A highly efficient method for hydrophilic modification of resins

Abstract

The application belongs to the field of medical biomaterials, and discloses a high-efficiency resin hydrophilic modification method, which comprises the following steps: dissolving CHP in ethanol to obtain a modification liquid; mixing resin containing double bonds on the surface with the modification liquid, and sufficiently reacting to obtain a hydrophilic modified resin after cleaning. The hydrophilic modification method of some examples of the application is simple in operation, has few residual double bonds after reaction, has good hydrophilic modification effect, and can be carried out at a low reaction temperature, and has little influence on the pore structure of the resin matrix.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of medical biomaterials, and particularly relates to a high-efficiency resin hydrophilic modification method. BACKGROUND

[0002] Blood purification technology generally refers to a process of leading blood out of a body, removing certain metabolic waste or toxic substances in the body through certain instruments and equipment, and leading the blood back into the body. Blood purification in vitro is achieved through a separation process of different substances, and blood purification adsorbents have been studied for many years. In the past 50 years, organic polymer ion exchange resins and finally synthesized porous polymers (mostly based on styrene or acrylic acid) have been applied to blood purification. However, as the resin skeleton structure of the adsorbent, most of which is highly non-polar and non-selective, has poor blood compatibility, early resin adsorbents easily cause adverse reactions such as thrombocytopenia, leukopenia, hypoglycemia, hypocalcemia, and the like, hindering the development and clinical application of blood purification adsorption technology.

[0003] In recent years, with the improvement of the biocompatibility of adsorbent materials, blood adsorption and purification technology has attracted people's attention and clinical application again. Commonly used resin types of adsorbents include polystyrene resins, polymethyl methacrylate resins, and polyvinyl alcohol resins, which are generally prepared by free radical suspension polymerization. In order to improve the blood compatibility of the adsorption resin, the double bonds remaining on the surface of the adsorption resin are usually oxidized to form epoxy groups or hydroxyl groups, the hydrophilicity of the resin is improved, and the biocompatibility is improved. For example, (1) the double bonds remaining on the surface of the resin are oxidized to form epoxy groups by using oxidizing substances such as meta-chloro-perbenzoic acid, hydrogen peroxide or a complex of hydrogen peroxide and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC), sodium hypochlorite, a complex of sodium bromide and sulfuric acid, etc. However, the modification method is relatively complicated to operate, and a large amount of organic solvents harmful to the human body is usually used for swelling in the reaction. By-products such as meta-chloro-benzoic acid and benzoic acid generated in the oxidation process of meta-chloro-perbenzoic acid and perbenzoic acid are also adsorbed by the resin, which is difficult to clean. The use of a large amount of organic solvents and harmful compounds also pollutes the environment, resulting in a very complex post-treatment process. (2) A combination of sulfuric acid and peroxyacetic acid, hypochlorite, periodate, or a combination of hydrogen peroxide and peroxyacetic acid is used as an oxidizing agent to directly form hydroxyl groups from the double bonds of the adsorption resin through a one-step oxidation reaction. However, the oxidation performance of the oxidizing agent is not high, the oxidation effect on the double bonds is poor, and the improvement of the blood compatibility is not obvious. SUMMARY

[0004] The present application aims to overcome at least one deficiency of the prior art and provide a high-efficiency resin hydrophilic modification method.

[0005] The technical solution adopted by the present application is as follows:

[0006] A method for hydrophilic modification of a resin, comprising the following steps:

[0007] Dissolving cumene hydroperoxide in ethanol to obtain a modification solution;

[0008] Mixing the resin with double bonds on the surface with the modification solution, allowing sufficient reaction, and washing to obtain the hydrophilically modified resin.

[0009] In some examples of the method for hydrophilic modification, a weak base is further added to the modification solution.

[0010] In some examples of the method for hydrophilic modification, the concentration of cumene hydroperoxide in the modification solution is 0.1-0.5 M.

[0011] In some examples of the method for hydrophilic modification, the concentration of the weak base in the modification solution is 0.1-0.7 mM.

[0012] In some examples of the method for hydrophilic modification, the concentration of cumene hydroperoxide in the modification solution is 0.1-0.5 M, and the concentration of the weak base is 0.1-0.7 mM.

[0013] In some examples of the method for hydrophilic modification, the weak base is an inorganic weak base.

[0014] In some examples of the method for hydrophilic modification, the inorganic weak base is selected from at least one of a carbonate, a bicarbonate, and a phosphate.

[0015] In some examples of the method for hydrophilic modification, the reaction temperature is 25-70°C, preferably 45-70°C.

[0016] In some examples of the method for hydrophilic modification, the reaction time is 2-10 h.

[0017] In some examples of the method for hydrophilic modification, the reaction temperature is 25-70°C, preferably 45-70°C, and the reaction time is 2-10 h.

[0018] In some examples of the method for hydrophilic modification, the molar ratio of cumene hydroperoxide to double bonds is 1:(5-20).

[0019] In some examples of the method for hydrophilic modification, the reaction temperature is 25-70°C, preferably 45-70°C, the reaction time is 2-10 h, and the molar ratio of cumene hydroperoxide to double bonds is 1:(5-20).

[0020] In some examples of the method for hydrophilic modification, the resin surface has at least one of an alkenyl group, a carbonyl group, and an aldehyde group.

[0021] In some examples of the hydrophilic modification method, the molar ratio of cumene hydroperoxide to double bond is 1: (5-20), and the resin surface has alkenyl groups.

[0022] The present application has the following advantages:

[0023] The hydrophilic modification method of some examples of the present application is simple to operate, has less residual double bonds after reaction, and has good hydrophilic modification effect.

[0024] The hydrophilic modification method of some examples of the present application can be carried out at a lower reaction temperature and has little effect on the pore structure of the resin matrix. BRIEF DESCRIPTION OF DRAWINGS

[0025] Figure 1 is the result after different samples are added to water.

[0026] Figure 2 is the contact angle test photo of different samples. DETAILED DESCRIPTION

[0027] Cumene hydroperoxide (CHP) is easily soluble in ethanol, acetone, esters, hydrocarbons and chlorinated hydrocarbons, slightly soluble in water, and has certain toxicity. CHP is a relatively stable peroxide, but it is still explosive. High-purity CHP should be avoided from heating and contacting with acids, reducing substances and transition metals, and should be stored in the dark and cold. CHP is often used for epoxidation of olefins, and can also be used for oxidation of sulfides to sulfoxides or sulfones. Under certain conditions, electron-rich aromatic compounds such as furan can also be oxidized by the reagent. CHP has good application in asymmetric oxidation reactions. In the Sharpless asymmetric epoxidation reaction, it can be used as an oxidizing agent to obtain epoxidation products with good yield and stereoselectivity. When CHP is used as an oxidizing agent, a solid catalyst such as transition metal and silicon dioxide is generally required, and a reaction temperature of 100℃ or higher is generally required for better epoxidation effect. The epoxy group is a hydrophobic group, which is also not conducive to the hydrophilic modification of the resin. The inventors break the convention and successfully use CHP to modify the hydrophilic modification of the adsorption resin by optimizing the reaction system.

[0028] A hydrophilic modification method of a resin, comprising the following steps:

[0029] Dissolving cumene hydroperoxide in ethanol to obtain a modification liquid;

[0030] Mixing the resin containing double bonds on the surface with the modification liquid, fully reacting, and washing to obtain a hydrophilically modified resin.

[0031] In some examples of the hydrophilic modification method, a weak base is further added to the modification liquid.

[0032] In some examples of the hydrophilic modification method, the weak base is an inorganic weak base.

[0033] In some examples of the hydrophilic modification method, the inorganic weak base is selected from at least one of carbonates, bicarbonates and phosphates. Specifically, the inorganic weak base includes, but is not limited to, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, disodium hydrogen phosphate, sodium dihydrogen phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate. These inorganic weak bases are safe, easy to remove and are better choices.

[0034] The concentration of cumene hydroperoxide can be adjusted as needed. The higher the concentration of cumene hydroperoxide, the more obvious the effect of hydrophilic modification of the resin and the shorter the reaction time. When the concentration exceeds a certain range, the effect of hydrophilic modification is not much different, and unpredictable side reactions may occur. In some examples of the hydrophilic modification method, the concentration of cumene hydroperoxide in the modification solution is 0.1-0.5 M.

[0035] The concentration of the weak base catalyst increases, the catalytic effect improves, the degree of double bond oxidation increases, and the reaction time shortens. However, with further increase in the concentration, the alkalinity of the solution increases, the possible side reactions increase, and the effect of hydrophilic modification decreases. In some examples of the hydrophilic modification method, the concentration of the weak base in the modification solution is 0.1-0.7 mM. Of course, the concentration of the weak base does not exceed the upper limit of its solubility.

[0036] In some examples of the hydrophilic modification method, the concentration of cumene hydroperoxide in the modification solution is 0.1-0.5 M, and the concentration of the weak base is 0.1-0.7 mM.

[0037] A high reaction temperature is conducive to the reaction, but a too high temperature may have an adverse effect on the structure of the resin itself and may cause adverse side reactions. The specific reaction temperature can be adjusted as needed. In some examples of the hydrophilic modification method, the reaction temperature is 25-70°C, preferably 45-70°C.

[0038] The reaction time can be adjusted according to the degree of reaction. In some examples of the hydrophilic modification method, the reaction time is 2-10 h.

[0039] In some examples of the hydrophilic modification method, the reaction temperature is 25-70°C, preferably 45-70°C, and the reaction time is 2-10 h.

[0040] The molar ratio of cumene hydroperoxide to double bonds can be adjusted according to the hydrophilicity requirements of the modified resin, so that the double bonds can be sufficiently modified without damaging the overall structure of the resin. In some examples of the hydrophilic modification method, the molar ratio of cumene hydroperoxide to double bonds is 1:(5-20).

[0041] In some examples of the hydrophilic modification method, the reaction is carried out at a temperature of 25-70°C, preferably 45-70°C, for a time period of 2-10 hours, and the molar ratio of cumene hydroperoxide to double bond is 1:(5-20).

[0042] In some examples of the hydrophilic modification method, the resin surface has at least one of an alkenyl group, a carbonyl group, and an aldehyde group.

[0043] In some examples of the hydrophilic modification method, the molar ratio of cumene hydroperoxide to double bond is 1:(5-20), and the resin surface has an alkenyl group.

[0044] The resin can be a commonly used blood dialysis acceptable resin having a double bond, in particular a resin containing an ethylenic bond. In some examples of the hydrophilic modification method, the resin includes, but is not limited to, polystyrene, polystyrene-divinylbenzene, polyethylene, and polypropylene.

[0045] For the convenience of comparison, the resin used in the following examples is the same batch of polystyrene resin, unless otherwise specified. Of course, other resins having a double bond on the surface, in particular resins having a -C=C- bond on the surface, can also be used.

[0046] Example 1:

[0047] A hydrophilic modification method of a resin using cumene hydroperoxide as an oxidizing agent, the steps of which are as follows:

[0048] (1) Accurately weigh the cumene hydroperoxide, and use anhydrous ethanol to prepare an oxidizing agent solution of different concentrations;

[0049] (2) Weigh 10 g of polystyrene adsorption resin, add 20 ml of the oxidizing agent solution, and mix well;

[0050] (3) The obtained reaction solution is reacted for a certain time under constant temperature and 180 rpm stirring speed;

[0051] (4) After the reaction is completed, the reaction solution is removed by suction filtration, and the resin is washed with anhydrous ethanol and purified water respectively to obtain the desired product.

[0052] The specific reaction conditions of different samples are shown in Table 1.

[0053] Table 1

[0054]

[0055] Example 2:

[0056] A hydrophilic modification method of a resin using a basic solution of cumene hydroperoxide as an oxidizing agent, the steps of which are as follows:

[0057] (1) Accurately weigh the hydrogen peroxide methylphenyl and the basic substance, and prepare different concentrations of oxidant solution with anhydrous ethanol;

[0058] (2) Weigh 10 g of polystyrene adsorption resin, add 20 ml of oxidant solution and mix evenly;

[0059] (3) The obtained reaction solution is reacted at a constant temperature and a stirring speed of 180 rpm for a certain time;

[0060] (4) After the reaction is completed, the reaction solution is removed by suction filtration, and the resin is washed with anhydrous ethanol and purified water respectively to obtain the desired product.

[0061] The specific reaction conditions of different samples are shown in Table 2.

[0062] Table 2

[0063]

[0064] Comparative Example 1:

[0065] A method for hydrophilic modification of an adsorption resin, the steps are as follows:

[0066] 1) Accurately weigh the content of the oxidant, and prepare 0.3M concentration of the oxidant solution with purified water using hydrogen peroxide as the oxidant;

[0067] 2) Weigh 10 g of adsorption resin, add 20 ml of oxidant solution and mix evenly;

[0068] 3) The obtained reaction solution is reacted at 25°C and a stirring speed of 180 rpm for 5h;

[0069] 4) After the reaction is completed, the reaction solution is removed by suction filtration, and the resin is washed with anhydrous ethanol and purified water respectively to obtain the desired sample.

[0070] Comparative Example 2:

[0071] A method for hydrophilic modification of an adsorption resin, the steps are as follows:

[0072] 1) Accurately weigh the content of the oxidant, and prepare 0.3M concentration of the oxidant solution with purified water using hydrogen peroxide as the oxidant;

[0073] 2) Weigh 10 g of adsorption resin, add 20 ml of oxidant solution and mix evenly;

[0074] 3) The obtained reaction solution is reacted at 25°C and a stirring speed of 180 rpm for 5h;

[0075] 4) After the reaction is completed, the reaction solution is removed by suction filtration, and the resin is washed with anhydrous ethanol and purified water respectively to obtain the desired sample.

[0076] Comparative Example 3:

[0077] 1) Accurately weigh the cumene hydroperoxide, and prepare a 0.3M oxidant solution with anhydrous ethanol, and add an appropriate amount of KOH, the concentration of KOH in the solution is 0.3mM;

[0078] 2) Weigh 10g of polystyrene adsorption resin, and mix 20ml of the above oxidant solution evenly;

[0079] 3) The obtained reaction solution is stirred at 45°C and 180rpm for 2h;

[0080] 4) After the reaction is completed, the reaction solution is removed by suction filtration, and the resin is washed with anhydrous ethanol and purified water respectively to obtain the desired sample.

[0081] Performance test:

[0082] 1. Double bond content determination:

[0083] (1) Solution preparation

[0084] Dioxane liquid bromine mixture: Take 0.8mL of liquid bromine and add it to 50mL of dioxane solution, shake well, and use immediately.

[0085] Starch indicator: Weigh 0.5g of starch and dissolve it in 100mL of water, heat and boil, and cool for use.

[0086] (2) Experimental steps

[0087] 1) Respectively obtain the examples, comparative examples and unmodified resins, wash with 20 times the volume of water, dry, grind to powder (the finer the better), dry at 105°C for 2h, cool to room temperature in a dry dish, and then take out and weigh;

[0088] 2) Weigh 0.5g of ground resin sample into an iodometric flask, accurately add 10mL of dioxane liquid bromine mixture, and react overnight after water sealing in the dark;

[0089] 3) After the reaction is completed, 15mL of purified water and 3g of potassium iodide are added to the iodometric flask, and the reaction is carried out in the dark for 5min, then 70mL of purified water is added, and titrated with sodium thiosulfate titration solution (0.1M) to light brown;

[0090] 4) Add 1mL of starch indicator, continue to titrate with sodium thiosulfate titration solution (0.1M) to light yellow suspension, and do not change color within 30s.

[0091] Under the same conditions, do a blank experiment without adding sample.

[0092] The calculation formula of the double bond content is as follows:

[0093] Double bond content (mmol / g) = (V0-V1) x c / m

[0094] V0: volume of sodium thiosulfate standard solution consumed by the blank experiment (mL)

[0095] V1: volume of sodium thiosulfate standard solution consumed by the sample (mL)

[0096] c: concentration of sodium thiosulfate titration solution (mol / L)

[0097] m: mass of the sample (g)

[0098] The test results are shown in Table 3.

[0099] Table 3, average double bond content of different samples

[0100]

[0101] From the test results, it can be seen that:

[0102] (1) The double bond content of the modified resin after reaction with different oxidizing agents decreases to varying degrees, indicating that the double bonds are activated to some extent;

[0103] (2) Using hydrogen peroxide as an oxidizing agent, its oxidizing performance is stronger, and the remaining double bond content is less after oxidation.

[0104] (3) Hydrogen peroxide has stronger oxidizing properties in weak alkaline conditions, and the double bond content decreases more. In strong alkaline conditions, the oxidizing property does not increase significantly, and the hydrophilic modification effect is poor.

[0105] 2. Contact angle test

[0106] The unmodified resin, Comparative Example 1, Comparative Example 2, Sample 1-2, and Sample 2-2 were ground into powders of the same particle size, and the same mass of powder was poured directly into a beaker containing water. After 10 minutes, the suspension of the samples was observed, and the results are shown in Table 4 and Figure 1 From the Figure 1 , it can be seen that the unmodified resin has poor hydrophilicity and floats on the water surface, and the modified resin has significantly increased hydrophilicity.

[0107] The unmodified resin, Comparative Example 1, Comparative Example 2, Sample 1-2, and Sample 2-2 were ground into powders of the same particle size, and the same mass of powder was poured directly into a beaker containing water. After 10 minutes, the suspension of the samples was observed, and the results are shown in Table 4 and Figure 2 .

[0108] Table 4, contact angle test results of different samples

[0109]

[0110] From Table 4 and Figure 2 It can be seen that the surface contact angle of the examples is significantly reduced compared with the comparative examples and the unmodified resin, and the hydrophilicity is enhanced.

[0111] 3. Hemolysis rate test

[0112] 2 g of unmodified resin, Comparative Example 1, Sample 1-2, and Sample 2-2 were weighed into test tubes, and 10 mL of normal saline was injected as a test sample. The test sample tube, negative tube (only 10 mL of normal saline was injected), and positive tube (only 10 mL of distilled water was injected) were placed in a 37°C water bath for 30 min. 0.2 mL of diluted anticoagulant rabbit blood was added to each of the test sample tube, negative tube, and positive tube, and mixed gently. The constant temperature water bath at 37°C was continued for 60 min. After the water bath was completed, the liquid in the tube was poured out, and the supernatant was centrifuged at 800g for 5 min and placed in a UV spectrophotometer. The absorbance value was measured at 545 nm, and the hemolysis rate (hemolysis rate should be ≤5%) was calculated. The hemolysis rate calculation formula is as follows:

[0113]

[0114] In the formula: A is the absorbance of the test sample solution;

[0115] B is the absorbance of the negative control solution;

[0116] C is the absorbance of the positive control solution.

[0117] The results are shown in Table 5.

[0118] Table 5, hemolysis rate test results of different samples

[0119]

[0120] As can be seen from Table 5, after hydrophilic modification, the hemolysis rate of Comparative Example 1 and Comparative Example 2 can meet the use requirements, and after further enhancement of the hydrophilicity, the hemolysis rate of Sample 1-2 and Sample 2-2 is also reduced, and the blood compatibility is enhanced.

[0121] 4. β2-microglobulin adsorption experiment

[0122] Healthy human plasma was taken and β2-microglobulin was added to prepare a β2-microglobulin solution with a concentration of 10 mg / L for standby use. 0.2 g of unmodified resin, Comparative Example 1, Comparative Example 2, Example 2, and Example 5 were weighed into conical flasks, 2 mL of the prepared β2-microglobulin solution was added, and the conical flasks were placed in a constant temperature oscillator. The temperature was adjusted to 37±1°C, the oscillation frequency was 180±10 times / min, and the conical flasks were taken out after oscillation adsorption for 2 hours. The concentration of β2-microglobulin solution before and after adsorption was detected, and the experiment was repeated 3 times. The experimental results are shown in Table 6.

[0123] Table 6. Results of β2-microglobulin adsorption experiment

[0124]

[0125] It can be seen from the experimental results that the adsorption effect of the hydrophilic modified resin carrier of the embodiment on β2-microglobulin does not change obviously, and the improvement of blood compatibility does not affect the adsorption performance of the material.

[0126] Conclusion:

[0127] (1) Using cumene hydroperoxide as an oxidizing agent to oxidize the adsorption resin has strong oxidation ability, high double bond conversion content, and more obvious improvement of blood compatibility.

[0128] (2) Using cumene hydroperoxide as an oxidizing agent to oxidize and activate the adsorption resin has simple reaction process and small environmental pollution in the reaction process.

[0129] (3) Using cumene hydroperoxide as an oxidizing agent has no obvious influence on the adsorption performance of the adsorption resin.

[0130] The above is a further detailed description of the present application, which cannot be regarded as a specific implementation of the present application. For ordinary skilled persons in the technical field to which the present application belongs, simple deduction or replacement without departing from the concept of the present application is within the protection scope of the present application.

Claims

1. A method for hydrophilic modification of resin, comprising the following steps: dissolving cumene hydroperoxide in ethanol to obtain a modification solution, wherein an inorganic weak base is also added in the modification solution, the concentration of cumene hydroperoxide in the modification solution is 0.1-0.5 M, and the concentration of the weak base is 0.1-0.7 mM; mixing the resin containing double bonds on the surface with the modification solution, the molar ratio of cumene hydroperoxide to double bonds is 1:(5-20), and the reaction is carried out at 25-70℃, and the hydrophilic modified resin is obtained by washing, wherein the resin surface has alkenyl groups, carbonyl groups and aldehyde groups.

2. The hydrophilic modification method according to claim 1, wherein, The inorganic weak base is selected from at least one of carbonates, bicarbonates and phosphates.

3. The hydrophilic modification method according to claim 1 or 2, characterized by, The reaction time is 2-10 h.

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