CN101343361B - Preparation method for hydrogel material based on ethylene diamine tetra-acetic anhydride - Google Patents
Preparation method for hydrogel material based on ethylene diamine tetra-acetic anhydride Download PDFInfo
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- CN101343361B CN101343361B CN2008100701576A CN200810070157A CN101343361B CN 101343361 B CN101343361 B CN 101343361B CN 2008100701576 A CN2008100701576 A CN 2008100701576A CN 200810070157 A CN200810070157 A CN 200810070157A CN 101343361 B CN101343361 B CN 101343361B
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Abstract
The invention relates to a preparation method for bio-degradable PH-sensitive hydrogel, which belongs to the technical field of the high molecular material. The preparation method adopts the steps that firstly, ethylenediaminetetraacetic acid (EDTAh) and diamine (DA) are taken as the raw material, copolymer with polyhydric annular imide (EDTAh-DA-Imide) is directly obtained through adopting a solution thermal polymerization method, and then cross bridging agent is filled to perform the cross bridging reaction, thus the bio-degradable hydrogel with pH sensitivity is generated. The method has the advantages that the synthetic route is short, the method is simple, and catalyzer is not required.
Description
Technical field:
The present invention relates to polymeric material field, more specifically relate to a kind of preparation method of biodegradability pH sensitive aquagel.
Background technology:
Hydrogel is a kind ofly can be had following character usually: wetting ability that (1) is extremely good and water-absorbent by water swollen semi-solid state crosslinking polymer network; (2) have after the suction and body tissue plesiomorphism, softness, lubricated surface, thereby provide and environment that the body tissue surface is affine, have excellent biological compatibility; (3) meet water or Digestive system and expand character (the Ratner BD that forms the gel barrier and have the stripping of control medicine, Hoffman AS.Synthetichydrogels for biomedical applications (bio-medical synthetic water gel) .Washington, DC:AmericanChemical Society.1976; 1-36).The ideal hydrogel should have a large amount of hydrophilic radicals and controlled crosslinking degree, thereby forms hydrophilic network.
Hydrogel mainly is to be made by natural macromolecular material and synthetic degradable biological macromolecular material.Natural macromolecular material mainly contains gelatin, osso-albumin, chitosan, sodium alginate and agarose etc.These natural materialss are paid attention to and be subjected to many scientific research persons because biocompatibility is better relatively, nontoxic.But,, their range of application is dwindled because its physicals has certain scope restriction.The synthetic macromolecular material mainly contains polyacrylic acid and derivative, polyethylene oxide and multipolymer thereof, polyvinyl alcohol, polyphosphate and polypeptide etc.Wherein, polyacrylamide, polyacrylic and polyvinyl alcohol etc. mainly are that the free radical reaction formation that relies on two keys is connected to main cross-linked network with C-C, and this cross-linked network that connects with C-C all is nondegradable usually.And based on the pH susceptibility or the biocompatibility of amino acid whose biodegradable polyamino acid or polypeptide class hydrogel remain further to be improved (Yao Kangde. " intelligent material ". Tianjin: the .1996 of press of University Of Tianjin; 269; .J Controlled Release.1996 such as Giammona; 41 (3): 195-203; .J Environ Polym Degrad.1996 such as Kunioka; 4 (2): 125-129; .J Polym Science such as Denis, Part A:PolymChemistry.1996; 34 (10): 2019-2027.)
We once designed and had prepared the hydrogel material of a class based on ethylene diamine tetra-acetic anhydride (EDTAh), and set up this hydrogel of cover preparation the preparation method (Luo Yanfeng etc. a class is based on the hydrogel material and the purposes .200710092614.7 of ethylene diamine tetra-acetic anhydride, 2007.08.27).The preparation method of this hydrogel comprises that three steps are: (1) at first is to adopt ethylene diamine tetra-acetic anhydride (EDTAh) and diamines (DA) to generate EDTAh-DA straight copolymer (pEDTAh-DA) by amidate action; (2) then, the pEDTAh-DA that purifying is obtained issues living intramolecular dehydration at heating condition and generates and contain polynary imido multipolymer EDTAh-DA-Imide; (3) last, EDTAh-DA-Imide and linking agent reaction generate the cross-linking products with pH susceptibility.This hydrogel has good biocompatibility, biodegradability and pH susceptibility, is expected to become a kind of novel intelligent aqueous gel capable drug release material.
Summary of the invention:
The objective of the invention is to disclose the preparation method of a kind of preparation based on the hydrogel material of ethylene diamine tetra-acetic anhydride (EDTAh), this method and disclosed preparation method (Luo Yanfeng etc. a class is based on the hydrogel material and the purposes .200710092614.7 of ethylene diamine tetra-acetic anhydride, 2007.08.27) compare, it is shorter to have synthetic route, method is simpler, and need not the advantage of catalyzer.
Preparation provided by the invention comprises two steps based on the preparation process of the hydrogel material of ethylene diamine tetra-acetic anhydride (EDTAh):
1. ethylene diamine tetra-acetic anhydride (EDTAh) and diamines (DA) directly form the multipolymer (pEDTAh-DA-Imide) that contains polynary cyclic imide by the solution thermal polycondensation process;
2. the multipolymer that contains polynary cyclic imide (pEDTAh-BDA-Imide) that is 1. made by step generates biodegradable pH sensitive hydrogel material with the linking agent reaction, promptly based on the hydrogel material of ethylene diamine tetra-acetic anhydride.
EDTA is that a kind of the proof at present can be widely used in human body chelating toxin expelling by the complete excretory material of human body.In the present invention, (under physiological pH condition, amine exists with the form of ammonium salt the amido linkage of EDTAh and diamines formation at scission of link generation EDTA and ammonium salt under the effect of enzyme or water.)。The general formula of used diamines (DA) is H
2N-R-NH
2, wherein R is an alkyl or aryl, comprises quadrol (EDA), propylene diamine (PDA), butanediamine (BDA) or hexanediamine aliphatie diamine and aromatic diamines such as Ursol D, mphenylenediamine such as (HAD).The reaction system of EDTAh and DA reaction is a solution reaction system, require used solvent can dissolve EDTAh and DA simultaneously, and boiling point is not less than 180 ℃.Such solvent comprises dimethyl sulfoxide (DMSO) (DMSO), N, dinethylformamide (DMF), N-Methyl pyrrolidone (NMP) etc.Compare with disclosed preparation method (Luo Yanfeng etc. a class is based on the hydrogel material and the purposes .200710092614.7 of ethylene diamine tetra-acetic anhydride, 2007.08.27), the present invention adopts solution thermal polycondensation process one step preparation pEDTAh-BDA-Imide, eliminated the preparation and the purifying of EDTAh-DA straight copolymer (pEDTAh-DA), building-up process is simpler, the cycle is shorter thereby make.Formation by the direct solution dehydrates realization of high temperature cyclic imide need not any catalyzer.Conditioned reaction temperature and reaction times can be regulated degree of imidisation among the pEDTAh-BDA-Imide.Rising temperature of reaction and prolongation reaction times can make degree of imidisation be tending towards complete; And reduce temperature of reaction or shorten the reaction times, can realize the part imidization, contain a small amount of-COOH in the pEDTAh-BDA-Imide side chain thereby make.In addition, the viscosity of solution thermal polycondensation reaction system is low, and the water that produces in the imide forming process can in time be got rid of, and can not cause the molecular weight degradation that causes because of in the long-time remaining system of water, helps to generate the high-molecular weight polyimide.Therefore, in the present invention, according to the difference of diamines, the solution reaction system of EDTAh and DA is 25 ℃-100 ℃ reactions 3-10 hour, then 120 ℃-160 ℃ reactions 1-6 hour, at last 160 ℃-220 ℃ reactions 2-8 hour.In order to obtain high as far as possible molecular weight, EDTAh is identical with the mole dosage of DA
Similar to anhydride group, imide is the very high group of a kind of reactive behavior, and as easy as rolling off a log and the group that contains reactive hydrogen are as-NH
2React with-OH, the imide scission of link generates the structure that contains two acid amides respectively and contains the structure of an amido linkage, an ester bond.Therefore, cyclic imide base among the multipolymer EDTAh-DA-Imide can be partially or completely and the material generation crosslinking reaction that contains a plurality of reactive hydrogens, generation contains the cross-linking copolymer of different side-chain radicals, promptly generates purpose product of the present invention---based on the hydrogel material of ethylene diamine tetra-acetic anhydride.These linking agents that contain reactive hydrogen comprise diamine, polyamine, hydramine, dibasic alcohol, polyvalent alcohol etc.Difference according to linking agent, temperature of reaction is controlled at-10 ℃～80 ℃, the used in amounts of linking agent is determined according to the polymerization degree n of EDTAh-DA-Imide, the cross-linked dosage that require to add is enough to open imide rings all among the EDTAh-DA-Imide and two EDTAh-DA-Imide molecules can be coupled at and forms crosslinked network structure together, also free-NH must be arranged simultaneously
2Or-OH or-COOH exists, to provide cross-linking agent suitable pH susceptibility.Therefore, the consumption of linking agent should be n～2n times of EDTAh-DA-Imide mole dosage, and n is the polymerization degree, n 〉=2.
In sum, adopt preparation method disclosed by the invention can make biodegradable hydrogel material, and the preparation method is simple, easy row, need not catalyzer based on ethylene diamine tetra-acetic anhydride.
Description of drawings:
The infrared spectrogram of the EDTAh-BDA-Imide that Fig. 1: embodiment 1 makes (KBr pressed disc method, instrument: PE GX type infrared spectrometer)
1736.40cm wherein
-1And 1678.30cm
-1Charateristic avsorption band for the six-membered cyclic imide group.
The pH susceptibility of the BDA-crosslinked-pEDTAh-BDA hydrogel that Fig. 2: embodiment 3 is prepared
When PH values was higher than 5, the swelling ratio of this hydrogel remained on about 9% substantially; When PH values when 5 drop to 2, the swelling ratio of this hydrogel has been raised to 24.8% from 9%; In particular, when PH values when 3 drop to 2, the swelling ratio of this hydrogel skyrockets high by 24.8% from 13%, show tangible pH susceptibility.
Embodiment:
Illustrated embodiment is for content of the present invention is described better, but be not that content of the present invention only is limited to illustrated embodiment, so those of ordinary skill in the art know under the situation that does not depart from spirit of the present invention or essential characteristic, can carry out suitable modification to the structure of proportion of raw materials, material and operational condition etc., therefore, think existing disclosed embodiment in all respects for illustrative, rather than restrictive.
Embodiment is divided into two portions: first part, the preparation of polynary imide copolymer (pEDTAh-DA-Imide); Second section is based on the preparation of the hydrogel material of EDTAh.
First part: the preparation of polynary imide copolymer (pEDTAh-DA-Imide)
Embodiment 1: ethylene diamine tetra-acetic anhydride (EDTAh) and the polynary imide copolymer of butanediamine (BDA) prepared in reaction (pEDTAh-BDA-Imide)
Get 0.1mol (25.6250g) EDTAh and be dissolved in the 250mLN-methyl-2-pyrrolidone (NMP), nitrogen protection adds 0.1mol BDA down.After 8 hours, again 150 ℃ of reactions 2 hours, 180 ℃ were reacted 2 hours 40 ℃ of reactions.After reaction finishes, reaction solution poured in the dehydrated alcohol precipitates, repeatedly washing, vacuum-drying obtains the purified polynary imide copolymer of 23.7542g (pEDTAh-BDA-Imide), its infrared spectrogram as shown in Figure 1, M
n=9300 (GPC mensuration), polymerization degree n ≈ 30.
Embodiment 2: ethylene diamine tetra-acetic anhydride (EDTAh) and the polynary imide copolymer of hexanediamine (HDA) prepared in reaction (pEDTAh-HDA-Imide)
Get 0.1mol (25.6250g) EDTAh and be dissolved among the 250mLNMP, nitrogen protection adds 0.1mol HDA down.After 3 hours, again 160 ℃ of reactions 3 hours, 190 ℃ were reacted 2 hours 80 ℃ of reactions.After reaction finishes, reaction solution poured in the dehydrated alcohol precipitate, repeatedly washing, vacuum-drying obtains the purified polynary imide copolymer of 29.2574g
(pEDTAh-HDA-Imide), M
n=8100 (GPC mensuration), polymerization degree n ≈ 24.
Second section: based on the preparation of the hydrogel material of EDTAh
Embodiment 3: with embodiment 1 product pEDTAh-BDA-Imide is raw material, and butanediamine (BDA) prepares the crosslinked hydrogel material based on EDTAh of butanediamine (BDA-crosslinked-pEDTAh-BDA) for linking agent
1.2389 gram (about 0.1332mmol) embodiment, 1 resulting pEDTAh-BDA-Imide is dissolved among the 12.4mLDMSO, after the dissolving fully, under magnetic agitation, is added dropwise to 450 μ L butanediamine (BDA) (about 4.86mmol); After dropwising, stirred 20 minutes, room temperature is static spends the night.To precipitate in the reaction solution impouring dehydrated alcohol, will precipitate, use distilled water wash, constantly change liquid, flush away solvent, unreacted BDA and small molecules polymkeric substance with behind the absolute ethanol washing several.Vacuum-drying obtains 1.1892g cross-linked network polymer B DA-crosslinked-pEDTAh-BDA, and the pH susceptibility of this network polymer as shown in Figure 2.
Example 4: with embodiment 1 product pEDTAh-BDA-Imide is raw material, and thanomin (EOA) prepares the crosslinked hydrogel material based on EDTAh of thanomin (EOA-crosslinked-pEDTAh-BDA) for linking agent
Get 1.2290 gram (about 0.1322mmol) embodiment, 1 resulting pEDTAh-BDA-Imide and be dissolved among the 12.4mLDMF, after the dissolving fully, under the condition of magnetic agitation, be added dropwise to 320 μ L thanomins (EOA) (about 4.98mmol), 40 ℃ of temperature of reaction.After dropwising, stirred 20 minutes, left standstill 8 hours under 40 ℃.After reaction is finished, will precipitate in the reaction solution impouring dehydrated alcohol, will precipitate, use distilled water wash, constantly change liquid, flush away solvent, unreacted EOA and small molecules polymkeric substance with behind the absolute ethanol washing several.Vacuum-drying obtains 1.1028gEOA-crosslinked-pEDTAh-BDA cross-linked network polymkeric substance.
Example 5: with embodiment 1 product pEDTAh-BDA-Imide is raw material, and butyleneglycol (BDO) prepares the crosslinked hydrogel material based on EDTAh of butyleneglycol (BDO-crosslinked-pEDTAh-BDA) for linking agent
Get 1.2378 gram (about 0.1331mmol) embodiment, 1 resulting pEDTAh-BDA-Imide and be dissolved among the 12.4mLDMF, after the dissolving fully, under the condition of magnetic agitation, be added dropwise to 420 μ L butyleneglycols (BDO) (about 4.43mmol), 60 ℃ of temperature of reaction.After dropwising, stirred 20 minutes, left standstill 12 hours under 60 ℃.After reaction is finished, will precipitate in the reaction solution impouring dehydrated alcohol, will precipitate, use distilled water wash, constantly change liquid, flush away solvent, unreacted BDO and small molecules polymkeric substance with behind the absolute ethanol washing several.Vacuum-drying obtains 1.1142gBDO-crosslinked-pEDTAh-BDA cross-linked network polymkeric substance.
Example 6: with embodiment 2 product pEDTAh-HDA-Imide is raw material, and butanediamine (BDA) prepares the crosslinked hydrogel material based on EDTAh of butanediamine (BDA-crosslinked-pEDTAh-HDA) for linking agent
Get 1.4022 gram (about 0.1731mmol) examples, 2 resulting pEDTAh-HDA-Imide and be dissolved among the 14.0mLDMSO, after the dissolving fully, under the condition of magnetic agitation, be added dropwise to 420 μ L butanediamine (BDA) (about mmol), 40 ℃ of temperature of reaction.After dropwising, stirred 20 minutes, left standstill 6 hours under 40 ℃.After reaction is finished, will precipitate in the reaction solution impouring dehydrated alcohol, will precipitate, use distilled water wash, constantly change liquid, flush away solvent, unreacted BDA and small molecules polymkeric substance with behind the absolute ethanol washing several.Vacuum-drying obtains 1.3642gBDA-crosslinked-pEDTAh-HDA cross-linked network polymkeric substance.
Example 7: with embodiment 2 product pEDTAh-HDA-Imide is raw material, and butanediamine (BDA) and thanomin (EOA) prepare butanediamine and the crosslinked hydrogel material based on EDTAh (BDAEOA-crosslinked-pEDTAh-HDA) of thanomin for linking agent
Getting 1.4008 gram (about 0.1729mmol) examples, 2 resulting pEDTAh-HDA-Imide is dissolved among the 14.0mLDMSO, after the dissolving fully, under the condition of magnetic agitation, be added dropwise to 385 μ L butanediamine (BDA) (about 4.15mmol) and 250 μ L thanomins (EOA) (about 3.89mmol), 60 ℃ of temperature of reaction.After dropwising, stirred 20 minutes, left standstill 8 hours under 60 ℃.After reaction is finished, will precipitate in the reaction solution impouring dehydrated alcohol, will precipitate, use distilled water wash, constantly change liquid, flush away solvent, unreacted BDA, EOA and small molecules polymkeric substance with behind the absolute ethanol washing several.Vacuum-drying obtains 1.2896g BDAEOA-crosslinked-pEDTAh-HDA cross-linked network polymkeric substance.
Claims (4)
1. a class is based on the preparation method of the hydrogel material of ethylene diamine tetra-acetic anhydride EDTAh, and its preparation process is:
1. ethylene diamine tetra-acetic anhydride EDTAh and diamines DA directly form the multipolymer pEDTAh-DA-Imide that contains polynary cyclic imide by the solution thermal polycondensation process;
2. the reaction of multipolymer pEDTAh-DA-Imide that contains polynary cyclic imide that is 1. made by step and linking agent generates biodegradable pH sensitive hydrogel material, promptly based on the hydrogel material of ethylene diamine tetra-acetic anhydride;
Described solution thermal polycondensation process is after being dissolved in equimolar EDTAh and DA in the solvent, earlier 25 ℃-100 ℃ reactions 3-10 hour, then 120 ℃-160 ℃ reactions 1-6 hour, at last 160 ℃-220 ℃ reactions 2-8 hour;
Describedly contain the multipolymer pEDTAh-DA-Imide of polynary cyclic imide and the reaction of linking agent, according to the difference of linking agent, temperature of reaction is controlled at-10 ℃-80 ℃, and the time is 5 hours-48 hours.
2. the preparation method of the hydrogel material based on ethylene diamine tetra-acetic anhydride EDTAh according to claim 1, it is characterized in that: described solvent can dissolve ethylene diamine tetra-acetic anhydride EDTAh and diamines DA simultaneously, and boiling point is higher than 180 ℃.
3. the preparation method of the hydrogel material based on ethylene diamine tetra-acetic anhydride EDTAh according to claim 2, it is characterized in that: described solvent is dimethyl sulfoxide (DMSO) DMSO, N, dinethylformamide DMF or N-Methyl pyrrolidone NMP.
4. the preparation method of the hydrogel material based on ethylene diamine tetra-acetic anhydride EDTAh according to claim 1 and 2, it is characterized in that described linking agent is polyamine, polyvalent alcohol, hydramine or their mixture, its consumption determines according to the polymerization degree n of polymkeric substance EDTAh-DA-Imide, for the n～2n of EDTAh-DA-Imide mole number doubly.
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| US10738039B2 (en) * | 2015-04-28 | 2020-08-11 | Rohm And Haas Electronic Materials Llc | Metal plating compositions |
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