Crystal form A, crystal form B and crystal form C of menbutone sodium as well as preparation method and application of crystal form A, crystal form B and crystal form C

Abstract

The invention discloses a menbutone sodium polymorph and a preparation method and application thereof, and belongs to the technical field of medicine crystal forms. The menbutone sodium polymorph comprises a menbutone sodium crystal form A, a menbutone sodium crystal form B and a menbutone sodium crystal form C. The menbutone sodium has the following structural formula: the brand-new menbutone sodium polymorph provided by the invention has good solubility and dissolution rate, has better mixing performance in a powder preparation process, has excellent preparation processability, and can be used for preparing the menbutone sodium crystal form. The crystal purity is high; the storage stability is good. The crystallization method of the crystal form A, the crystal form B and the crystal form C of the menbutone sodium provided by the invention has a good removal effect on a specific impurity A in the menbutone, and is simple in process, easy to operate and suitable for industrial production.

Description

Technical Field

[0001] The present invention belongs to the technical field of chemical drug crystallization, and particularly relates to menbutone sodium crystal form A, crystal form B, crystal form C, and preparation methods and applications 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 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] Based on the above problems, the present invention aims to provide a new crystal form of menbutone sodium with high water solubility and high crystallinity, as well as a preparation method and application thereof.

[0009] The technical solutions adopted in the present invention are as follows:

[0010] In a first aspect of the present invention, polymorphs of sodium menbutone represented by formula (I) are provided, including sodium menbutone form A, sodium menbutone form B and sodium menbutone form C.

[0011] The structure of Menbutone sodium shown in formula (I) is as follows:

[0012]

[0013] The X-ray powder diffraction pattern of the menbutone sodium form A measured using CuKa rays has characteristic peaks at 2θ values ​​of 6.9±0.2°, 9.8±0.2°, 10.9±0.2°, 11.2±0.2°, 12.6±0.2°, 14.1±0.2°, 14.8±0.2°, 17.3±0.2°, 20.7±0.2°, 21.9±0.2°, and 24.3±0.2°.

[0014] Preferably, the X-ray powder diffraction pattern of the Menbutone sodium crystalline form A measured using CuKa radiation is 6.9±0.2°, 7.8±0.2°, 8.7±0.2°, 9.8±0.2°, 10.9±0.2°, 11.2±0.2°, 11.6±0.2°, 12.6±0.2°, 13.6±0.2°, 14.1±0.2°, 14.8±0.2°, 15. There are characteristic peaks at 0.2°, 15.5±0.2°, 17.3±0.2°, 18.6±0.2°, 19.0±0.2°, 20.7±0.2°, 21.9±0.2°, 22.3±0.2°, 23.6±0.2°, 24.3±0.2°, 24.8±0.2°, 25.2±0.2°, 26.2±0.2°, and 27.8±0.2°.

[0015] The DSC curve of the Menbutone sodium crystal form A has an endothermic peak at 229±2°C (peak temperature).

[0016] The X-ray powder diffraction pattern of the sodium menbutone form B measured using CuKa rays has characteristic peaks at 2θ values ​​of 6.9±0.2°, 10.5±0.2°, 12.0±0.2°, 14.5±0.2°, 15.1±0.2°, 17.6±0.2°, 18.0±0.2°, and 21.2±0.2°.

[0017] Preferably, the X-ray powder diffraction pattern of the menbutone sodium form B measured using CuKa rays has characteristic peaks at 2θ values ​​of 6.9±0.2°, 7.2±0.2°, 8.0±0.2°, 8.3±0.2°, 10.5±0.2°, 12.0±0.2°, 14.5±0.2°, 15.1±0.2°, 17.6±0.2°, 18.0±0.2°, 18.3±0.2°, 21.2±0.2°, 23.4±0.2°, 25.2±0.2°, 27.7±0.2°, and 29.6±0.2°.

[0018] The DSC curve of the menbutone sodium crystal form B has two endothermic peaks at 214±2°C (peak temperature) and 227±2°C (peak temperature).

[0019] The X-ray powder diffraction pattern of the menbutone sodium form C measured using CuKa rays has characteristic peaks at 2θ values ​​of 5.6±0.2°, 7.3±0.2°, 9.3±0.2°, 11.1±0.2°, 13.1±0.2°, 14.8±0.2°, 17.0±0.2°, and 22.2±0.2°.

[0020] Preferably, the X-ray powder diffraction pattern of the menbutone sodium form C measured using CuKa rays has characteristic peaks at 2θ values ​​of 5.6±0.2°, 7.3±0.2°, 8.0±0.2°, 8.6±0.2°, 9.3±0.2°, 11.1±0.2°, 13.1±0.2°, 14.8±0.2°, 17.0±0.2°, 22.2±0.2°, 25.6±0.2°, 28.3±0.2°, 29.8±0.2°, and 31.3±0.2°.

[0021] The DSC curve of the Menbutone sodium crystal form C has two endothermic peaks at 212±2°C (peak temperature) and 228±2°C (peak temperature).

[0022] The second aspect of the present invention provides a method for preparing the above-mentioned Menbutone Sodium Crystal Form A, Menbutone Sodium Crystal Form B and Menbutone Sodium Crystal Form C:

[0023] The preparation steps of Menbutone Sodium Crystal Form A are as follows:

[0024] (1) Disperse menbutone in a solvent at 20-25° C., then add a sodium hydroxide aqueous solution, stir thoroughly to dissolve, and filter to obtain a menbutone sodium solution.

[0025] (2) Slowly add water to the sodium menbutone solution at 20-25°C while stirring. After the addition is complete, continue to keep the solution at 20-25°C and stir for a while, then cool it down to 0-5°C.

[0026] (3) After filtration, the mixture is washed with cold water, and the filter cake is suspended in a poor solvent to obtain Menbutone sodium crystal form A.

[0027] The solvent in step (1) is one or more of methanol, ethanol, isopropanol, acetone and tetrahydrofuran.

[0028] The ratio of menbutone to the solvent in step (1) is (m:v) 1:3 to 8 (g:mL).

[0029] The concentration of the sodium hydroxide aqueous solution in step (1) is 4-20wt%, and the amount of the sodium hydroxide aqueous solution used is such that the molar ratio of the contained sodium hydroxide to menbutone is 1.0-1.2:1.

[0030] The ratio of menbutone to water in step (2) is (m:v) 1:3 to 6 (g:mL).

[0031] The time for adding water in step (2) should be controlled within 2 to 4 hours, and the suspension stirring time after the addition should be 1 to 2 hours.

[0032] The poor solvent used for the suspension equilibrium in step (3) is one or more of acetone, acetonitrile, ethanol, methanol, and ethyl acetate, the ratio of menbutone to the poor solvent is 1:5 to 30 (g:mL), and the suspension equilibrium time is 12 to 72h.

[0033] The preparation steps of Menbutone Sodium Crystal Form B are as follows:

[0034] (1) Disperse menbutone in a solvent at 20-25° C., then add a sodium hydroxide aqueous solution, stir thoroughly to dissolve, and filter to obtain a menbutone sodium solution.

[0035] (2) Slowly add water to the sodium menbutone solution at 20-25°C while stirring. After the addition is complete, continue to keep the solution at 20-25°C and stir for a while, then cool it down to 0-5°C.

[0036] (3) Filter by suction, wash with cold water, and adopt the dissolution crystallization method to dissolve the wet filter cake in an alcohol solvent, and then add an ester solvent to precipitate to obtain sodium menbutone crystal form B.

[0037] The solvent in step (1) is one or more of methanol, ethanol, isopropanol, acetone and tetrahydrofuran.

[0038] The ratio of menbutone to the solvent in step (1) is (m:v) 1:3 to 8 (g:mL).

[0039] The concentration of the sodium hydroxide aqueous solution in step (1) is 4-20wt%, and the amount of the sodium hydroxide aqueous solution used is such that the molar ratio of the contained sodium hydroxide to menbutone is 1.0-1.2:1.

[0040] The ratio of menbutone to water in step (2) is (m:v) 1:3 to 6 (g:mL).

[0041] The time for adding water in step (2) should be controlled within 2 to 4 hours, and the suspension stirring time after the addition should be 1 to 2 hours.

[0042] The alcohol solvent used in the dissolution crystallization method in step (3) is selected from methanol, ethanol, isopropanol, etc., wherein the ratio of menbutone to the alcohol solvent (m:v) is 1:2.5 to 3; the ester solvent is selected from ethyl acetate, butyl acetate, isopropyl acetate, etc., and the ratio of menbutone to the ester solvent (m:v) is 1:10 to 15, and the crystallization time is 3 to 12 hours.

[0043] The preparation steps of Menbutone Sodium Crystal Form C are as follows:

[0044] (1) Disperse menbutone in a solvent at 20-25° C., then add a sodium hydroxide aqueous solution, stir thoroughly to dissolve, and filter to obtain a menbutone sodium solution.

[0045] (2) Slowly add water to the sodium menbutone solution at 20-25°C while stirring. After the addition is complete, continue to keep the solution at 20-25°C and stir for a while, then cool it down to 0-5°C.

[0046] (3) Filter by suction, wash with cold water, dry the filter cake, and suspend it in a poor solvent for a certain period of time to obtain Menbutone sodium crystal form C.

[0047] The solvent in step (1) is one or more of methanol, ethanol, isopropanol, acetone and tetrahydrofuran.

[0048] The ratio of menbutone to the solvent in step (1) is (m:v) 1:3 to 8 (g:mL).

[0049] The concentration of the sodium hydroxide aqueous solution in step (1) is 4-20wt%, and the amount of the sodium hydroxide aqueous solution used is such that the molar ratio of the contained sodium hydroxide to menbutone is 1.0-1.2:1.

[0050] The ratio of menbutone to water in step (2) is (m:v) 1:3 to 6 (g:mL).

[0051] The time for adding water in step (2) should be controlled within 2 to 4 hours, and the suspension stirring time after the addition should be 1 to 2 hours.

[0052] The drying conditions in step (3) are vacuum drying or blast drying, and the vacuum degree under vacuum drying conditions is not less than 0.08 MPa; the drying temperature range is 40 to 70° C., and the drying time is 8 to 12 hours.

[0053] The poor solvent used for the suspension equilibrium in step (3) is one or more of acetone, ethanol, methanol, and ethyl acetate, the ratio of menbutone to the poor solvent is 1:5 to 30 (g:mL), and the suspension equilibrium time is 12 to 72h.

[0054] In a third aspect, the present invention provides a pharmaceutical composition comprising the Menbutone Sodium Crystal Form A, Menbutone Sodium Crystal Form B, Menbutone Sodium Crystal Form C, or a mixture of any two or three of Menbutone Sodium Crystal Forms A, B, and C.

[0055] Alternatively, the pharmaceutical composition further contains one or more pharmaceutically acceptable carriers and / or excipients.

[0056] The fourth aspect of the present invention provides the use of the Menbutone Sodium Crystal Form A, Menbutone Sodium Crystal Form B, Menbutone Sodium Crystal Form C, or the pharmaceutical composition of the present invention in the preparation of a pharmaceutical preparation for animal choleretics.

[0057] 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.

[0058] Beneficial effects:

[0059] (1) The solubility of the sodium menbutone form A provided by the present invention in water is increased by 107 times compared with the sodium menbutone form I, the solubility of the sodium menbutone form B in water is increased by 112 times compared with the sodium menbutone form I, and the solubility of the sodium menbutone form C is increased by 121 times compared with the sodium menbutone form I, all of which greatly improve the water solubility of menbutone and have significant advantages for the preparation of soluble preparations.

[0060] (2) Compared with Menbutone Sodium Forms I and II, the Menbutone Sodium Forms A, B, and C provided by the present invention have a faster dissolution rate in the injection preparation process and better mixing performance in the powder preparation process.

[0061] (3) The crystallization methods of sodium menbutone crystalline form A, form B and form C provided by the present invention have 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 0.13%. The crystallization methods of sodium menbutone crystalline form A, form B and form C provided by the present invention have 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 0.16% or less, and obtain a high-purity product with HPLC purity ≥99%.

[0062] (4) The preparation method provided by the present invention is simple in process, easy to operate, and suitable for industrial production. The obtained crystal has good crystal form stability and is not prone to crystal form transformation. BRIEF DESCRIPTION OF THE DRAWINGS

[0063] Figure 1 PXRD spectrum of Menbutone sodium form A;

[0064] Figure 2 DSC curve of Menbutone sodium crystal form A;

[0065] Figure 3 PXRD spectrum of Menbutone sodium form B;

[0066] Figure 4 DSC curve of Menbutone sodium crystal form B;

[0067] Figure 5 PXRD spectrum of Menbutone sodium form C;

[0068] Figure 6 DSC curve of Menbutone sodium crystal form C;

[0069] Figure 7 PXRD spectrum of mixed crystals of Menbutone sodium Form B and Form C;

[0070] Figure 8 DSC curve of mixed crystal of Menbutone sodium Form B and Form C. DETAILED DESCRIPTION

[0071] 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.

[0072] Example 1

[0073] 4.95 g of menbutone was dispersed in 15 mL of methanol at 20-25 ° C, and then 19.36 g of a 4 wt% aqueous sodium hydroxide solution was added. After dissolution, the mixture was filtered to obtain a menbutone sodium solution. Under stirring, 15 mL of water was slowly added to the menbutone sodium solution at 20-25 ° C for 2 hours. After the addition, the mixture was kept at 20-25 ° C and stirred for 1 hour. Filtered with suction, washed with cold water, and the filter cake was suspended in 75 mL of a methanol / ethyl acetate (v:v = 1:3) mixed solvent at room temperature for 12 hours to obtain 4.88 g of menbutone sodium crystalline form A product with a molar yield of 90% (based on menbutone).

[0074] Example 2

[0075] 5.00 g of menbutone was dispersed in 30 mL of ethanol at 20-25 ° C, and then 12.91 g of a 6 wt% aqueous sodium hydroxide solution was added. After dissolution, the mixture was filtered to obtain a menbutone sodium solution. Under stirring, 30 mL of water was slowly added to the menbutone sodium solution at 20-25 ° C for 3 hours. After the addition, the mixture was kept at 20-25 ° C and stirred for 1 hour. Filtered with suction, washed with cold water, and the filter cake was suspended in 25 mL of acetone at room temperature for 16 hours to obtain 4.77 g of menbutone sodium crystal form A product with a molar yield of 88% (based on menbutone).

[0076] Example 3

[0077] 5.00 g of menbutone was dispersed in 15 mL of isopropanol at 20-25 ° C, and then 7.75 g of a 10 wt% aqueous sodium hydroxide solution was added. After dissolution, the mixture was filtered to obtain a menbutone sodium solution. Under stirring, 25 mL of water was slowly added to the menbutone sodium solution at 20-25 ° C for 2 hours. After the addition, the mixture was kept at 20-25 ° C and stirred for 2 hours. Filtered with suction, washed with cold water, and the filter cake was suspended in 30 mL of ethanol at room temperature for 24 hours to obtain 4.99 g of menbutone sodium crystal form A product with a molar yield of 92% (based on menbutone).

[0078] Example 4

[0079] 5.00 g of menbutone was dispersed in 40 mL of acetone at 20-25 ° C, and then 3.88 g of a 20 wt% aqueous sodium hydroxide solution was added. After dissolution, the mixture was filtered to obtain a menbutone sodium solution. Under stirring, 30 mL of water was slowly added to the menbutone sodium solution at 20-25 ° C for 3 hours. After the addition, the mixture was kept at 20-25 ° C and stirred for 2 hours. Filtered with suction, washed with cold water, and the filter cake was suspended in 25 mL of ethyl acetate at room temperature for 24 hours to obtain 4.61 g of menbutone sodium crystal form A product with a molar yield of 85% (based on menbutone).

[0080] Example 5

[0081] 5.00 g of menbutone was dispersed in 30 mL of tetrahydrofuran at 20-25 ° C, and then 3.88 g of a 20 wt% aqueous sodium hydroxide solution was added. After dissolution, the mixture was filtered to obtain a menbutone sodium solution. Under stirring, 25 mL of water was slowly added to the menbutone sodium solution at 20-25 ° C for 2 hours. After the addition, the mixture was kept at 20-25 ° C and stirred for 2 hours. Filtered with suction, washed with cold water, and the filter cake was suspended in 25 mL of acetone at room temperature for 30 hours to obtain 5.05 g of menbutone sodium crystal form A product with a molar yield of 93% (based on menbutone).

[0082] Example 6

[0083] 5.00 g of menbutone was dispersed in 20 mL of methanol at 20-25 ° C, and then 19.36 g of a 4 wt% aqueous sodium hydroxide solution was added. After dissolution, the mixture was filtered to obtain a menbutone sodium solution. Under stirring, 20 mL of water was slowly added to the menbutone sodium solution at 20-25 ° C for 2 hours. After the addition, the mixture was kept at 20-25 ° C and stirred for 1 hour. Filtered with suction, washed with cold water, and the filter cake was dissolved in 15 mL of methanol. 50 mL of ethyl acetate was added and crystallized for 8 hours to obtain 4.67 g of menbutone sodium crystal form B product with a molar yield of 86% (based on menbutone).

[0084] Example 7

[0085] 5.00 g of menbutone was dispersed in 40 mL of ethanol at 20-25 ° C, and then 12.91 g of a 6 wt% aqueous sodium hydroxide solution was added. After dissolution, the mixture was filtered to obtain a menbutone sodium solution. Under stirring, 20 mL of water was slowly added to the menbutone sodium solution at 20-25 ° C for 2 hours. After the addition, the mixture was kept at 20-25 ° C and stirred for 1 hour. Filtered with suction, washed with cold water, the filter cake was dissolved in 15 mL of ethanol, 65 mL of butyl acetate was added, and the crystallization time was 12 hours to obtain 4.56 g of menbutone sodium crystal form B product with a molar yield of 84% (based on menbutone).

[0086] Example 8

[0087] 5.00 g of menbutone was dispersed in 15 mL of isopropanol at 20-25 ° C, and then 7.75 g of a 10 wt% aqueous sodium hydroxide solution was added. After dissolution, the mixture was filtered to obtain a menbutone sodium solution. Under stirring, 25 mL of water was slowly added to the menbutone sodium solution at 20-25 ° C for 2 hours. After the addition, the mixture was kept at 20-25 ° C and stirred for 2 hours. Filtered with suction, washed with cold water, and the filter cake was dissolved in 15 mL of methanol. 50 mL of isopropyl acetate was added and crystallized for 10 hours to obtain 4.77 g of menbutone sodium crystal form B product with a molar yield of 88% (based on menbutone).

[0088] Example 9

[0089] Mengbutone 5.00 g was dispersed in 40 mL of acetone at 20-25 °C, then 3.88 g of 20 wt% sodium hydroxide aqueous solution was added, after dissolution, Mengbutone sodium liquor was obtained by filtration. Under stirring, 30 mL of water was slowly added to the Mengbutone sodium liquor at 20-25 °C, the addition time was 3 h, after addition, continue to suspend stirring at 20-25 °C for 2 h. Filtration, cold water washing, the filter cake was dissolved in 15 mL of isopropyl alcohol, 60 mL of ethyl acetate was added, the crystallization time was 5 h, to obtain Mengbutone sodium crystal form B product 4.61 g, the molar yield was 85% (based on Mengbutone).

[0090] Example 10

[0091] Mengbutone 5.00 g was dispersed in 30 mL of tetrahydrofuran at 20-25 °C, then 3.88 g of 20 wt% sodium hydroxide aqueous solution was added, after dissolution, Mengbutone sodium liquor was obtained by filtration. Under stirring, 25 mL of water was slowly added to the Mengbutone sodium liquor at 20-25 °C, the addition time was 3 h, after addition, continue to suspend stirring at 20-25 °C for 2 h. Filtration, cold water washing, the filter cake was dissolved in 15 mL of methanol, 75 mL of ethyl acetate was added, the crystallization time was 12 h, to obtain Mengbutone sodium crystal form B product 5.00 g, the molar yield was 92% (based on Mengbutone).

[0092] Example 11

[0093] Mengbutone 4.98 g was dispersed in 15 mL of methanol at 20-25 °C, then 19.36 g of 4 wt% sodium hydroxide aqueous solution was added, after dissolution, Mengbutone sodium liquor was obtained by filtration. Under stirring, 15 mL of water was slowly added to the Mengbutone sodium liquor at 20-25 °C, the addition time was 2 h, after addition, continue to suspend stirring at 20-25 °C for 1 h. Filtration, cold water washing, the filter cake was dried at 65 °C under air blowing for 10 h, after drying, the material was suspended in 75 mL of methanol / ethyl acetate (v:v = 1:3) mixed solvent at room temperature for 12 h to obtain Mengbutone sodium crystal form C product 4.72 g, the molar yield was 87% (based on Mengbutone).

[0094] Example 12

[0095] 5.00 g of menbutone was dispersed in 30 mL of ethanol at 20-25 ° C, and then 12.92 g of a 6 wt% aqueous sodium hydroxide solution was added. After dissolution, the mixture was filtered to obtain a menbutone sodium solution. Under stirring, 30 mL of water was slowly added to the menbutone sodium solution at 20-25 ° C for 2.5 hours. After the addition, the mixture was kept at 20-25 ° C and stirred for 1.5 hours. The mixture was filtered and washed with cold water. The filter cake was vacuum dried at 40 ° C for 8 hours. After drying, the filter cake was suspended in 25 mL of acetone at room temperature for 24 hours to obtain 4.77 g of menbutone sodium crystal form C product with a molar yield of 88% (based on menbutone).

[0096] Example 13

[0097] 5.00 g of menbutone was dispersed in 15 mL of isopropanol at 20-25 ° C, and then 7.75 g of a 10 wt% aqueous sodium hydroxide solution was added. After dissolution, the mixture was filtered to obtain a menbutone sodium solution. Under stirring, 25 mL of water was slowly added to the menbutone sodium solution at 20-25 ° C for 2 hours. After the addition, the mixture was kept at 20-25 ° C and stirred for 2 hours. Filtered with suction, washed with cold water, and the filter cake was air-dried at 60 ° C for 8 hours. After drying, the filter cake was suspended in 40 mL of ethanol at room temperature for 12 hours to obtain 4.88 g of menbutone sodium crystal form C product with a molar yield of 90% (based on menbutone).

[0098] Example 14

[0099] 5.00 g of menbutone was dispersed in 40 mL of acetone at 20-25 ° C, and then 3.88 g of a 20 wt% aqueous sodium hydroxide solution was added. After dissolution, the mixture was filtered to obtain a menbutone sodium solution. Under stirring, 30 mL of water was slowly added to the menbutone sodium solution at 20-25 ° C for 3 hours. After the addition, the mixture was kept at 20-25 ° C and stirred for 2 hours. Filtered with suction, washed with cold water, and the filter cake was air-dried at 70 ° C for 8 hours. After drying, the filter cake was suspended in 25 mL of ethyl acetate at room temperature for 24 hours to obtain 4.60 g of menbutone sodium crystal form C product with a molar yield of 85% (based on menbutone).

[0100] Example 15

[0101] 5.00 g of menbutone was dispersed in 40 mL of tetrahydrofuran at 20-25 ° C, and then 3.90 g of a 20 wt% aqueous sodium hydroxide solution was added. After dissolution, the mixture was filtered to obtain a menbutone sodium solution. Under stirring, 25 mL of water was slowly added to the menbutone sodium solution at 20-25 ° C for 2 hours. After the addition, the mixture was kept at 20-25 ° C and stirred for 2 hours. Filtered with suction, washed with cold water, and the filter cake was air-dried at 60 ° C for 12 hours. After drying, the filter cake was suspended in 25 mL of acetone at room temperature for 30 hours to obtain 5.00 g of menbutone sodium crystal form C product with a molar yield of 92% (based on menbutone).

[0102] Example 16

[0103] 5.00 g of menbutone was dispersed in 40 mL of tetrahydrofuran at 20-25 ° C, and then 3.90 g of a 20 wt% sodium hydroxide aqueous solution was added. After dissolution, the mixture was filtered to obtain a menbutone sodium solution. Under stirring, 25 mL of water was slowly added to the menbutone sodium solution at 20-25 ° C for 2 hours. After the addition, the mixture was kept at 20-25 ° C and stirred for 2 hours. Filtered with suction, washed with cold water, and the filter cake was dried at 60 ° C for 12 hours to obtain 5.00 g of a mixed crystal product of menbutone sodium form B and form C, with a molar yield of 92% (based on menbutone).

[0104] Example 17 Solubility Test of Menbutone Sodium Crystal Form A, Crystal Form B and Crystal Form C

[0105] An excess amount of sample was placed in a 5 mL test tube, 2.5 mL of water was added, and the sample was vortexed for half a minute and then placed in a constant temperature oscillator at 20 ± 5 ° C for 24 hours. The sample 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 and the average value was taken. The results are shown in Table 1.

[0106] Table 1 Comparison of the solubility of sodium menbutone hydrate and different menbutone crystal forms (20°C, mg / ml)

[0107]

[0108] As shown in Table 1, the solubility of Menbutone Sodium Form A is 107 times higher than that of Menbutone Form I and 2810 times higher than that of Menbutone Form II; the solubility of Menbutone Sodium Form B is 112 times higher than that of Menbutone Form I and 2952 times higher than that of Menbutone Form II; the solubility of Menbutone Sodium Form C is 121 times higher than that of Menbutone Form I and 3175 times higher than that of Menbutone Form II. It can be seen that the new crystal form of Menbutone Sodium prepared by the present invention greatly improves the solubility of Menbutone.

[0109] Example 18 Investigation of the Crystallization Purification Effects of Menbutone Sodium Form A, Form B, and Form C

[0110] 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.

[0111] Through the crystallization process of sodium menbutone, it was found that this crystallization method and system can effectively remove impurity A, thereby improving the quality of the menbutone product. The experimental results are shown in Table 2.

[0112] Table 2 Purification effect of crude menbutone with high impurity A content in the preparation method of the present invention

[0113]

[0114] Example 19 Stability Test of Menbutone Sodium Crystal Form A, Crystal Form B and Crystal Form C

[0115] The quality changes of Menbutone sodium Form A, Form B and Form C placed under 25°C / 60RH%, 25°C / 92.5RH% and 40°C / 75RH% conditions for 30 days were investigated. The results are shown in Table 3.

[0116] Table 3 Stability study of Menbutone and Menbutone Sodium Crystal Form A, Crystal Form B and Crystal Form C

[0117]

[0118] As shown in Table 3, the appearance, crystal form, and purity of the sodium menbutone form A, form B, and form C prepared by the present invention did not change significantly after being placed under 25°C / 60RH% conditions, 25°C / 92.5RH% conditions, and 40°C / 75RH% conditions for 30 days. This shows that its crystal structure is relatively stable and suitable for long-term storage.

[0119] Example 20 Investigation of mixing performance in powders

[0120] The composition of the Menbutone powder is: Menbutone (10wt%) and starch (90wt%).

[0121] Table 4 Comparison of the mixing performance of the crystal forms A-C powder of sodium menbutone and the crystal forms I and II powder of menbutone

[0122]

[0123]

[0124] As can be seen from Table 4, it takes 20 minutes to mix the menbutone sodium crystal forms I and II with starch, while it takes 10 minutes to mix the menbutone sodium crystal forms A, B, and C with starch, which is half the mixing time. This shows that menbutone sodium crystal forms A, B, and C all have excellent mixing performance and better powder properties, and all indicators of the obtained powders meet the requirements.

[0125] Example 21 Investigation of API Dissolution Rate in Injection

[0126] 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 crystal form A, or an equimolar amount of menbutone sodium crystal form B, or an equimolar amount of menbutone sodium crystal form C, or an equimolar amount of menbutone sodium crystal form I, or an equimolar amount of menbutone sodium 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.

[0127] Table 5 Comparison of dissolution rates of Menbutone sodium crystal form A, crystal form B and Menbutone crystal form Ⅰ / Ⅱ

[0128]

[0129] As shown in Table 5, the dissolution rates of Menbutone sodium crystal form A, crystal form B and crystal form C are significantly faster than that of Menbutone crystal form I / II, indicating that they have good solubility in injection.

Claims

1. Polymorphs of sodium menbutone represented by formula (I), including sodium menbutone form A, sodium menbutone form B, and sodium menbutone form C:

2. The crystalline form A of sodium menbutone as shown in formula (I) of claim 1, characterized in that: The X-ray powder diffraction pattern of the menbutone sodium form A measured using CuKa rays has characteristic peaks at 2θ values ​​of 6.9±0.2°, 9.8±0.2°, 10.9±0.2°, 11.2±0.2°, 12.6±0.2°, 14.1±0.2°, 14.8±0.2°, 17.3±0.2°, 20.7±0.2°, 21.9±0.2°, and 24.3±0.2°.

3. The crystalline form A according to claim 2, characterized in that The X-ray powder diffraction pattern of the Menbutone sodium crystal form A measured using CuKa radiation was 6.9±0.2°, 7.8±0.2°, 8.7±0.2°, 9.8±0.2°, 10.9±0.2°, 11.2±0.2°, 11.6±0.2°, 12.6±0.2°, 13.6±0.2°, 14.1±0.2°, 14.8±0. There are characteristic peaks at 2°, 15.5±0.2°, 17.3±0.2°, 18.6±0.2°, 19.0±0.2°, 20.7±0.2°, 21.9±0.2°, 22.3±0.2°, 23.6±0.2°, 24.3±0.2°, 24.8±0.2°, 25.2±0.2°, 26.2±0.2°, and 27.8±0.2°.

4. Menbutone sodium crystal form A according to claim 3, characterized in that The DSC curve of the Menbutone sodium crystal form A has an endothermic peak at 229±2°C.

5. The Menbutone sodium crystal form B as shown in formula (I) of claim 1, characterized in that: The X-ray powder diffraction pattern of the sodium menbutone form B measured using CuKa rays has characteristic peaks at 2θ values ​​of 6.9±0.2°, 10.5±0.2°, 12.0±0.2°, 14.5±0.2°, 15.1±0.2°, 17.6±0.2°, 18.0±0.2°, and 21.2±0.2°.

6. Menbutone sodium crystal form B according to claim 5, characterized in that The X-ray powder diffraction pattern of the menbutone sodium form B measured using CuKa rays has characteristic peaks at 2θ values ​​of 6.9±0.2°, 7.2±0.2°, 8.0±0.2°, 8.3±0.2°, 10.5±0.2°, 12.0±0.2°, 14.5±0.2°, 15.1±0.2°, 17.6±0.2°, 18.0±0.2°, 18.3±0.2°, 21.2±0.2°, 23.4±0.2°, 25.2±0.2°, 27.7±0.2°, and 29.6±0.2°.

7. Menbutone sodium crystal form B according to claim 6, characterized in that The DSC curve of the Menbutone sodium crystal form B has two endothermic peaks at 214±2°C and 227±2°C.

8. The Menbutone sodium crystal form C as shown in formula (I) of claim 1, characterized in that: The X-ray powder diffraction pattern of the menbutone sodium form C measured using CuKa rays has characteristic peaks at 2θ values ​​of 5.6±0.2°, 7.3±0.2°, 9.3±0.2°, 11.1±0.2°, 13.1±0.2°, 14.8±0.2°, 17.0±0.2°, and 22.2±0.2°.

9. Menbutone sodium crystal form C according to claim 8, characterized in that The X-ray powder diffraction pattern of the menbutone sodium form C measured using CuKa radiation has characteristic peaks at 2θ values ​​of 5.6±0.2°, 7.3±0.2°, 8.0±0.2°, 8.6±0.2°, 9.3±0.2°, 11.1±0.2°, 13.1±0.2°, 14.8±0.2°, 17.0±0.2°, 22.2±0.2°, 25.6±0.2°, 28.3±0.2°, 29.8±0.2°, and 31.3±0.2°.

10. The Menbutone sodium crystal form C according to claim 9, characterized in that The DSC curve of the Menbutone sodium crystal form C has two endothermic peaks at 212±2°C and 228±2°C.

11. A method for preparing the polymorph of menbutone sodium represented by formula (I) as claimed in claim 1, comprising the following steps: (1) dispersing menbutone in a solvent at 20-25° C., adding a sodium hydroxide aqueous solution, stirring thoroughly to dissolve, and filtering to obtain a menbutone sodium solution; (2) Slowly add water to the 20-25°C menbutone sodium solution while stirring. After the addition is complete, continue to heat and suspend at 20-25°C, stirring, and then cool to 0-5°C. (3) After filtration, washing with cold water, the filter cake is suspended in a poor solvent to obtain the menbutone sodium crystal form A; Alternatively, after filtration, washing with cold water, dissolving the wet filter cake in an alcohol solvent by a dissolution crystallization method, and then adding an ester solvent to precipitate to obtain the sodium menbutone crystal form B; Alternatively, after filtration, the mixture is washed with cold water, and the filter cake is dried and then suspended in a poor solvent for equilibrium for a certain period of time to obtain the menbutone sodium crystal form C.

12. The method for preparing polymorphic forms of menbutone sodium according to claim 11, wherein: The solvent in step (1) is one or more of methanol, ethanol, isopropanol, acetone, and tetrahydrofuran; the mass volume ratio of menbutone to the solvent is 1:3 to 8; the concentration of the sodium hydroxide aqueous solution is 4 to 20 wt%, and the amount of the sodium hydroxide aqueous solution is such that the molar ratio of the contained sodium hydroxide to menbutone is 1.0 to 1.2:

1.

13. The method for preparing polymorphic forms of menbutone sodium according to claim 11, wherein: The mass volume ratio of menbutone to water in step (2) is 1:3-6; the addition time of the water is controlled at 2-4 hours, and the suspension stirring time after the addition is 1-2 hours.

14. The method for preparing polymorphic forms of menbutone sodium according to claim 11, wherein: The poor solvent for preparing the sodium menbutone crystalline form A in step (3) is selected from one or more of acetone, acetonitrile, ethanol, methanol, and ethyl acetate; the mass volume ratio of menbutone to the poor solvent is 1:5 to 30, and the suspension equilibrium time is 12 to 72 hours.

15. The method for preparing polymorphic forms of menbutone sodium according to claim 11, wherein: When preparing the sodium menbutone crystalline form B in step (3), the alcohol solvent used in the dissolution crystallization method is one or more of methanol, ethanol, and isopropanol; wherein the mass volume ratio of menbutone to the alcohol solvent is 1:2.5 to 3; the ester solvent used is one or more of ethyl acetate, butyl acetate, and isopropyl acetate; the mass volume ratio of menbutone to the ester solvent is 1:10 to 15, and the crystallization time is 3 to 12 hours.

16. The method for preparing polymorphic forms of menbutone sodium according to claim 11, wherein: When preparing the sodium menbutone crystal form C in step (3), the drying condition is vacuum drying or forced air drying, the vacuum degree under the vacuum drying condition is not less than 0.08 MPa, the drying temperature range is 40 to 70 ° C, and the drying time is 8 to 12 hours; the poor solvent used for the suspension equilibrium in step (3) is one or more of acetone, ethanol, methanol, and ethyl acetate; the mass volume ratio of menbutone to the poor solvent is 1:5 to 30, and the suspension equilibrium time is 12 to 72 hours.

17. A pharmaceutical composition comprising the menbutone sodium crystalline form A according to claims 2-4, the menbutone sodium crystalline form B according to claims 5-7, or the menbutone sodium crystalline form C according to claims 8-10, and one or more pharmaceutically acceptable carriers and / or excipients; the pharmaceutical composition is used for preparing a pharmaceutical preparation for promoting bile secretion in animals.

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