Preparation method of sevelamer carbonate

Abstract

The invention discloses a preparation method of sevelamer carbonate. The preparation method comprises the following steps: (1) dropwise adding V50 and AIBI composite initiator into allylamine hydrochloride at a set polymerization temperature at a controlled speed to carry out polymerization reaction, so as to prepare polyallylamine hydrochloride; (2) adjusting the pH value of the polyallylamine hydrochloride solution to 10-12 by using a sodium hydroxide aqueous solution, and then adding epoxy chloropropane for cross-linking to obtain a cross-linked polymer; and (3) adding a sodium bicarbonate solution into the cross-linked polymer to carry out ion exchange, and carrying out solid-liquid separation to obtain sevelamer carbonate. According to the preparation process of sevelamer carbonate disclosed by the invention, the reaction time is shortened, and the material consumption is reduced, so that the production efficiency is improved, and the production cost is reduced.

Description

Technical Field

[0001] The invention belongs to the field of medicine and discloses a preparation method of sevelamer carbonate. Background Art

[0002] Hyperphosphatemia refers to a pathological state in which the concentration of inorganic phosphorus in human serum is higher than normal levels. Kidney diseases (such as chronic kidney disease, renal failure, etc.) are the main causes of the disease. Sevelamer carbonate is a non-absorbable phosphate-binding cross-linked polymer. It is a new calcium-free phosphate binder used to control hyperphosphatemia in adult patients with chronic kidney disease (CKD) who are undergoing dialysis treatment. It does not contain calcium or other metals; it contains multiple amine groups, each connected to the polymer backbone by a carbon atom. Amine groups exist in the intestine in a protonated form and interact with phosphate molecules through ionic bonds and hydrogen bonds. Sevelamer carbonate can reduce the concentration of phosphate in serum by binding to phosphate in the digestive tract and reducing its absorption.

[0003] In the disclosed invention CN111499784A, a method for preparing sevelamer carbonate is described, wherein a single V50 is used as an initiator in the polymerization step. In actual production, due to the influence of the half-life of the initiator, V50 needs to be added twice, with an interval of about 24 hours, and the total reaction time exceeds 40 hours. The amount of initiator used exceeds 0.02 times, the reaction time is long, and the material consumption is large. In the disclosed invention CN113045693A, a method for preparing sevelamer carbonate is described, wherein a single V50 is used as an initiator in the polymerization step, and the material is added in 5 times, with an interval of 24 hours each time, and the amount of V50 used each time is 0.004-0.005 times, the total reaction time is about 120 hours, and the amount of V50 added exceeds 0.02 times, which also has the problems of long reaction time and large initiator consumption.

[0004] The prior art usually uses a single initiator as the initiator of the polymerization step. Due to its half-life, the single initiator needs to be added in small amounts multiple times. At the same time, in order to prevent the excessive decomposition of the initiator from causing the polymerization reaction to run away, the polymerization reaction temperature needs to be controlled at a lower temperature, resulting in a longer polymerization reaction time and a larger amount of initiator used. At the same time, since the initiator is added all at once, it is easy to cause different polymerization degrees and uneven polymer molecular weight distribution under the condition of uneven stirring and dispersion of the system. Summary of the invention

[0005] In view of the existing problems, the present invention provides a preparation process of sevelamer carbonate, which has the advantages of shortening the reaction time, reducing the amount of material used, thereby improving production efficiency and reducing production costs; and solves the problems of low production efficiency and high cost of the current preparation process.

[0006] The purpose of the present invention can be achieved through the following technical solutions:

[0007] A preparation process of sevelamer carbonate, comprising the following steps:

[0008] (1) Using an aqueous solution of allylamine hydrochloride as a raw material, after heating to the polymerization temperature, a composite initiator is added dropwise, and polyallylamine hydrochloride is obtained through polymerization;

[0009] (2) After adjusting the pH of the polyallylamine hydrochloride solution obtained in (1) to 10 - 12, 0.05 - 0.15 times the mass of epichlorohydrin is added under a certain solid content condition, and crosslinking and curing are carried out at 10 - 40 °C for about 3 - 10 h to obtain a crosslinked polymer;

[0010] (3) The crosslinked polymer obtained in (2) is subjected to ion exchange with a 5 - 15 wt% sodium bicarbonate solution, and sevelamer carbonate is obtained after filtration.

[0011] In the step (1), the polymerization reaction temperature is 50 - 75 °C, preferably 60 - 70 °C.

[0012] In the step (1), the composite initiator is a composite of V50 and AIBI in a ratio of 1:0.2 - 0.5, preferably, the composite ratio of the two initiators is 1:0.20 - 0.25.

[0013] In the step (1), the usage amount of the composite initiator is 0.005 - 0.015 times the weight of allylamine hydrochloride, preferably 0.008 - 0.011 times.

[0014] In the step (1), the composite initiator is dissolved in a certain amount of water and then added dropwise to the reactant while controlling the dropping rate, and the dropping time is controlled within 1 - 6 h; after the dropping is completed, the reaction continues for 1 - 4 h, preferably, the reaction continues for 3 h after the dropping; the concentration of the composite initiator in water is 10 - 30 wt%, preferably 15 - 20 wt%.

[0015] In the step (2), before adding epichlorohydrin, the solid content of the polyallylamine hydrochloride solution is controlled to be 10 - 40%, preferably, the solid content is controlled to be 20 - 30%;

[0016] In the step (3), after adding the sodium bicarbonate solution, the ion exchange temperature is controlled at 40 - 70 °C, and the ion exchange time is 4 - 8 h, preferably, the ion exchange temperature is 50 - 60 °C.

[0017] Beneficial effects:

[0018] In the research on the selection of initiators, our company found that increasing the temperature can significantly accelerate the rate of the polymerization reaction. However, it will also cause the rapid decomposition of the initiator, resulting in a slower polymerization rate in the later stage. At the same time, we found that at a higher temperature, AIBI has higher activity than V50 in the early stage of the reaction, and the polymerization reaction rate is fast, but its activity is not as good as V50 in the later stage of the reaction. Based on this, we tried to use a composite initiator. The purpose is to use AIBI as the main initiator in the early stage of the polymerization process under a controlled higher reaction temperature. After it quickly reaches its half-life and continues to decompose rapidly, V50 will continue to initiate. At the same time, in order to avoid the problem of uneven polymerization caused by the one-time addition of the initiator, the composite initiator is dispersed in water and added dropwise continuously to the reaction to control the concentration of the composite initiator in water at about 10-30 wt%.

[0019] The present invention uses a composite initiator. V50 and AIBI have different half-lives and continuously decompose in stages in the polymerization system to generate free radicals to initiate the polymerization of allylamine hydrochloride. At the same time, by controlling the continuous addition of the initiator by the method of dropwise addition throughout the process, and increasing the temperature of the polymerization reaction, the polymerization proceeds continuously at multiple points and the polymerization rate is accelerated, shortening the polymerization reaction time, which can be shortened from 24-120 h to 3-10 h; improving the utilization rate of the initiator, reducing the amount of initiator added, and significantly reducing the material cost. Detailed implementation mode

[0020] The following will combine the embodiments of the present invention to clearly and completely describe the technology of the present invention; obviously, the described embodiments are only a part of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, other embodiments obtained by those skilled in the art without creative work fall within the scope of protection of the present invention.

[0021] Comparative experimental research:

[0022] Experiment (1): Add 350 g of allylamine hydrochloride solution (equivalent to 250 g of allylamine hydrochloride) to a 500 ML three-necked flask, start stirring, and heat up to 65 °C after nitrogen replacement; weigh 2.5 g of V50, add 12.2 g of water for dispersion, and then use a precision metering pump to drop it into the reaction flask. Set the dropping rate to 0.13 ml / min, and it will be dropped completely in about 1.5 h. Keep the temperature and continue to react for 3 h to obtain a polyallylamine hydrochloride solution; take samples to detect the molecular weight and allylamine residue at about 1.5 h and 3 h of the heat-retaining reaction respectively.

[0023] Experiment (2): Add 350 g of allylamine hydrochloride solution (equivalent to 250 g of allylamine hydrochloride) into a 500 mL three-necked flask, start stirring, heat up to 65 °C after nitrogen replacement; weigh 2.5 g of V50, disperse it in 12.0 g of water and then use a precision metering pump to drip it into the reaction flask. Set the dripping speed to 0.13 ml / min, and it takes about 1.5 h to finish dripping. Keep the temperature and continue the reaction for 3 h. Then weigh another 2.5 g of V50, disperse it in 12.4 g of water and use a precision metering pump to drip it into the reaction flask. Set the dripping speed to 0.13 ml / min, and it takes about 1.5 h to finish dripping. Keep the temperature and continue the reaction for 3 h; Take the samples after the first addition of V50 and reaction for 1.5 h and 3 h and the sample after the second addition and reaction for 3 h to detect the molecular weight and allylamine residue.

[0024] Experiment (3): Add 350 g of allylamine hydrochloride solution (equivalent to 250 g of allylamine hydrochloride) into a 500 mL three-necked flask, start stirring, heat up to 65 °C after nitrogen replacement; weigh 3.4 g of AIBI, disperse it in 16.0 g of water and then use a precision metering pump to drip it into the reaction flask. Set the dripping speed to 0.19 ml / min, and it takes about 1.5 h to finish dripping. Keep the temperature and continue the reaction for 3 h to obtain a polyallylamine hydrochloride solution; Take samples at about 1.5 h and 3 h of the heat preservation reaction respectively to detect the molecular weight and allylamine residue.

[0025] Experiment (4): Add 350 g of allylamine hydrochloride solution (equivalent to 250 g of allylamine hydrochloride) into a 500 mL three-necked flask, start stirring, heat up to 65 °C after nitrogen replacement; weigh 2 g of V50 and 0.4 g of AIBI, disperse them in 12.2 g of water and then use a precision metering pump to drip them into the reaction flask. Set the dripping speed to 0.13 ml / min, and it takes about 1.5 h to finish dripping. Keep the temperature and continue the reaction for 3 h to obtain a polyallylamine hydrochloride solution; Take samples at about 1.5 h and 3 h of the heat preservation reaction respectively to detect the molecular weight and allylamine residue.

[0026] Detection method for allylamine: Determine according to the high performance liquid chromatography method (General Principles 0512, Part IV of Chinese Pharmacopoeia). Use octadecylsilane chemically bonded silica gel as the filler, and use phosphate solution (weigh 4.08 g of potassium dihydrogen phosphate and 2.08 g of phosphoric acid, dissolve them in 600 ml of water, and then add 400 ml of acetonitrile) as the mobile phase; Use a fluorescence detector, with the excitation wavelength of 390 nm and the emission wavelength of 475 nm; The flow rate is 1.5 ml per minute; The column temperature is 25 °C. Take 10 μl of the derivatization blank solution, derivatization reference solution, derivatization test solution 1 and derivatization test solution 2 respectively, inject them into the liquid chromatograph, record the chromatogram, and calculate the amount of allylamine. Molecular weight detection method: Determine according to the molecular exclusion chromatography method (0514, Part IV of Chinese Pharmacopoeia)

[0027] Chromatographic column: A gel column filled with hydrophilic cationic vinyl polymer

[0028] Mobile phase: 0.1 mol / L sodium acetate

[0029] Column temperature: 25 °C

[0030] Flow rate: 1.0 ml / min

[0031] Detector: refractive index detector

[0032] Preparation of standard solution: Take a series of molecular weight standards with known molecular weights (Mp) ranging from 3000 Da to 500,000 Da, place them in different volumetric flasks respectively, dilute them with the mobile phase to make solutions with a concentration of about 2 mg / ml, and let them stand for 24 hours to swell evenly, then it is obtained.

[0033] Preparation of test solution: Take an appropriate amount of the test sample, dilute it with the mobile phase to make a solution with a concentration of about 2 mg / ml.

[0034] Determination method: Take 25 μl of the standard solution and the test solution respectively, inject them into the liquid chromatograph, record the chromatogram. The molecular weight standards elute in descending order of molecular weight (Mp). Import the chromatogram into the GPC software, draw a standard curve based on the peak apex molecular weight (Mp) to obtain a third-order regression equation, and use the GPC special software to calculate the molecular weight of this product. The comparison of detection data is as follows:

[0035]

[0036] The above data shows that when using a single V50 or AIBI initiator, there are situations such as insufficient polymerization. To achieve sufficient polymerization, operations such as increasing the initiator dosage and prolonging the reaction time need to be taken; when using a composite initiator of V50 and AIBI, after 3 h, the molecular weight of the polymerization solution has met the preferred range of process control, and the residual amount of allylamine is also less.

[0037] Example 1:

[0038] Add 6.5 kg of allylamine hydrochloride solution (equivalent to 4.6 kg of allylamine hydrochloride) to a 10 L reaction kettle, start stirring, heat with TCU after nitrogen replacement, and raise the temperature to 65 °C; weigh 38 g of V50 and 8.8 g of AIBI, disperse them in 250 g of water and then use a precision metering pump to drip them into the reaction flask, set the dripping speed to 1.55 ml / min, and finish dripping in about 3 h, then keep the temperature and continue to react for 3 h to obtain a polyallylamine hydrochloride solution.

[0039] All of the previous polyallylamine hydrochloride solution was transferred to a 20 L reaction flask, 9.3 kg of purified water was added, and the pH was adjusted to 11 using 30 wt% sodium hydroxide solution; about 7.3 kg of condensate was distilled off under vacuum distillation, and then 6.6 g of purified water was added. The solid content of the solution was sampled and detected to be about 26%; 0.45 kg of epichlorohydrin was added to the above solution, and the temperature was controlled at 30 °C for cross-linking and curing for 6 h to obtain sevelamer gel.

[0040] Weigh 3.8 kg of sodium bicarbonate and add 34.5 kg of water and stir until dissolved and clear. Transfer the above sevelamer gel to a 50 L reaction flask, stir rapidly, add the prepared sodium bicarbonate solution, heat up to 55 °C and start timing. After stirring for 1 h, add 35 kg of purified water and continue stirring for 6 h, maintaining the temperature at 50 - 60 °C during the process; filter and dry to obtain sevelamer carbonate.

[0041] Swelling index detection and calculation method: Place a magnetic stir bar in the inner tube of an ultrafiltration centrifuge tube, and accurately weigh the total weight of the inner tube of the ultrafiltration centrifuge tube (including the lid and the stir bar). Accurately weigh about 20 mg of the sample into the inner tube of the centrifuge tube, add 1.0 ml of buffer solution (dissolve 0.375 g of sodium chloride and 9.595 g of N,N-bis(2-hydroxyethyl)-2-aminoethanesulfonic acid (BES) in 100 mL of water, adjust the pH to 7.0 with 1 mol / L sodium hydroxide, and dilute to 150 mL with water), vortex for 30 seconds, invert and stir on a magnetic stirrer for 30 minutes. Centrifuge at a speed of 4500 revolutions per minute for 60 minutes, take out the inner tube of the centrifuge tube (including the core and the stir bar) and weigh. Three parallel samples are required, and the swelling index is calculated based on the dried product.

[0042] Detection and calculation method for soluble oligomers: According to the ultraviolet-visible spectrophotometry (General Principles 0401, Part IV of the Chinese Pharmacopoeia), measure at a wavelength of 570 nm, zero with the derivatization blank solution, and measure the absorbance of the system suitability solution respectively. The average absorbance of 3 portions of the system suitability solution shall not be less than 0.20, and the relative standard deviation shall not be greater than 5%. Use the absorption values of the derivatized test sample solutions 1, 2, and 3 as the ordinate, and the amount of polyallylamine hydrochloride added (ppm) as the abscissa to plot a standard curve, and calculate the slope S and the intercept I; soluble oligomers (%) = I / S * F, where F is the unit conversion factor for ppm, and the value is 10000.

[0043] Titratable amine detection method: Detect according to the potentiometric titration method (General Principles 0701, Part IV of the Chinese Pharmacopoeia). Use a pH glass electrode and titrate with sodium hydroxide titrant (1.0 mol / L).

[0044] Method for detecting allylamine: Determined according to the high performance liquid chromatography method (General Principles 0512, Volume IV of Chinese Pharmacopoeia). Use octadecylsilyl silica gel as the filler, and phosphate solution (weigh 4.08 g of potassium dihydrogen phosphate and 2.08 g of phosphoric acid, dissolve in 600 ml of water, and then add 400 ml of acetonitrile) as the mobile phase; use a fluorescence detector, with an excitation wavelength of 390 nm and an emission wavelength of 475 nm; the flow rate is 1.5 ml per minute; the column temperature is 25 °C. Take 10 μl each of the derivatized blank solution, derivatized reference solution, derivatized test solution 1, and derivatized test solution 2, inject them into the liquid chromatograph respectively, record the chromatogram, and calculate the amount of allylamine.

[0045] The detection data are as follows:

[0046] Detection results of polyallylamine hydrochloride solution:

[0047] Sample Name Molecular Weight Residual Allylamine Polyallylamine Hydrochloride Solution 61010Da 0.74％

[0048] Detection results of sevelamer carbonate

[0049] Inspection Items Control Standards Test Values Swelling Index 5.0 - 12.0 ml / g 8.2 ml / g Soluble Oligomers Not Exceeding 0.1% 0.002％ Titratable Amine 11.3 - 14.1 mmol / g 12.2 mmol / g Residual Allylamine Less than or Equal to 2 ppm Not Detected

[0050] Example 2:

[0051] Add 300 kg of polyallylamine hydrochloride solution to a 1000 L polymerization reactor, start stirring, displace with nitrogen 3 times, start heating up, and heat up to 70 °C inside the reactor; weigh 2.6 kg of V50 and 0.5 kg of AIBI, add 16 kg of purified water for dispersion, and then use a precision metering pump to drip-feed into the reactor. Set the drip-feed rate of the metering pump to 55 g / min. After the dripping is completed, keep the temperature for reaction for 3 h, and take samples to detect the molecular weight of polyallylamine hydrochloride and the residual amount of allylamine.

[0052] Transfer all the above polymerization reaction liquid to a 1500 L distillation kettle, use 30% sodium hydroxide solution to adjust the pH to 11; heat up and distill under reduced pressure to distill out about 260 kg of condensate; then add 380 kg of purified water, take samples to detect the solid content of 25%; transfer the above solution to a 3000 L dispersion kettle, disperse quickly for about 30 min, add 21 kg of epichlorohydrin to the kettle, control the temperature at 30 °C for cross-linking and curing for about 6 h to obtain sevelamer gel.

[0053] Weigh 180 kg of sodium bicarbonate into a preparation kettle, add 1620 kg of water and stir until it is clear; after it is clear, filter it under pressure into the dispersion kettle containing sevelamer gel for ion exchange, control the temperature of the dispersion kettle at 50 - 60 °C, disperse quickly for 1 h, then add 1800 kg of purified water, continue stirring for 6 h, and separate the solid and liquid by a centrifuge to obtain the wet product, and the wet product is dried to obtain sevelamer carbonate.

[0054] The detection data are as follows:

[0055] (1) Detection results of polyallylamine hydrochloride solution

[0056] Sample Name Molecular Weight Residual Allylamine Polyallylamine Hydrochloride Solution 61010Da 0.74％

[0057] (2) Detection results of sevelamer carbonate

[0058] Inspection Items Control Standards Test Values Swelling Index 5.0 - 12.0 ml / g 8.6 ml / g Soluble Oligomers Not Exceeding 0.1% 0.002％ Titratable Amine 11.3 - 14.1 mmol / g 12.1 mmol / g Residual Allylamine Less than or Equal to 2 ppm Not Detected

Claims

1. A preparation method of sevelamer carbonate, characterized in that It includes the following steps: (1) Using an aqueous solution of allylamine hydrochloride as a raw material, after heating to the polymerization temperature, a composite initiator is added dropwise, and polyallylamine hydrochloride is obtained through polymerization; (2) After adjusting the pH of the polyallylamine hydrochloride solution obtained in (1) to 10 - 12, 0.05 - 0.15 times the mass of epichlorohydrin is added under a certain solid content condition, and cross-linking and curing are carried out at 10 - 40 °C for about 3 - 10 h to obtain a cross-linked polymer; (3) The cross-linked polymer obtained in (2) is subjected to ion exchange with a 5 - 15 wt% sodium bicarbonate solution, and after filtration, sevelamer carbonate is obtained.

2. The preparation method of sevelamer carbonate according to claim 1, characterized in that In step (1), the polymerization reaction temperature is 50 - 75 °C.

3. The preparation method of sevelamer carbonate according to claim 1, characterized in that In step (1), the composite initiator is V50 and AIBI with a weight ratio of 1:0.2 - 0.

5.

4. The preparation method of sevelamer carbonate according to claim 3, characterized in that In step (1), the composite initiator is V50 and AIBI with a weight ratio of 1:0.2 - 0.

25.

5. The preparation method of sevelamer carbonate according to claim 1 or 3, characterized in that In step (1), the usage amount of the composite initiator is 0.005 - 0.015 times the mass of allylamine hydrochloride, the dropping time is 1 - 6 h, and after the dropping is completed, stirring reaction continues for 1 - 4 h.

6. The preparation method of sevelamer carbonate according to claim 5, characterized in that In step (1), the usage amount of the composite initiator is 0.008 - 0.011 times the mass of allylamine hydrochloride, the dropping time is 1 - 4 h, and after the dropping is completed, stirring reaction continues for 3 h.

7. The preparation method of sevelamer carbonate according to claim 1, characterized in that In step (2), sodium hydroxide solution is used to adjust the pH.

8. The preparation method of sevelamer carbonate according to claim 1, characterized in that In step (2), before adding epichlorohydrin, the solid content of the polyallylamine hydrochloride solution is controlled to be 10 - 40%.

9. The preparation method of sevelamer carbonate according to claim 8, characterized in that In step (2), before adding epichlorohydrin, the solid content of the polyallylamine hydrochloride solution is controlled to be 20 - 30%.

10. The preparation method of sevelamer carbonate according to claim 1, characterized in that In step (3), after adding the sodium bicarbonate solution, the ion exchange temperature is controlled at 40 - 70 °C, and the ion exchange time is 4 - 8 h. Preferably, the ion exchange temperature is 50 - 60 °C.

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