A method for preparing sodium zirconium cyclosilicate ZS-9

Abstract

The application provides a preparation method of sodium zirconium silicate ZS-9 and belongs to the technical field of pharmacy. The preparation method comprises the following steps: firstly, a sodium silicate solution and an alkali solution are mixed, a zirconium-containing solution is added dropwise, the mixture is transferred into a high-pressure reaction kettle, ZS-9 crystal seeds are added, and a mixed solution is obtained; the obtained mixed solution is heated and kept warm and pressure, and reaction is carried out; after the reaction is completed, cooling is carried out, and the pH value is adjusted; and then filtering is carried out, so as to obtain the sodium zirconium silicate ZS-9 crystal form. The preparation method overcomes the special process conditions of traditional high temperature and high pressure, does not need a reaction equipment with an internally-structured special modification, is more suitable for industrial production, and can meet the medicinal requirements of the potassium ion exchange capacity of the obtained sodium zirconium silicate.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of pharmacy, and particularly relates to a preparation method of sodium zirconium silicate ZS-9. BACKGROUND

[0002] Hyperkalemia refers to a pathological state in which the concentration of potassium ions (K+) in the blood abnormally increases. Under normal circumstances, the potassium concentration in the blood is maintained within a relatively stable range, and hyperkalemia indicates that the potassium concentration in the blood exceeds the normal range. Hyperkalemia is a common electrolyte disorder of the body, and can be life-threatening in severe cases. Hyperkalemia can be caused by a variety of reasons, including abnormal kidney function, drug use, acid-base imbalance, cell damage, etc. It is more common in patients with chronic kidney disease (CKD) and heart failure. At present, CKD has a high incidence worldwide, and elevated blood potassium in the body can accelerate the progression of CKD in patients, leading to many adverse consequences such as emergency hospitalization, and increase the risk of death. In addition, hyperkalemia is prone to repeated and sustained occurrence, which brings psychological pressure and economic burden to patients and their families. Therefore, the treatment of hyperkalemia needs to be taken according to the specific circumstances, including adjusting diet, stopping the use of drugs that cause hyperkalemia, correcting acid-base imbalance, increasing potassium excretion, etc. Potassium excretion agents can help promote the excretion of potassium ions from the body and reduce the concentration of potassium ions in the blood. Commonly used drugs include sodium polystyrene sulfonate and diuretics such as furosemide. Sodium zirconium silicate belongs to inorganic crystal class, and is a potassium-lowering drug listed in the past 5 years (listed in the United States and China in 2018 and 2019), which has a unique cubic crystal structure and high binding capacity for potassium ions. After taking, it combines with potassium ions in the gastrointestinal tract and is excreted through feces, thereby reducing blood potassium levels.

[0003] Patent US5891417 first disclosed sodium zirconium cyclosilicate, and has ZS-1~ZS-11 different crystal forms. The patent CN106170283A of the original research company discloses that among the various different crystal forms of sodium zirconium cyclosilicate ZS-1~ZS-11, sodium zirconium cyclosilicate ZS-9 is a new type of high selectivity potassium ion selective adsorption resin. Its main component is sodium zirconium cyclosilicate. It selectively adsorbs potassium ions, can effectively reduce the potassium concentration in the blood, and treats hyperkalemia. The resin structure is ring-shaped, and the selectivity of the linear resin for adsorbing potassium ions is stronger. It has good compatibility with the gastrointestinal tract and is safe to the human body. It has strong repeated use ability, and can re-adsorb potassium ions after elution after adsorption. However, in the preparation process of sodium zirconium cyclosilicate ZS-9, other undesired crystal forms are also formed. The unwanted forms must be controlled in the manufacturing process itself, because the product is not soluble in all solvents, so it is difficult to reprocess. The patent CN106170283A also discloses a preparation method of ZS-9 - preparation by hydrothermal crystallization reaction: in a reactor with the "baffle" structure shown in the following figure, the mixed solution of sodium silicate solution, sodium hydroxide solution and zirconium acetate solution is reacted at a temperature above 200 DEG C and a pressure above 2.5 MPa to obtain ZS-9. The reaction conditions are relatively harsh, and the reaction equipment needs special modification (the baffle-shaped structure related to the stirrer needs to be used in the crystallization container and positioned correctly relative to the stirrer, and the serpentine coil along the inner wall of the reactor tube is used). In order to find a more economically meaningful method for preparing pure sodium zirconium cyclosilicate, Indian patents IN202041056388 and IN201941046191 also disclose an improved preparation method of sodium zirconium cyclosilicate ZS-9, in which sodium silicate, sodium hydroxide and zirconium acetate are mixed and placed in a special reaction device, and reacted at 210-230 DEG C under a nitrogen pressure of 20-30 kg to obtain sodium zirconium cyclosilicate ZS-9.

[0004] The existing disclosed technology for preparing sodium zirconium cyclosilicate ZS-9 needs to be carried out in an improved high-pressure reactor, which requires a high temperature above 200 DEG C, and the conditions are relatively harsh, which is not conducive to large-scale industrialization. Therefore, a relatively mild technology is needed to realize the industrialized preparation of sodium zirconium cyclosilicate ZS-9. SUMMARY

[0005] Therefore, the purpose of the present application is to provide a preparation method of sodium zirconium cyclosilicate ZS-9, which does not require harsh high-temperature and high-pressure process conditions, does not require special modification of high-pressure reaction equipment, has relatively mild reaction conditions, is easy to realize industrialization, and obtains sodium zirconium cyclosilicate ZS-9 with higher purity, yield and potassium ion exchange capacity.

[0006] In order to achieve the above-mentioned purpose of the application, the technical scheme of the present application is as follows:

[0007] A method for preparing sodium zirconium cyclosilicate ZS-9, comprising the following steps:

[0008] (1) mixing a sodium silicate solution and a base solution, adding a zirconium-containing solution dropwise, transferring to a high-pressure reaction kettle, adding ZS-9 seed crystals, and obtaining a mixed solution;

[0009] (2) heating the mixed solution obtained in step (1) and reacting under pressure;

[0010] (3) after the reaction is completed, cooling and adjusting the pH value;

[0011] (4) filtering, and obtaining the product.

[0012] Preferably, in step (1), the concentration of the sodium silicate solution is 30-45%, and most preferably 37%; the concentration of the base solution is 5-10%, and most preferably 7%; and the concentration of the zirconium-containing solution is 50-70%, and most preferably 60%.

[0013] Preferably, in step (1), the molar ratio of sodium silicate, base, and zirconium is 1:3.5-6:3-5, and most preferably 1:4.4:4.

[0014] Preferably, in step (1), the base is at least one selected from sodium hydroxide, potassium hydroxide, barium hydroxide, ammonium hydroxide, calcium hydroxide, sodium methoxide, potassium ethoxide, potassium tert-butoxide, butyllithium, and phenyllithium, and is further preferably at least one selected from sodium hydroxide, potassium hydroxide, and barium hydroxide, and most preferably sodium hydroxide.

[0015] Preferably, in step (1), the zirconium-containing solution is at least one selected from zirconium acetate solution and zirconium carbonate solution, and is further preferably zirconium acetate solution.

[0016] Preferably, in step (1), the material of the high-pressure reaction kettle is at least one selected from hastelloy, monel, zirconium alloy, stainless steel, inconel, and industrial pure titanium, and is further preferably at least one selected from hastelloy and monel, and most preferably monel, and the internal structure of the high-pressure kettle does not need to be specially modified, and a commercially available ordinary high-pressure kettle can be used.

[0017] Preferably, in step (1), the volume of the high-pressure reaction kettle is 1-10 L, and is further preferably 1-5 L, and is more further preferably 1-2 L.

[0018] Preferably, in step (1), the amount of ZS-9 seed crystals added is 0.2-10%, and is further preferably 0.5-5%, and is more further preferably 0.5-2%.

[0019] Preferably, in step (2), the temperature of the reaction is 140-160°C, further preferably 140-150°C, and more preferably 145-150°C.

[0020] Preferably, in step (2), the time of the reaction is 4-10 days, further preferably 4-8 days, and more preferably 4-6 days.

[0021] Preferably, in step (3), the temperature of the cooling is 30°C or lower, and further preferably room temperature.

[0022] Preferably, in step (3), the acid used for adjusting the pH is hydrochloric acid, sulfuric acid or acetic acid, further preferably hydrochloric acid or sulfuric acid, and most preferably hydrochloric acid.

[0023] Preferably, in step (3), the pH is 7-9, further preferably 7.5-9, and more preferably 7.5-8.5, and most preferably 8.5.

[0024] Preferably, in step (4), after the filtration, the wet product obtained from the filtration is further subjected to a step of beating and drying.

[0025] Further preferably, the beating is beating with water.

[0026] Further preferably, the drying is drying under reduced pressure, further preferably 70-120°C under reduced pressure, more preferably 80-110°C under reduced pressure, and most preferably 95-100°C under reduced pressure to constant weight.

[0027] According to the preparation method described above, the sodium zirconium cyclotetrasilicate obtained has a potassium ion exchange capacity of not less than 3.0 mEq / g.

[0028] Compared with the prior art, the present application has the following advantages:

[0029] (1) The preparation method of the sodium zirconium cyclotetrasilicate ZS-9 provided by the present application does not require harsh high-temperature and high-pressure process conditions, and the reaction conditions are relatively mild.

[0030] (2) The present application does not require special modification of high-pressure reaction equipment, and is easy to realize industrialization.

[0031] (3) The sodium zirconium cyclotetrasilicate ZS-9 obtained has higher purity, yield and potassium ion exchange capacity. BRIEF DESCRIPTION OF DRAWINGS

[0032] Figure 1 XRD pattern of the sodium zirconium cyclotetrasilicate ZS-9 obtained according to the preparation method of Example 1.

[0033] Figure 2IR chart of the sodium zirconium cyclotetrasilicate ZS-9 obtained according to the preparation method of Example 1.

[0034] Figure 3 Photo of the internal structure of the autoclave for preparing the sodium zirconium cyclotetrasilicate ZS-9 according to Example 1. DETAILED DESCRIPTION

[0035] The following non-limiting examples can make the ordinary skilled in the art more comprehensive understanding of the present application, but not in any way limit the present application. The following content is only an exemplary description of the scope of the present application claimed by the person skilled in the art can make many changes and modifications to the application disclosed in the present application, and it should also belong to the scope of the present application claimed.

[0036] The present application is further described below in the form of specific examples. The various chemical reagents used in the examples of the present application are obtained by conventional commercial routes unless otherwise specified. If not otherwise specified, the content described below is the mass content. If not otherwise specified, it is understood to be carried out at room temperature.

[0037] In the following examples, the raw materials are as follows:

[0038]

[0039]

[0040] Example 1

[0041] (1) 112.6 g of sodium silicate solution (concentration of 37%) was mixed with 210 g of sodium hydroxide solution (concentration of 7%), stirred uniformly, and 46.8 g of zirconium acetate solution (concentration of 60%) was added dropwise, stirred uniformly, and the reaction mixture was transferred to a 1 L Hastelloy autoclave, and 0.18 g of ZS-9 seed (0.5%) was added.

[0042] (2) The reaction liquid was heated to 150°C, at which time the reaction pressure reached 0.5 MPa, and the reaction was carried out at constant temperature and pressure for 4 days.

[0043] (3) The reaction liquid was cooled to room temperature, and 6 M hydrochloric acid solution was added dropwise to adjust the pH of the reaction liquid to about 8.5.

[0044] (4) Filtration was carried out to obtain a filter cake, 900 mL of purified water was added to pulp, filtration was carried out, and the filter cake was placed in a vacuum oven and dried at 100°C under reduced pressure to constant weight to obtain 35 g of sodium zirconium cyclotetrasilicate. The crystal form of the obtained sodium zirconium cyclotetrasilicate was ZS-9 by XRD and IR detection.

[0045] Example 2

[0046] (1) 225.2 g of sodium silicate solution (concentration of 37%) was mixed with 420 g of sodium hydroxide solution (concentration of 7%), stirred uniformly, and 93.6 g of zirconium acetate solution (concentration of 60%) was added dropwise, and the reaction mixture was transferred to a 2 L Monel autoclave, and 1.4 g of ZS-9 seed crystals (2%) was added.

[0047] (2) The reaction liquid was heated to 145°C, at which time the reaction pressure reached 0.4 MPa, and the reaction was carried out at constant temperature and pressure for 6 days.

[0048] (3) The reaction liquid was cooled to room temperature, and 3M sulfuric acid solution was added dropwise to adjust the pH of the reaction liquid to about 8.5.

[0049] (4) Filtration was performed to obtain a filter cake, 1500 mL of purified water was added for pulping, filtration was performed, and the filter cake was placed in a vacuum oven and dried at 95°C under reduced pressure until a constant weight was obtained, thereby obtaining 70 g of zirconium sodium cyclotrisilicate. XRD and IR detection showed that the crystal form of the obtained zirconium sodium cyclotrisilicate was ZS-9.

[0050] Comparative Example 1

[0051] Zirconium sodium cyclotrisilicate ZS-9 prepared according to Example 12 of patent application CN 106170283A.

[0052] Comparative Example 2

[0053] Zirconium sodium cyclotrisilicate ZS-9 prepared according to Example 14 of patent application CN 106170283A.

[0054] Comparative Example 3

[0055] Zirconium sodium cyclotrisilicate ZS-9 prepared according to Example 1 of patent application IN201941046191.

[0056] Comparative Example 4

[0057] Comparative to Example 1, only the molar ratio of sodium silicate, base, and zirconium in step (1) was changed to 1:2:2, and the others were the same.

[0058] Comparative Example 5

[0059] Comparative to Example 1, only the pH in step (3) was changed to 10.

[0060] The test methods used in the examples and comparative examples are as follows:

[0061] 1. XRPD detection method

[0062] 1.1 Instrument information

[0063]

[0064] 1.2 Method parameters

[0065]

[0066] 2. Infrared (IR) detection method

[0067] 2.1 Instrument information

[0068]

[0069] 2.2 Detection method

[0070] (1) Parameter setting

[0071]

[0072]

[0073] (2) Sample preparation

[0074] Put the well-grounded KBr into the oven, dry at 120°C for 2h, and then put it into the desiccator.

[0075] Blank: Take 200mg KBr powder, grind again, press the tablet and scan

[0076] Sample: Take 2mg sample, add into 200mg dried KBr powder, grind well, mix evenly, press the tablet and scan.

[0077] 3. Potassium exchange capacity (KEC) detection method

[0078] 3.1 Instrument information

[0079]

[0080] 3.2 Analysis method

[0081] (1) Reagents:

[0082] All reagents used should be of analytical grade and quality suitable for ion chromatography analysis.

[0083] Deionized water (resistance not less than 18MΩcm), methanesulfonic acid, potassium chloride

[0084] (2) Preparation of reagents:

[0085] Mobile phase: 20mM methanesulfonic acid aqueous solution. For example, to prepare 1 liter of mobile phase, take 50mL of 0.4M methanesulfonic acid aqueous solution, put it into a suitable size container (such as: 1000mL volumetric flask or 1000mL plastic graduated cylinder), add 950mL deionized water, mix well.

[0086] Preparation of reference solution:

[0087] Potassium ion control stock solution (5000 ppm K+): accurately prepare an aqueous potassium chloride solution (9.53 mg / mL) using deionized water. For example, accurately weigh 953 mg of potassium chloride into a 100 mL volumetric flask, dissolve and dilute to the mark with deionized water.

[0088] Potassium ion control solution (50 ppm K+): accurately prepare an aqueous potassium chloride solution (0.0953 mg / mL) using deionized water.

[0089] For example, take 1.0 mL of the potassium stock solution (5000 ppm K+), place it in a 100 mL volumetric flask, dilute to the mark with deionized water, and mix thoroughly.

[0090] Blank solution preparation: use deionized water as a blank.

[0091] Sample preparation: accurately weigh 500 mg of sodium zirconium cyclosilicate into a 50 mL centrifuge tube. Add 40 mL of the potassium control stock solution (5000 ppm K+) to the centrifuge tube, mix thoroughly for at least 3 hours. Filter the sample solution through a 0.45 μm filter. Take 1.0 mL of the filtrate into a 100 mL volumetric flask, dilute to the mark with deionized water, and mix thoroughly.

[0092] (3) Chromatographic conditions:

[0093]

[0094] The results of the determination are as follows:

[0095]

[0096]

[0097] As can be seen, the sodium zirconium cyclosilicate ZS-9 prepared by the preparation method of the sodium zirconium cyclosilicate ZS-9 provided by the present application has a pure ZS-9 crystal form and a higher potassium ion exchange capacity, and does not require special process conditions such as high temperature and high pressure, does not require special reaction equipment, has low cost, and is easier to realize large-scale production.

[0098] The above examples have described the technical solutions and beneficial effects of the present application in detail. It should be understood that the above description is only a specific embodiment of the present application and is not intended to limit the present application. Any modifications, supplements, and equivalent replacements made within the principle range of the present application should be included in the protection range of the present application.

Claims

1. A process for the preparation of sodium zirconosilicate ZS-9, characterized in that, It is prepared by the following steps: (1) mixing sodium silicate solution and alkali solution, adding zirconium-containing solution dropwise, transferring into a high-pressure reaction kettle, adding ZS-9 seed crystal, and obtaining a mixed solution; (2) heating the mixed solution obtained in step (1) and reacting under pressure; (3) after the reaction is completed, cooling, and adjusting the pH value; (4) filtering, and obtaining the product; The molar ratio of sodium silicate, alkali and zirconium in step (1) is 1:3.5-6:3-5; The temperature of the reaction in step (2) is 140-160℃, and the reaction time is 4-10 days; The pH value in step (3) is 7-9.

2. A process for the preparation of sodium zirconium silicate ZS-9 as claimed in claim 1, wherein, The concentration of the sodium silicate solution in step (1) is 30-45%, the concentration of the alkali solution is 5-10%, and the concentration of the zirconium-containing solution is 50-70%.

3. The method of preparing sodium zirconium silicate ZS-9 according to claim 1, characterized by, The molar ratio of sodium silicate, alkali and zirconium in step (1) is 1:4.4:

4.

4. A process for the preparation of sodium zirconium silicate ZS-9 as claimed in claim 1, wherein, The alkali in step (1) is at least one selected from the group consisting of sodium hydroxide, potassium hydroxide, barium hydroxide, ammonium hydroxide, calcium hydroxide, sodium methoxide, potassium ethoxide, potassium tert-butoxide, butyllithium and phenyllithium; and the zirconium-containing solution is at least one selected from the group consisting of zirconium acetate solution and zirconium carbonate solution.

5. A process for the preparation of sodium zirconium silicate ZS-9 as claimed in claim 4, wherein, The alkali in step (1) is sodium hydroxide, and the zirconium-containing solution is zirconium acetate solution.

6. The process for the preparation of sodium zirconium silicate ZS-9 as claimed in claim 1, wherein, The amount of the ZS-9 seed crystal added in step (1) is 0.2-10%.

7. The process for the preparation of ZS-9 according to claim 1, characterized in that, The temperature of the cooling in step (3) is below 30℃.

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