Sodium zirconium cyclosilicate for controlling particle size distribution and method of preparation

Abstract

The application provides sodium zirconium cyclosilicate with controlled particle size distribution, which has less particles less than 3 microns, thereby improving drug safety, and has more than 95% ZS-9 crystal form, thereby having high KEC, and ensuring drug efficacy. The application further provides a preparation method and use of the sodium zirconium cyclosilicate.

Description

TECHNICAL FIELD

[0001] The present application relates to a sodium zirconium cyclosilicate particle, its preparation method and pharmaceutical use. BACKGROUND

[0002] Hyperkalemia is a serious electrolyte disorder disease, which has significant harm to the health of patients. According to epidemiological data in China, the prevalence rate of chronic kidney disease (CKD) in China is about 10.8%, with about 120 million patients, and about 1.92 million patients with end-stage renal disease (ESRD). Hyperkalemia is common in patients with CKD, and it is estimated that there are at least 2 million patients with hyperkalemia in China. Hyperkalemia can lead to malignant arrhythmia, sudden cardiac death, and increase the risk of death in patients. In patients with maintenance hemodialysis (MHD), repeated episodes of hyperkalemia also increase the risk during dialysis, which seriously affects the quality of life and prognosis of patients.

[0003] Since AstraZeneca's sodium zirconium cyclosilicate powder (Zytiga) has been listed in China since 2019, it has been the mainstream drug for treating hyperkalemia. The drug instruction book records its chemical name as sodium zirconium silicate hydrate, with a molecular formula of Na ~1.5 H ~ 0.5 ZrSi3O9•2-3H2O, which is suitable for treating adult hyperkalemia. The product is a white to gray powder, and the recommended starting dose is 10 grams. The small bag of medicine is completely poured into a water cup of about 45 ml of water and stirred thoroughly, and taken while still cloudy. If the powder is precipitated, it should be stirred again to ensure that all the medicine is taken. Among the total number of subjects in the clinical study, 58% were 65 years of age and older, and 25% were 75 years of age and older.

[0004] Elderly patients move more slowly, and their observation ability is limited, so it is often difficult for them to take all the medicine before the powder precipitates. If they take it after stirring again after adding water, it will increase the amount of water the patient drinks. The National Health Commission Office issued the Blood Purification Standard Operating Procedures (2021 Edition) Notice, which clearly states that one of the volume management of hemodialysis patients is to limit water. When kidney failure patients have oliguria, water accumulates in the body, causing increased cardiovascular system load, loss of heart cell activity, and then edema and weight gain throughout the body, shortness of breath in the supine position, and decreased blood viscosity. Patients may also develop hypertension, heart failure, and pericarditis. Too much filtration and water volume load during hemodialysis can easily cause heart failure; during peritoneal dialysis, excessive fluid intake can also cause lower extremity edema, leading to pleural effusion, ascites, and even heart and lung compression in severe cases. Therefore, in order to prevent this situation from occurring, the amount of water consumed by dialysis patients must be strictly controlled. The clinical practice recommendation is that dialysis patients with daily urine output greater than 1500 mL have no limit on their water intake, as long as their interdialytic weight gain does not exceed 5% of their dry body weight. Patients with no or oliguria should consume 500 mL of water per day, 300 mL of water per day, or 100 mL of water per day, respectively, for three, two, or one dialysis per week. Therefore, it is necessary to reduce the powder precipitation rate to ensure that patients do not need to consume excessive amounts of water when taking their medication.

[0005] The U.S. FDA Center for Drug Evaluation and Research describes zirconium silicate cyclosilicate as an inorganic compound that is insoluble in water, and that no more than 3% of the particles have a particle size of less than 3 microns. Small particles can enter the human blood circulation and cause damage, so reducing the content of small particles is important for improving drug safety. However, larger particle sizes can result in a decrease in surface area, affecting the ability to adsorb potassium ions and reducing drug efficacy. Therefore, the industry has been seeking suitable preparation processes to obtain zirconium silicate cyclosilicate products with no or as few small particles as possible.

[0006] CN103534209A mentions that ZS-9 crystals have a wide particle size distribution. The theory also suggests that small particles with a particle size of less than 3 microns can be absorbed into the patient's blood, causing unwanted effects such as the accumulation of particles in the patient's urinary tract, particularly in the patient's kidneys. Commercially available zirconium silicate is prepared by filtering out some particles below 1 micron. However, it has been found that small particles are retained in the filter cake, and removing particles with a particle size of less than 3 microns requires the use of additional sieving techniques. Many techniques for particle sieving include manual sieving, air jet sieving, sieving or filtering, floating, or any other known particle classification method. Sieving increases production costs and does not completely remove particles below 3 microns.

[0007] Patent CN104619639A obtained a highly uniform particle size of zirconium silicate cation composition by controlling the stirring speed without sieving, wherein the different particle size ranges were obtained by sampling and analyzing at different stirring speeds and time periods in Examples 1-3. However, the potassium exchange capacity (KEC) of the final product obtained in Examples 1-3 was very low, only 3.07 to 3.23 mEq / g, showing that although the particle size distribution was ideal, the drug efficacy was reduced. The reason should be that the undesired crystal form was generated, and the content of ZS-9 crystal form was less than 95%.

[0008] US5891417 disclosed several different crystal forms of zirconium silicate, ZS-1-ZS-11, in 1999. According to subsequent studies, the X-ray diffraction parameters of ZS-9 are as follows:

[0009]

[0010] Or expressed as:

[0011]

[0012] Wherein I represents the intensity of the diffraction peak, and vs, s, m and w represent the relative intensity of the peak corresponding to the d-spacing. The above data can be obtained that the X-ray characteristic diffraction peak 2 theta angle of ZS-9 is 12.12, 13.98, 15.65, 29.00 and 32.30.

[0013] According to the record of Chinese patent CN106170283B, the selectivity and binding capacity of ZS-9 crystal form to potassium ion are optimal, and the selectivity to potassium ion is as high as 100%, and the binding capacity is 10 times that of traditional drug sodium polystyrene sulfonate (SPS). In Example 20, hydrothermal reaction was carried out in a 200L reactor, the reactor was set at 210℃±5℃, the stirring speed was 150rpm, and the duration was ≥60 hours. But the product obtained had 1.69-6.37% of particles less than 3 microns, and three batches of products showed a relatively uneven particle size distribution, and the potassium exchange rate was 2.94-3.1 mEq / g. The patentee attributed this reason to the increased filling rate of the reactor. However, under the same stirring speed, one batch of product with the same level of yield and output as the other three batches was obtained, which had a uniform particle size, and the particles less than 3 microns were 1.69%, and the particles less than 2.5 microns were 0.4%. In Example 23, the patentee enlarged the reactor scale to 500L, and prepared zirconium silicate with a content of ZS-9 greater than or equal to 95% using zirconium silicate as raw material, and the product had about 1.7% of particles less than 3 microns, D 90= 38.013 pm, its potassium exchange capacity (KEC) value reached 3.5 mEq / g, and its patent Fig. 33 clearly shows that as the percentage of ZS-9 material reaches 95%, the capacity significantly increases. Although the patent claims that the KEC of its product can reach 4.7 mEq / g, it has not actually prepared a product with a KEC higher than 3.5 mEq / g.

[0014] Patent CN108137620B reports the effect of different raw materials on the heavy metal residue of the final product in the preparation of ZS-9. Colloidal silicon dioxide and zirconium acetate were used as raw materials, the crystallization temperature was 210°C, and the stirring speed was also 150 rpm at a 500L reactor scale. The prepared sodium zirconium silicate (ZS-9) had a uniform particle size distribution, but the product had 2% of particles below 3 microns, which still had potential toxicity.

[0015] Patent CN118439624A obtained high-purity sodium zirconium silicate by using multiple stirring paddles. The reactor scale was 1L and the stirring speed was 300 rpm. The product was characterized and determined to be high-purity sodium zirconium silicate with a ZS-9 content of more than 99%. However, according to the sample prepared in Example 1 of the patent, the particles less than 3 microns reached 5.35%, which was not conducive to the safety of the drug. It is also difficult to ensure that there are no particles less than 3 microns after filtering by common means.

[0016] Therefore, how to improve the high content of ZS-9 in the product and control the particle size distribution, ensure the effectiveness of the drug, and strictly control the particles below 3 microns to reduce the toxic side effects of patients will become extremely critical, have great clinical value, and truly reflect the safety, effectiveness and quality controllability of the drug. In addition, controlling the daily water intake of patients is also a problem that needs to be solved in clinical practice, and it is of great significance to the safety of medication for special groups. SUMMARY

[0017] To solve the above problems, the present application provides a sodium zirconium silicate particle, wherein more than 95% of the sodium zirconium silicate is in the ZS-9 crystal form, and the particles with a particle size less than 3 pm are not more than 1%.

[0018] The sodium zirconium silicate is partially protonated.

[0019] Preferably, more than 97% of the sodium zirconium silicate is in the ZS-9 crystal form, more preferably more than 99% of the sodium zirconium silicate is in the ZS-9 crystal form.

[0020] Preferably, the particles with a particle size less than 3 pm are not more than 0.5%, more preferably not more than 0.4%, and most preferably not more than 0.1%.

[0021] Preferably, the D 50≤ 20 μm.

[0022] As preferred, the KEC of the sodium zirconium cyclosilicate is ≥ 3.5 mEq / g. The KEC as used herein refers to potassium exchange rate.

[0023] The present application also provides a pharmaceutical composition comprising the sodium zirconium cyclosilicate particles and pharmaceutically acceptable excipients.

[0024] The present application also provides a method for preparing the sodium zirconium cyclosilicate particles, using zirconium acetate, colloidal silicon dioxide, and sodium hydroxide as raw materials, hydrothermal reaction at 200-215°C under stirring at 80-120 rpm for 24-48 hours.

[0025] By using the combination of specific raw materials, temperature, stirring speed, and reaction time, the particles with controlled particle size distribution and ZS-9 content can be prepared.

[0026] The present inventors have solved the problem of balancing safety and effectiveness by using a 22L reactor, adding colloidal silicon dioxide to a solution of sodium hydroxide and water, then adding a zirconium acetate solution, using a multi-layer propeller stirring paddle, reducing the stirring speed to 150 rpm at a crystallization temperature of 200-215°C, and filtering after 40 hours, washing, acidifying, and drying the obtained sodium zirconium cyclosilicate particles. No particles less than 3 microns were detected, and the KEC was above 3.5 mEq / g. However, the particle size distribution was not uniform, the obtained product had a short settling time, and a large amount of water was still needed for auxiliary medication, which was not beneficial to dialysis patients.

[0027] When a reactor with a scale of 1000L or above is used, 2-8 baffles are evenly arranged around the inner wall of the reactor cavity after upgrading the reactor under the condition of a multi-layer propeller stirring paddle. The present inventors have surprisingly found that by using such an optimized reactor, colloidal silicon dioxide is added to a solution of sodium hydroxide and water, then a zirconium acetate solution is added, and after stirring, the stirring speed is reduced to 80-120 rpm at a crystallization temperature of 200-215°C for 24-48 hours, and then the product is filtered, washed, acidified, and dried. The content detection shows that the purity of ZS-9 is higher than 99%, the KEC is not less than 3.5 mEq / g, and under low stirring speed, particles less than 3 microns can be reduced or not produced, and the particle size distribution range is uniform. The particle size distribution range of the product is as follows:

[0028] 10 μm ≥ D 10 ≥ 5 μm, 20 μm ≥ D 50 ≥ 10 μm, 60 μm ≥ D 90 ≥ 25 μm.

[0029] The present inventors have further found that when D50 When the particle size is ≤20 μm, the product does not settle obviously, and no additional water is needed for taking the product, which can help the dialysis patients with hyperkalemia to effectively control the daily water consumption.

[0030] The application also provides the use of the zirconium sodium cyclosilicate particles in the preparation of a medicament for treating chronic hyperkalemia. In particular, the medicament is used for treating chronic hyperkalemia of patients who clinically need to limit the water consumption and patients who need dialysis treatment.

[0031] Compared with the prior art, the application has the following beneficial effects:

[0032] (1) The product ZS-9 obtained by the application has a content of more than 95%, preferably more than 97%, and more preferably more than 99%, and reduces or does not produce particles less than 3 microns, which balances the efficacy and safety;

[0033] (2) The preferred zirconium sodium silicate hydrate D provided by the application has a highly uniform particle size distribution 50 ≤20 μm, which effectively improves the effect of not rapidly settling of the material and controls the daily water consumption requirement of the dialysis patients;

[0034] (3) The new preparation method and device provided by the application can efficiently produce the zirconium sodium cyclosilicate product, and do not need to remove small particles less than 3 microns through filtration or the like. BRIEF DESCRIPTION OF DRAWINGS

[0035] Other features, objects and advantages of the application will become more apparent from the following detailed description of non-limiting embodiments made with reference to the following drawings:

[0036] Figure 1 is a schematic diagram of the crystal structure of zirconium sodium cyclosilicate ZS-9;

[0037] Figure 2 is a particle size spectrum of the product prepared in Example 1;

[0038] Figure 3 is a comparison diagram of the X-ray diffraction spectrum of the product prepared in Example 2 and the PXRD diagram calculated according to the indexation result (the upper part is the calculated diagram);

[0039] Figure 4 is a particle size spectrum of the product prepared in Example 2;

[0040] Figure 5 is a solid-state nuclear magnetic resonance Si spectrum of the product prepared in Example 2; 29

[0041] Figure 6 is a particle size spectrum of the product prepared in Comparative Example 1;

[0042] ​Figure 7 is a photograph of the experimental results of Experimental Example 1 (mixed up);

[0043] Figure 8 is a photograph of the experimental results of Experimental Example 1 (one minute rest);

[0044] Figure 9 is a photograph of the experimental results of Experimental Example 1 (one minute rest, lower portion of container magnified);

[0045] Figure 10 is a photograph of the experimental results of Experimental Example 1 (ten minute rest);

[0046] Figure 11 is a photograph of the experimental results of Experimental Example 2 (Example 1-4 sample after pouring);

[0047] Figure 12 is a photograph of the experimental results of Experimental Example 2 (Example 1-2 sample after pouring, magnified). DETAILED DESCRIPTION

[0048] For a better understanding of the present application, reference will be made to the detailed description of the application in connection with the accompanying drawings in which: It is to be understood that the detailed description is only exemplary of the application and is not intended to limit the scope of the application in any way. Throughout this document, the same reference numerals are used to refer to similar or like elements. The expression “and / or” includes any and all combinations of one or more of the associated listed items.

[0049] In the drawings, the size, proportions and shapes of the figures have been slightly adjusted for ease of illustration. The drawings are merely examples and are not drawn to scale. As used in this document, the terms “approximately,” “about,” and similar terms are used as terms of approximation and not as terms of degree, and are intended to account for the inherent deviations in a measuring or computing process.

[0050] It should also be understood that expressions such as “include”, “including”, “have”, “has”, “contain” and / or “containing” are open-ended expressions that are used to specify the presence of stated features, elements, and / or components, but do not preclude the presence or addition of one or more other features, elements, components, and / or combinations of them. Furthermore, when such expressions as “at least one of” appear in a list of two or more items, each individual item can be present and / or combined with one or more of the other items. In addition, when describing applications, the use of “can” means “one or more applications of the present application”. Also, the word “exemplary” is intended to mean an example or an illustration.

[0051] Unless otherwise defined, all terms (including technical and scientific terms) used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. It will be further understood that terms, such as those defined in commonly used dictionaries, should be interpreted as having a meaning that is consistent with their meaning in the context of the relevant art and will not be interpreted in an idealized or overly formal sense unless expressly so defined herein.

[0052] It should be noted that the features of the embodiments and examples in the present application can be combined with each other as long as there is no conflict. In addition, the specific steps contained in the methods described in the present application are not necessarily limited to the order described, but can be executed in any order or in parallel, unless expressly limited or contradicted by the context. The present application will be described in detail below with reference to the accompanying drawings and in conjunction with the embodiments.

[0053] The particle size test method in the present application: refer to the method for particle size detection in the imported registration standard of sodium zirconium cyclosilicate. According to the third method of Chinese Pharmacopoeia 2015 edition four general rules 0982, water is used as the dispersion medium, and the wet method is used for determination (such as Malven 3000 or other laser particle size analyzers with equivalent performance).

[0054] The detection method of ZS-9 in the present application: refer to example 23 in CN106170283B, and use Rietveld full spectrum fitting method for calculation.

[0055] Example 1

[0056] In a 22L stainless steel pressure container, sodium hydroxide (0.9kg) was mixed with water (5.6kg) and cooled to room temperature, then colloidal silicon dioxide (2.4kg) was added at a stirring speed of 150rpm. At the same time, the stirring speed was maintained, zirconium acetate (1.6kg) was added, after the addition was completed, a slurry was generated, then water (5kg) was added to maintain the stirring speed, the reactor was heated to 200-210℃, and after maintaining for 40 hours, it was cooled to room temperature, filtered, and the crude product was washed with purified water (3kg) for three times. The washed crude product was transferred to another container and purified water (6kg) was added, and hydrochloric acid was used to adjust the pH to 4.75-5.25 (partially protonated), then filtered and washed with purified water twice, each time for 3kg. After filtration, the material was placed in a 100℃ oven and dried under reduced pressure to constant weight. The potassium ion exchange rate KEC was measured to be 3.5mEq / g, the particle size distribution was as shown in Figure 2 10 =10.9μm, D 50 =23.5μm, D 90 =50.6μm. After structure refinement of the sample by Rietveld full spectrum fitting method, the purity of ZS-9 in the product was 97.1%.

[0057] Example 2​

[0058] In a 1000 L stainless steel pressure vessel, sodium hydroxide (45 kg) was mixed with water (280 kg) and cooled to room temperature, then colloidal silicon dioxide (120 kg) was added with a stirring speed of 120 rpm. While maintaining the stirring speed, zirconium acetate (32 kg) was added, after which a slurry was formed. After adding water (100 kg) while maintaining the stirring speed, the reactor was heated to 200-210 °C and maintained for 24 hours, then cooled to room temperature, filtered, and the crude product was washed with purified water (150 kg) x 3. The washed crude product was transferred to another vessel and purified water (300 kg) was added, then the pH was adjusted to 4.75-5.25 with hydrochloric acid, filtered, and washed twice more with purified water, 150 kg each time. After filtration, the material was placed in a 100 °C oven and dried under reduced pressure to a constant weight. The potassium ion exchange rate was measured to be 3.6 mEq / g, and the PXRD is shown in FIG. 1. Figure 3

[0059] After the sample was refined by the Rietveld full spectrum fitting method, it belonged to the cubic crystal system, P-3a (205#) space group, and the crystallographic parameters were as follows:

[0060] Crystal system: cubic

[0061] Space group: P-3a

[0062] Cell parameters: a = b = c = 12.7523(1) Å, α = β = γ = 90°, cell volume V = 2073.81 Å3, number of molecules in the cell Z = 8. The comparison of the X-ray diffraction pattern (PXRD pattern) and the PXRD pattern calculated according to the indexing results shows that the experimental pattern is completely consistent with the calculated pattern, indicating that the product is a single phase, and the purity of ZS-9 in the product is greater than 99.9%.

[0063] The particle size detection results were 0.00% of particles less than 3 μm, and D 90 = 21.2 μm, D 50 = 12.9 μm, and D 10 = 7.69 μm, see FIG. 2. Figure 4

[0064] The product was confirmed by solid-state nuclear magnetic resonance (nuclear magnetic resonance instrument model BRUKE AVANCE III 400) to have one type of silicon, further supporting its high single crystal purity, see FIG. 3. Figure 5

[0065] Example 3

[0066] ​​​In a 1000 L stainless steel pressure vessel, sodium hydroxide (45 kg) was mixed with water (280 kg) and cooled to room temperature, then colloidal silicon dioxide (120 kg) was added at a stirring speed of 80 rpm. While maintaining the stirring speed, zirconium acetate (32 kg) was added, after which a slurry was formed. After adding water (100 kg) while maintaining the stirring speed, the reactor was heated to 200-210 °C, and maintained for 40 hours before being cooled to room temperature. The crude product was filtered, washed with purified water (150 kg) three times, and then transferred to another container and purified water (300 kg) was added. The pH was adjusted to 4.75-5.25 with hydrochloric acid, and the product was filtered and washed twice with purified water (150 kg each time). After filtration, the material was placed in a 100 °C oven and dried under reduced pressure until the weight was constant. The potassium ion exchange rate was 3.5 mEq / g, the particle size detection results were 0.00% of particles less than 3 μm, and D 90 = 52.8 μm, D 50 = 17.4 μm, and D 10 = 5.58 μm. After structural refinement of the sample by Rietveld full spectrum fitting method, the purity of ZS-9 in the product was 99.0%.

[0067] Example 4

[0068] In a 1000 L stainless steel pressure vessel, sodium hydroxide (45 kg) was mixed with water (280 kg) and cooled to room temperature, then colloidal silicon dioxide (120 kg) was added at a stirring speed of 80 rpm. While maintaining the stirring speed, zirconium acetate (32 kg) was added, after which a slurry was formed. After adding water (100 kg) while maintaining the stirring speed, the reactor was heated to 200-210 °C, and maintained for 40 hours before being cooled to room temperature. The crude product was filtered, washed with purified water (150 kg) three times, and then transferred to another container and purified water (300 kg) was added. The pH was adjusted to 4.75-5.25 with hydrochloric acid, and the product was filtered and washed twice with purified water (150 kg each time). After filtration, the material was placed in a 100 °C oven and dried under reduced pressure until the weight was constant. The potassium ion exchange rate was 3.5 mEq / g, the particle size detection results were 0.00% of particles less than 3 μm, and D 90 = 43.9 μm, D 50 = 18.0 μm, and D 10 = 6.45 μm. After structural refinement of the sample by Rietveld full spectrum fitting method, the purity of ZS-9 in the product was greater than 99.0%.

[0069] Comparative Example 1

[0070] Refer to patent CN118439624A Example 1.

[0071] In a 1L stainless steel pressure vessel, using a double-layer propeller, sodium hydroxide (190g) and water (300mL) were mixed and cooled to room temperature. Then, colloidal silica Ludox, which does not contain ammonium ion stabilizers, was added. TM -HS-40 (200g), stirring at 300rpm. While maintaining this stirring speed, add zirconium acetate (160g). After the addition is complete, a slurry is formed. Then add water (120mL) and maintain the stirring speed. Heat the reactor to 200-210℃ and maintain this temperature for 24 hours. Then cool to room temperature and filter. Wash the crude product with purified water (200mL) three times. Transfer the washed crude product to a glass bottle and add purified water (200mL). Adjust the pH to 4.75-5.25 with hydrochloric acid, filter, and wash twice more with purified water, 200mL each time. After filtration, place the material in a 100℃ oven and dry under reduced pressure to constant weight.

[0072] The obtained product, after particle size analysis, yielded the following results: Figure 6 As shown, its D 90 =42.1μm, D 50 =14.9μm and D 10 =4.26μm, but its particles smaller than 3μm account for 5.35%.

[0073] Experimental Example 1

[0074] Take 5g of the sample to be tested, place it in a stoppered graduated cylinder, add 45mL of water, seal tightly, shake vigorously for 1 minute, let stand, and observe under a canopy light at 0 minutes, 1 minute, and 10 minutes respectively. Figures 7-10 The products in the image, from left to right, represent Examples 1-4.

[0075] Observing the settlement diagram above, we can see that D 50 Products larger than 20 μm, i.e., the product of Example 1, began to sink after 1 minute, and the sinking was very obvious after 10 minutes, while D 50 For products smaller than 20μm, i.e., the liquid level of the three batches of samples in Examples 2-4 was at a relatively high position, indicating that dialysis patients can take the medication in one dose without the need for additional water.

[0076] Experimental Example 2

[0077] Take 5g of the sample to be tested, place it in a 150mL beaker, add 45mL of water, stir thoroughly, and pour it out while it is still cloudy after 1 minute (invert the beaker 90 degrees). See Figure 11 From left to right, these are products from Examples 1-4. See the enlarged image below. Figure 12, from left to right are the products of Example 1-2, it can be seen that the product of Example 1 has more residues, the weight after drying is 0.8g (the average of three experiments), while the products prepared by Examples 2-4 have very few residues in the beaker, and the weights after drying are 0.0g, 0.1g, 0.0g (accurate to 0.1g, the average of three experiments) respectively. It shows that D 50 Not more than 20 μm is more conducive to patients to take medicine completely without the need to use additional water for assistance.

[0078] The above description is only an embodiment of the present application and an explanation of the technical principles used. Those skilled in the art should understand that the protection scope of the present application is not limited to the technical solutions formed by the specific combinations of the above technical features, and should also cover other technical solutions formed by any combination of the above technical features or equivalent features without departing from the technical concept. For example, the above features are replaced with the technical features disclosed in the present application (but not limited to) having similar functions to form technical solutions.

Claims

1. Sodium zirconium silicate particles, characterized in that: More than 95% of the sodium zirconium silicate is in the ZS-9 crystal form, and the particles with a particle size less than 3 μm are not more than 1%, and the D 50 <20 μm.

2. The sodium zirconium silicate particles according to claim 1, characterized in that: the sodium zirconium silicate is partially protonated, and particles having a size of less than 3 μm are not more than 0.5%.

3. The sodium zirconium silicate particles according to claim 1, characterized in that: more than 97% of the sodium zirconium silicate is in the ZS-9 crystalline form.

4. The sodium zirconium silicate particles according to claim 1, characterized in that: more than 99% of the sodium zirconium silicate is in the ZS-9 crystalline form.

5. A pharmaceutical composition comprising the sodium zirconium silicate particles of any one of claims 1 to 4, and a pharmaceutically acceptable excipient.

6. The process for the preparation of sodium zirconium cyclosilicate particles according to any one of claims 1 to 4, characterized in that, Zirconium acetate, colloidal silicon dioxide, sodium hydroxide are used as raw materials, and hydrothermal reaction is carried out at 200-215°C under stirring at 80-120 rpm for 24-48 hours.

7. Use of the sodium zirconium silicate particles of any one of claims 1 to 4 for the manufacture of a medicament for the treatment of hyperkalemia.

8. Use according to claim 7, characterized in that, The medicament is for the treatment of hyperkalemia in patients who are clinically required to limit the amount of water intake.

9. Use according to claim 8, characterized in that, The medicament is for the treatment of hyperkalemia in patients who are clinically required to undergo dialysis treatment.

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