CN102408288B - Method for separating chiral drug by using protein-functionalized magnetic nanoparticles - Google Patents
Method for separating chiral drug by using protein-functionalized magnetic nanoparticles Download PDFInfo
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- 239000003814 drug Substances 0.000 title claims abstract description 40
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- GSDSWSVVBLHKDQ-UHFFFAOYSA-N 9-fluoro-3-methyl-10-(4-methylpiperazin-1-yl)-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylic acid Chemical compound FC1=CC(C(C(C(O)=O)=C2)=O)=C3N2C(C)COC3=C1N1CCN(C)CC1 GSDSWSVVBLHKDQ-UHFFFAOYSA-N 0.000 claims description 5
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- 229960002009 naproxen Drugs 0.000 claims description 5
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- 229960001699 ofloxacin Drugs 0.000 claims description 5
- ADIMAYPTOBDMTL-UHFFFAOYSA-N oxazepam Chemical compound C12=CC(Cl)=CC=C2NC(=O)C(O)N=C1C1=CC=CC=C1 ADIMAYPTOBDMTL-UHFFFAOYSA-N 0.000 claims description 5
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- 229960005080 warfarin Drugs 0.000 claims description 5
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- 108090001008 Avidin Proteins 0.000 claims description 4
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 4
- SXRSQZLOMIGNAQ-UHFFFAOYSA-N Glutaraldehyde Chemical group O=CCCCC=O SXRSQZLOMIGNAQ-UHFFFAOYSA-N 0.000 claims description 4
- 230000001461 cytolytic effect Effects 0.000 claims description 4
- 229920001464 poly(sodium 4-styrenesulfonate) Polymers 0.000 claims description 4
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- OMWQUXGVXQELIX-UHFFFAOYSA-N bitoscanate Chemical compound S=C=NC1=CC=C(N=C=S)C=C1 OMWQUXGVXQELIX-UHFFFAOYSA-N 0.000 claims description 3
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- DCPMPXBYPZGNDC-UHFFFAOYSA-N hydron;methanediimine;chloride Chemical compound Cl.N=C=N DCPMPXBYPZGNDC-UHFFFAOYSA-N 0.000 claims description 3
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- Peptides Or Proteins (AREA)
Abstract
The invention discloses a method for separating a chiral drug by using protein-functionalized magnetic nanoparticles. The method comprises the following steps: (1) modifying the surfaces of superparamagnetic particles by adopting a physical adsorption method; (2) loading a protein with a chiral recognition function; and (3) filling the protein-modified superparamagnetic nanoparticles in a glass tube for a magnetically stabilized bed, placing the glass tube in an axial magnetically stabilized bed, pumping a chiral drug racemic aqueous solution in the glass tube from the bottom of the filled cylindrical container to continuously obtain liquid containing the separation product of one enantiomer on the top of the cylindrical container, wherein the superparamagnetic particle adsorbate is the separation product of the other enantiomer. The method is simple to operate, and has mild conditions, short reaction time and large protein loading quantity; the drug recognition function of protein can be maintained; and by adopting the magnetically stabilized bed technology to reinforce the separation process, the optical purity of the product can be obviously increased and the continuous operation of chiral separation can be realized.
Description
Technical field
The invention belongs to medical technical field, concrete relate to a kind of method of applying protein function magnetic nanoparticle resolving chiral medicine.
Background technology
The enantiomer of chiral drug shows different physiological behaviors usually---they often a kind of steric isomer drug effect is arranged, and its mirror image molecule or there is toxic side effect or there is contrary drug effect or just there is no drug effect [J.Chromat.A at all, 2001,906,3-33].Therefore, research and develop the focus that high efficiency single enantiomer chipal compounds production technology has become scientific research department and industry member, the chipal compounds for preparing single enantiomer will rely on stereoselectivity to synthesize and the chiral separation technology.At present, the method split for enantiomers of chiral drugs mainly contains crystallization process, film Split Method, chromatography, capillary electrophoresis etc.Chromatogram and capillary electrophoresis are widely used, though separation efficiency is high, operation can not serialization, does not reach preparative-scale, is only applicable to pharmaceutical analysis and detection; And crystallization process can reach preparative-scale, but require the medicine racemic modification to exist with aggregate form, thereby limited the kind of separable medicine; Film splits can carry out operate continuously, but the contradiction between the equilibrium separation factor and flux is problem demanding prompt solution [Anal.Chem.2010,82,4712-4722].
Albumen extensively is used as chiral selector because of its unique drug binding site and stereoselectivity, wherein bovine serum albumin, ovoglycoprotein, glycoprotein, ovomucoid, cellobiohydrolase, avidin, Quimotrase etc. have been successfully applied to high performance liquid chromatography and capillary electrophoresis fractionation drug enantiomer, there is good separation effect [J.Chromat.A, 2000,875,235-254; J.Chromat.A, 2001,906,253-273].The immobilized albumen of Chinese patent 200510110689.4 a kind of carbon nanotube of invention as stationary phase be filled in the PMMA chip separate logical in, carry out the method for chiral separation analysis based on micro flow chip, this method compartment analysis speed is fast, be applicable to drug testing and analysis, but, because volume containing the sample is little, be unsuitable for the preparative that treatment capacity is large and separate.Chinese patent 200810113779.2 has been invented a kind of tandem continuous multilevel chiral disassemble apparatus, at first utilize macromole chiral selector (BSA etc.) and medicine to be split to carry out the site recognition reaction, then by ripe ultrafiltration or nanofiltration membrane, realize splitting, this method has overcome chiral film and has separated flux and the lower shortcoming of enantio-selectivity, but device is comparatively complicated, disengaging time 1-4h.
The functional magnetic composite nano-granule, owing to thering is magnetic responsiveness and surface-functional simultaneously, by magnetic stablizing bed technology, separate targets molecule from medium fast and efficiently, at field widespread use [Biotechnol.Bioeng. such as biomedicine, cytology and physiotechnologys, 1997,53,79-87; Angew.Chem.Int.Ed., 2009,48,1620-1624].In recent years, due to the demand of biological detection and enzyme technology, the method for the magnetic nanoparticle surface being carried out to protein modification has obtained increasing concern.At present, supperparamagnetic particles area load functionalization albumen is split for enantiomers of chiral drugs, and also do not report by the research of magnetic stablizing bed technique.
Summary of the invention
The objective of the invention is to overcome deficiency of the prior art, the method for application protein function magnetic nanoparticle resolving chiral medicine is provided.
Technical scheme of the present invention is summarized as follows:
The method of application protein function magnetic nanoparticle resolving chiral medicine, comprise the steps:
(1) adopt physisorphtion to the supperparamagnetic particles modifying surface:
The Ionomer aqueous solution equal-volume that the supperparamagnetic particles aqueous solution that is 2-10g/L by mass concentration is 0.02-1g/L with mass concentration mixes, and at 10-45 ℃, adsorbs 20-40 minute, obtains the supperparamagnetic particles of surface modification;
(2) load has the protein of chiral recognition effect:
The protein water soln equal-volume that the supperparamagnetic particles aqueous solution of the described surface modification that is 2-10g/L by mass concentration is 0.8-10g/L with concentration mixes, and adsorbs 2-5h, obtains the magnetic nanoparticle of protein modification; Described protein is bovine serum albumin, human serum albumin, α 1 acid glycoprotein, ovomucoid, ovoglycoprotein or avidin;
(3) superparamagnetic nano particle of described protein modification is filled into for magnetic stablizing bed Glass tubing, and be placed in the axial magnetic stable bed, under the condition that is the 100-5000 oersted in magneticstrength, the column shape container bottom of the chiral drug racemic modification aqueous solution that is 1-500mg/L by mass concentration from filling pumps into the 0.2-10mL/min flow velocity, obtain continuously the liquid of the separated product that contains a kind of enantiomer at the column shape container top, and the separated product that the supperparamagnetic particles adsorptive is another kind of enantiomer.
Described supperparamagnetic particles is that median size is the Fe that 10-80nm, saturation magnetization are 10-80emu/g
3o
4, γ-Fe
2o
3, CoFe
2o
4, NiFe
2o
4or Ni
0.5zn
0.5fe
2o
4.
Described Ionomer is diallyl dimethyl ammoniumchloride, polymine, glycol-chitosan, polypropylene amine, polyacrylic acid or poly (sodium 4-styrenesulfonate).
Described in described step (1), the mass concentration of the Ionomer aqueous solution is 0.1-0.5g/L, and described temperature is 20-30 ℃.
Described in described step (3), magneticstrength is the 2000-4000 oersted, and described chiral drug racemic modification aqueous solution mass concentration is 5-100mg/L, and described flow velocity is 1-5mL/min.
Described chiral drug is Ibuprofen BP/EP, warfarin, Ofloxacine USP 23, Naproxen Base, Ketoprofen, oxazepam, flurbiprofen, citalopram, Proprasylyte or Toldrin.
The method of the second application protein function magnetic nanoparticle resolving chiral medicine, comprise the steps:
(1) adopt chemical bonding to the supperparamagnetic particles modifying surface:
Making the concentration of supperparamagnetic particles powder in the silylating reagent solution that is 0.3-10% by supperparamagnetic particles powder immersion concentration expressed in percentage by volume is 1-10g/L, and at 25-130 ℃, reaction 3-48h, separate, and obtains the supperparamagnetic particles of surface modification; The solvent of described silylating reagent solution is: toluene, hexanaphthene or ethanol;
(2) load has the protein of chiral recognition effect:
The protein water soln equal-volume that the supperparamagnetic particles aqueous solution of the described surface modification that is 2-10g/L by mass concentration is 0.8-10g/L with mass concentration mixes, add again covalently bound reagent, making covalently bound reagent volumetric molar concentration is 0.005-0.2mol/L, react 2-5h, obtain the magnetic nanoparticle of protein modification; Described protein is bovine serum albumin, human serum albumin, α 1 acid glycoprotein, ovomucoid, ovoglycoprotein, stomach en-or cellulolytic enzyme I;
(3) superparamagnetic nano particle of described protein modification is filled into for magnetic stablizing bed Glass tubing, and be placed in the axial magnetic stable bed, under the condition that is the 100-5000 oersted in magneticstrength, the column shape container bottom of the chiral drug racemic modification aqueous solution that is 1-500mg/L by mass concentration from filling pumps into the 0.2-10mL/min flow velocity, obtain continuously the liquid of the separated product that contains a kind of enantiomer at the column shape container top, and the separated product that the supperparamagnetic particles adsorptive is another kind of enantiomer.
Described supperparamagnetic particles is that median size is the Fe that 10-80nm, saturation magnetization are 10-80emu/g
3o
4, γ-Fe
2o
3, CoFe
2o
4, NiFe
2o
4or Ni
0.5zn
0.5fe
2o
4.
Described silylating reagent is aminopropyl trimethoxysilane or mercaptopropyl trimethoxysilane.
Described covalently bound reagent is glutaraldehyde, ethyl-(3-dimethyl propyl) carbodiimide hydrochloride, nitrogen-succinimido-3 (2-pyridine dithio)-propionic ester or bitoscanate.
Described in described step (1), the concentration expressed in percentage by volume of silylating reagent solution is 1-5%, and described temperature is 40-80 ℃, and the described reaction times is 6-12h.
Described in described step (3), magneticstrength is the 2000-4000 oersted, and described chiral drug racemic modification aqueous solution mass concentration is 5-100mg/L, and described flow velocity is 1-5mL/min.
Described chiral drug is Ibuprofen BP/EP, warfarin, Ofloxacine USP 23, Naproxen Base, Ketoprofen, oxazepam, flurbiprofen, citalopram, Proprasylyte or Toldrin.
Advantage of the present invention:
(1) method of the present invention is easy and simple to handle, mild condition, and the reaction times is short, and the proteinaceous solid carrying capacity is large and can keep its medicine recognition capability;
(2) magnetic stablizing bed technique split process significantly improves optical purity of products, has realized the continuous operation of chiral separation.
Embodiment
The following examples are in order to enable those skilled in the art to understand better the present invention, but the present invention are not imposed any restrictions.
The preparation of supperparamagnetic particles is even with the synthetic particle diameter of the methods such as low-temperature co-precipitation method, overcritical comminution granulation, hydrothermal synthesis method, sol-gel method, micro emulsion method, presoma thermal decomposition method, as to have superparamagnetism nano particle.
Embodiment 1
A kind of method of applying protein function magnetic nanoparticle resolving chiral medicine, comprise the steps:
(1) adopt physisorphtion to the supperparamagnetic particles modifying surface:
The diallyl dimethyl ammoniumchloride aqueous solution equal-volume that the supperparamagnetic particles aqueous solution that is 2g/L by mass concentration is 0.1g/L with mass concentration mixes, and at 25 ℃, adsorbs 25 minutes, obtains the supperparamagnetic particles of surface modification; Described supperparamagnetic particles is that median size is the Fe that 15nm, saturation magnetization are 70emu/g
3o
4;
(2) load has the protein of chiral recognition effect:
The Bovine Serum Albumin in Aqueous Solution equal-volume that the supperparamagnetic particles aqueous solution of the described surface modification that is 5g/L by mass concentration is 1g/L with concentration mixes, and adsorbs 3h, obtains the magnetic nanoparticle of protein modification;
(3) superparamagnetic nano particle of described protein modification is filled into for magnetic stablizing bed Glass tubing, and be placed in the axial magnetic stable bed, under the condition that is 2400 oersteds in magneticstrength, the column shape container bottom of the chirality Ibuprofen BP/EP racemic modification aqueous solution that is 5mg/L by mass concentration from filling pumps into the 1mL/min flow velocity, obtain continuously the liquid of the separated product that contains a kind of enantiomer at the column shape container top, enantiomeric excess value is 99.0%, and the separated product that the supperparamagnetic particles adsorptive is another kind of enantiomer.
The method of the present embodiment also can be used for resolving chiral Ofloxacine USP 23, warfarin or Racemic propranolol.
Embodiment 2
A kind of method of applying protein function magnetic nanoparticle resolving chiral medicine, comprise the steps:
(1) adopt physisorphtion to the supperparamagnetic particles modifying surface:
The polyethyleneimine: amine aqueous solution equal-volume that the supperparamagnetic particles aqueous solution that is 4g/L by mass concentration is 0.02g/L with mass concentration mixes, and at 30 ℃, adsorbs 20 minutes, obtains the supperparamagnetic particles of surface modification; Described supperparamagnetic particles is that median size is γ-Fe that 10nm, saturation magnetization are 80emu/g
2o
3;
(2) load has the protein of chiral recognition effect:
The human serum albumin aqueous solution equal-volume that the supperparamagnetic particles aqueous solution of the described surface modification that is 2g/L by mass concentration is 0.8g/L with concentration mixes, and adsorbs 2h, obtains the magnetic nanoparticle of protein modification;
(3) superparamagnetic nano particle of described protein modification is filled into for magnetic stablizing bed Glass tubing, and be placed in the axial magnetic stable bed, under the condition that is 2000 oersteds in magneticstrength, the column shape container bottom of the chirality Naproxen Base racemic modification aqueous solution that is 1mg/L by mass concentration from filling pumps into the 5mL/min flow velocity, obtain continuously the liquid of the separated product that contains a kind of enantiomer at the column shape container top, enantiomeric excess value is 98.0%, and the separated product that the supperparamagnetic particles adsorptive is another kind of enantiomer.
The method of the present embodiment also can be used for resolving chiral Ibuprofen BP/EP, Ketoprofen, oxazepam or flurbiprofen racemic modification.
Embodiment 3
A kind of method of applying protein function magnetic nanoparticle resolving chiral medicine, comprise the steps:
(1) adopt physisorphtion to the supperparamagnetic particles modifying surface:
The polypropylene amine aqueous solution equal-volume that the supperparamagnetic particles aqueous solution that is 6g/L by mass concentration is 1g/L with mass concentration mixes, and at 45 ℃, adsorbs 30 minutes, obtains the supperparamagnetic particles of surface modification; Described supperparamagnetic particles is that median size is the CoFe that 20nm, saturation magnetization are 50emu/g
2o
4;
(2) load has the protein of chiral recognition effect:
The ovomucoid aqueous solution equal-volume that the supperparamagnetic particles aqueous solution of the described surface modification that is 7g/L by mass concentration is 5g/L with concentration mixes, and adsorbs 3h, obtains the magnetic nanoparticle of protein modification;
(3) superparamagnetic nano particle of described protein modification is filled into for magnetic stablizing bed Glass tubing, and be placed in the axial magnetic stable bed, under the condition that is 5000 oersteds in magneticstrength, the column shape container bottom of the chirality Toldrin racemic modification aqueous solution that is 100mg/L by mass concentration from filling pumps into the 10mL/min flow velocity, obtain continuously the liquid of the separated product that contains a kind of enantiomer at the column shape container top, enantiomeric excess value is 93.0%, and the separated product that the supperparamagnetic particles adsorptive is another kind of enantiomer.
Also can adopt ovoglycoprotein to substitute the ovomucoid in the present embodiment, resolving chiral Toldrin racemic modification.
Embodiment 4
A kind of method of applying protein function magnetic nanoparticle resolving chiral medicine, comprise the steps:
(1) adopt physisorphtion to the supperparamagnetic particles modifying surface:
The poly (sodium 4-styrenesulfonate) aqueous solution equal-volume that the supperparamagnetic particles aqueous solution that is 8g/L by mass concentration is 0.2g/L with mass concentration mixes, and at 10 ℃, adsorbs 25 minutes, obtains the supperparamagnetic particles of surface modification; Described supperparamagnetic particles is that median size is the NiFe that 30nm, saturation magnetization are 30emu/g
2o
4;
(2) load has the protein of chiral recognition effect:
The avidin aqueous solution equal-volume that the supperparamagnetic particles aqueous solution of the described surface modification that is 5g/L by mass concentration is 2g/L with concentration mixes, and adsorbs 3h, obtains the magnetic nanoparticle of protein modification;
(3) superparamagnetic nano particle of described protein modification is filled into for magnetic stablizing bed Glass tubing, and be placed in the axial magnetic stable bed, under the condition that is 4000 oersteds in magneticstrength, the column shape container bottom of the chirality Ketoprofen racemic modification aqueous solution that is 500mg/L by mass concentration from filling pumps into the 2mL/min flow velocity, obtain continuously the liquid of the separated product that contains a kind of enantiomer at the column shape container top, enantiomeric excess value is 99.0%, and the separated product that the supperparamagnetic particles adsorptive is another kind of enantiomer.
Also can adopt polyacrylic acid to substitute the poly (sodium 4-styrenesulfonate) in the present embodiment, the chirality Ketoprofen is split.
Embodiment 5
A kind of method of applying protein function magnetic nanoparticle resolving chiral medicine, comprise the steps:
(1) adopt physisorphtion to the supperparamagnetic particles modifying surface:
The glycol-chitosan aqueous solution equal-volume that the supperparamagnetic particles aqueous solution that is 10g/L by mass concentration is 0.5g/L with mass concentration mixes, and at 20 ℃, adsorbs 40 minutes, obtains the supperparamagnetic particles of surface modification; Described supperparamagnetic particles is that median size is the Ni that 80nm, saturation magnetization are 10emu/g
0.5zn
0.5fe
2o
4;
(2) load has the protein of chiral recognition effect:
The α 1 acid glycoprotein aqueous solution equal-volume that the supperparamagnetic particles aqueous solution of the described surface modification that is 10g/L by mass concentration is 10g/L with concentration mixes, and adsorbs 5h, obtains the magnetic nanoparticle of protein modification;
(3) superparamagnetic nano particle of described protein modification is filled into for magnetic stablizing bed Glass tubing, and be placed in the axial magnetic stable bed, under the condition that is 100 oersteds in magneticstrength, the column shape container bottom of the chirality citalopram racemic modification aqueous solution that is 50mg/L by mass concentration from filling pumps into the 0.2mL/min flow velocity, obtain continuously the liquid of the separated product that contains a kind of enantiomer at the column shape container top, enantiomeric excess value is 97.0%, and the separated product that the supperparamagnetic particles adsorptive is another kind of enantiomer.
Embodiment 6
The method of the second application protein function magnetic nanoparticle resolving chiral medicine, comprise the steps:
(1) adopt chemical bonding to the supperparamagnetic particles modifying surface:
Making the concentration of supperparamagnetic particles powder in the cyclohexane solution of the aminopropyl trimethoxysilane that is 2% by supperparamagnetic particles powder immersion concentration expressed in percentage by volume is 5g/L, and at 80 ℃, reaction 8h, separate, and obtains the supperparamagnetic particles of surface modification; Described supperparamagnetic particles is that median size is the Fe that 15nm, saturation magnetization are 70emu/g
3o
4;
(2) load has the protein of chiral recognition effect:
The Bovine Serum Albumin in Aqueous Solution equal-volume that the supperparamagnetic particles aqueous solution of the described surface modification that is 5g/L by mass concentration is 2g/L with mass concentration mixes, add again covalently bound reagent glutaraldehyde, making covalently bound reagent volumetric molar concentration is 0.1mol/L, react 4h, obtain the magnetic nanoparticle of protein modification;
(3) superparamagnetic nano particle of described protein modification is filled into for magnetic stablizing bed Glass tubing, and be placed in the axial magnetic stable bed, under the condition that is 2400 oersteds in magneticstrength, the column shape container bottom of the chirality Ibuprofen BP/EP racemic modification aqueous solution that is 5mg/L by mass concentration from filling pumps into the 1mL/min flow velocity, obtain continuously the liquid of the separated product that contains a kind of enantiomer at the column shape container top, enantiomeric excess value is 97.0%, and the separated product that the supperparamagnetic particles adsorptive is another kind of enantiomer.
Present method also can be used for resolving chiral Ofloxacine USP 23, warfarin or Racemic propranolol.
Embodiment 7
The method of the second application protein function magnetic nanoparticle resolving chiral medicine, comprise the steps:
(1) adopt chemical bonding to the supperparamagnetic particles modifying surface:
Making the concentration of supperparamagnetic particles powder in the cyclohexane solution of the mercaptopropyl trimethoxysilane that is 0.3% by supperparamagnetic particles powder immersion concentration expressed in percentage by volume is 1g/L, and at 40 ℃, reaction 12h, separate, and obtains the supperparamagnetic particles of surface modification; Described supperparamagnetic particles is that median size is γ-Fe that 10nm, saturation magnetization are 80emu/g
2o
3;
(2) load has the protein of chiral recognition effect:
The human serum albumin aqueous solution equal-volume that the supperparamagnetic particles aqueous solution of the described surface modification that is 2g/L by mass concentration is 0.8g/L with mass concentration mixes, add again covalently bound reagent nitrogen-succinimido-3 (2-pyridine dithio)-propionic ester, making covalently bound reagent volumetric molar concentration is 0.005mol/L, react 3h, obtain the magnetic nanoparticle of protein modification;
(3) superparamagnetic nano particle of described protein modification is filled into for magnetic stablizing bed Glass tubing, and be placed in the axial magnetic stable bed, under the condition that is 2000 oersteds in magneticstrength, the column shape container bottom of the chirality Naproxen Base racemic modification aqueous solution that is 1mg/L by mass concentration from filling pumps into the 5mL/min flow velocity, obtain continuously the liquid of the separated product that contains a kind of enantiomer at the column shape container top, enantiomeric excess value is 99.0%, and the separated product that the supperparamagnetic particles adsorptive is another kind of enantiomer.
Present method also can be used for resolving chiral Ibuprofen BP/EP, Ketoprofen, oxazepam or flurbiprofen racemic modification.
Embodiment 8
The method of the second application protein function magnetic nanoparticle resolving chiral medicine, comprise the steps:
(1) adopt chemical bonding to the supperparamagnetic particles modifying surface:
Making the concentration of supperparamagnetic particles powder in the ethanolic soln of the aminopropyl trimethoxysilane that is 5% by supperparamagnetic particles powder immersion concentration expressed in percentage by volume is 5g/L, and at 25 ℃, reaction 48h, separate, and obtains the supperparamagnetic particles of surface modification; Described supperparamagnetic particles is that median size is the CoFe that 20nm, saturation magnetization are 50emu/g
2o
4;
(2) load has the protein of chiral recognition effect:
The ovomucoid aqueous solution equal-volume that the supperparamagnetic particles aqueous solution of the described surface modification that is 5g/L by mass concentration is 3g/L with mass concentration mixes, add again covalently bound reagent glutaraldehyde, making covalently bound reagent volumetric molar concentration is 0.1mol/L, react 2h, obtain the magnetic nanoparticle of protein modification;
(3) superparamagnetic nano particle of described protein modification is filled into for magnetic stablizing bed Glass tubing, and be placed in the axial magnetic stable bed, under the condition that is 5000 oersteds in magneticstrength, the column shape container bottom of the chirality Toldrin racemic modification aqueous solution that is 100mg/L by mass concentration from filling pumps into the 10mL/min flow velocity, obtain continuously the liquid of the separated product that contains a kind of enantiomer at the column shape container top, enantiomeric excess value is 95.0%, and the separated product that the supperparamagnetic particles adsorptive is another kind of enantiomer.
Also can adopt ovoglycoprotein to substitute the ovomucoid in the present embodiment, resolving chiral Toldrin racemic modification.
Embodiment 9
The method of the second application protein function magnetic nanoparticle resolving chiral medicine, comprise the steps:
(1) adopt chemical bonding to the supperparamagnetic particles modifying surface:
Making the concentration of supperparamagnetic particles powder in the toluene solution of the mercaptopropyl trimethoxysilane that is 10% by supperparamagnetic particles powder immersion concentration expressed in percentage by volume is 10g/L, and at 130 ℃, reaction 3h, separate, and obtains the supperparamagnetic particles of surface modification; Described supperparamagnetic particles is that median size is the NiFe that 30nm, saturation magnetization are 30emu/g
2o
4;
(2) load has the protein of chiral recognition effect:
The cellulolytic enzyme I aqueous solution equal-volume that the supperparamagnetic particles aqueous solution of the described surface modification that is 5g/L by mass concentration is 5g/L with mass concentration mixes, add again covalently bound reagent bitoscanate, making covalently bound reagent volumetric molar concentration is 0.2mol/L, react 4h, obtain the magnetic nanoparticle of protein modification;
(3) superparamagnetic nano particle of described protein modification is filled into for magnetic stablizing bed Glass tubing, and be placed in the axial magnetic stable bed, under the condition that is 4000 oersteds in magneticstrength, the column shape container bottom of the chirality Racemic propranolol aqueous solution that is 500mg/L by mass concentration from filling pumps into the 2mL/min flow velocity, obtain continuously the liquid of the separated product that contains a kind of enantiomer at the column shape container top, enantiomeric excess value is 97.0%, and the separated product that the supperparamagnetic particles adsorptive is another kind of enantiomer.
Also can adopt stomach en-to substitute the cellulolytic enzyme I in the present embodiment, resolving chiral Racemic propranolol.
Embodiment 10
The method of the second application protein function magnetic nanoparticle resolving chiral medicine, comprise the steps:
(1) adopt chemical bonding to the supperparamagnetic particles modifying surface:
Making the concentration of supperparamagnetic particles powder in the toluene solution of the aminopropyl trimethoxysilane that is 1% by supperparamagnetic particles powder immersion concentration expressed in percentage by volume is 2g/L, and at 80 ℃, reaction 6h, separate, and obtains the supperparamagnetic particles of surface modification; Described supperparamagnetic particles is that median size is the N that 80nm, saturation magnetization are 10emu/g
0.5zn
0.5fe
2o
4;
(2) load has the protein of chiral recognition effect:
The α 1 acid glycoprotein aqueous solution equal-volume that the supperparamagnetic particles aqueous solution of the described surface modification that is 10g/L by mass concentration is 10g/L with mass concentration mixes, add again covalently bound reagent ethyl-(3-dimethyl propyl) carbodiimide hydrochloride, making covalently bound reagent volumetric molar concentration is 0.2mol/L, react 5h, obtain the magnetic nanoparticle of protein modification;
(3) superparamagnetic nano particle of described protein modification is filled into for magnetic stablizing bed Glass tubing, and be placed in the axial magnetic stable bed, under the condition that is 100 oersteds in magneticstrength, the column shape container bottom of the chirality citalopram racemic modification aqueous solution that is 50mg/L by mass concentration from filling pumps into the 0.2mL/min flow velocity, obtain continuously the liquid of the separated product that contains a kind of enantiomer at the column shape container top, enantiomeric excess value is 94.0%, and the separated product that the supperparamagnetic particles adsorptive is another kind of enantiomer.
Claims (9)
1. a method of applying protein function magnetic nanoparticle resolving chiral medicine, its feature comprises the steps:
(1) adopt physisorphtion to the supperparamagnetic particles modifying surface:
The Ionomer aqueous solution equal-volume that the supperparamagnetic particles aqueous solution that is 2-10g/L by mass concentration is 0.02-1g/L with mass concentration mixes, and at 10-45 ℃, adsorbs 20-40 minute, obtains the supperparamagnetic particles of surface modification;
(2) load has the protein of chiral recognition effect:
The protein water soln equal-volume that the supperparamagnetic particles aqueous solution of the described surface modification that is 2-10g/L by mass concentration is 0.8-10g/L with concentration mixes, and adsorbs 2-5h, obtains the magnetic nanoparticle of protein modification; Described protein is bovine serum albumin, human serum albumin, α 1 acid glycoprotein, ovomucoid, ovoglycoprotein or avidin;
(3) superparamagnetic nano particle of described protein modification is filled into for magnetic stablizing bed Glass tubing, and be placed in the axial magnetic stable bed, under the condition that is the 100-5000 oersted in magneticstrength, the column shape container bottom of the chiral drug racemic modification aqueous solution that is 1-500mg/L by mass concentration from filling pumps into the 0.2-10mL/min flow velocity, obtain continuously the liquid of the separated product that contains a kind of enantiomer at the column shape container top, and the separated product that the supperparamagnetic particles adsorptive is another kind of enantiomer, described Ionomer is diallyl dimethyl ammoniumchloride, polymine, glycol-chitosan, polypropylene amine, polyacrylic acid or poly (sodium 4-styrenesulfonate).
2. a method of applying protein function magnetic nanoparticle resolving chiral medicine, its feature comprises the steps:
(1) adopt chemical bonding to the supperparamagnetic particles modifying surface:
Making the concentration of supperparamagnetic particles powder in the silylating reagent solution that is 0.3-10% by supperparamagnetic particles powder immersion concentration expressed in percentage by volume is 1-10g/L, and at 25-130 ℃, reaction 3-48h, separate, and obtains the supperparamagnetic particles of surface modification; The solvent of described silylating reagent solution is: toluene, hexanaphthene or ethanol;
(2) load has the protein of chiral recognition effect:
The protein water soln equal-volume that the supperparamagnetic particles aqueous solution of the described surface modification that is 2-10g/L by mass concentration is 0.8-10g/L with mass concentration mixes, add again covalently bound reagent, making covalently bound reagent volumetric molar concentration is 0.005-0.2mol/L, react 2-5h, obtain the magnetic nanoparticle of protein modification; Described protein is bovine serum albumin, human serum albumin, α 1 acid glycoprotein, ovomucoid, ovoglycoprotein, stomach en-or cellulolytic enzyme I;
(3) superparamagnetic nano particle of described protein modification is filled into for magnetic stablizing bed Glass tubing, and be placed in the axial magnetic stable bed, under the condition that is the 100-5000 oersted in magneticstrength, the column shape container bottom of the chiral drug racemic modification aqueous solution that is 1-500mg/L by mass concentration from filling pumps into the 0.2-10mL/min flow velocity, obtain continuously the liquid of the separated product that contains a kind of enantiomer at the column shape container top, and the separated product that the supperparamagnetic particles adsorptive is another kind of enantiomer.
3. method according to claim 1 and 2, is characterized in that described supperparamagnetic particles is that median size is the Fe that 10-80nm, saturation magnetization are 10-80emu/g
3o
4, γ-Fe
2o
3, CoFe
2o
4, NiFe
2o
4or Ni
0.5zn
0.5fe
2o
4.
4. method according to claim 2, is characterized in that described silylating reagent is aminopropyl trimethoxysilane or mercaptopropyl trimethoxysilane.
5. method according to claim 2, is characterized in that described covalently bound reagent is glutaraldehyde, ethyl-(3-dimethyl propyl) carbodiimide hydrochloride, nitrogen-succinimido-3 (2-pyridine dithio)-propionic ester or bitoscanate.
6. method according to claim 1, the mass concentration that it is characterized in that the Ionomer aqueous solution described in described step (1) is 0.1-0.5g/L, described temperature is 20-30 ℃.
7. method according to claim 2, the concentration expressed in percentage by volume that it is characterized in that silylating reagent solution described in described step (1) is 1-5%, and described temperature is 40-80 ℃, and the described reaction times is 6-12h.
8. method according to claim 1 and 2, is characterized in that described in described step (3), magneticstrength is the 2000-4000 oersted, and described chiral drug racemic modification aqueous solution mass concentration is 5-100mg/L, and described flow velocity is 1-5mL/min.
9. method according to claim 1 and 2, is characterized in that described chiral drug is Ibuprofen BP/EP, warfarin, Ofloxacine USP 23, Naproxen Base, Ketoprofen, oxazepam, flurbiprofen, citalopram, Proprasylyte or Toldrin.
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| CN104359995B (en) * | 2014-12-04 | 2015-12-30 | 延边大学 | The separation of biopolymer method of flow-type Stationary liquid in the post utilizing electromagnetic field |
| CN108333346B (en) * | 2017-01-19 | 2021-07-06 | 深圳市新产业生物医学工程股份有限公司 | dsDNA immunomagnetic microsphere system, preparation method and application thereof, and preservation solution |
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