A b crystal form of sodium zirconium cyclosilicate and a preparation method and application thereof

Abstract

The application belongs to the technical field of medicines, and particularly relates to a B crystal form of sodium zirconium cyclosilicate and a preparation method and application thereof. θ has one or more characteristic diffraction peaks at 13.50+0.2°, 13.80+0.2°, 15.09+0.2°, 15.74+0.2°, 18.77+0.2°, 20.53+0.2°, 22.63+0.2°, 23.23+0.2°, 23.71+0.2°, 26.68+0.2°, 28.60+0.2°, 28.85+0.2°, 30.47+0.2°, 37.39+0.2°. The B crystal form obtained by the preparation method has a potassium ion exchange capacity equivalent to that of the ZS-9 crystal form, and does not need a serpentine coil and a baffle, thereby significantly saving production cost and being more suitable for industrialized production.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of medicine, and particularly relates to a B crystal form of sodium zirconium cyclosilicate and a preparation method and application thereof. BACKGROUND

[0002] Hyperkalemia is a common electrolyte disorder of the body, which can be life-threatening in severe cases, and is often seen in patients with chronic kidney disease (CKD) and heart failure. Sodium zirconium cyclosilicate belongs to inorganic crystal class, and is a recently launched potassium-lowering drug (listed in the United States and China in 2018 and 2019). It has a unique cubic crystal structure and a high binding capacity for potassium ions. After taking the drug, it binds with potassium ions in the gastrointestinal tract and is excreted through feces, thereby reducing blood potassium levels.

[0003] Sodium zirconium cyclosilicate was first disclosed in US5891417, and has different crystalline forms ZS-1-ZS-11. The patent CN106170283 of the original research company discloses that among the various different crystal forms ZS-1-ZS-11 of sodium zirconium cyclosilicate, ZS-9 has a higher potassium ion exchange capacity, which can significantly improve the potassium ion absorption characteristics in the body and rapidly reduce the elevated serum potassium level.

[0004] Chinese patent application CN109106725A discloses a microporous zirconium silicate for treating hyperkalemia, and also discloses a method for preparing high-purity crystals of ZS-9 showing an improved level of potassium exchange capacity. In its preparation method, a hydrothermal reaction at 200℃ for 72 hours is required, and the reaction conditions are relatively harsh. The reactor relies on additional cooling coils and baffle structures. The potassium exchange capacity of the ZS-9 crystal form prepared in Example 12 (without cooling coils and baffle structures) is only 1.7-2.3 meq / gm.

[0005] Chinese patent application CN108137620A discloses a zirconium silicate composition with a lead content of less than 0.6 ppm, and a method for manufacturing zirconium silicate with a lead content of less than 1.1 ppm in a reactor volume of more than 200 L. In its preparation process, the reactor is maintained at 210±5℃ for at least 36 hours, and the reactor also relies on a cooling coil baffle structure.

[0006] The preparation process conditions of sodium zirconium cyclosilicate in the form of ZS-9 crystal in the prior art currently retrieved (including CN109106725A, CN108137620A, IN202041056388A, and IN201941046191A, etc.) are relatively harsh, such as a high temperature of 200℃ or higher, a pressure of 2.5 MPa or higher, and the need for special reaction equipment (such as the need to add a baffle to the inner wall of the reactor), which makes it difficult to achieve large-scale industrial production. SUMMARY

[0007] In view of the defects in the prior art, the inventors need to increase the selection range of raw materials required for the preparation of sodium zirconium cyclosilicate, and need a new crystal form of sodium zirconium cyclosilicate which is similar to the potassium ion exchange capacity and other physical and chemical properties of ZS-9, and has low preparation method cost and is easy to realize large-scale production.

[0008] In order to achieve the above technical purpose, the present application provides the following technical scheme:

[0009] In one aspect, the present application provides a B crystal form of sodium zirconium cyclosilicate, which has one or more of the following characteristic diffraction peaks at the following 2 θ angles: 13.50±0.2°, 13.80±0.2°, 15.09±0.2°, 15.74±0.2°, 18.77±0.2°, 20.53±0.2°, 22.63±0.2°, 23.23±0.2°, 23.71±0.2°, 26.68±0.2°, 28.60±0.2°, 28.85±0.2°, 30.47±0.2°, 37.39±0.2°.

[0010] In some preferred examples, the X-ray powder diffraction pattern has the following characteristic diffraction peaks at the following 2 θ angles: 13.50±0.2°, 13.80±0.2°, 15.09±0.2°, 15.74±0.2°, 18.77±0.2°, 20.53±0.2°, 22.63±0.2°, 23.23±0.2°, 23.71±0.2°, 26.68±0.2°, 28.60±0.2°, 28.85±0.2°, 30.47±0.2°, 37.39±0.2°.

[0011] In some examples, the infrared spectrum has one or more of the following characteristic absorption peaks at the following absorption wave numbers: 3408±5cm -1 , 1689±5cm -1 , 990±5cm -1 , 959±5cm -1 , 920±5cm -1 , 762±5cm -1 , 707±5cm -1 , 529±5cm -1 , 479±5cm -1 .

[0012] In some preferred examples, the infrared spectrum has the following characteristic absorption peaks at the following absorption wave numbers: 3408±5cm -1 , 1689±5cm -1, 990 ± 5 cm -1 , 959 ± 5 cm -1 , 920 ± 5 cm -1 , 762 ± 5 cm -1 , 707 ± 5 cm -1 , 529 ± 5 cm -1 , 479 ± 5 cm -1 .

[0013] In another aspect, the present application provides a method for preparing any one of the foregoing B crystal forms, comprising the following steps:

[0014] (1) adding colloidal silicon dioxide and a zirconium-containing solution into a basic medium in an autoclave, mixing uniformly to obtain a mixed solution;

[0015] (2) heating the mixed solution to the end of the reaction, cooling to room temperature to obtain a reaction solution;

[0016] (3) filtering, washing and drying the reaction solution to obtain the B crystal form of sodium zirconium silicate.

[0017] In some examples, the molar ratio of the basic medium, colloidal silicon dioxide and the zirconium-containing solution is (3-3.5) : (13-15) : 1.

[0018] In some preferred examples, the molar ratio of the basic medium, colloidal silicon dioxide and the zirconium-containing solution is 3.2: 13.8: 1.

[0019] In some examples, the mass-volume ratio of the basic medium is 10%-20%.

[0020] In some preferred examples, the mass-volume ratio of the basic medium is 14%.

[0021] In some examples, the mass-volume ratio of the zirconium-containing solution is 30%-35%.

[0022] In some preferred examples, the mass-volume ratio of the zirconium-containing solution is 32.6%.

[0023] In the mass-volume ratio of the present application, the mass is measured in grams and the volume is measured in milliliters.

[0024] In some examples, the basic medium is selected from at least one of sodium hydroxide, potassium hydroxide, barium hydroxide, ammonium hydroxide, calcium hydroxide, sodium methoxide, potassium ethoxide, potassium tert-butoxide, butyl lithium or phenyl lithium.

[0025] In some preferred examples, the basic medium is selected from at least one of sodium hydroxide, potassium hydroxide, barium hydroxide.

[0026] In some preferred examples, the basic medium is sodium hydroxide.

[0027] In some examples, the zirconium-containing solution includes, but is not limited to, zirconium oxychloride.

[0028] In some examples, the temperature of the heating in step (2) is 120-210 °C.

[0029] In some preferred examples, the temperature of the heating in step (2) is 170-200 °C.

[0030] In some preferred examples, the time of the reaction in step (2) is 3-10 days.

[0031] In some examples, the washing in step (3) includes:

[0032] washing with purified water to pH 7-9.

[0033] In some examples, the drying in step (3) is drying under reduced pressure.

[0034] In some examples, the drying under reduced pressure includes:

[0035] 80-150 °C for 24 h under reduced pressure.

[0036] In some preferred examples, the drying under reduced pressure includes:

[0037] 100 °C for 24 h under reduced pressure.

[0038] In yet another aspect, the present application provides a B crystal form obtained by any one of the aforementioned preparation methods.

[0039] In yet another aspect, the present application provides use of any one of the aforementioned B crystal forms in the preparation of a medicament for preventing and / or treating hyperkalemia.

[0040] In yet another aspect, the present application provides a pharmaceutical composition comprising any one of the aforementioned B crystal forms and at least one pharmaceutically acceptable excipient.

[0041] In some examples, the excipient is selected from at least one of a solvent, a diluent, a disintegrant, a precipitation inhibitor, a surfactant, a glidant, a binder, a lubricant, a dispersant, a suspending agent, an isotonic agent, a thickening agent, an emulsifying agent, a preservative, a stabilizer, a hydrating agent, an emulsification accelerator, a buffer, an absorbent, a coloring agent, a flavoring agent, a sweetening agent, an ion exchanger, a release agent, a coating agent, a flavoring agent, or an antioxidant.

[0042] In some examples, the pharmaceutical composition further comprises other drugs for treating hyperkalemia, such as loop diuretics, thiazide diuretics, calcium agents, sodium polystyrene sulfonate (SPS), calcium polystyrene sulfonate (CPS), and the like.

[0043] In yet another aspect, the present application provides a method for preventing and / or treating hyperkalemia, the method comprising:

[0044] administering to a subject in need thereof a therapeutically effective amount of any of the aforementioned pharmaceutical compositions.

[0045] The B crystal form obtained by the preparation method provided by the present application has a potassium ion exchange capacity equivalent to that of the ZS-9 crystal form, which expands the selection range of the preparation for the raw drug, and the preparation process does not need a serpentine coil and a baffle, which significantly saves the production cost and is more suitable for industrialized production. BRIEF DESCRIPTION OF DRAWINGS

[0046] Figure 1 The XRD detection graph of the B crystal form of sodium zirconium cyclosilicate.

[0047] Figure 2 The infrared detection graph of the B crystal form of sodium zirconium cyclosilicate. DETAILED DESCRIPTION

[0048] Unless otherwise defined, all 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. The following definitions are applied, for the purposes of interpreting this specification, and shall have the meanings set forth below, and such terminology includes equivalents and like meanings.

[0049] As used herein, the singular forms "a", "an" and "the" include plural referents unless the context clearly dictates otherwise. For example, reference to "a cell" includes a plurality of such cells and equivalents thereof known to those skilled in the art, and so forth.

[0050] The present application relates to devices and materials:

[0051] Table 1

[0052] Name Model Supplier X-ray diffractometer Bruker D8 advance Bruker Infrared spectrometer NICOLET iS5 Thermo Fisher Ion chromatograph Dionex ICS-5000 IC Dionex

[0053] In order to make the objectives, technical solutions, and advantages of the present application clearer, the present application will be further described in detail below with reference to examples. If specific conditions are not specified in the examples, the conventional conditions or the conditions recommended by the manufacturers are used. If the manufacturers of all reagents or instruments are not specified, the conventional products available on the market are used. In order to better illustrate the present application, numerous specific details are given in the following specific embodiments. The specific embodiments described herein are only used to explain the present application and do not constitute any limitation on the present application. In addition, in the following description, the description of the well-known structures and technologies is omitted to avoid unnecessary confusion of the concept of the present application. Such structures and technologies are also described in many publications.

[0054] Example 1 Preparation of sodium zirconium cyclotriphosphate B crystal form

[0055] In a 500 mL autoclave (room temperature, normal pressure), 233.2 g of sodium hydroxide solution (33.2 g of sodium hydroxide dissolved in 200 g of water) was added with 11.4 g of colloidal silicon dioxide, stirred for 5-10 min, and then 59.4 g of zirconium oxychloride solution (19.4 g of zirconium oxychloride octahydrate dissolved in 40 g of water) was added dropwise, and stirred for 20 min. The temperature was raised to 120°C, and the reaction progress was monitored online by infrared spectroscopy (the reaction was completed after about 10 days), after the reaction was completed, the temperature was cooled to room temperature, and then filtered, and washed with purified water until the pH of the filtrate was 7-9, to obtain sodium zirconium cyclotriphosphate wet product, which was placed in a 100°C vacuum dryer for 24 h to obtain sodium zirconium cyclotriphosphate B crystal form.

[0056] Example 2 Preparation of sodium zirconium cyclotriphosphate B crystal form

[0057] In a 500 mL autoclave, 233.2 g of sodium hydroxide solution (33.2 g of sodium hydroxide dissolved in 200 g of water) was added with 11.4 g of colloidal silicon dioxide, stirred for 5-10 min, and then 59.4 g of zirconium oxychloride solution (19.4 g of zirconium oxychloride octahydrate dissolved in 40 g of water) was added dropwise, and stirred for 20 min. The temperature was raised to 210°C, and the reaction progress was monitored online by infrared spectroscopy (the reaction was completed after about 3 days), after the reaction was completed, the temperature was cooled to room temperature, and then filtered, and washed with purified water until the pH of the filtrate was 7-9, to obtain sodium zirconium cyclotriphosphate wet product, which was placed in a 100°C vacuum dryer for 24 h to obtain sodium zirconium cyclotriphosphate B crystal form.

[0058] Example 3 XRD detection of sodium zirconium cyclotriphosphate B crystal form

[0059] The sodium zirconium cyclotriphosphate B crystal form obtained in Example 1 was subjected to XRD detection, and the results are shown in Figure 1 The results show that the 2 θhaving the following characteristic diffraction peaks: 13.50±0.2°, 13.80±0.2°, 15.09±0.2°, 15.74±0.2°, 18.77±0.2°, 20.53±0.2°, 22.63±0.2°, 23.23±0.2°, 23.71±0.2°, 26.68±0.2°, 28.60±0.2°, 28.85±0.2°, 30.47±0.2°, 37.39±0.2°.

[0060] Example 4 Infrared detection of sodium zirconium cyclosilicate B crystal form

[0061] The infrared detection of the sodium zirconium cyclosilicate B crystal form obtained in Example 1 was performed, and the results are shown in Table 1. Figure 2 The results show that the infrared spectrum of the sodium zirconium cyclosilicate B crystal form has characteristic absorption peaks at the following absorption wavenumbers: 3408±5cm-1, 1689±5cm-1, 990±5cm-1, 959±5cm-1, 920±5cm-1, 762±5cm-1, 707±5cm-1, 529±5cm-1, 479±5cm-1. -1 -1 -1 -1 -1 -1 -1 -1 -1

[0062] Example 5 Potassium ion exchange capacity detection of sodium zirconium cyclosilicate crystal form

[0063] The experimental group is the B crystal form of sodium zirconium cyclosilicate prepared in Example 1 and Example 2.

[0064] The control group is the ZS-9 crystal form of sodium zirconium cyclosilicate, and the preparation method is described in Example 14 of CN106170283A.

[0065] The ion chromatograph was used to detect the potassium ion exchange capacity (KEC) of each crystal form, and the detection results are shown in Table 2.

[0066] Table 2

[0067] Crystal form Form B (Example 1) Form B (Example 2) Form ZS-9 KEC (mEq / g) 3.1 3.2 3.2

[0068] It can be seen that the potassium ion exchange capacity of the sodium zirconium cyclosilicate B crystal form obtained in the present application is similar to that of the reference preparation (ZS-9 crystal form).

[0069] Finally, it should be noted that the above content is only used to illustrate the technical solutions of the present application, and is not a limitation on the protection scope of the present application. Simple modifications or equivalent replacements of the technical solutions of the present application made by those skilled in the art do not deviate from the essence and scope of the technical solutions of the present application.​​​​​​​​​

Claims

1. A B crystalline form of sodium zirconium silicate characterized in that, Its X-ray powder diffraction pattern is shown in the following 2 θ The following characteristic diffraction peaks are observed at the corners: 13.50±0.2°, 13.80±0.2°, 15.09±0.2°, 15.74±0.2°, 18.77±0.2°, 20.53±0.2°, 22.63±0.2°, 23.23±0.2°, 23.71±0.2°, 26.68±0.2°, 28.60±0.2°, 28.85±0.2°, 30.47±0.2°, 37.39±0.2°; The preparation method of the B crystal form comprises the following steps: (1) adding colloidal silicon dioxide and a zirconium-containing solution into an alkaline medium in an autoclave, mixing uniformly to obtain a mixed solution; (2) heating the mixed solution to the end of the reaction, cooling to room temperature to obtain a reaction solution; (3) filtering, washing and drying the reaction solution to obtain the B crystal form of sodium zirconium silicate.

2. The B-type crystal according to claim 1, characterized in that, Its infrared spectrum exhibits a characteristic absorption peak at the following absorption wavenumber: 3408±5 cm⁻¹ -1 1689±5 cm -1 990±5 cm -1 959±5 cm -1 920±5 cm -1 762±5 cm -1 707±5 cm -1 529±5 cm -1 479±5 cm -1 .

3. Process for the preparation of the B crystalline form according to any one of claims 1-2, characterized in that, The preparation method comprises the following steps: (1) adding colloidal silicon dioxide and a zirconium-containing solution into an alkaline medium in an autoclave, mixing uniformly to obtain a mixed solution; (2) heating the mixed solution to the end of the reaction, cooling to room temperature to obtain a reaction solution; (3) filtering, washing and drying the reaction solution to obtain the B crystal form of sodium zirconium silicate.

4. The production method according to claim 3, characterized by, The molar ratio of the alkaline medium, colloidal silicon dioxide and the zirconium-containing solution is (3-3.5):(13-15):

1.

5. The preparation method according to claim 4, characterized in that, The molar ratio of the alkaline medium, colloidal silicon dioxide and the zirconium-containing solution is 3.2:13.8:

1.

6. The method of any one of claims 3-5, wherein, The mass-volume ratio of the alkaline medium is 10%-20%, and the mass-volume ratio of the zirconium-containing solution is 30%-35%, wherein the mass is measured in grams and the volume is measured in milliliters.

7. The production method according to claim 6, wherein The mass-volume ratio of the alkaline medium is 14%, and the mass-volume ratio of the zirconium-containing solution is 32.6%.

8. The preparation method according to claim 6, characterized in that, The alkaline medium is selected from at least one of sodium hydroxide, potassium hydroxide, barium hydroxide, ammonium hydroxide, calcium hydroxide, sodium methoxide, potassium ethoxide, potassium tert-butoxide, butyl lithium or phenyl lithium.

9. The production method according to claim 8, characterized by, The alkaline medium is selected from at least one of sodium hydroxide, potassium hydroxide and barium hydroxide.

10. The method of claim 9, wherein, The alkaline medium is sodium hydroxide.

11. The method of claim 10, wherein, The zirconium-containing solution comprises zirconium oxychloride.

12. The method of claim 3, wherein, The temperature of the heating in step (2) is 120-210°C, and the reaction time is 3-10 days.

13. The method of claim 12, wherein, The temperature of the heating in step (2) is 170-200°C.

14. Use of the B crystal form according to any one of claims 1-2 or the B crystal form obtained by the preparation method according to any one of claims 3-13 in the preparation of a drug for preventing and / or treating hyperkalemia.

15. A pharmaceutical composition comprising, The pharmaceutical composition comprises the B crystal form according to any one of claims 1-2 or the B crystal form obtained by the preparation method according to any one of claims 3-13, and at least one pharmaceutically acceptable excipient.

16. The pharmaceutical composition of claim 15, wherein, The excipient is selected from at least one of a solvent, a diluent, a disintegrant, a precipitation inhibitor, a surfactant, a glidant, a binder, a lubricant, a dispersant, a suspending agent, an isotonic agent, a thickening agent, an emulsifying agent, a preservative, a stabilizer, a hydrating agent, an emulsification accelerator, a buffer, an absorbent, a coloring agent, a flavoring agent, a sweetening agent, an ion exchanger, a release agent, a coating agent, a flavoring agent or an antioxidant.

17. The pharmaceutical composition of claim 16, wherein, The pharmaceutical composition further comprises a drug for treating hyperkalemia.

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