Tolvaptan sodium phosphate compound as well as preparation method and application thereof

Abstract

The invention discloses a tolvaptan sodium phosphate compound as well as a preparation method and application thereof. The tolvaptan sodium phosphate compound is a tolvaptan sodium phosphate crystal and / or a tolvaptan sodium phosphate amorphous substance. The crystal form of the tolvaptan sodium phosphate crystal is a crystal form A, and an X-ray powder diffraction pattern of the crystal form A has diffraction peaks at the following 2 theta angles: 4.4 degrees + / -0.2 degrees, 8.7 degrees + / -0.2 degrees, 10.4 degrees + / -0.2 degrees, 14.4 degrees + / -0.2 degrees, 17.3 degrees + / -0.2 degrees, 21.3 degrees + / -0.2 degrees, 23.0 degrees + / -0.2 degrees and 23.8 degrees + / -0.2 degrees; no crystal diffraction peak exists in an X-ray powder diffraction pattern of the tolvaptan sodium phosphate amorphous substance; the water content of the tolvaptan sodium phosphate compound is greater than or equal to 8.0%. The tolvaptan sodium phosphate compound provided by the invention shows excellent stability, can be stably stored for a long time, and is suitable for being used as a pharmaceutical raw material.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical technology, and more specifically to a tolvaptan sodium phosphate compound and a preparation method and application thereof. Background Art

[0002] Tolvaptan (Formula I) is a selective vasopressin receptor antagonist used to treat hyponatremia caused by congestive heart failure, cirrhosis and inappropriate antidiuretic hormone syndrome. Tolvaptan has low water solubility and permeability, resulting in insufficient intestinal absorption, and limited dosage forms and routes of administration. In order to improve the solubility of tolvaptan in water, researchers have developed a diuretic tolvaptan sodium phosphate (Formula II) for intravenous injection. Tolvaptan sodium phosphate (Formula II), chemical name: (5RS)-7-chloro-1-[2-methyl-4-(2-methylbenzamido)benzoyl]-2,3,4,5-tetrahydro-1L-benzazepine-5-phosphate disodium salt, has good solubility in water and is a prodrug of oral tolvaptan. It is hydrolyzed into tolvaptan by phosphatase in the body, providing a new treatment option for patients with fluid retention who have difficulty taking tolvaptan orally:

[0003]

[0004] Different crystal forms of APIs may have different physical and chemical properties, which may affect the stability of APIs and preparations, the production process of preparations, dissolution and bioavailability, etc., and may further affect the safety, effectiveness and quality controllability of the drug. The inventors found in the early stage of research that the stability of tolvaptan sodium phosphate is poor, and it is easy to degrade and form tolvaptan (Formula I) during long-term storage. Since tolvaptan has poor water solubility, when its content is too high, the clarity of the tolvaptan sodium phosphate (Formula II) API is unqualified, and the insoluble foreign matter and insoluble particulate matter in the preparation product do not meet the requirements of the pharmacopoeia. Therefore, studying the stability of tolvaptan sodium phosphate API is of great significance to the research and development of preparations.

[0005] Therefore, it is of great economic value to develop a stable tolvaptan sodium phosphate compound. Summary of the invention

[0006] The purpose of the present invention is to solve the problem of poor stability of tolvaptan sodium phosphate in the prior art and to provide a tolvaptan sodium phosphate compound with strong stability and a preparation method and application thereof.

[0007] To achieve the above object, the technical solution adopted by the present invention is:

[0008] In a first aspect, the present invention provides a tolvaptan sodium phosphate compound, wherein the tolvaptan sodium phosphate compound is tolvaptan sodium phosphate crystals and / or tolvaptan sodium phosphate amorphous material;

[0009] The crystal form of the tolvaptan sodium phosphate crystal is crystal form A, and the X-ray powder diffraction spectrum of the crystal form A has diffraction peaks at the following 2θ angles: 4.4°±0.2°, 8.7°±0.2°, 10.4°±0.2°, 14.4°±0.2°, 17.3°±0.2°, 21.3°±0.2°, 23.0°±0.2° and 23.8°±0.2°;

[0010] The X-ray powder diffraction pattern of the amorphous tolvaptan sodium phosphate has no crystal diffraction peaks;

[0011] The water content of the tolvaptan sodium phosphate compound is ≥8.0%.

[0012] The inventors found during the research process that when the water content of the tolvaptan sodium phosphate compound is ≥8.0%, it exhibits excellent stability and can be stably stored for a long time.

[0013] It is worth noting that when the water content of tolvaptan sodium phosphate crystals drops to 6%-8%, Form A will be converted into mixed crystals containing amorphous and Form A with a water content of 6%-8%; when the water content of tolvaptan sodium phosphate crystals drops to <6%, Form A will be converted into amorphous with a water content of <6%; and the stability of the mixed crystals with a water content of 6%-8% and the amorphous with a water content of <6% are both poor and cannot be stably stored for a long time.

[0014] In the present invention, the tolvaptan sodium phosphate compound has a structure shown in Formula II, and the water content is expressed in mass percentage.

[0015] Preferably, the water content of the tolvaptan sodium phosphate compound is 8.0%-30.0%.

[0016] Preferably, the differential scanning calorimetry curve of the crystalline form A has endothermic peaks at 142°C±2°C and 335°C±2°C.

[0017] In a second aspect, the present invention provides a method for preparing a tolvaptan sodium phosphate compound, comprising:

[0018] A. dissolving tolvaptan sodium phosphate in an aqueous solvent, cooling and crystallizing, and adjusting the water content to obtain tolvaptan sodium phosphate crystals having a water content of ≥8.0%;

[0019] and / or

[0020] B. dissolving tolvaptan sodium phosphate in an organic solvent, cooling and crystallizing, and adjusting the water content to obtain tolvaptan sodium phosphate amorphous material with a water content of ≥8.0%.

[0021] Preferably, in step A, the solid-to-liquid ratio of tolvaptan sodium phosphate and water is 1 g: (0.5-5) mL.

[0022] More preferably, in step A, the solid-to-liquid ratio of tolvaptan sodium phosphate and water is in the range of one or any two of 1g:0.5mL, 1g:1mL, 1g:1.5mL, 1g:2mL, 1g:2.5mL, 1g:3mL, 1g:3.5mL, 1g:4mL, 1g:4.5mL, 1g:5mL.

[0023] More preferably, in step A, the solid-to-liquid ratio of tolvaptan sodium phosphate and water is 1 g:(1-5) mL.

[0024] More preferably, in step A, the solid-to-liquid ratio of tolvaptan sodium phosphate and water is 1 g:(2-4) mL, specifically 1 g:3 mL.

[0025] Preferably, in step A, the aqueous solvent is water, or the aqueous solvent is a mixture of water and an organic solvent.

[0026] More preferably, in step A, in the aqueous solvent, the organic solvent is at least one of acetone, ethanol, methanol, isopropanol, tetrahydrofuran and acetonitrile.

[0027] More preferably, in step A, in the aqueous solvent, the organic solvent is at least one of acetone, isopropanol and acetonitrile.

[0028] More preferably, in step A, the solid-to-liquid ratio of tolvaptan sodium phosphate and the organic solvent is 1 g:(0.5-150) mL, specifically 1 g:10 mL.

[0029] Preferably, in step A and / or B, the temperature of the cooling crystallization is ≤30°C.

[0030] More preferably, in step A and / or B, the temperature of the cooling crystallization is 0°C, 1°C, 2°C, 3°C, 4°C, 5°C, 6°C, 7°C, 8°C, 9°C, 10°C, 11°C, 12°C, 13°C, 14°C, 15°C, 16°C, 17°C, 18°C, 19°C, 20°C, 21°C, 22°C, 23°C, 24°C, 25°C, 26°C, 27°C, 28°C, 29°C, 30°C, or any two of the range values.

[0031] More preferably, in step A and / or B, the temperature of the cooling crystallization is 0-30°C.

[0032] More preferably, in step A, the temperature of the cooling crystallization is 0-25°C.

[0033] More preferably, in step B, the temperature of the cooling crystallization is 0-20°C.

[0034] Preferably, in step A and / or B, the dissolving temperature is 45-75°C.

[0035] More preferably, in step A and / or B, the dissolving temperature is 50-70°C.

[0036] Preferably, in step A and / or B, filtering and washing are further performed after the cooling and crystallization and before the water content is adjusted.

[0037] Preferably, in step A and / or B, the method for adjusting the moisture content is drying and / or placing in a humid environment.

[0038] More preferably, in step A and / or B, in the method for adjusting the moisture content, the drying temperature is 25-60°C, specifically 30-60°C.

[0039] More preferably, in step A and / or B, in the method for adjusting the moisture content, the drying time is 2-40 hours.

[0040] More preferably, in step A and / or B, in the method for adjusting the water content, the drying method is vacuum drying.

[0041] More preferably, in step A and / or B, in the method for adjusting the moisture content, the relative humidity of the humid environment is ≥ 50%.

[0042] More preferably, in step A and / or B, in the method for adjusting the moisture content, the relative humidity of the humid environment is 60%-80%, specifically 65%-75%.

[0043] More preferably, in step A and / or B, in the method for adjusting the moisture content, the temperature of the humid environment is 25-40°C.

[0044] More preferably, in step A and / or B, in the method for adjusting the moisture content, the time of placing in a humid environment is ≥ 10 min.

[0045] More preferably, in step A and / or B, in the method for adjusting the moisture content, the time of placing in a humid environment is 0.3-48 hours.

[0046] Preferably, in step B, the solid-to-liquid ratio of tolvaptan sodium phosphate and the organic solvent is 1 g:(1-20) mL.

[0047] More preferably, in step B, the solid-to-liquid ratio of tolvaptan sodium phosphate and the organic solvent is 1g:1mL, 1g:2mL, 1g:3mL, 1g:4mL, 1g:5mL, 1g:6mL, 1g:7mL, 1g:8mL, 1g:9mL, 1g:10mL, 1g:11mL, 1g:12mL, 1g:13mL, 1g:14mL, 1g:15mL, 1g:16mL, 1g:17mL, 1g:18mL, 1g:19mL, 1g:20mL or any two of the range values.

[0048] Furthermore, in step B, the solid-to-liquid ratio of tolvaptan sodium phosphate and the organic solvent is 1 g:(4-20) mL.

[0049] More preferably, in step B, the solid-to-liquid ratio of tolvaptan sodium phosphate to the organic solvent is 1 g:(4-16) mL, specifically 1 g:(4-10) mL.

[0050] Preferably, in step B, the organic solvent is at least one of acetone, methanol, ethanol, isopropanol, tetrahydrofuran and acetonitrile.

[0051] More preferably, in step B, the organic solvent is one of a mixture of acetone and methanol, a mixture of acetone and ethanol, a mixture of acetone and isopropanol, a mixture of methanol and tetrahydrofuran, and a mixture of methanol and acetonitrile.

[0052] More preferably, in step B, the organic solvent is one of a mixture of acetone and methanol in a volume ratio of 1:1, a mixture of acetone and ethanol in a volume ratio of 1:1, a mixture of acetone and isopropanol in a volume ratio of 1:1, a mixture of methanol and tetrahydrofuran in a volume ratio of 1:1, and a mixture of methanol and acetonitrile in a volume ratio of 1:1.

[0053] In a third aspect, the present invention provides use of a tolvaptan sodium phosphate compound in the preparation of a drug.

[0054] Preferably, the tolvaptan sodium phosphate compound is used as a raw material for preparing medicines.

[0055] Compared with the prior art, the present invention has the following beneficial effects:

[0056] When the water content of the tolvaptan sodium phosphate compound of the present invention is ≥8.0%, it exhibits excellent stability, can be stably stored for a long time, and is suitable as a raw material for pharmaceuticals.

[0057] It is worth noting that when the water content of tolvaptan sodium phosphate crystals drops to 6%-8%, Form A will be converted into mixed crystals containing amorphous and Form A with a water content of 6%-8%; when the water content of tolvaptan sodium phosphate crystals drops to <6%, Form A will be converted into amorphous with a water content of <6%; and the stability of the mixed crystals with a water content of 6%-8% and the amorphous with a water content of <6% are both poor and cannot be stably stored for a long time. BRIEF DESCRIPTION OF THE DRAWINGS

[0058] Figure 1 This is the X-ray powder diffraction pattern of tolvaptan sodium phosphate crystal form A in Example 1.

[0059] Figure 2 This is the differential scanning calorimetry curve (DSC curve) of tolvaptan sodium phosphate crystal form A in Example 1.

[0060] Figure 3 This is the X-ray powder diffraction pattern of the mixed crystals of tolvaptan sodium phosphate containing amorphous form and form A in Comparative Example 1.

[0061] Figure 4 This is the X-ray powder diffraction pattern of the amorphous tolvaptan sodium phosphate of Example 18. DETAILED DESCRIPTION

[0062] In order to better illustrate the purpose, technical solutions and advantages of the present invention, the present invention will be further described below in conjunction with specific embodiments.

[0063] The experimental methods in the following examples without specifying specific conditions are generally carried out according to conventional conditions in the art or according to conditions recommended by the manufacturer; the raw materials, reagents, etc. used, unless otherwise specified, are all raw materials and reagents that can be obtained from commercial channels such as conventional markets.

[0064] In the present invention, the X-ray powder diffraction pattern is measured by using an Ultima IV X-ray diffractometer (Rigaku Corporation, Japan) under the following conditions:

[0065] X-Ray: 40 kV, 40 mA; target-filter: Cu K-beta filter; detector: D / text Ultra; scanning mode: continuous; scanning speed: 10° / min; step size: 0.02°; scanning axis: θ / 2θ; scanning range: 3.0-60.0°; incident slit: 1 / 2°.

[0066] In the present invention, the differential scanning calorimetry curve (DSC curve) is measured by using a DSC vesta differential scanning calorimeter (Rigaku Co., Ltd.) under the following conditions:

[0067] Heating rate: 10°C / min; atmosphere: nitrogen; measuring temperature range: 30-300°C.

[0068] In the present invention, the purity of tolvaptan sodium phosphate crystals and / or amorphous matter and / or mixed crystals is detected by high performance liquid chromatography, and the detection conditions are as follows:

[0069] Chromatographic column: ZORBAX-SB-C18 (4.6x150mmx5μm); mobile phase: 0.1% trifluoroacetic acid (ultrapure water as solvent) as mobile phase A, acetonitrile as mobile phase B; flow rate: 1.0ml / min; column temperature: 40°C; injection volume: 5μl; detection wavelength: 265nm; running time: 35min.

[0070] In the present invention, the water content of tolvaptan sodium phosphate crystals and / or amorphous matter and / or mixed crystals is tested by the following method:

[0071] Take 0.2 g of this product and determine it according to the water content determination method (Method 0832, General Rules of Part 4, 2020 Edition of the Chinese Pharmacopoeia).

[0072] In the present invention, the utilization rate of tolvaptan sodium phosphate (%) = tolvaptan sodium phosphate in the product tolvaptan sodium phosphate compound / tolvaptan sodium phosphate in the raw material × 100%.

[0073] In the present invention, only changing the experimental parameters of the method for adjusting the water content does not substantially affect the utilization rate of tolvaptan sodium phosphate without changing other conditions.

[0074] Example 1

[0075] This embodiment provides a tolvaptan sodium phosphate compound, wherein the tolvaptan sodium phosphate compound is a tolvaptan sodium phosphate crystal, and a method for preparing the tolvaptan sodium phosphate crystal comprises:

[0076] A. 5.00 g of tolvaptan sodium phosphate was added to 75 mL of an aqueous solvent (15 mL of water and 50 mL of acetone), the mixture was heated to 50 ° C and stirred until the solid was completely dissolved, then cooled to 20 ° C for crystallization by cooling, filtered, the filter cake was washed with 10 mL of acetone, and vacuum dried at 50 ° C for 4 h to adjust the water content to obtain 5.28 g of tolvaptan sodium phosphate crystals (form A). After testing, the purity was 99.96%, the water content was 15.6%, the yield was 105.6%, and the utilization rate of tolvaptan sodium phosphate was 89.1%;

[0077] like Figure 1As shown, the crystalline form of the tolvaptan sodium phosphate crystal is crystalline form A, and the X-ray powder diffraction pattern of the crystalline form A has diffraction peaks at the following 2θ angles: 4.4°±0.2°, 8.7°±0.2°, 10.4°±0.2°, 14.4°±0.2°, 17.3°±0.2°, 21.3°±0.2°, 23.0°±0.2° and 23.8°±0.2°; Figure 2 As shown, the differential scanning calorimetry curve of the crystal form A has endothermic peaks at 142°C±2°C and 335°C±2°C;

[0078] The solid-to-liquid ratio of tolvaptan sodium phosphate and water is 1 g:3 mL;

[0079] The solid-to-liquid ratio of tolvaptan sodium phosphate and the organic solvent (acetone) is 1 g:10 mL;

[0080] The utilization rate of tolvaptan sodium phosphate (%) = tolvaptan sodium phosphate in the product tolvaptan sodium phosphate crystals / tolvaptan sodium phosphate in the raw material = [5.28×(1-15.6%)] / 5.00×100%=89.1%.

[0081] Examples 2-7 and Comparative Examples 1-2

[0082] Examples 2-7 and Comparative Examples 1-2 provide different tolvaptan sodium phosphate compounds, which differ from Example 1 in that the solid-to-liquid ratio of tolvaptan sodium phosphate and water and the drying time in step A are different, and the rest are consistent with Example 1, as shown in the following table:

[0083] Table 1 Experimental parameters of step A of Examples 1-7 and Comparative Examples 1-2

[0084]

[0085]

[0086] In the above table, the crystalline form of the tolvaptan sodium phosphate compound is determined by X-ray powder diffraction patterns. The X-ray powder diffraction patterns of the tolvaptan sodium phosphate compounds of Examples 2-7 are substantially as follows: Figure 1 The differential scanning calorimetry curve (DSC curve) of tolvaptan sodium phosphate compound of Example 2-7 is substantially as shown in Figure 2 As shown; the X-ray powder diffraction pattern of the tolvaptan sodium phosphate compound of Comparative Example 1 is as shown Figure 3 As shown; the X-ray powder diffraction pattern of the amorphous tolvaptan sodium phosphate of Comparative Example 2 is substantially as shown Figure 4 shown.

[0087] from Figure 1-2 It can be seen that the tolvaptan sodium phosphate compound of Example 2-7 is a tolvaptan sodium phosphate crystal having a crystalline form A. Figure 3 It can be seen that the tolvaptan sodium phosphate compound of Comparative Example 1 is tolvaptan sodium phosphate crystals and tolvaptan sodium phosphate amorphous, that is, Comparative Example 1 is a mixed crystal of tolvaptan sodium phosphate containing amorphous and crystalline form A. Figure 4 It can be seen that the tolvaptan sodium phosphate compound of Comparative Example 2 is tolvaptan sodium phosphate amorphous substance.

[0088] Examples 8-12

[0089] Examples 8-12 provide different tolvaptan sodium phosphate compounds, which differ from Example 1 in that the type of organic solvent in step A is different, and the rest is consistent with Example 1, as shown in the following table:

[0090] Table 2 Experimental parameters of Example 1, 8-12 Step A

[0091]

[0092]

[0093] In the above table, the crystalline form of the tolvaptan sodium phosphate compound is determined by X-ray powder diffraction patterns. The X-ray powder diffraction patterns of the tolvaptan sodium phosphate compounds of Examples 8-12 are substantially as follows: Figure 1 The differential scanning calorimetry curves (DSC curves) of the tolvaptan sodium phosphate compounds of Examples 8-12 are substantially as shown in Figure 2 shown.

[0094] It can be seen from this that the tolvaptan sodium phosphate compounds of Examples 8-12 are tolvaptan sodium phosphate crystals having crystal form A.

[0095] Examples 13-16

[0096] Examples 13-16 provide different tolvaptan sodium phosphate compounds, which differ from Example 1 in that the temperature of the cooling crystallization in step A is different, and the rest is consistent with Example 1, as shown in the following table:

[0097] Table 3 Experimental parameters of Example 1, 13-16 Step A

[0098]

[0099] In the above table, the crystalline form of the tolvaptan sodium phosphate compound is determined by X-ray powder diffraction patterns. The X-ray powder diffraction patterns of the tolvaptan sodium phosphate compounds of Examples 13-16 are substantially as follows: Figure 1 The differential scanning calorimetry curves (DSC curves) of the tolvaptan sodium phosphate compounds of Examples 13-16 are substantially as shown in Figure 2 shown.

[0100] It can be seen from this that the tolvaptan sodium phosphate compounds of Examples 13-16 are tolvaptan sodium phosphate crystals having crystal form A.

[0101] Embodiment 17

[0102] This embodiment provides a tolvaptan sodium phosphate compound, wherein the tolvaptan sodium phosphate compound is a tolvaptan sodium phosphate crystal, and a method for preparing the tolvaptan sodium phosphate crystal comprises:

[0103] A. 5.00 g of tolvaptan sodium phosphate was added to 75 mL of an aqueous solvent (15 mL of water and 50 mL of acetone), the mixture was heated to 50 ° C and stirred until the solid was completely dissolved, then cooled to 20 ° C for crystallization by cooling, filtered, and the filter cake was washed with 10 mL of acetone to adjust the water content to obtain 6.36 g of tolvaptan sodium phosphate crystals (form A). After testing, the purity was 99.93%, the water content was 30.0%, the yield was 127.2%, and the tolvaptan sodium phosphate utilization rate was 89.0%;

[0104] The method for adjusting the moisture content is: first vacuum drying at 50°C for 4 hours, and then placing it in a humid environment (temperature 30±2°C, relative humidity 75±5%) for 48 hours;

[0105] The solid-to-liquid ratio of tolvaptan sodium phosphate and water is 1 g:3 mL;

[0106] The solid-to-liquid ratio of tolvaptan sodium phosphate and the organic solvent (acetone) is 1 g:10 mL;

[0107] The utilization rate of tolvaptan sodium phosphate (%) = tolvaptan sodium phosphate in the product tolvaptan sodium phosphate crystals / tolvaptan sodium phosphate in the raw material = [6.36 × (1-30.0%)] / 5.00 × 100% = 89.0%;

[0108] The X-ray powder diffraction pattern of the tolvaptan sodium phosphate compound is substantially as follows Figure 1 The differential scanning calorimetry curve (DSC curve) of the tolvaptan sodium phosphate compound is substantially as shown in Figure 2 shown.

[0109] Embodiment 18

[0110] This embodiment provides a tolvaptan sodium phosphate compound, wherein the tolvaptan sodium phosphate compound is tolvaptan sodium phosphate amorphous material, and a method for preparing the tolvaptan sodium phosphate amorphous material comprises:

[0111] B. 5.00g of tolvaptan sodium phosphate was added to 50mL of organic solvent (25mL of acetone and 25mL of methanol), the mixture was heated to 50°C and stirred until the solid was completely dissolved, then cooled to 0°C for crystallization by cooling, filtered, and the filter cake was washed with 10mL of acetone, and the water content was adjusted to obtain 4.62g of tolvaptan sodium phosphate amorphous material. After testing, the purity was 99.95%, the water content was 8.0%, the yield was 92.4%, and the tolvaptan sodium phosphate utilization rate was 85.0%;

[0112] The method for adjusting the moisture content is: first vacuum drying at 50°C for 12 hours, and then placing it in a humid environment (temperature 30±2°C, relative humidity 65±5%) for 15 minutes;

[0113] The solid-to-liquid ratio of tolvaptan sodium phosphate and the organic solvent is 1 g:10 mL;

[0114] The utilization rate of tolvaptan sodium phosphate (%) = tolvaptan sodium phosphate in the product tolvaptan sodium phosphate amorphous substance / tolvaptan sodium phosphate as raw material = [4.62×(1-8.0%)] / 5.00×100%=85.0%;

[0115] The X-ray powder diffraction pattern of the amorphous tolvaptan sodium phosphate has no crystal diffraction peak; the X-ray powder diffraction pattern of the amorphous tolvaptan sodium phosphate is as follows Figure 4 shown.

[0116] Examples 19-22

[0117] Examples 19-22 provide different tolvaptan sodium phosphate compounds, which differ from Example 18 in that the solid-to-liquid ratio of tolvaptan sodium phosphate and the organic solvent in step B is different, and the rest are consistent with Example 18, as shown in the following table:

[0118] Table 4 Experimental parameters of step B of Examples 18-22

[0119]

[0120] In the above table, the crystalline form of the tolvaptan sodium phosphate compound is determined by X-ray powder diffraction patterns. The X-ray powder diffraction patterns of the tolvaptan sodium phosphate compounds of Examples 18-22 are substantially as follows: Figure 4 shown.

[0121] It can be seen from this that the tolvaptan sodium phosphate compounds of Examples 18-22 are amorphous tolvaptan sodium phosphate.

[0122] Examples 23-26

[0123] Examples 23-26 provide different tolvaptan sodium phosphate compounds, which differ from Example 18 in that the type of organic solvent in step B is different, and the rest are consistent with Example 18, as shown in the following table:

[0124] Table 5 Experimental parameters of step B of Examples 18, 23-26

[0125]

[0126] In the above table, the crystalline form of the tolvaptan sodium phosphate compound is determined by X-ray powder diffraction patterns. The X-ray powder diffraction patterns of the tolvaptan sodium phosphate compounds of Examples 23-26 are substantially as follows: Figure 4 shown.

[0127] It can be seen from this that the tolvaptan sodium phosphate compounds of Examples 23-26 are amorphous tolvaptan sodium phosphate.

[0128] Examples 27-30

[0129] Examples 27-30 provide different tolvaptan sodium phosphate compounds, which differ from Example 18 in that the temperature of the cooling crystallization in step B is different, and the rest are consistent with Example 18, as shown in the following table:

[0130] Table 6 Experimental parameters of step B of Examples 18, 27-30

[0131]

[0132]

[0133] In the above table, the crystalline form of the tolvaptan sodium phosphate compound is determined by X-ray powder diffraction patterns. The X-ray powder diffraction patterns of the tolvaptan sodium phosphate compounds of Examples 27-30 are substantially as follows: Figure 4 shown.

[0134] It can be seen from this that the tolvaptan sodium phosphate compounds of Examples 27-30 are tolvaptan sodium phosphate amorphous substances.

[0135] Embodiment 31

[0136] This embodiment provides a tolvaptan sodium phosphate compound, wherein the tolvaptan sodium phosphate compound is tolvaptan sodium phosphate amorphous material, and the preparation method of the tolvaptan sodium phosphate amorphous material comprises:

[0137] B. 5.00g of tolvaptan sodium phosphate was added to 50mL of organic solvent (25mL of acetone and 25mL of methanol), the mixture was heated to 50°C and stirred until the solid was completely dissolved, then cooled to 0°C for crystallization by cooling, filtered, and the filter cake was washed with 10mL of acetone, and the water content was adjusted to obtain 6.07g of tolvaptan sodium phosphate amorphous material. After testing, the purity was 99.96%, the water content was 30.0%, the yield was 121.4%, and the tolvaptan sodium phosphate utilization rate was 85.0%;

[0138] The method for adjusting the moisture content is: first vacuum drying at 50°C for 12 hours, and then placing it in a humid environment (temperature 30±2°C, relative humidity 65±5%) for 48 hours;

[0139] The solid-to-liquid ratio of tolvaptan sodium phosphate and the organic solvent is 1 g:10 mL;

[0140] The utilization rate of tolvaptan sodium phosphate (%) = tolvaptan sodium phosphate in the product tolvaptan sodium phosphate amorphous substance / tolvaptan sodium phosphate as raw material = [6.07×(1-30.0%)] / 5.00×100%=85.0%;

[0141] The X-ray powder diffraction pattern of the amorphous tolvaptan sodium phosphate has no crystal diffraction peaks; the X-ray powder diffraction pattern of the amorphous tolvaptan sodium phosphate is substantially as follows Figure 4 shown.

[0142] Comparative Example 3

[0143] This comparative example provides a tolvaptan sodium phosphate compound, wherein the tolvaptan sodium phosphate compound is tolvaptan sodium phosphate amorphous material, and the preparation method of the tolvaptan sodium phosphate amorphous material comprises:

[0144] B. 5.00g of tolvaptan sodium phosphate was added to 50mL of organic solvent (25mL of acetone and 25mL of methanol), the mixture was heated to 50°C and stirred until the solid was completely dissolved, then cooled to 0°C for crystallization by cooling, filtered, the filter cake was washed with 10mL of acetone, and vacuum dried at 50°C for 12h to adjust the water content to obtain 4.28g of tolvaptan sodium phosphate amorphous material. After testing, the purity was 99.93%, the water content was 0.6%, the yield was 85.6%, and the tolvaptan sodium phosphate utilization rate was 85.1%;

[0145] The utilization rate of tolvaptan sodium phosphate (%) = tolvaptan sodium phosphate in the product tolvaptan sodium phosphate amorphous substance / tolvaptan sodium phosphate as raw material = [4.28×(1-0.6%)] / 5.00×100%=85.1%;

[0146] The X-ray powder diffraction pattern of the amorphous tolvaptan sodium phosphate has no crystal diffraction peaks; the X-ray powder diffraction pattern of the amorphous tolvaptan sodium phosphate is substantially as follows Figure 4 shown.

[0147] Comparative Example 4

[0148] This comparative example provides a tolvaptan sodium phosphate compound, wherein the tolvaptan sodium phosphate compound is tolvaptan sodium phosphate amorphous material, and the preparation method of the tolvaptan sodium phosphate amorphous material comprises:

[0149] B. 5.00g of tolvaptan sodium phosphate was added to 50mL of organic solvent (25mL of acetone and 25mL of methanol), the mixture was heated to 50°C and stirred until the solid was completely dissolved, then cooled to 0°C for crystallization by cooling, filtered, and the filter cake was washed with 10mL of acetone, and the water content was adjusted to obtain 4.46g of tolvaptan sodium phosphate amorphous material. After testing, the purity was 99.94%, the water content was 4.6%, the yield was 89.2%, and the tolvaptan sodium phosphate utilization rate was 85.1%;

[0150] The method for adjusting the moisture content is: first vacuum drying at 50°C for 12 hours, and then placing it in a humid environment (temperature 30±2°C, relative humidity 65±5%) for 10 minutes;

[0151] The solid-to-liquid ratio of tolvaptan sodium phosphate and the organic solvent is 1 g:10 mL;

[0152] The utilization rate of tolvaptan sodium phosphate (%) = tolvaptan sodium phosphate in the product tolvaptan sodium phosphate amorphous substance / tolvaptan sodium phosphate in the raw material = [4.46×(1-4.6%)] / 5.00×100%=85.1%;

[0153] The X-ray powder diffraction pattern of the amorphous tolvaptan sodium phosphate has no crystal diffraction peaks; the X-ray powder diffraction pattern of the amorphous tolvaptan sodium phosphate is substantially as follows Figure 4 shown.

[0154] Comparative Example 5

[0155] This comparative example provides a tolvaptan sodium phosphate compound, wherein the tolvaptan sodium phosphate compound is tolvaptan sodium phosphate amorphous material, and the preparation method of the tolvaptan sodium phosphate amorphous material comprises:

[0156] B. 5.00g of tolvaptan sodium phosphate was added to 50mL of organic solvent (25mL of acetone and 25mL of methanol), the mixture was heated to 50°C and stirred until the solid was completely dissolved, then cooled to 0°C for crystallization by cooling, filtered, and the filter cake was washed with 10mL of acetone, and the water content was adjusted to obtain 4.53g of tolvaptan sodium phosphate amorphous material. After testing, the purity was 99.94%, the water content was 6.2%, the yield was 90.6%, and the tolvaptan sodium phosphate utilization rate was 85.0%;

[0157] The method for adjusting the moisture content is: first vacuum drying at 50°C for 12 hours, and then placing it in a humid environment (temperature 30±2°C, relative humidity 65±5%) for 12 minutes;

[0158] The solid-to-liquid ratio of tolvaptan sodium phosphate and the organic solvent is 1 g:10 mL;

[0159] The utilization rate of tolvaptan sodium phosphate (%) = tolvaptan sodium phosphate in the product tolvaptan sodium phosphate amorphous substance / tolvaptan sodium phosphate in the raw material = [4.53 × (1-6.2%)] / 5.00 × 100% = 85.0%;

[0160] The X-ray powder diffraction pattern of the amorphous tolvaptan sodium phosphate has no crystal diffraction peaks; the X-ray powder diffraction pattern of the amorphous tolvaptan sodium phosphate is substantially as follows Figure 4 shown.

[0161] Performance Testing

[0162] Referring to the guidelines for stability tests of raw materials and preparations in the 2020 edition of the Chinese Pharmacopoeia, the crystals (crystalline form A), amorphous substances and mixed crystals of each embodiment and comparative example were subjected to accelerated tests to investigate their stability. The test sample was 2 g and sealed in a pharmaceutical polyethylene bag and stored at a temperature of 40°C ± 2°C and a relative humidity of 75% ± 5% for 6 months. The crystal form, tolvaptan production, purity and solution clarity of the samples were detected at 0 days and 6 months, respectively; wherein the crystal form test of the sample was performed by the above-mentioned X-ray powder diffraction method, and confirmed by the obtained X-ray powder diffraction pattern; the tolvaptan production was detected by the above-mentioned high performance liquid chromatography; the purity of tolvaptan sodium phosphate crystals and / or amorphous substances and / or mixed crystals was detected by high performance liquid chromatography; the solution clarity test was performed by the 0902 clarity inspection method of the four general rules of the 2020 edition of the Chinese Pharmacopoeia; the experimental results are as follows:

[0163] Table 7 Test results of tolvaptan sodium phosphate compounds in various embodiments and comparative examples placed for 0 days

[0164]

[0165]

[0166]

[0167] In the above table, “mixed crystal” means “containing amorphous and form A”, and “ / ” means “not detected”.

[0168] Table 8 Test results of tolvaptan sodium phosphate compound placed for 6 months in each embodiment and comparative example

[0169]

[0170]

[0171] In the above table, “mixed crystal” means “containing amorphous and form A”, and “ / ” means “not detected”.

[0172] It can be seen from Tables 7-8 that when the water content of the tolvaptan sodium phosphate compound of the present invention is ≥8.0%, it exhibits excellent stability, can be stably stored for a long time, and is suitable as a pharmaceutical raw material.

[0173] It is worth noting that when the water content of tolvaptan sodium phosphate crystals drops to 6%-8%, Form A will be converted into mixed crystals containing amorphous and Form A with a water content of 6%-8%; when the water content of tolvaptan sodium phosphate crystals drops to <6%, Form A will be converted into amorphous with a water content of <6%; and the stability of the mixed crystals with a water content of 6%-8% and the amorphous with a water content of <6% are both poor and cannot be stably stored for a long time.

[0174] Finally, it should be noted that the above embodiments are only used to illustrate the technical solution of the present invention rather than to limit the scope of protection of the present invention. Although the present invention has been described in detail with reference to the preferred embodiments, those skilled in the art should understand that the technical solution of the present invention can be modified or replaced by equivalents without departing from the essence and scope of the technical solution of the present invention.

Claims

1. Tolvaptan sodium phosphate compound, characterized in that, The tolvaptan sodium phosphate compound is tolvaptan sodium phosphate crystals and / or tolvaptan sodium phosphate amorphous material; The crystal form of the tolvaptan sodium phosphate crystal is crystal form A, and the X-ray powder diffraction spectrum of the crystal form A has diffraction peaks at the following 2θ angles: 4.4°±0.2°, 8.7°±0.2°, 10.4°±0.2°, 14.4°±0.2°, 17.3°±0.2°, 21.3°±0.2°, 23.0°±0.2° and 23.8°±0.2°; The X-ray powder diffraction pattern of the amorphous tolvaptan sodium phosphate has no crystal diffraction peaks; The water content of the tolvaptan sodium phosphate compound is ≥8.0%.

2. The tolvaptan sodium phosphate compound according to claim 1, characterized in that The water content of the tolvaptan sodium phosphate compound is 8.0%-30.0%.

3. The tolvaptan sodium phosphate compound according to claim 1, characterized in that The differential scanning calorimetry curve of the crystal form A has endothermic peaks at 142°C±2°C and 335°C±2°C.

4. The method for preparing the tolvaptan sodium phosphate compound according to any one of claims 1 to 3, characterized in that: include: A. dissolving tolvaptan sodium phosphate in an aqueous solvent, cooling and crystallizing, and adjusting the water content to obtain tolvaptan sodium phosphate crystals having a water content of ≥8.0%; and / or B. dissolving tolvaptan sodium phosphate in an organic solvent, cooling and crystallizing, and adjusting the water content to obtain tolvaptan sodium phosphate amorphous material with a water content of ≥8.0%.

5. The method for preparing tolvaptan sodium phosphate compound according to claim 4, characterized in that: Including at least one of the following (1)-(6): (1) In step A, the solid-to-liquid ratio of tolvaptan sodium phosphate and water is 1 g: (0.5-5) mL; (2) In step A, the aqueous solvent is water, or the aqueous solvent is a mixture of water and an organic solvent; (3) In step A and / or B, the temperature of the cooling crystallization is ≤30°C; (4) In step A and / or B, the dissolution temperature is 45-75°C; (5) In step A and / or B, filtering and washing are further performed after the cooling and crystallization and before the water content is adjusted; (6) In step A and / or B, the method for adjusting the moisture content is drying and / or placing in a humid environment.

6. The method for preparing tolvaptan sodium phosphate compound according to claim 5, characterized in that: Including at least one of the following (1)-(7): (1) In step A, the solid-to-liquid ratio of tolvaptan sodium phosphate and water is 1 g: (1-5) mL; (2) In step A, the organic solvent in the aqueous solvent is at least one of acetone, ethanol, methanol, isopropanol, tetrahydrofuran, and acetonitrile; (3) In step A, the solid-to-liquid ratio of tolvaptan sodium phosphate and the organic solvent is 1 g: (0.5-150) mL; (4) In step A and / or B, the temperature of the cooling crystallization is 0-30°C; (5) In step A and / or B, the dissolution temperature is 50-70°C; (6) In step A and / or B, in the method for adjusting the moisture content, the drying temperature is 25-60°C; (7) In step A and / or B, in the method for adjusting the moisture content, the relative humidity of the humid environment is ≥50%.

7. The method for preparing tolvaptan sodium phosphate compound according to claim 6, characterized in that: Including at least one of the following (1)-(5): (1) In step A, the solid-to-liquid ratio of tolvaptan sodium phosphate and water is 1 g: (2-4) mL; (2) In step A, the temperature of the cooling crystallization is 0-25°C; (3) In step B, the temperature of the cooling crystallization is 0-20°C; (4) In step A and / or B, in the method for adjusting the moisture content, the drying temperature is 30-60°C; (5) In step A and / or B, in the method for adjusting the moisture content, the relative humidity of the humid environment is 60%-80%.

8. The method for preparing tolvaptan sodium phosphate compound according to claim 4, characterized in that: Include at least one of the following (1)-(2): (1) In step B, the solid-to-liquid ratio of tolvaptan sodium phosphate and the organic solvent is 1 g: (1-20) mL; (2) In step B, the organic solvent is at least one of acetone, methanol, ethanol, isopropanol, tetrahydrofuran, and acetonitrile.

9. The method for preparing tolvaptan sodium phosphate compound according to claim 8, characterized in that: Include at least one of the following (1)-(2): (1) In step B, the solid-to-liquid ratio of tolvaptan sodium phosphate and the organic solvent is 1 g: (4-20) mL; (2) In step B, the organic solvent is one of a mixture of acetone and methanol, a mixture of acetone and ethanol, a mixture of acetone and isopropanol, a mixture of methanol and tetrahydrofuran, and a mixture of methanol and acetonitrile.

10. Use of the tolvaptan sodium phosphate compound according to any one of claims 1 to 3 in the preparation of medicines.

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