A crystalline form of sodium zirconium cyclosilicate and methods of making the same

Abstract

The application discloses a kind of sodium zirconium cyclosilicate A crystal form and preparation method thereof, it is related to pharmaceutical technical field.The X-ray powder diffraction pattern of the crystal form has characteristic diffraction peaks at 2θ angle 10.63±0.2°, 12.24±0.2°, 13.89±0.2°, 14.62±0.2°, 15.24±0.2°, 15.55±0.2°, 17.86±0.2°, 21.48±0.2°, 21.93±0.2°, 25.55±0.2°, 26.18±0.2°, 28.88±0.2°, 29.52±0.2°, 30.19±0.2°, 36.19±0.2°.The sodium zirconium cyclosilicate A crystal form of the application has similar physicochemical properties with reference preparation (ZS-9 crystal form), and the preparation method does not require special process conditions such as high temperature and high pressure, does not require special reaction equipment, is low in cost and easy to scale up.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, and in particular to an A-crystal form of sodium zirconium cyclosilicate and its preparation method. Background Technology

[0002] Hyperkalemia is a common electrolyte imbalance that can be life-threatening in severe cases, and is most prevalent in patients with chronic kidney disease (CKD) and heart failure. Currently, CKD has a high incidence rate worldwide, and elevated blood potassium levels can accelerate disease progression in CKD patients, leading to adverse consequences such as emergency hospitalization and increasing the risk of death. Furthermore, hyperkalemia is prone to recurrence, placing psychological and financial burdens on patients and their families. Sodium zirconium cyclosilicate is an inorganic crystalline substance and a recently marketed potassium-lowering drug (launched in the US and China in 2018 and 2019). It has a unique cubic crystal structure with a high binding affinity for potassium ions. After ingestion, it binds to potassium ions in the gastrointestinal tract and is excreted in feces, thereby lowering blood potassium levels.

[0003] Sodium zirconium cyclosilicate was first disclosed in patent US5891417, and it has different crystal forms from ZS-1 to ZS-11. The original manufacturer's patent CN1061708831 discloses that among the various crystal forms of sodium zirconium cyclosilicate from ZS-1 to ZS-11, ZS-9 has a high potassium ion exchange capacity, which can significantly improve the in vivo potassium ion absorption characteristics and rapidly reduce elevated serum potassium levels.

[0004] Chinese patent CN109106725A discloses a microporous zirconium silicate for treating hyperkalemia, and also discloses a method for preparing high-purity crystals of ZS9 that exhibit improved potassium exchange capacity. The preparation method requires a hydrothermal reaction at 200°C for 72 hours, which are relatively harsh reaction conditions.

[0005] Chinese patent 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. During the preparation process, the reactor is maintained at 210±5℃ for at least 36 hours.

[0006] The existing technologies that have been retrieved (including CN109106725A, CN108137620A, IN202041056388A, and IN201941046191A, etc.) all have relatively harsh process conditions for the preparation of ZS-9 crystal form sodium zirconium silicate, such as high temperature above 200℃, pressure above 2.5MPa, and special reaction equipment (such as adding baffles to the inner wall of the reactor), making it difficult to achieve large-scale industrial production.

[0007] Therefore, in order to increase the range of active pharmaceutical ingredients (APIs) required for sodium zirconium cyclosilicate formulations, there is a need for a new crystalline form of sodium zirconium cyclosilicate that has similar potassium ion exchange capacity and other physicochemical properties to ZS-9, and whose preparation method is inexpensive and easy to scale up. Summary of the Invention

[0008] In view of this, the purpose of the present invention is to provide a new crystal form of sodium zirconium cyclosilicate (named crystal form A) and its preparation method. The preparation reaction conditions of this crystal form are mild, no special reaction equipment is required, the cost is low, and it is easier to achieve large-scale production.

[0009] To achieve the above-mentioned objectives, the technical solution of this invention is as follows:

[0010] On one hand, the present invention provides a crystal form of sodium zirconium cyclosilicate, wherein the X-ray powder diffraction pattern of the crystal form is at 2θ angles of 10.63±0.2°, 12.24±0.2°, 13.89±0.2°, 14.62±0.2°, and 15.24±0.2°.

[0011] 15.55±0.2°, 17.86±0.2°, 21.48±0.2°, 21.93±0.2°, 25.55±0.2°, 26.18±0.2°

[0012] Characteristic diffraction peaks are observed at 28.88±0.2°, 29.52±0.2°, 30.19±0.2°, and 36.19±0.2°.

[0013] Furthermore, the infrared spectrum of the crystal form at an absorption wavenumber of 1121±5 cm⁻¹ -1 967±5cm -1 773±5cm -1 444±5cm -1 541±5cm -1 489±5cm -1 It has a characteristic absorption peak.

[0014] On the other hand, the present invention provides a method for preparing the crystal form of the above-mentioned sodium zirconium cyclosilicate, comprising the following steps:

[0015] (1) Mix sodium silicate solution with alkaline solution, add zirconium-containing solution dropwise, and mix well;

[0016] (2) Heat to reflux;

[0017] (3) After the reaction is complete, cool.

[0018] (4) Filter and wash until pH is 7-9;

[0019] (5) Drying to obtain sodium zirconium cyclosilicate of the crystal form.

[0020] Preferably, the molar ratio of sodium silicate, alkali and zirconium is 1:3.5-6:3-5, and most preferably 1:4.4:4.

[0021] Preferably, the sodium silicate solution concentration is 70-85%, most preferably 77.7%; the alkaline solution concentration is 5-10%, most preferably 7.2%; and the zirconium-containing solution concentration is 50-70%, most preferably 60%.

[0022] Preferably, in step (1), the alkali is selected from at least one of sodium hydroxide, potassium hydroxide, barium hydroxide, ammonium hydroxide, calcium hydroxide, sodium methoxide, potassium ethoxide, potassium tert-butoxide, butyllithium, and phenyllithium, more preferably at least one of sodium hydroxide, potassium hydroxide, and barium hydroxide, and most preferably sodium hydroxide.

[0023] Preferably, in step (1), the zirconium-containing solution is selected from at least one of zirconium acetate solution and zirconium carbonate solution, and more preferably zirconium acetate solution.

[0024] Preferably, in step (3), the reaction time is 1-9 days.

[0025] Preferably, in step (3), the cooling temperature is below 30°C, and more preferably room temperature.

[0026] Preferably, in step (5), the drying refers to vacuum drying, more preferably vacuum drying at 80-150℃, and even more preferably vacuum drying at 100℃ for 24 hours.

[0027] The beneficial effects of this invention are as follows:

[0028] The sodium zirconium cyclosilicate A crystal form obtained by this invention has a potassium ion exchange capacity similar to that of the reference preparation (ZS-9 crystal form) and other physicochemical properties, which expands the range of active pharmaceutical ingredients for sodium zirconium cyclosilicate preparations. The preparation method of this crystal form does not require special process conditions such as high temperature and high pressure, does not require special reaction equipment, is low in cost, and is easier to achieve large-scale production. Attached Figure Description

[0029] Figure 1 The image shows the XRD pattern of sodium zirconium cyclosilicate of crystal form A prepared in this invention.

[0030] Figure 2 The image shows the IR spectrum of sodium zirconium cyclosilicate of crystal form A prepared in this invention. Detailed Implementation

[0031] The following non-limiting embodiments are intended to enable those skilled in the art to gain a more comprehensive understanding of the present invention, but do not limit the invention in any way. The following description is merely an exemplary illustration of the scope of protection of the present invention, and those skilled in the art can make various changes and modifications to the invention based on the disclosed content, which should also fall within the scope of protection of the present invention.

[0032] The present invention will be further described below by way of specific embodiments. Unless otherwise specified, all chemical reagents used in the embodiments of the present invention were obtained through conventional commercial means. Unless otherwise specified, all contents mentioned below are mass contents. Unless otherwise specified, it is understood that the process was carried out at room temperature.

[0033] In the following examples, the reference formulation ZS-9 was sourced from AatraZeneca, batch number: MK2232A;

[0034] The concentrations of sodium hydroxide solution, zirconium acetate solution, and sodium silicate solution were 7.2%, 60%, and 37.7%, respectively.

[0035] XRD inspection machine brand and model:

[0036]

[0037] Infrared detection machine brand and model:

[0038]

[0039]

[0040] Potassium ion exchange capacity (KEC) measuring instrument brand and model:

[0041]

[0042] Example 1

[0043] In a 1L four-necked glass reaction flask, add 206g of sodium silicate solution and 377g of sodium hydroxide solution, stir for 5-10 minutes, and then add 82g of zirconium acetate solution dropwise. The molar ratio of sodium silicate, alkali, and zirconium is 1:4.4:4. After the addition is complete, stir for 5-10 minutes, heat to reflux, and monitor the reaction progress with online infrared spectroscopy (the reaction ends after about 7 days). After the reaction is complete, cool to room temperature, filter, and wash with purified water until the pH of the filtrate is 7-9 to obtain wet sodium zirconium cyclosilicate. Dry the wet product under reduced pressure at 100℃ for 24 hours to obtain sodium zirconium cyclosilicate in crystal form A.

[0044] XRD detection patterns are as follows: Figure 1 As shown, the infrared spectrum is as follows Figure 2 As shown.

[0045] The potassium ion exchange capacity test results of sodium zirconium cyclosilicate of crystal form A obtained in this embodiment were compared with those of the reference formulation, and the results are as follows:

[0046] project Crystal type A Reference formulation (ZS-9) Potassium ion exchange capacity 3.1 3.2

[0047] As can be seen from the comparison, the sodium zirconium cyclosilicate A crystal form obtained by the present invention has a potassium ion exchange capacity similar to that of the reference preparation (ZS-9 crystal form), 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 achieve large-scale production.

[0048] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A method for preparing sodium zirconium cyclosilicate, characterized in that, Includes the following steps: (1) Mix sodium silicate solution with alkaline solution, add zirconium-containing solution dropwise, and mix well; (2) Heat to reflux; (3) After the reaction is complete, cool it; (4) Filter and wash until pH is 7-9; (5) Drying to obtain the sodium zirconium cyclosilicate; The molar ratio of sodium silicate, alkali, and zirconium is 1:3.5-6:3-5; The X-ray powder diffraction pattern of the sodium zirconium cyclosilicate exhibits characteristic diffraction peaks at 2θ angles of 10.63±0.2°, 12.24±0.2°, 13.89±0.2°, 14.62±0.2°, 15.24±0.2°, 15.55±0.2°, 17.86±0.2°, 21.48±0.2°, 21.93±0.2°, 25.55±0.2°, 26.18±0.2°, 28.88±0.2°, 29.52±0.2°, 30.19±0.2°, and 36.19±0.2°. The infrared spectrum of the sodium zirconium cyclosilicate has an absorption wavenumber of 1121±5 cm⁻¹. -1 967±5 cm -1 773±5 cm -1 444±5 cm -1 541±5 cm -1 489±5 cm -1 It has a characteristic absorption peak.

2. The preparation method according to claim 1, characterized in that, The molar ratio of sodium silicate, alkali, and zirconium is 1:4.4:

4.

3. The preparation method according to claim 1, characterized in that, The sodium silicate solution has a concentration of 70-85%; the alkaline solution has a concentration of 5-10%; and the zirconium-containing solution has a concentration of 50-70%.

4. The preparation method according to claim 1, characterized in that, In step (1), the alkali is selected from at least one of sodium hydroxide, potassium hydroxide, barium hydroxide, ammonium hydroxide, calcium hydroxide, sodium methoxide, potassium ethoxide, potassium tert-butoxide, butyllithium, and phenyllithium; the zirconium-containing solution is selected from at least one of zirconium acetate solution and zirconium carbonate solution.

5. The preparation method according to claim 4, characterized in that, The alkali is sodium hydroxide; the zirconium-containing solution is zirconium acetate solution.

6. The preparation method according to claim 1, characterized in that, In step (3), the reaction time is 1-9 days.

7. The preparation method according to claim 1, characterized in that, In step (3), the cooling temperature is below 30°C.

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