Method for preparing sodium polystyrenesulfonate resin through centrifugal interfacial membrane emulsification technology and application of sodium polystyrenesulfonate resin

Abstract

The invention belongs to the field of pharmaceutic adjuvants, and particularly relates to a method for preparing sodium polystyrenesulfonate resin through a centrifugal interfacial membrane emulsification technology and application of the sodium polystyrenesulfonate resin. The method comprises the following steps: by taking a mixed solvent of styrene, divinylbenzene and benzoyl peroxide as a dispersion phase and a polyvinyl alcohol solution as a continuous phase, carrying out centrifugal interfacial membrane emulsification, then carrying out suspension polymerization reaction to obtain polystyrene-divinylbenzene microspheres with narrow particle size distribution, and finally, carrying out sulfonation reaction and alkali exchange to obtain the polystyrene-divinylbenzene composite microsphere. The final product sodium polystyrenesulfonate resin is obtained. The resin prepared by controlling the centrifugal rotating speed, the centrifugal time and the using amount of the dispersing agent, the cross-linking agent and the sulfonating agent and combining a centrifugal interfacial membrane emulsification technology is in a dry golden brown powder shape, the average particle size is 60-100 microns after the resin is dispersed in water, and particles of the resin are uniformly distributed and are of a spherical structure. Meanwhile, the preparation method is simple in preparation process, short in operation time, low in energy consumption, good in economic benefit, suitable for industrial production and wide in market application prospect.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical excipients, and particularly relates to a method for preparing sodium polystyrene sulfonate resin by centrifugal boundary film emulsification technology and its application. Background Art

[0002] Oral sustained and controlled release preparations are a class of oral drug delivery systems that achieve an ideal therapeutic effect by controlling the drug release rate. Compared with conventional preparations, oral sustained and controlled release preparations have many advantages in clinical treatment, and their development cycle is short, the product technology content is high, and the added value can be significantly improved. In the process of making oral sustained and controlled release preparations, ion exchange resin is a key excipient, which is related to the stable loading and reasonable release of drugs in oral sustained and controlled release preparations. In view of the characteristics that acidic and basic drugs can be adsorbed and dispersed inside the ion exchange resin, it has many advantages, such as masking the unpleasant taste of drugs, promoting the dissolution of poorly soluble drugs, improving the stability of drug dissolution in the storage environment and in vivo, and controlling the slow release of drugs. Ion exchange resins (IER) are a type of cross-linked functional molecular polymer containing active groups in the molecule and capable of ion exchange with other substances, which are composed of an inert skeleton and a fixed ionizable functional group. Currently, common synthesis methods of polymer materials include suspension polymerization, precipitation polymerization, dispersion polymerization, emulsion polymerization, solution polymerization, bulk polymerization, seed polymerization, swelling polymerization, radiation polymerization, etc. The traditional suspension polymerization method refers to the polymerization reaction in which monomers, initiators, cross-linking agents, etc. are mixed with a dispersant, and the monomers are dispersed into countless small droplets by strong stirring and suspended in water, so it is also called bead polymerization. Suspension polymerization is widely used in industry. The advantages of this method are that the reaction is easy to control, and the polymerized product can be obtained only through simple separation, washing, drying and other processes; however, the disadvantages are also very obvious. The obtained microspheres have a wide particle size distribution, ranging from dozens to thousands of micrometers. The microspheres need to be pulverized to reach the particle size required for the preparation carrier, and the pulverization will partially damage the structure of the resin, destroy the surface active group sulfonic acid group of the resin, and generate a new surface, making the drug loading performance and drug release performance of sodium polystyrene sulfonate resin unstable. In addition, when the particle size range of sodium polystyrene sulfonate resin is wide, small particles will fill between large particles, making it difficult for sodium polystyrene sulfonate to be redispersed due to mutual filling during the preparation process, thereby reducing the drug loading performance and drug release performance of sodium polystyrene sulfonate resin. Summary of the Invention

[0003] Aiming at the deficiencies of the prior art, the purpose of the present invention is to provide a method for preparing sodium polystyrene sulfonate resin based on the centrifugal boundary film emulsification technology. The centrifugal boundary film emulsification technology is to centrifuge the counter-rotating self-rotation. When the aqueous phase and the oil phase are mixed, a uniform emulsification film is formed by centrifugal force to control the formation of microspheres. At the same time, the formation speed of the boundary film and the microspheres is controlled by the centrifugal speed to meet the industrialization requirements. The centrifugal boundary film emulsifier will also self-rotate and mix while centrifuging, and good mixing effects can be obtained even for materials with a large difference in specific gravity.

[0004] In the present invention, a mixed solvent of styrene, divinylbenzene and benzoyl peroxide is used as the dispersed phase, and a polyvinyl alcohol solution is used as the continuous phase for centrifugal boundary film emulsification, followed by suspension polymerization reaction to obtain polystyrene-divinylbenzene microspheres with a narrow particle size distribution. Finally, the final product sodium polystyrene sulfonate resin is obtained through sulfonation reaction and base exchange. By controlling the centrifugal speed, centrifugation time, dispersant, crosslinking agent and the dosage of the sulfonating agent, a sodium polystyrene sulfonate resin meeting the particle size range is prepared. The particle size uniformity of the sodium polystyrene sulfonate resin is improved, and its particle size distribution becomes narrower, which also provides technological innovation for the development of microspheres with similar properties.

[0005] To achieve the above object, the technical solution adopted by the present invention is as follows:

[0006] A method for preparing sodium polystyrene sulfonate resin by centrifugal boundary film emulsification technology is carried out according to the following steps:

[0007] (1) Preparation of the dispersed phase: Dissolve benzoyl peroxide (BPO) in a mixed solvent of styrene (St) and divinylbenzene (DVB), and vortex until completely dissolved to prepare solution A;

[0008] Furthermore, in step (1), the dosage of benzoyl peroxide is 0.1%-2% of the mass of styrene; divinylbenzene is 5%-15% of the total mass of styrene and divinylbenzene;

[0009] (2) Preparation of the continuous phase: Weigh polyvinyl alcohol (PVA) and add it to water, heat and stir to dissolve, and then cool to room temperature to prepare solution B;

[0010] Furthermore, in step (2), the water is purified water, the temperature of heating and stirring is 60-90°C, and the concentration of solution B is 3-9 mg / mL.

[0011] (3) Add solution A to solution B to form an oil-water system, and then carry out centrifugal boundary film emulsification (since it contacts the aqueous phase, the oil phase will form emulsion droplets, and there will be a liquid film between the oil phase and the aqueous phase. Under the action of the centrifugal vector synthesis force during centrifugation, the emulsion droplets are subjected to the shear force of the liquid film), and finally an O / W type emulsion is formed;

[0012] Further, in step (3), the centrifugal membrane emulsification is processed by a centrifugal membrane emulsifier, and the processing conditions are: rotation speed 2300 - 2500 rpm, duration 4 min.

[0013] (4) Suspension polymerization reaction: The O / W emulsion prepared in step (3) is placed under an oil bath condition while stirring for the first temperature increase reaction. After the reaction, continue with the second temperature increase reaction, and then continue with the third temperature increase reaction after the second reaction. After the reaction ends, maintain stirring and cool to room temperature, then stop stirring and perform suction filtration to obtain microspheres; then wash the microspheres with water and methanol in sequence, collect the microspheres after suction filtration, and perform drying to obtain a solid product, which is polystyrene - divinylbenzene (PS - DVB) microspheres;

[0014] Further, in step (4), the conditions for stirring are 500 rpm, the temperature for the first temperature increase reaction is 70 °C, and the reaction time is 3 h; the temperature for the second temperature increase reaction is 80 °C, and the reaction time is 5 h; the temperature for the third temperature increase reaction is 95 °C, and the reaction time is 2 h; the temperature for the drying is 50 °C - 60 °C, and the time is 5 - 7 h.

[0015] (5) Sulfonation reaction: Add the polystyrene - divinylbenzene (PS - DVB) microspheres obtained in step (4) into a swelling agent. After swelling for a period of time, dropwise add concentrated sulfuric acid under stirring, maintain stirring and perform the first temperature increase reaction. After the reaction, continue with the second temperature increase reaction, and then continue with the third temperature increase reaction after the second reaction. After the reaction ends, stop stirring. After the solution cools to room temperature, collect the product by filtration and wash it until neutral. After suction filtration, add acetone for cleaning, and then perform suction filtration and washing with ethanol and water in sequence. Finally, after drying and sieving, the PS - DVB sulfonated microspheres are obtained;

[0016] Further, in step (5), the swelling agent is chloroform, and the swelling time is 0.5 h; the conditions for stirring are 500 rpm, the temperature for the first temperature increase reaction is 65 °C, and the reaction time is 2 h; the temperature for the second temperature increase reaction is 70 °C, and the reaction time is 3 h; the temperature for the third temperature increase reaction is 75 °C, and the reaction time is 6 h;

[0017] The dosage relationship of polystyrene - divinylbenzene (PS - DVB) microspheres, swelling agent, and concentrated sulfuric acid is 1 mg: 3 mL: 3 mL.

[0018] The temperature for the drying is 50 °C - 60 °C, and the time is 5 - 7 h; the mesh number for sieving is 80 mesh.

[0019] (6) Base exchange: Immerse the PS-DVB sulfonated microspheres obtained in step (5) in a phenolphthalein indicator, and perform a basic titration using an NaOH solution as the titrant. Wait until the solution turns red and does not fade, stir, wash until neutral, then filter by suction and dry to obtain a dry product, which is the sodium polystyrene sulfonate resin.

[0020] Furthermore, in step (6), the concentration of the phenolphthalein indicator is 1%, and the concentration of the NaOH solution is 10%; specifically, waiting until the solution turns red and does not fade means it does not fade within 1 minute. The stirring time is 1 h, the drying temperature is 50°C - 60°C, and the drying time is 5 - 7 h.

[0021] By adopting the above technical solution, first, the dispersant is fully dissolved in water under heating conditions, improving the solubility of the dispersant in water, which helps the styrene, divinylbenzene, and initiator added later to come into full contact with the dispersant.

[0022] In the traditional suspension polymerization process, the stirring speed is used to form polystyrene resin microspheres from styrene and divinylbenzene during the reaction. However, it is difficult to control the stirring speed. If the stirring speed is low, the forming speed of the polystyrene resin microspheres and the polymerization reaction degree of styrene and divinylbenzene cannot reach a good balance, easily making the formed polystyrene resin microspheres irregular in shape and having a wide particle size distribution range, which is not conducive to the drug loading and release process of the later sodium polystyrene sulfonate microspheres. If the stirring speed is high, it is not conducive to the formation of polystyrene resin microspheres either, and the initially formed microspheres are easily broken under high stirring speed, also not conducive to forming polystyrene resin microspheres with a suitable and uniform particle size. The centrifugal boundary film emulsification technology is a counter-rotating self-rotating centrifugal technology. When the aqueous phase and the oil phase are mixed, a uniform emulsification film is formed by centrifugal force, thereby controlling the formation of microspheres. The present invention adopts the centrifugal boundary film emulsification technology, which can centrifuge the oil-water system to form spherical emulsion droplets with a uniform and stable particle size, making the particle size distribution range of the later-prepared sodium polystyrene sulfonate microspheres narrow and the particle size appropriate. When preparing the sustained-release pharmaceutical later, it is not necessary to break the sodium polystyrene sulfonate, which helps to improve the batch-to-batch drug loading stability and drug release uniformity of sodium polystyrene sulfonate.

[0023] The sodium polystyrene sulfonate resin prepared by the present invention is in the form of golden-brown powder, and after redispersion in water, the average particle size is 60 - 100 μm, showing a regular spherical shape.

[0024] The sodium polystyrene sulfonate resin prepared by the present invention can be used as a pharmaceutical excipient.

[0025] Beneficial effects

[0026] (1) The present invention adopts centrifugal boundary membrane emulsification technology through counter-rotating centrifugal technology. When the water phase and the oil phase are mixed, a uniform emulsified film is formed by centrifugal force, thereby controlling the formation of microspheres. At the same time, the centrifugal speed is used to control the boundary membrane and microsphere forming speed to meet industrial requirements.

[0027] (2) The present invention provides a promising method for preparing sodium polystyrene sulfonate resin. The sodium polystyrene sulfonate resin prepared by centrifugal membrane emulsification technology is in the form of a dry golden brown powder. After the sodium polystyrene sulfonate resin is dispersed in water, the average particle size is 60-100 μm. Scanning electron microscopy shows that the particles are evenly distributed and spherical in structure, and the sphericity of the microspheres is good.

[0028] (3) The preparation process of the present invention is simple, the operation time is short, and the energy consumption is low, which has good economic benefits, is suitable for industrial production, and has broad market application prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] Figure 1 This is a scanning electron microscope image of the sodium polystyrene sulfonate resin prepared in Example 10.

[0030] Figure 2 This is the particle size distribution diagram of the sodium polystyrene sulfonate resin prepared in Example 10. DETAILED DESCRIPTION

[0031] The following examples are intended to help those skilled in the art better understand the present invention, but are not intended to limit the present invention in any way.

[0032] The main instruments and materials used in the following examples

[0033] Experimental Materials:

[0034] Styrene (Shanghai MacLean Biochemical Technology Co., Ltd.); divinylbenzene (Shanghai Aladdin Biochemical Technology Co., Ltd.); PVA1788, concentrated sulfuric acid, chloroform, acetone, methanol, sodium hydroxide (Sinopharm Chemical Reagent Co., Ltd.).

[0035] Experimental instruments:

[0036] Centrifugal membrane emulsifier (ATS Antos Nano Technology (Suzhou) Co., Ltd.); GL124-1SCN electronic balance (Sartorius Scientific Instruments (Beijing) Co., Ltd.); MS 3000 laser particle size analyzer (Malvern Instruments Ltd., UK); HJ-6B heating magnetic stirrer (Changzhou Surui Instruments Co., Ltd.); XH-C vortex mixer (Jintan Baita Xinbao Instrument Factory); HWCL-3 heating type constant temperature magnetic stirrer (Zhengzhou Great Wall Scientific Industry and Trade Co., Ltd.); JJ-1A digital display electric stirrer (Changzhou Surui Instruments Co., Ltd.); MIRA field emission scanning electron microscope (TESCAN Trading (Shanghai) Co., Ltd.).

[0037] Example 1:

[0038] (1) Preparation of the dispersed phase: Dissolve benzoyl peroxide (BPO) in a mixed solvent of styrene (St) and divinylbenzene (DVB), and vortex until completely dissolved to prepare Solution A; wherein benzoyl peroxide (BPO) is 1% of the mass of styrene (St); divinylbenzene (DVB) is 10% of the total mass of styrene (St) and divinylbenzene (DVB).

[0039] (2) Preparation of the continuous phase: Weigh polyvinyl alcohol (PVA) and dissolve it in purified water, heat it (80 °C) under stirring conditions to make it fully dissolve, and then cool it to room temperature to obtain a polyvinyl alcohol solution, denoted as Solution B, with a concentration of 6 mg / mL.

[0040] (3) Centrifugal membrane emulsification: Pour Solution B into a container box, and then slowly pour Solution A along the wall into the container box to form an oil-water system; then set the rotation speed of the centrifugal membrane emulsifier to 2400 rpm for centrifugal membrane emulsification treatment, and the treatment duration is 4 min, finally forming an O / W type emulsion.

[0041] (4) Suspension polymerization reaction: Mix the above-obtained O / W type emulsion and add it to a three-necked flask, set the mechanical stirring speed to 500 rpm, quickly raise the oil bath temperature to 70 °C and keep it warm for 3 h, continue to raise the temperature to 80 °C, keep it warm for 5 h, and then raise the temperature to 95 °C and keep it warm for 2 h. After the reaction is completed, turn off the heating and remove the three-necked flask from the oil bath, continue to keep stirring, cool it to room temperature and then stop stirring, and perform suction filtration to obtain microspheres; then wash the surface impurities of the microspheres with water and methanol in turn, perform suction filtration again, collect the microspheres, and dry them (50 °C, 6 h) to obtain polystyrene-divinylbenzene (PS-DVB) microspheres.

[0042] Example 2:

[0043] The difference from Example 1 is that the centrifugal speed in step (3) is 2300 rpm.

[0044] Example 3:

[0045] The difference from Example 1 is that the centrifugation speed in step (3) is 2500 rpm.

[0046] Example 4:

[0047] The difference from Example 1 is that the concentration of the polyvinyl alcohol solution in step (2) is 3 mg / mL.

[0048] Example 5:

[0049] The difference from Example 1 is that the concentration of the polyvinyl alcohol solution in step (2) is 9 mg / mL.

[0050] Example 6:

[0051] The difference from Example 1 is that benzoyl peroxide (BPO) in step (1) is 0.5% of the mass of styrene (St).

[0052] Example 7:

[0053] The difference from Example 1 is that benzoyl peroxide (BPO) in step (1) is 2% of the mass of styrene (St).

[0054] Example 8:

[0055] The difference from Example 1 is that divinylbenzene (DVB) in step (1) is 5% of the total mass of styrene (St) and divinylbenzene (DVB).

[0056] Example 9:

[0057] The difference from Example 1 is that divinylbenzene (DVB) in step (1) is 15% of the total mass of styrene (St) and divinylbenzene (DVB).

[0058] Example 10:

[0059] The difference from Example 1 is that a sulfonation reaction and an alkali exchange reaction are added.

[0060] (1) Sulfonation reaction: Place the polystyrene-divinylbenzene microspheres obtained in Example 1 in a three-necked flask, add the swelling agent chloroform to swell for 0.5 h, slowly drop concentrated sulfuric acid under stirring, and stir evenly after dropping to form a mixed solution, where the dosage relationship of polystyrene-divinylbenzene microspheres, chloroform, and concentrated sulfuric acid is 1 mg: 3 mL: 3 mL.

[0061] Subsequently, the mixed solution was heated to 65 °C for sulfonation reaction, and the reaction was carried out under stirring for 2 h; after the reaction, it was continuously heated to 70 °C and kept warm for 3 h, and then heated to 75 °C after the reaction and kept warm for 6 h. After the reaction was completed, heating and stirring were stopped. After the temperature of the reaction solution dropped to room temperature, the swelling agent and concentrated sulfuric acid were poured into the waste liquid bucket, and the product was collected, washed with purified water until neutral, then filtered by suction, and then centrifuged and washed twice with acetone. After washing, it was filtered by suction and washed with ethanol and water in turn. Finally, it was dried and passed through an 80-mesh sieve to obtain PS-DVB sulfonated microspheres;

[0062] (3) Base exchange: The PS-DVB sulfonated microspheres were immersed in 1% phenolphthalein indicator, and titrated with 10% NaOH solution as the titrant. When the solution turned red and did not fade within 1 min, magnetic stirring was carried out for 1 h. After the stirring was completed, it was washed with a large amount of purified water until neutral, filtered by suction, and placed in an oven to dry the moisture, thus obtaining sodium polystyrene sulfonate resin. Figure 1 is the scanning electron micrograph of sodium polystyrene sulfonate resin, Figure 2 is the particle size distribution diagram of sodium polystyrene sulfonate resin.

[0063] Example 11:

[0064] The difference from Example 11 is that in step (1), the ratio of concentrated sulfuric acid to polystyrene microspheres is 1 mL:1 mg (v:m).

[0065] Example 12:

[0066] The difference from Example 11 is that in step (1), the ratio of concentrated sulfuric acid to polystyrene microspheres is 5 mL:1 mg (v:m).

[0067] Performance detection test

[0068] I. Apparent performance detection

[0069] The determination of microsphere particle size and particle size distribution is the basis for evaluating the centrifugal boundary film emulsification technology. Selecting a suitable particle size determination method is the premise for accurately evaluating the microsphere particle size. The wet method is the most commonly used method in particle size distribution determination, which can obtain good reproducibility. Its measured particle size range is very wide, and samples from sub-micron to hundreds of micron levels can be measured. For micron-sized resins, the particles are not easily brittle, and deionized water can be directly used as the dispersant, and the method is simple and effective. This experimental method is carried out according to the light scattering method in the general chapter 0982 of the Chinese Pharmacopoeia 2020 edition. The instrument used for measurement is the MS 3000 laser particle size analyzer (Malvern Instruments, UK). The measurement method is as follows: The samples of Examples 1-12 and commercially available resin samples were ultrasonically dispersed in purified water to make the microspheres evenly dispersed. After setting the refractive index coefficient, the samples were added to the sample test cell and measured for their particle size distribution when the laser reading reached 80%. The particle size distribution data are shown in Table 1.

[0070] D50, namely the median particle size, represents that 50% of the microspheres in the microspheres have a particle size smaller than this value. Similarly, D10 and D90 respectively represent that 10% and 90% of the microspheres in the prepared microspheres have a particle size smaller than this value.

[0071]

[0072] The Span value represents the span of the particle size of the microparticles. The smaller the Span value, the narrower the particle size distribution of the microparticles and the more uniform the particle size.

[0073] II. Detection of drug loading

[0074] In this experiment, the static method was used for drug loading. Weigh 0.2 g of the model drug guanfacine hydrochloride, accurately measure 50 mL of purified water, place it in a 150 mL beaker, and stir magnetically until completely dissolved to obtain the test solution. Subsequently, weigh the same weight of Examples 10 - 12, place them in the test solution for drug loading, and the drug loading conditions are a temperature of 65 °C, a rotation speed of 1000 - 1100 rpm, and a time of 10 h. Measure the absorbance of guanfacine hydrochloride at a wavelength of 271 nm, calculate its concentration, calculate the drug loading of the polystyrene sulfonate resin, and calculate according to the following formula. The calculation results are shown in Table 2:

[0075]

[0076] C0 (mg·mL -1 ): The initial concentration of the drug solution;

[0077] C t (mg·mL -1 ): The concentration of the drug solution at time t;

[0078] V (mL): The volume of pure water added;

[0079] W R (mg): The mass of the resin added;

[0080] Q t (mg·mL -1 ): The drug loading of the resin at time t.

[0081] Table 1: Data table of particle size distribution of the samples prepared in Examples 1 - 12

[0082]

[0083] It can be clearly seen from the data of Examples 1 - 3 in Table 1 that the centrifugal speed in the centrifugal boundary film emulsification technology has a greater impact on the particle size distribution range of polystyrene microspheres. The average particle size of the microspheres decreases with the increase of the rotation speed. Since the drug loading of ordinary ion exchange resins is relatively low, the smaller the particle size of the ion exchange resin, the larger its specific surface area, which is beneficial to improving the drug loading of the resin.

[0084] The particle size of the microspheres in Example 1 is not much different from that in Example 3. When the centrifugal speed gradually increases, after the droplets decrease to a certain extent, the increase in the centrifugal speed instead increases the probability of droplet collision, promoting the coalescence of droplets, resulting in not particularly obvious reduction in particle size. Based on the Span value of the microsphere particle size distribution, it is thus selected that within the range of centrifugal speed of 2300 - 2500 rpm. Considering comprehensively, including taking into account issues such as energy consumption, the preferred speed is 2400 rpm.

[0085] It can be clearly seen from the data of Examples 1, 4, and 5 in Table 1 that as the dosage of the dispersant (PVA) increases, the D50 particle size decreases. This is because when the concentration of the monomer (St) remains unchanged, the increase in the concentration of the dispersant (PVA) leads to an increase in the number of nucleation sites and an increase in the number of secondary particles, thus forming smaller polymer particles and resulting in a smaller particle size. However, the Span value of the microspheres prepared in Example 5 is significantly higher than that in Example 1. This is because the increase in the number of particles and the decrease in particle size will increase the probability of "secondary nucleation", resulting in poor redispersibility of the product and a wide particle size distribution. Therefore, it is selected that within the range of the dispersant (PVA) concentration of 3 - 9 mg / mL, the PVA concentration of 6 mg / mL in Example 1 has the best effect.

[0086] It can be obtained from the data of Examples 1, 6, and 7 in Table 1 that the D90 of Example 6 and Example 7 is significantly larger than that of Example 1. The reason is that when the dosage of the initiator is too small, the number of free radicals generated is small, resulting in insufficient reaction; when the dosage of the initiator (BPO) is too large, too many free radicals are generated, the reaction rate is too fast, resulting in adhesion between microspheres and the occurrence of "explosive polymerization" phenomenon. Therefore, the dosage of the initiator should be appropriate and needs to be specifically selected through labor. In the present invention, benzoyl peroxide (BPO) is preferably 1% of the mass of styrene (St).

[0087] From the data of Examples 1, 8, and 9 in Table 1 and Example 9 in Table 2, when the dosage of the crosslinking agent is 5%, the particle size distribution is wide; while when the dosage of the crosslinking agent (DVB) reaches more than 10%, with the increase of the DVB dosage, the degree of phase separation gradually increases, and the particle size of the microspheres also slightly increases. This is because when the crosslinking degree is too low, it is difficult for the monomer (St) to be fully crosslinked, and it is difficult to construct a tightly crosslinked network of microspheres, making it difficult to form a stable spherical shape. When the crosslinking degree increases, the crosslinking effect is enhanced, promoting the tight crosslinking between monomer molecules to form a tightly crosslinked network structure, so the spherical shape is good. The larger the dosage of the crosslinking agent, the denser the crosslinking points, the more compact the structure of the microspheres, and the more difficult the movement of the molecular chains. When the subsequent sulfonation reaction occurs, it is difficult for concentrated sulfuric acid to penetrate into the interior of the microspheres, resulting in a decrease in sulfonation efficiency, a decrease in sulfonation degree, and a reduction in the number of introduced sulfonic acid groups, leading to a decline in the drug-loading performance of the resin. Therefore, it is best to choose a DVB dosage of 10% in Example 1 within the range of 5%-15% of the crosslinking agent (DVB) dosage.

[0088] It can be seen from Examples 10-12 in Table 1 that with the increase in the amount of concentrated sulfuric acid, the particle size of the sulfonated microspheres gradually increases, which may be due to the introduction of sulfonic acid groups resulting in changes in the particle size of the microspheres; at the same time, considering the data of the drug-loading capacity in Table 2, the amount of the sulfonating agent also affects the drug-loading performance of the sodium polystyrene sulfonate resin. However, the drug-loading capacity of Example 10 and that of Example 12 do not differ much. Considering both the operation safety of the sulfonation reaction and the treatment of three wastes, it is best to choose a concentrated sulfuric acid dosage (mL) of 3 times the dosage of the microspheres (g) in Example 10 within the range of 1-5 times.

[0089] Table 2: Data table of the drug-loading performance of sodium polystyrene sulfonate prepared in Examples 10-12

[0090]

[0091] From the above analysis, it can be known that by using the preparation method of the present application, sodium polystyrene sulfonate resin with uniform particle size, narrow particle size distribution, and an average particle size of basically 60-100 μm can be obtained. At the same time, during the later pharmaceutical process, since sodium polystyrene sulfonate does not need to be crushed and is also easily redispersed, the drug-loading stability of the prepared sodium polystyrene sulfonate resin is good; moreover, the drug-loading capacity of the sodium polystyrene sulfonate prepared in Examples 10 and 12 is large, indicating that the drug-loading performance of the sodium polystyrene sulfonate resin prepared by the preparation method of the present application is good.

[0092] Note: The above embodiments are only used to illustrate the present invention rather than limiting the technical solutions described in the present invention; therefore, although this specification has described the present invention in detail with reference to the above embodiments, those of ordinary skill in the art should understand that the present invention can still be modified or equivalently replaced; and all technical solutions and their improvements that do not depart from the spirit and scope of the present invention should be covered within the scope of the claims of the present invention.

Claims

1. A preparation method of sodium polystyrene sulfonate resin prepared by a centrifugal boundary film emulsification technique, characterized in that, It includes the following steps: (1) Preparation of the dispersed phase: Dissolve benzoyl peroxide in a mixed solvent of styrene and divinylbenzene, and vortex until completely dissolved to prepare solution A; (2) Preparation of the continuous phase: Weigh polyvinyl alcohol and add it to water, heat and stir to dissolve, and then cool to room temperature to prepare solution B; (3) Add solution A in step (1) to solution B in step (2) to form an oil-water system, and then carry out centrifugal membrane emulsification to finally form an O / W emulsion; (4) Suspension polymerization reaction: Place the O / W emulsion prepared in step (3) under stirring in an oil bath condition for the first temperature increase reaction. After the reaction, continue the second temperature increase reaction, and then continue the third temperature increase reaction after the reaction again. After the reaction is completed, maintain stirring and cool to room temperature, then stop stirring and carry out suction filtration to obtain microspheres; then wash the microspheres with water and methanol in sequence, collect the microspheres after suction filtration, and carry out drying to obtain a solid product, which is polystyrene-divinylbenzene microspheres; (5) Sulfonation reaction: Add the polystyrene-divinylbenzene microspheres obtained in step (4) to a swelling agent. After swelling for a period of time, dropwise add concentrated sulfuric acid under stirring, maintain stirring and carry out the first temperature increase reaction. After the reaction, continue the second temperature increase reaction, and then continue the third temperature increase reaction after the reaction again. After the reaction is completed, stop stirring. After the solution cools to room temperature, filter to collect the product and wash it to neutrality. After suction filtration, add acetone for cleaning, and then carry out suction filtration and cleaning with ethanol and water in sequence. Finally, after drying and sieving, PS-DVB sulfonated microspheres are obtained; (6) Base exchange: Immerse the PS-DVB sulfonated microspheres obtained in step (5) in a phenolphthalein indicator, and carry out basic titration with a NaOH solution as the titrant. Wait until the solution turns red and does not fade, then stir and wash to neutrality, then carry out suction filtration and drying to obtain a dried product, which is sodium polystyrene sulfonate resin.

2. The method for preparing sodium polystyrene sulfonate resin by the centrifugal boundary film emulsification technique according to claim 1, characterized in that, In step (1), the dosage of benzoyl peroxide is 0.1%-2% of the mass of styrene; divinylbenzene is 5%-15% of the total mass of styrene and divinylbenzene.

3. The method for preparing sodium polystyrene sulfonate resin by the centrifugal boundary film emulsification technique according to claim 1, wherein In step (2), the water is purified water, the temperature of heating and stirring is 60-90°C, and the concentration of solution B is 3-9 mg / mL.

4. The method for preparing sodium polystyrene sulfonate resin by the centrifugal boundary film emulsification technology according to claim 1, wherein In step (3), the centrifugal membrane emulsification is processed by a centrifugal membrane emulsifier, and the processing conditions are: rotation speed 2300-2500 rpm, duration 4 min.

5. The method for preparing sodium polystyrene sulfonate resin by the centrifugal boundary film emulsification technology according to claim 1, characterized in that, In step (4), the conditions of the stirring are 500 rpm, the temperature of the first temperature increase reaction is 70°C, and the reaction time is 3 h; the temperature of the second temperature increase reaction is 80°C, and the reaction time is 5 h; the temperature of the third temperature increase reaction is 95°C, and the reaction time is 2 h; the temperature of the drying is 50°C-60°C, and the time is 5-7 h.

6. The method for preparing sodium polystyrene sulfonate resin by the centrifugal boundary film emulsification technology according to claim 1, characterized in that, In step (5), the swelling agent is chloroform, and the swelling time is 0.5 h; the conditions of the stirring are 500 rpm, the temperature of the first temperature increase reaction is 65°C, and the reaction time is 2 h; the temperature of the second temperature increase reaction is 70°C, and the reaction time is 3 h; the temperature of the third temperature increase reaction is 75°C, and the reaction time is 6 h.

7. The method for preparing sodium polystyrene sulfonate resin by the centrifugal boundary film emulsification technique according to claim 1, characterized in that, In step (5), the dosage relationship of the polystyrene-divinylbenzene microspheres, the swelling agent, and concentrated sulfuric acid is 1 mg: 3 mL: 3 mL; the drying temperature is 50°C - 60°C, and the time is 5 - 7 h; the mesh number of sieving is 80 mesh.

8. The method for preparing sodium polystyrene sulfonate resin by the centrifugal boundary film emulsification technique according to claim 1, characterized in that, In step (6), the concentration of the phenolphthalein indicator is 1%, and the concentration of the NaOH solution is 10%; specifically, when the solution turns red and does not fade, it means that it does not fade within 1 minute. The stirring time is 1 h, the drying temperature is 50°C - 60°C, and the time is 5 - 7 h.

9. A sodium polystyrene sulfonate resin prepared by the centrifugal boundary film emulsification technique according to the method described in any one of claims 1-8, characterized in that, The average particle size of the sodium polystyrene sulfonate resin is 60 - 100 μm, and it is in a regular spherical shape.

10. Use of the sodium polystyrene sulfonate resin prepared by the centrifugal boundary film emulsification technology according to claim 9 as a pharmaceutical excipient.

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