12% the butyl acetate aqueous solution, adopt the method wash-out microsphere of ultrasonic extraction, ultrasonic elution time is 45min, till can not detecting the erythromycin molecule, remove residual methanol, acetic acid solution with the distilled water cyclic washing again at the 492nm place.52 ℃ of vacuum drying of resulting polymers microballoon.Obtain the azithromycin molecular blotting polymer microsphere.
After testing, prepared azithromycin molecular blotting polymer microsphere average grain diameter is 60 μ m.The competition substrate is a ROX, and separation factor is 2.35.
Embodiment 7: take by weighing the 0.0451g hydroxyethylcellulose and add in the 90ml redistilled water, stir and be warming up to 60 ℃ with its dissolving, become aqueous dispersion liquid, change in the 250ml reactor after being cooled to room temperature.Take by weighing the 0.880g azithromycin and be dissolved in the 7.5ml second eyeball, add the 0.3g acrylamide, ultrasonication 60min under 20 ℃ of conditions, make azithromycin and acrylamide fully act on the formation compound, add 4.655g ethylene glycol dimethyl double methacrylate again, ultrasonic 10min becomes the oil phase mixed liquor.1 part oil phase mixed liquor slowly is added drop-wise under the stirring of 460r/min in 11 parts the aqueous dispersion liquid, rate of addition is controlled at 2ml/min, makes it form milky little suspension emulsion.Feed N
222min, N
2Flow 0.5ml/min.Then the 0.0760g azobisisobutyronitrile is added and stirs, stirring condition 460r/min, thermal-initiated polymerization is 16 hours in 65 ℃ of water-baths, be cooled to room temperature after, filter processing, obtain polymer microballoon.
With above-mentioned polymer microballoon under 20 ℃ of conditions, in the methanol solution of 10% acetate, adopt the method wash-out microsphere of ultrasonic extraction, ultrasonic elution time is 55min, till can not detecting the erythromycin molecule, remove residual methanol, acetic acid solution with the distilled water cyclic washing again at the 492nm place.51 ℃ of vacuum drying of resulting polymers microballoon.Obtain the azithromycin molecular blotting polymer microsphere.
After testing, prepared azithromycin molecular blotting polymer microsphere average grain diameter is 45 μ m.The competition substrate is a ROX, and separation factor is 2.18.
Embodiment 8: the hydroxyethylcellulose that takes by weighing 0.0451g joins in the 90ml redistilled water, stirs to be warming up to 50 ℃ with its dissolving, becomes aqueous dispersion liquid, changes in the 250ml reactor after being cooled to room temperature.Take by weighing 0.850g 9; 3 "-diacetyl medecamycin is dissolved in the 8ml acetonitrile, add 0.4ml acrylic acid, ultrasonication 40min under 20 ℃ of conditions makes 9,3 "-diacetyl medecamycin and acrylic acid fully acts on the formation compound; and add 2.16g N ' again; N '-2 methyl bisacrylamide ethylene glycol dimethacrylate, ultrasonic 20min becomes the oil phase mixed liquor.1 part oil phase mixed liquor slowly is added drop-wise under the stirring of 470r/min in 12 parts the aqueous dispersion liquid, rate of addition is controlled at 2ml/min, makes it form milky little suspension emulsion.Feed N
224min, N
2Flow 0.6ml/min.Then the 0.0469g azobisisobutyronitrile is added and stirring, stirring condition 470r/min, thermal-initiated polymerization is 20 hours in 55 ℃ of water-baths.After being cooled to room temperature, filter processing, obtain polymer microballoon.
With above-mentioned polymer microballoon under 30 ℃ of conditions, in the methanol solution of 15% acetate, adopt the method wash-out microsphere of ultrasonic extraction, ultrasonic elution time is 30min, till can not detecting the erythromycin molecule, remove residual methanol, acetic acid solution with the distilled water cyclic washing again at the 492nm place.56 ℃ of vacuum drying of resulting polymers microballoon.Obtain 9,3 "-diacetyl medecamycin molecular blotting polymer microsphere.
After testing, prepared 9,3 "-diacetyl medecamycin molecular blotting polymer microsphere average grain diameter is 55 μ m.The competition substrate is an erythromycin, and separation factor is 1.88.
Embodiment 9: the polyvinyl alcohol that takes by weighing 0.622g joins in the 120ml redistilled water, stirs to be warming up to 90 ℃ with its dissolving, becomes aqueous dispersion liquid, changes in the 250ml reactor after being cooled to room temperature.Take by weighing 0.850g 9; 3 "-diacetyl medecamycin is dissolved in the 8ml acetonitrile, add the 0.3g acrylamide, ultrasonication 60min under 25 ℃ of conditions makes 9,3 "-diacetyl medecamycin and acrylamide fully act on the formation compound; and add 2.16gN ' again; N '-2 methyl bisacrylamide ethylene glycol dimethacrylate, ultrasonic 20min becomes the oil phase mixed liquor.1 part oil phase mixed liquor slowly is added drop-wise under the stirring of 480r/min in 13 parts the aqueous dispersion liquid, rate of addition is controlled at 3ml/min, makes it form milky little suspension emulsion.Feed N
226min, N
2Flow 0.8ml/min.Then the 0.0469g azobisisobutyronitrile is added and stirring, stirring condition 480r/min, thermal-initiated polymerization is 20 hours in 60 ℃ of water-baths.After being cooled to room temperature, filter processing, obtain polymer microballoon.
With above-mentioned polymer microballoon under 25 ℃ of conditions, in the methanol solution of 13% acetate, adopt the method wash-out microsphere of ultrasonic extraction, ultrasonic elution time is 60min, till can not detecting the erythromycin molecule, remove residual methanol, acetic acid solution with the distilled water cyclic washing again at the 492nm place.57 ℃ of vacuum drying of resulting polymers microballoon.Obtain 9,3 "-diacetyl medecamycin molecular blotting polymer microsphere.
After testing, prepared 9,3 "-diacetyl medecamycin molecular blotting polymer microsphere average grain diameter is 60 μ m.The competition substrate is an erythromycin, and separation factor is 1.91.
Embodiment 10: the hydroxyethylcellulose that takes by weighing 0.0451g joins in the 90ml redistilled water, stirs to be warming up to 50 ℃ with its dissolving, becomes aqueous dispersion liquid, changes in the 250ml reactor after being cooled to room temperature.Taking by weighing the 0.922g acetyl spiramycin is dissolved in the 8ml second eyeball, add the 0.3g acrylamide, ultrasonication 40min under 30 ℃ of conditions, make acetyl spiramycin and acrylamide fully act on the formation compound, add 2.16gN ' again, N '-2 methyl bisacrylamide ethylene glycol dimethacrylate, ultrasonic 10min becomes the oil phase mixed liquor.1 part oil phase mixed liquor slowly is added drop-wise under the stirring of 490r/min in 10 parts the aqueous dispersion liquid, rate of addition is controlled at 2ml/min, makes it form milky little suspension emulsion.Feed N
228min, N
2Flow 0.5ml/min.Then the 0.0469g azobisisobutyronitrile is added and stirring, stirring condition 490r/min, thermal-initiated polymerization is 16 hours in 50 ℃ of water-baths.After being cooled to room temperature, filter processing, obtain polymer microballoon.
With above-mentioned polymer microballoon under 26 ℃ of conditions, in the methanol solution of 11% acetate, adopt the method wash-out microsphere of ultrasonic extraction, ultrasonic elution time is 40min, till can not detecting the erythromycin molecule, remove residual methanol, acetic acid solution with the distilled water cyclic washing again at the 492nm place.58 ℃ of vacuum drying of resulting polymers microballoon.Obtain the acetyl spiramycin molecular blotting polymer microsphere.
After testing, prepared acetyl spiramycin molecular blotting polymer microsphere average grain diameter is 47 μ m.The competition substrate is a medecamycin, and separation factor is 1.93.
Embodiment 11: take by weighing the 0.622g polyvinyl alcohol and join in the 90ml redistilled water, stir and to be warming up to 90 ℃ with its dissolving, become aqueous dispersion liquid, change in the 250ml reactor after being cooled to room temperature.Taking by weighing the 0.922g acetyl spiramycin is dissolved in the 8ml acetonitrile, add the 0.5ml methacrylic acid, ultrasonication 60min under 30 ℃ of conditions, make acetyl spiramycin and methacrylic acid fully act on the formation compound, add 2.16gN ' again, N '-2 methyl bisacrylamide ethylene glycol dimethacrylate, ultrasonic 20min becomes the oil phase mixed liquor.1 part oil phase mixed liquor slowly is added drop-wise under the stirring of 450r/min in 8 parts the aqueous dispersion liquid, rate of addition is controlled at 3ml/min, makes it form milky little suspension emulsion.Feed N
229min, N
2Flow 0.9ml/min.Then the 0.0469g azodiisobutyronitrile is added and stirring, stirring condition 410r/min, thermal-initiated polymerization is 18 hours in 70 ℃ of water-baths.After being cooled to room temperature, filter processing, obtain polymer microballoon.
With above-mentioned polymer microballoon under 21 ℃ of conditions, in the methanol solution of 12% acetate, adopt the method wash-out microsphere of ultrasonic extraction, ultrasonic elution time is 50min, till can not detecting the erythromycin molecule, remove residual methanol, acetic acid solution with the distilled water cyclic washing again at the 492nm place.59 ℃ of vacuum drying of resulting polymers microballoon.Obtain the acetyl spiramycin molecular blotting polymer microsphere.
After testing, prepared acetyl spiramycin molecular blotting polymer microsphere average grain diameter is 55 μ m.The competition substrate is a medecamycin, and separation factor is 1.95.
Claims (1)
1. the preparation method of a macrolide antibiotics molecular engram polymer microsphere is characterized in that may further comprise the steps:
(a) polyethylene of dispersing agent alcohol or hydroxyethylcellulose are dissolved in 50～90 ℃ the redistilled water, are stirred to whole dissolvings, become aqueous dispersion liquid, dispersant dosage is 0.8%～1.5% of a function monomer consumption;
(b) microsphere and function monomer are dissolved in the organic solvent, behind ultrasonication 30～60min, add crosslinking agent under 20～30 ℃ of conditions, ultrasonication 10～20min becomes the oil phase mixed liquor; Microsphere: function monomer: crosslinking agent=1: 2～6: 5～40 (mol ratio);
(c) under 400～500r/min stirring action, the oil phase mixed liquor that step (b) is prepared slowly is added drop-wise in the aqueous dispersion liquid of step (a) preparation, and the volume ratio of oil phase mixed liquor and aqueous dispersion liquid is 1: 6～14; Rate of addition is controlled at 2～3ml/min; Feed N
215～30min, N
2Flow 0.5～1ml/min;
(d) under 400～500r/min stirring action, in the mixed liquor of step (c) preparation, add the initator azodiisobutyronitrile, adopt heat to cause and carry out suspension polymerization, initiator amount is 0.5～1.5% of a function monomer consumption, thermal-initiated polymerization 10～24h in 50～70 ℃ of water-baths, be cooled to room temperature, suction filtration is handled, and obtains polymer microballoon;
(e) polymer microballoon that step (d) is obtained is in the methanol solution of 20～30 ℃, 10～15% butyl acetate aqueous solution or 10～15% acetate, adopt the method wash-out microsphere of ultrasonic extraction, ultrasonic elution time is 30～60min, till can not detecting antibiotic;
(f) use the distilled water cyclic washing, remove residual butyl acetate, methyl alcohol and acetate;
(g) with the molecular blotting polymer microsphere behind the wash-out 50～60 ℃ of following vacuum drying, obtain macrolide antibiotics molecular engram polymer microsphere;
Described microsphere is erythromycin, ROX, azithromycin, 9,3 "-any of diacetyl medecamycin or acetyl spiramycin; Described function monomer is any of α-Jia Jibingxisuan, acrylic acid or acrylamide; Described crosslinking agent is trimethylolpropane triacrylate, N ', any of N '-dimethyl bisacrylamide or ethylene glycol dimethacrylate; Described organic solvent is any of chloroform, acetonitrile, toluene, butyl acetate, acetate or methyl alcohol.
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| CN109254062B (en) * | 2018-11-05 | 2021-01-29 | 济南大学 | Preparation method and application of macrolide antibiotic molecularly imprinted electrochemical sensor |
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| CN109942749B (en) * | 2019-03-01 | 2021-10-15 | 浙江工业大学 | Molecularly imprinted polymer and application thereof in adsorption of ascorbic acid |
| CN110204735B (en) * | 2019-05-31 | 2021-10-22 | 中国药科大学 | Preparation method and application of magnetic core-hollow porous molecularly imprinted polymer satellite assembly of macrolide antibiotics |
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| CN1811411A (en) * | 2006-02-16 | 2006-08-02 | 上海交通大学 | Process for producing chloromycetin molecular engram polymer microsphere |
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