Monbutone sodium hydrate as well as preparation method and application thereof

Abstract

The invention discloses a menbutone sodium hydrate as well as a preparation method and application thereof, and belongs to the technical field of chemical medicine crystallization. The structure of the menbutone sodium hydrate is shown as a formula (I). The X-ray powder diffraction pattern of the menbutone sodium hydrate measured by using CuKa rays has characteristic peaks when the 2 theta value is 10.3 + / -0.2 degrees, 10.7 + / -0.2 degrees, 12.0 + / -0.2 degrees, 14.3 + / -0.2 degrees, 15.1 + / -0.2 degrees, 16.5 + / -0.2 degrees, 18.9 + / -0.2 degrees, 25.2 + / -0.2 degrees and 26.5 + / -0.2 degrees. The menbutone sodium hydrate has good solubility and dissolution rate, has excellent preparation processability, and is high in crystal purity, good in storage stability and wide in clinical application prospect.

Description

Technical Field

[0001] The present invention belongs to the technical field of chemical drug crystallization, and particularly relates to a menbutone sodium hydrate and a preparation method and application thereof. Background Art

[0002] Menbutone (MBT) is a choleretic drug specifically for animals. It can promote the secretion of bile, gastric juice, and pancreatic juice to 2-5 times the normal secretion volume, thereby increasing the supply of bile salts, pepsin, and pancreatic amylase. It effectively treats gastrointestinal dysfunction such as indigestion, loss of appetite, constipation, and abdominal distension in animals, and improves digestion and absorption. It is widely used in pigs, cattle, sheep, goats, horses, and dogs to treat indigestion, anorexia, constipation, toxemia, and digestive dysfunction caused by liver and pancreatic insufficiency. It can be used in both pregnant and non-pregnant animals and has broad market prospects and strong market competitiveness. Menbutone has a LogP of approximately 2.5 and a pKa of approximately 4.4. Its chemical name is: 3-(4-methoxy-1-naphthyl)propionic acid, and its chemical formula is as follows:

[0003]

[0004] Currently, only powder and injection of Menbutone are available on the market. Menbutone injection is suitable for the treatment of indigestion, loss of appetite, constipation and abdominal distension, ketosis, toxemia, toxic liver function impairment, liver malnutrition, and liver degenerative diseases (such as fatty liver) in animals such as pigs, cattle, sheep, horses, and dogs. Since Menbutone has a LogP of approximately 2.5 and a pKa of approximately 4.4, it is difficult to dissolve in both hydrophilic and lipophilic solvents. Although alkali can be added to aid dissolution, the strong alkalinity of the injection solution causes strong irritation to the body and may cause adverse reactions such as local muscle edema, bleeding, or necrosis. Menbutone powder is suitable for the treatment of symptoms such as indigestion, constipation and abdominal distension in pigs. Due to its poor water solubility, Menbutone cannot be administered in drinking water and can only be administered by mixing with feed. However, when mixing with feed, its poor fluidity often leads to uneven mixing, uncontrollable dosage, and a lot of dust, which limits the application of Menbutone powder.

[0005] Chinese patent CN104370734B discloses a crystal form of menbutone with a solubility of 0.08 mg / mL in water at 20°C. Patent CN112979459B discloses a crystal form I of menbutone, which has a solubility of 2.1 mg / mL in water at 20°C. The solubility of the two crystal forms still cannot meet the clinical medication needs. Therefore, there is an urgent need to develop a new solid form with better solubility in clinical practice.

[0006] There are many methods to improve drug solubility, such as micronization, cyclodextrin inclusion complexes, solid dispersions, microcapsule preparations, cocrystals and salt formation, among which drug salt formation is the most commonly used method.

[0007] The researchers of the present invention conducted a large number of experiments to investigate the salt formation of menbutone with various substances, and examined the solvent system, crystallization conditions and drying conditions. After continuous improvement, the present invention obtained a new menbutone sodium hydrate crystal through a specific method. The crystal is a white crystalline powder with good solubility and dissolution rate, excellent formulation processability, high crystal purity and good storage stability. Summary of the Invention

[0008] The present invention aims to solve the technical problems in the prior art and provides a sodium menbutone hydrate with high water solubility and high crystallinity, and a preparation method and application thereof.

[0009] In order to achieve the above purpose, the specific technical solutions of the present invention are as follows:

[0010] In the first aspect of the present invention, there is provided a sodium menbutone hydrate, the structure of which is shown in the following formula (I):

[0011]

[0012] The menbutone sodium hydrate is in crystalline form.

[0013] The asymmetric structural unit in the crystal structure of menbutone sodium hydrate is composed of a menbutone anion, a sodium ion and four water molecules. It is a monoclinic crystal with a space group of P21 / c. The crystallographic data are: α=90°, β=98.405(2)°, γ=90°, Z=4, T=100.00K, μ(MoKα=0.135mm -1 , Dcalc=1.408g / cm 3 The total number of diffraction points is 26052 (4.462°≤2Θ≤55.042°), and the number of independent diffraction points is 3803 (R int =0.0698, R sigma =0.0414) The final reliability factor R1 =0.0383 (I>2σ(I)), wR2 =0.1041 (all data).

[0014] The X-ray powder diffraction pattern of the menbutone sodium hydrate measured using CuKa rays has characteristic peaks at 2θ values ​​of 10.3±0.2°, 10.7±0.2°, 12.0±0.2°, 14.3±0.2°, 15.1±0.2°, 16.5±0.2°, 18.9±0.2°, 25.2±0.2°, and 26.5±0.2°.

[0015] Preferably, the X-ray powder diffraction pattern of the sodium mephenesin hydrate measured using CuKa radiation has characteristic peaks at 2-theta values of 9.5±0.2°, 10.3±0.2°, 10.7±0.2°, 12.0±0.2°, 13.0±0.2°, 14.3±0.2°, 15.1±0.2°, 16.5±0.2°, 17.2±0.2°, 18.9±0.2°, 20.7±0.2°, 22.0±0.2°, 23.1±0.2°, 24.9±0.2°, 25.2±0.2°, 25.8±0.2°, 26.5±0.2°, 27.6±0.2°, 28.2±0.2°, 28.5±0.2°, 29.4±0.2°.

[0016] The TGA spectrum of the sodium mephenesin hydrate shows a mass loss of 20.57 wt% in the range of 35-125°C.

[0017] In a second aspect of the present application, a method for preparing the sodium mephenesin hydrate as described above is provided, which is characterized by using a concurrent solventing method for crystallization, and comprises the following four steps:

[0018] (1) A mixed solvent is prepared by mixing a good solvent for sodium mephenesin and a poor solvent A, and the temperature of the system is maintained at 0-5°C. Seed crystals of sodium mephenesin hydrate are added, and the mixture is stirred until all the particles are dispersed to form a suspension. The suspension is then added to a crystallizer to obtain a seed crystal dispersion system.

[0019] (2) Mephenesin sodium is dispersed in a solvent at 20-25°C, and an aqueous sodium hydroxide solution is added. The mixture is stirred until the mephenesin sodium is dissolved.

[0020] (3) The mephenesin sodium solution obtained in step (2) and a poor solvent B are simultaneously added dropwise to the seed crystal dispersion system of step (1) to perform concurrent solventing, and the concentration of water in the process of concurrent solventing is maintained substantially unchanged.

[0021] (4) The solution system in step (3) is continuously maintained at 0-5°C, and then filtered, washed with cold water, and dried to obtain mephenesin hydrate crystalline powder.

[0022] The good solvent in step (1) is one or more of methanol, ethanol, isopropanol, acetone, and tetrahydrofuran, and the poor solvent is water. The mass fraction of the good solvent in the mixed solvent system is 15-35%.

[0023] The amount of the seed crystals of sodium mephenesin hydrate in step (1) is 2-5% of the mass fraction of the mixed solvent.

[0024] The preparation method of the sodium menbutone hydrate seed crystals in step (1) is as follows: dispersing menbutone in methanol (the mass volume ratio of menbutone to methanol is 1:6) at 20-25°C, adding 10% sodium hydroxide (the molar ratio of menbutone to sodium hydroxide is 1:1.1) aqueous solution, stirring and dissolving to obtain a sodium menbutone solution, adding the solution and water (the mass volume ratio of menbutone to water is 1:16) to a crystallizer in parallel, stirring and balancing for 1 week, cooling to 0-5°C, keeping the mixture stirred, filtering, washing with cold water, and drying the filter cake at 35°C with air to obtain a crystalline powder of menbutone hydrate.

[0025] The solvent in step (2) is one or more of methanol, ethanol, isopropanol, acetone or tetrahydrofuran; or, the solvent in step (2) is a mixed solution of methanol, ethanol, isopropanol, acetone, tetrahydrofuran and water.

[0026] The concentration of the sodium hydroxide aqueous solution in step (2) is 4 to 20 wt %, and the amount of the sodium hydroxide aqueous solution used is such that the molar ratio of the sodium hydroxide contained in the sodium hydroxide solution to menbutone is 1.0 to 1.2:1.

[0027] The mass fraction of water in the sodium menbutone solution in step (2) is not greater than 25 wt %, and the concentration of sodium menbutone is 0.05 to 0.25 g / g solvent.

[0028] The poor solvent in step (3) is water; or the poor solvent in step (3) is a mixture of one or more of methanol, ethanol, isopropanol, acetone, tetrahydrofuran and water, wherein the mass fraction of water is not less than 65%.

[0029] The concentration of water in the parallel elution process in step (3) remains unchanged, the process temperature is controlled at 0-5°C, and the elution time is 1-2h.

[0030] The heat preservation and suspension process in step (4) lasts for 1 to 2 hours.

[0031] The drying conditions in step (4) are vacuum drying or blast drying, the vacuum degree under vacuum drying conditions is not less than 0.08 MPa; the drying temperature range is 25-40° C., and the drying time is not more than 72 h.

[0032] The third aspect of the present invention provides a pharmaceutical composition containing the menbutone sodium hydrate of the present invention.

[0033] The pharmaceutical composition is a mixture containing the menbutone sodium hydrate and other menbutone sodiums.

[0034] Alternatively, the pharmaceutical composition further contains one or more pharmaceutically acceptable carriers and / or excipients.

[0035] The fourth aspect of the present invention provides the use of the menbutone sodium hydrate or the pharmaceutical composition of the present invention in the preparation of a pharmaceutical preparation for animal choleretics.

[0036] The pharmaceutical preparation can be prepared in dosage forms including but not limited to tablets, soluble powders, injections, oral solutions, granules, powder injections, pellets, suspensions, and the like.

[0037] Beneficial effects:

[0038] (1) The solubility of the sodium menbutone hydrate crystals provided by the present invention in water is increased by 171 times compared with the menbutone crystal form I, which greatly improves the water solubility of menbutone and has significant advantages for the preparation of soluble preparations.

[0039] (2) Compared with menbutone, the menbutone sodium hydrate crystals provided by the present invention have a faster dissolution rate in the injection preparation process and better mixing performance in the powder preparation process.

[0040] (3) The parallel-flow dissolution crystallization method provided by the present invention for preparing sodium menbutone hydrate overcomes the disadvantage of the dissolution method having a large local supersaturation, maintains the water content of the system unchanged during the crystallization process, ensures high purity of the product crystal form, and is also convenient for industrial production.

[0041] (4) The crystallization method of sodium menbutone hydrate provided by the present invention has a good removal effect on the specific impurity A in menbutone, and can reduce the impurity A in the crude menbutone from 0.98% to 0.14%, obtaining a high-purity product with HPLC purity ≥99%. BRIEF DESCRIPTION OF THE DRAWINGS

[0042] Figure 1 Ellipsoid diagram of the crystal structure of single crystal of Menbutone sodium hydrate;

[0043] Figure 2 Projection diagram of the unit cell stacking of a single crystal of sodium menbutone hydrate along the b-axis;

[0044] Figure 3 PXRD pattern of Menbutone sodium hydrate;

[0045] Figure 4 TGA spectrum of Menbutone sodium hydrate;

[0046] Figure 5 Microscopic photograph of the menbutone sodium hydrate crystals prepared in the present invention (10× eyepiece + 20× objective lens). DETAILED DESCRIPTION

[0047] The following will further explain the above content in detail through specific implementation methods in the form of examples. However, this should not be understood as limiting the scope of the above subject matter to the following examples. All technologies implemented based on the content of the present invention are within the scope.

[0048] Example 1

[0049] Take 10g of a methanol-water solution with a methanol content of 25wt%, maintain the system temperature at 0-5°C, add 0.4g of menbutone sodium hydrate seed crystals, stir until the particles are completely dispersed, and add the suspension to a crystallizer to obtain a seed crystal dispersion system. Disperse 4.95g of menbutone in 60g of methanol at 20-25°C, then add 19.36g of a 4wt% sodium hydroxide aqueous solution, dissolve, and then filter to obtain a menbutone sodium solution. Using a double-feed method, the menbutone sodium solution and poor solvent water are simultaneously added dropwise to the seed crystal dispersion system, ensuring that the water concentration remains essentially unchanged during the co-current elution process. 161g of water is required; the elution time is set to 2h, the process temperature is 0-5°C, and the stirring speed is 150r / min. After the parallel dissolution process, the mixture was kept warm and suspended for 2 hours, filtered, washed with cold water, and the filter cake was dried by forced air at 35° C. for 8 hours to obtain 5.80 g of sodium menbutone hydrate with a molar yield of 85% (based on menbutone).

[0050] Example 2

[0051] Take 15g of a methanol-water solution with a methanol content of 25wt%, maintain the system temperature at 0-5°C, add 0.50g of menbutone sodium hydrate seed crystals, stir until the particles are completely dispersed, and add the suspension to a crystallizer to obtain a seed crystal dispersion system. Disperse 5.00g of menbutone in 30g of methanol at 20-25°C, then add 7.75g of a 10wt% sodium hydroxide aqueous solution, dissolve, and then filter to obtain a menbutone sodium solution. Using a double-feed method, the menbutone sodium solution and poor solvent water are simultaneously added dropwise to the seed crystal dispersion system, ensuring that the water concentration remains essentially unchanged during the co-current elution process. 83g of water is required; the elution time is set to 1.5h, the process temperature is 0-5°C, and the stirring speed is 150r / min. After the parallel dissolution process, the mixture was kept warm and suspended for 2 hours, filtered, washed with cold water, and the filter cake was dried by forced air at 30° C. for 12 hours to obtain 6.27 g of sodium menbutone hydrate with a molar yield of 92% (based on menbutone).

[0052] Example 3

[0053] Take 10g of a methanol-water solution with a methanol content of 25wt%, maintain the system temperature at 0-5°C, add 0.30g of menbutone sodium hydrate seed crystals, stir until the particles are completely dispersed, and add the suspension to a crystallizer to obtain a seed crystal dispersion system. Disperse 5.00g of menbutone in 17.5g of methanol at 20-25°C, then add 4.26g of a 20wt% sodium hydroxide aqueous solution, dissolve, and then filter to obtain a menbutone sodium solution. Using a double-feed method, the menbutone sodium solution and poor solvent water are simultaneously added dropwise to the above seed crystal dispersion system, ensuring that the water concentration remains essentially unchanged during the co-current elution process. 49g of water needs to be added; set the elution time to 1.5h, the process temperature to 0-5°C, and the stirring speed to 150r / min. After the parallel dissolution process, the mixture was kept warm and suspended for 2 hours, filtered, washed with cold water, and the filter cake was dried by forced air at 35° C. for 8 hours to obtain 6.20 g of sodium menbutone hydrate with a molar yield of 91% (based on menbutone).

[0054] Example 4

[0055] Take 10g of a methanol-water solution with a methanol content of 35wt%, maintain the system temperature at 0-5°C, add 0.45g of menbutone sodium hydrate seed crystals, stir until the particles are completely dispersed, and add the suspension to a crystallizer to obtain a seed crystal dispersion system. Disperse 5.00g of menbutone in 17.5g of methanol at 20-25°C, then add 3.88g of a 20wt% sodium hydroxide aqueous solution, dissolve, and then filter to obtain a menbutone sodium solution. Using a double-feed method, the menbutone sodium solution and poor solvent water are simultaneously added dropwise to the seed crystal dispersion system, ensuring that the water concentration remains essentially unchanged during the co-current elution process. 29g of pure water is required; the elution time is set to 1.5h, the process temperature is 0-5°C, and the stirring speed is 150r / min. After the parallel dissolution process, the mixture was kept warm and suspended for 1.5 hours, filtered, washed with cold water, and the filter cake was dried by forced air at 35° C. for 8 hours to obtain 6.14 g of sodium menbutone hydrate with a molar yield of 90% (based on menbutone).

[0056] Example 5

[0057] Take 10g of a methanol-water solution with a methanol content of 15wt%, maintain the system temperature at 0-5°C, add 0.30g of menbutone sodium hydrate seed crystals, stir until the particles are completely dispersed, and add the suspension to a crystallizer to obtain a seed crystal dispersion system. Disperse 5.00g of menbutone in 17.5g of methanol at 20-25°C, then add 3.88g of a 20wt% sodium hydroxide aqueous solution, dissolve, and then filter to obtain a menbutone sodium solution. Using a double-feed method, the menbutone sodium solution and poor solvent water are simultaneously added dropwise to the seed crystal dispersion system, ensuring that the water concentration remains essentially unchanged during the co-current elution process. 95g of pure water is required; the elution time is set to 1h, the process temperature is 0-5°C, and the stirring speed is 150r / min. After the parallel elution process was completed, the mixture was kept warm and suspended for 1 hour, filtered, washed with cold water, and the filter cake was vacuum dried at 25° C. for 18 hours to obtain 6.48 g of sodium menbutone hydrate with a molar yield of 95% (based on menbutone).

[0058] Example 6

[0059] Take 10g of a methanol-water solution with a methanol content of 25wt%, maintain the system temperature at 0-5°C, add 0.40g of menbutone sodium hydrate seed crystals, stir until the particles are completely dispersed, and add the suspension to a crystallizer to obtain a seed crystal dispersion system. Disperse 5.00g of menbutone in 25g of methanol at 20-25°C, then add 7.75g of a 10wt% sodium hydroxide aqueous solution, dissolve, and then filter to obtain a menbutone sodium solution. Using a double-feed method, the menbutone sodium solution and poor solvent water are simultaneously added dropwise to the seed crystal dispersion system, ensuring that the water concentration remains essentially unchanged during the co-current elution process. 67g of pure water is required; the elution time is set to 1h, the process temperature is 0-5°C, and the stirring speed is 150r / min. After the parallel dissolution process, the mixture was kept warm and suspended for 1.5 hours, filtered, washed with cold water, and the filter cake was dried by forced air at 35° C. for 8 hours to obtain 6.27 g of sodium menbutone hydrate with a molar yield of 92% (based on menbutone).

[0060] Example 7

[0061] Take 10g of an ethanol-water solution with a 25wt% ethanol content, maintain the system temperature at 0-5°C, add 0.40g of menbutone sodium hydrate seed crystals, stir until the particles are completely dispersed, and add the suspension to a crystallizer to obtain a seed crystal dispersion system. Disperse 5.01g of menbutone in 25g of ethanol at 20-25°C, then add 7.76g of a 10wt% sodium hydroxide aqueous solution, dissolve, and then filter press to obtain a menbutone sodium solution. Using a double-feed method, the menbutone sodium solution and poor solvent water are simultaneously added dropwise to the seed crystal dispersion system, ensuring that the water concentration remains essentially unchanged during the co-current elution process. 67g of pure water is required; the elution time is set to 1.5h, the process temperature is 0-5°C, and the stirring speed is 150r / min. After the parallel dissolution process was completed, the mixture was kept warm and suspended for 1.5 hours, filtered, and the filter cake was dried by air at 35° C. for 8 hours to obtain 6.54 g of sodium menbutone hydrate with a molar yield of 96% (based on menbutone).

[0062] Example 8

[0063] Take 10g of an isopropanol-water solution with a 25wt% isopropanol content, maintain the system temperature at 0-5°C, add 0.40g of menbutone sodium hydrate seed crystals, stir until the particles are completely dispersed, and add the suspension to a crystallizer to obtain a seed crystal dispersion system. Disperse 5.00g of menbutone in 17.5g of isopropanol at 20-25°C, then add 3.88g of a 20wt% sodium hydroxide aqueous solution, dissolve, and then filter to obtain a menbutone sodium solution. Using a double-feed method, the menbutone sodium solution and poor solvent water are simultaneously added dropwise to the seed crystal dispersion system, ensuring that the water concentration remains essentially unchanged during the co-current elution process. 49g of pure water is required; the elution time is set to 1h, the process temperature is 0-5°C, and the stirring speed is 150r / min. After the parallel dissolution process, the mixture was kept warm and suspended for 1.5 hours, filtered, washed with cold water, and the filter cake was dried by forced air at 35° C. for 12 hours to obtain 6.41 g of sodium menbutone hydrate with a molar yield of 94% (based on menbutone).

[0064] Example 9

[0065] Take 10g of a tetrahydrofuran-water solution with a tetrahydrofuran content of 25wt%, maintain the system temperature at 0-5°C, add 0.30g of menbutone sodium hydrate seed crystals, stir until the particles are completely dispersed, and add the suspension to a crystallizer to obtain a seed crystal dispersion system. Disperse 5.02g of menbutone in 17.5g of tetrahydrofuran at 20-25°C, then add 3.89g of a 20wt% sodium hydroxide aqueous solution, dissolve, and then filter press to obtain a menbutone sodium solution. Using a double-feed method, the menbutone sodium solution and poor solvent water are simultaneously added dropwise to the seed crystal dispersion system, ensuring that the water concentration remains essentially unchanged during the co-current elution process. 50g of pure water is required; the elution time is set to 1.5h, the process temperature is 0-5°C, and the stirring speed is 150r / min. After the parallel dissolution process was completed, the mixture was kept warm and suspended for 1 hour, filtered, and the filter cake was dried by air at 25° C. for 24 hours to obtain 6.20 g of sodium menbutone hydrate with a molar yield of 91% (based on menbutone).

[0066] Example 10

[0067] Take 10g of an acetone-water solution with a 25wt% acetone content, maintain the system temperature at 0-5°C, add 0.30g of menbutone sodium hydrate seed crystals, stir until the particles are completely dispersed, and add the suspension to a crystallizer to obtain a seed crystal dispersion system. Disperse 4.98g of menbutone in 25g of acetone at 20-25°C, then add 7.74g of a 10wt% sodium hydroxide aqueous solution, dissolve, and then filter to obtain a menbutone sodium solution. Using a double-feed method, the menbutone sodium solution and poor solvent water are simultaneously added dropwise to the seed crystal dispersion system, ensuring that the water concentration remains essentially unchanged during the co-current elution process. 67g of pure water is required; the elution time is set to 1h, the process temperature is 0-5°C, and the stirring speed is 150r / min. After the parallel dissolution process was completed, the mixture was kept warm and suspended for 1.5 hours, filtered, and the filter cake was dried by forced air at 40° C. for 8 hours to obtain 6.07 g of sodium menbutone hydrate with a molar yield of 89% (based on menbutone).

[0068] Example 11 Solubility test of Menbutone sodium hydrate

[0069] An excess amount of the sodium hydrate of Menbutone of the present invention was placed in a 5 mL test tube, 2.5 mL of pure water was added, and the mixture was vortexed for half a minute and then placed in a constant temperature oscillator at 20±5°C for 24 hours. The mixture was filtered through a 0.45 μm filter membrane and appropriately diluted before testing by high performance liquid chromatography. Different crystalline forms of Menbutone were used as controls, and the controls and samples were tested in triplicate for solubility. The average value was taken, and the results are shown in Table 1.

[0070] Table 1 Comparison of the solubility of Menbutone sodium hydrate and different crystalline forms of Menbutone

[0071]

[0072] As shown in Table 1, the solubility of menbutone sodium hydrate is increased by 171 times compared with the menbutone crystal form I with better solubility. It can be seen that the menbutone sodium hydrate prepared by the present invention greatly improves the solubility of menbutone.

[0073] Example 12 Investigation of the crystallization and purification effect of Menbutone sodium hydrate

[0074] During the actual production process, menbutone usually contains several impurities, such as the molecular compound menbutone methyl ester (impurity A), which has a high structural similarity to menbutone. This makes the removal of this impurity during the refining process unsatisfactory, thus affecting the quality of the menbutone product.

[0075] Through the crystallization process of sodium menbutone hydrate, it was found that this crystallization method and system can effectively remove impurity A, thereby improving the quality of menbutone products. The experimental results are shown in Table 2.

[0076] Table 2 Purification effect of crude menbutone with high impurity A content in the preparation method of the present invention

[0077] substance Membutone crude product Menbutone sodium hydrate was prepared according to the process of Example 1 Menbutone (%) 98.78 99.67 Impurity A (%) 0.98 0.14

[0078] Example 13 Stability Test of Menbutone Sodium Hydrate

[0079] Three batches of test samples were prepared according to Example 1 of the present invention, and the quality changes of menbutone sodium hydrate after being placed under 25°C / 60RH% conditions, 25°C / 92.5RH% conditions, and 40°C / 75RH% conditions for 30 days were investigated. The results are shown in Table 3.

[0080] Table 3 Stability study of Menbutone sodium hydrate

[0081]

[0082] As shown in Table 3, the appearance, crystal form, and purity of the sodium menbutone hydrate prepared by the present invention did not change after being stored for 30 days under the conditions of 25°C / 60RH%, 25°C / 92.5RH%, and 40°C / 75RH%. This shows that its crystal structure is relatively stable and suitable for long-term storage.

[0083] Example 14 Investigation of Mixing Performance in Powders

[0084] The composition of the Menbutone powder is: Menbutone (10wt%) and starch (90wt%).

[0085] Table 4 Comparison of mixing performance of sodium menbutone hydrate powder, menbutone crystal form I powder and crystal form II powder

[0086]

[0087] As can be seen from Table 4, both Menbutone Form I and Form II require 20 minutes of mixing with starch, while the Menbutone sodium hydrate of the present invention requires 10 minutes of mixing with starch, which is half the mixing time. This indicates that Menbutone sodium hydrate has excellent mixing performance and better powder properties, and all indicators of the obtained powder meet the requirements.

[0088] Example 15 Investigation of API Dissolution Rate in Injection

[0089] The composition of the injection is as follows: 100 mL of the injection is composed of the following components: 10 g of menbutone (or an equimolar amount of menbutone sodium hydrate, or menbutone crystal form I, or menbutone crystal form II), 5.5 g of diethanolamine, 0.2 g of chlorocresol, 0.2 g of sodium metabisulfite or sodium sulfite, 0.2 g of edetic acid, and the balance is water for injection.

[0090] Table 5 Comparison of the dissolution rates of Menbutone Sodium Hydrate and Menbutone

[0091]

[0092] From the results in Table 5, it can be seen that the dissolution rate of Menbutone Sodium Hydrate is significantly faster than that of Menbutone Form I and Menbutone Form II, indicating that it has good solubility in injection.

Claims

1. A sodium hydrate of Menbutone, wherein the structure of the sodium hydrate of Menbutone is shown in the following formula (I):

2. Menbutone sodium hydrate according to claim 1, characterized in that The sodium menbutone hydrate is in a crystalline form; the X-ray powder diffraction pattern of the sodium menbutone hydrate measured using CuKa radiation has characteristic peaks at 2θ values ​​of 10.3±0.2°, 10.7±0.2°, 12.0±0.2°, 14.3±0.2°, 15.1±0.2°, 16.5±0.2°, 18.9±0.2°, 25.2±0.2°, and 26.5±0.2°.

3. Menbutone sodium hydrate according to claim 2, characterized in that The X-ray powder diffraction pattern of the sodium menbutone hydrate measured using CuKa rays has characteristic peaks at 2θ values ​​of 9.5±0.2°, 10.3±0.2°, 10.7±0.2°, 12.0±0.2°, 13.0±0.2°, 14.3±0.2°, 15.1±0.2°, 16.5±0.2°, 17.2±0.2°, 18.9±0.2°, 20.7±0.2°, 22.0±0.2°, 23.1±0.2°, 24.9±0.2°, 25.2±0.2°, 25.8±0.2°, 26.5±0.2°, 27.6±0.2°, 28.2±0.2°, 28.5±0.2°, and 29.4±0.2°.

4. Menbutone sodium hydrate according to claim 3, characterized in that The TGA spectrum of the sodium menbutone hydrate shows a mass loss of 20.57 wt % in the range of 35° C. to 125° C.

5. A method for preparing a sodium menbutone hydrate according to any one of claims 1 to 4, wherein the method adopts a parallel flow dissolution crystallization method, and the preparation steps are as follows: (1) A good solvent for menbutone sodium and a poor solvent A are prepared into a mixed solvent, the system temperature is maintained at 0-5°C, menbutone sodium hydrate seed crystals are added, and the mixture is stirred until all particles are dispersed to form a suspension, and the suspension is added to a crystallizer to obtain a seed crystal dispersion system; (2) dispersing menbutone in a solvent at 20-25° C., adding a sodium hydroxide aqueous solution, and stirring thoroughly to dissolve, thereby obtaining a menbutone sodium solution; (3) adding the sodium menbutone solution obtained in step (2) and the poor solvent B dropwise to the seed crystal dispersion system in step (1) simultaneously, and performing parallel dissolution, ensuring that the water concentration remains unchanged during the parallel dissolution process; (4) The solution system in step (3) is continued to be kept warm at 0-5°C, suspended and stirred, filtered, washed with cold water, and the filter cake is dried to obtain a crystalline powder of menbutone hydrate.

6. The preparation method according to claim 5, characterized in that The good solvent in step (1) is one or more of methanol, ethanol, isopropanol, acetone, and tetrahydrofuran, the poor solvent A is water, and the mass fraction of the good solvent in the mixed solvent system is 15 to 35%; the amount of the menbutone sodium hydrate seed crystals added in step (1) is 2 to 5% of the mass fraction of the mixed solvent.

7. The preparation method according to claim 5, characterized in that The solvent in step (2) is one or more of methanol, ethanol, isopropanol, acetone or tetrahydrofuran; or, the solvent in step (2) is a mixed solution of one or more of methanol, ethanol, isopropanol, acetone, tetrahydrofuran and water; the concentration of the sodium hydroxide aqueous solution in step (2) is 4 to 20 wt%, and the amount of the sodium hydroxide aqueous solution used is such that the molar ratio of sodium hydroxide to menbutone in the sodium hydroxide aqueous solution is 1.0 to 1.2:1; the mass fraction of water in the menbutone sodium solution in step (2) is not greater than 25 wt%, and the concentration of menbutone sodium is 0.05 to 0.25 g / g solvent.

8. The preparation method according to claim 5, characterized in that The poor solvent B in step (3) is water; or, the poor solvent B is a mixture of one or more of methanol, ethanol, isopropanol, acetone, tetrahydrofuran and water, wherein the mass fraction of water is not less than 65%; the parallel flow elution process in step (3) is controlled at a temperature of 0 to 5° C.; and the elution time is 1 to 2 h.

9. The preparation method according to claim 5, characterized in that The heat preservation and suspension time in step (4) is 1 to 2 hours; the drying condition is vacuum drying or blast drying, and the vacuum degree under the vacuum drying condition is not less than 0.08 MPa; the drying temperature range is 25 to 40° C., and the drying time is not more than 72 hours.

10. A pharmaceutical composition, characterized in that The pharmaceutical composition contains the menbutone sodium hydrate according to any one of claims 1 to 5 and one or more pharmaceutically acceptable carriers and / or excipients; the pharmaceutical composition can be used to prepare a pharmaceutical preparation for animal choleretics.

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