WO2012171377A1

WO2012171377A1 - Crystal forms of asiatic acid trometamol salt and preparation methods thereof

Info

Publication number: WO2012171377A1
Application number: PCT/CN2012/072701
Authority: WO
Inventors: 任国宾; 刘�英; 陈金瑶; 黄晓玲; 齐明辉; 刘珉宇; 张瑱; 肖璘; 吴学军; 邓轶方; 陈仁海; 汤生荣; 刘全海
Original assignee: 上海医药工业研究院
Priority date: 2011-06-17
Filing date: 2012-03-21
Publication date: 2012-12-20
Also published as: CN105237611A; CN102827237B; CN105237611B; CN102827237A

Abstract

Disclosed is a crystal form A of asiatic acid trometamol salt, showing main peaks at diffraction angle (2θ) of 5.98, 6.87, 9.12, 10.38, 12.00, 12.47, 12.93, 13.42, 14.72, 15.10, 17.01 and 18.14 degree, and minor peaks at diffraction angle (2θ) of 3.44, 13.87, 15.89, 19.04, 19.64, 20.17, 20.94, 21.75, 22.56, 23.33, 24.18, 26.38, 26.98 and 27.75 degree. Also disclosed is a crystal form B of asiatic acid trometamol salt, showing main peaks at diffraction angle (2θ) of 3.54, 7.05, 10.04, 11.88, 13.38, 14.29 and 15.18 degree, and minor peaks at diffraction angle (2θ) of 9.28, 9.59, 12.43, 16.68, 17.03, 17.57, 18.16, 18.91, 19.24, 20.07, 20.68, 22.46, 24.84, 25.20, 26.86, 27.73, 28.30, 28.85, 30.43, 30.83 and 33.93 degree. Also disclosed are the preparation methods of said crystal form A and form B. The crystal form A and form B of asiatic acid trometamol salt are new and have excellent stability. The preparation methods are easily operated and realized.

Description

Crystal form of a type of asiatic acid tromethamine salt and preparation method thereof

The present invention relates to crystals A and B of asiatic acid tromethamine salt and a process for the preparation thereof.

Background technique

Asparagus oxalic acid (2α, 3β, 23-trihydroxyurea-12-ene-28-acid), also known as asiatic acid, was first isolated from Centella asiatica by Bondmunds et al. It has a wide range of effects and is often used to treat skin damage caused by burns or chronic ulcers, tuberculosis or leprosy, and also has a certain effect on cardiovascular diseases and liver poisoning. In addition, studies have shown that asiatic acid has anti-depression, anti-fibrosis, anti-bacterial, anti-tumor and anti-oxidation effects.

Although there are four hydrophilic groups (three alcoholic hydroxyl groups and one carboxyl group) in the molecular structure of asiatic acid, it has poor wettability and is almost insoluble in water, and its physical and chemical properties require configuration suitable for local use. Formulations, especially hydrophilic formulations, require the use of unique methods and special excipients. In addition, skin absorption is mainly carried out in an epidermal manner (intracellular and through cells) and is mainly controlled by the action of an effective component on the stratum corneum composed mainly of keratin and water. Therefore, in addition to the configuration problems, the problem of the appropriate bioavailability of asiatic acid at the epidermal level has still not been solved.

Snow oxalate is a protonated salt formed by the combination of asiatic acid and a medically acceptable base. The water solubility of asiatic oxalate is greater than that of asiatic acid, which makes the development of asiatic acid oxalate very important.

The snow oxalates that have been reported in the patents include the asiatic acid succinic acid and hemisuccinates disclosed in USP 3. 3,366,669, and the decylamino chain sterols and dimethylamino chain sterols of asiatic acid. salt. A salt such as ethylenediamine, ethanolamine, diethanolamine, lysine, benzyltrimethylamine hydroxide or tetramethylammonium hydroxide of asiatic acid is disclosed in CN1238330C. Ammonium, sodium, potassium, sodium carbonate, sodium phosphate, and triacetic acid amino salts of asiatic acid are disclosed in WO2009/089365 And tromethamine salt.

All of the above compounds can be used in the preparation of aqueous solutions for topical administration.

Compared with asiatic acid free acid and other forms of asiatic oxalate, the solubility of asiatic acid tromethamine salt is better. At present, the asiatic acid tromethamine salt in the prior art is a semi-crystal

(semi-crystal) or amorphous state, there is no report of the crystal form of asiatic acid succinate. Summary of the invention

The technical problem to be solved by the present invention is to provide a new type of crystal form of asiatic acid tromethamine salt having excellent stability and a preparation method thereof in order to meet pharmaceutical needs.

The present invention provides a crystal form A of asiatic acid tromethamine salt in a powder X-ray diffraction spectrum using a radiation source of Cu- Κα at diffraction angles of 2Θ = 5.98, 6.87, 9.12, 10.38, 12.00, Main peaks at 12.47, 12.93, 13.42, 14.72, 15.10, 17.01 and 18.14 degrees; at 2Θ=3.44, 13.87, 15.89, 19.04, 19.64, 20.17, 20.94, 21.75, 22.56, 23.33, 24.18, 26.38, 26.98 and 27.75 degrees There are secondary peaks, and the error range is ± 0.2.

The present invention also provides a method for preparing the crystal form of the asiatic acid tromethamine salt, which adopts any one of the following schemes:

Scheme 1: The method comprises the steps of: suspending the raw material asiatic acid tromethamine in an organic solvent to form a paddle under stirring; separating the crystal form A of asiatic acid tromethamine salt, and drying; Wherein, the organic solvent is a single solvent or a mixed solvent of two or more solvents; when the organic solvent is a single solvent, the solvent is acetonitrile and/or butanone; When the solvent is mixed, the mixed solvent includes an alcohol solvent and a non-alcohol solvent, and the alcohol solvent includes one or more of methanol, ethanol, and isopropyl alcohol, and the non-alcohol solvent includes acetonitrile. And one or more of acetone and methyl ethyl ketone; and the volume ratio of the non-alcoholic solvent to the alcohol solvent is 4:1 or more.

Scheme 2: The method comprises the steps of: dissolving the raw material asiatic acid tromethamine salt in an organic solvent; removing the organic solvent to obtain the crystal form A of asiatic acid tromethamine salt; wherein The organic solvent is a single solvent or a mixed solvent of two or more solvents; when the organic solvent is a single solvent, the solvent is ethyl acetate and/or butyl acetate; when the organic solvent is a mixed solvent The mixed solvent includes an alcohol solvent including methanol and/or ethanol, and the non-alcohol solvent includes acetonitrile, acetone, ethyl acetate, butyl acetate, and One or more of the butanone; the volume ratio of the alcohol solvent to the non-alcohol solvent is 1: 1 to 4: 1.

Scheme 3: The method comprises the steps of: dissolving the raw material asiatic acid tromethamine salt in an alcohol solvent; adding an anti-solvent of asiatic acid tromethamine salt to obtain a suspension; filtering the obtained suspension, The filter cake is dried; wherein the alcohol solvent is methanol and/or ethanol; and the anti-solvent is one or more of ethyl acetate, butyl acetate, acetonitrile and methyl ethyl ketone.

In the first embodiment, the organic solvent is used in an amount such that the asiatic acid tromethamine salt is sufficiently dissolved, preferably 50 to 100 ml/g of asiatic acid tromethamine. When the organic solvent is a mixed solvent, the mixed solvent is preferably methanol and acetonitrile, methanol and methyl ethyl ketone, or isopropanol and acetonitrile. Among them, the volume ratio of acetonitrile to methanol, the volume ratio of butanone to methanol, or the volume of acetonitrile and isopropyl alcohol is preferably 4:1 or more, more preferably 4:1. The paddleting time is preferably 24 hours or longer, more preferably 24 to 72 hours. The temperature at which the paddle is formed in the present invention may be a paddle temperature commonly used in the art, preferably 20 to 40 °C. The separation can be carried out by a separation method conventional in the art, such as suction filtration. The drying can be carried out by various conventional drying methods in the art, and is generally vacuum dried at room temperature.

In the second embodiment, the organic solvent is preferably used in an amount of 40 to 100 ml/g of asiatic acid tromethamine. When the organic solvent is a mixed solvent, the mixed solvent is preferably methanol and ethyl acetate, methanol and acetonitrile, ethanol and methyl ethyl ketone, or ethanol and butyl acetate. Wherein, the volume ratio of methanol to ethyl acetate, the volume ratio of methanol to acetonitrile, the volume ratio of ethanol to methyl ethyl ketone, or the volume of ethanol and butyl acetate is preferably 1: 1 to 4: 1, more preferably 1: 1. Preferably, the dissolution can be carried out under agitation. In the present invention, there is no particular requirement for the temperature of the dissolution, and it is preferably 20 to 40 ° C as long as the asiatic acid tromethamine salt can be dissolved. The method for removing the organic solvent may be various conventional methods for removing the organic solvent in the art, preferably at a pressure of 0.05 to 0.1 MP. The evaporation is carried out under force, and the evaporation temperature is preferably 20 to 50 °C.

In the third embodiment, the amount of the alcohol solvent is such that the asiatic acid tromethamine salt is sufficiently dissolved, preferably 10 to 20 ml/g of asiatic acid tromethamine. When the organic solvent is methanol, the anti-solvent is preferably ethyl acetate or acetonitrile; and when the organic solvent is ethanol, the anti-solvent is preferably butyl acetate or methyl ethyl ketone. The anti-solvent is used in an amount such that the crystal form A of the asiatic acid tromethamine salt can be analyzed, and the anti-solvent is used in an amount of from 1 to 4 times the volume of the alcohol solvent. In the present invention, there is no particular requirement for the temperature of the dissolution, as long as the asiatic acid tromethamine salt can be dissolved, preferably 20 to 30 °C. The drying can be carried out by various conventional drying methods in the art, generally at room temperature under vacuum drying.

The present invention provides a crystal form B of asiatic acid tromethamine salt, which has a diffraction angle of 2Θ = 3.54, 7.05, 10.04, 11.88, 13.38 in a powder X-ray diffraction spectrum using a radiation source of Cu-Κα. There are main peaks at 14.29 and 15.18 degrees; at 2Θ=9.28, 9.59, 12.43, 16.68, 17.03, 17.57, 18.16, 18.91, 19.24, 20.07, 20.68, 22.46, 24.84, 25.20, 26.86, 27.73, 28.30, 28.85, 30.43, 30.83 There are secondary peaks at 33.93 degrees, and the range of 2 误差 values is ±0.2.

The invention also provides a preparation method of the crystal yttrium succinate salt crystal form bismuth, which comprises the following steps: suspending the raw material asiatic acid tromethamine in an organic solvent under stirring; Separating the crystal form of the asiatic acid tromethamine salt and drying it; wherein the organic solvent is a single solvent or a mixed solvent of two or more solvents, when the organic solvent is a single solvent, The solvent is acetone; when the organic solvent is a mixed solvent, the mixed solvent includes an alcohol solvent and a non-alcohol solvent, and the alcohol solvent includes n-butanol and/or n-propanol. The non-alcoholic solvent includes one or more of acetonitrile, acetone and methyl ethyl ketone.

Wherein, the organic solvent is used in an amount such that the asiatic acid tromethamine salt is sufficiently dissolved, preferably 40 to 60 ml/g of asiatic acid tromethamine. When the organic solvent is a mixed solvent, the volume of the non-alcoholic solvent and the alcohol solvent in the mixed solvent is preferably 4:1 or more. The mixed solvent is preferably acetone and n-butanol, butanone and n-propanol, or acetonitrile and n-propanol, in which case acetone and n-butanol, butanone and n-propanol, or acetonitrile and n-propanol are compared in volume. The good land is 4:1 or more. The time for the paddle is preferably 24 hours or more, more preferably 24 to 72 hours; and the temperature of the paddle is preferably 20 to 40 °C. The separation can be carried out by conventional separation methods in the art, such as suction filtration. The drying can be carried out by various conventional drying methods in the art, generally at room temperature under vacuum drying.

In the present invention, the raw material asiatic acid tromethamine salt may be selected from a semi-crystal of amorphous stearoxylic acid tromethamine salt or asiatic acid tromethamine salt. The amorphous asiatic acid tromethamine salt can be prepared according to the patent CN 201110069862.6, and is specifically prepared by the following method: (1) dissolving asiatic acid in an organic solvent under heating, heating temperature The reflux temperature of the organic solvent; (2) mixing with tromethamine at 50 to 100 ° C; (3) stirring and performing a salt formation reaction at 50 to 100 ° C for 0.5 to 9 hours, removing organic The solvent may be: wherein the molar ratio of the asiatic acid to the tromethamine is 0.8:1 to 1:1.5; in the step (1), the organic solvent is an alcohol solvent, more preferably One or more of a saturated monohydric alcohol having 1 to 5 carbon atoms and an aromatic alcohol having 7 to 8 carbon atoms, more preferably methanol, absolute ethanol, isopropanol, n-butanol, n-pentanol, One or more of benzyl alcohol and n-propanol, most preferably one or more of methanol, absolute ethanol and isopropanol; the organic solvent is generally used in an amount of 50 to 150 ml/g of asiatic acid . The semi-crystal of the asiatic acid tromethamine salt can be prepared according to the description of paragraph 0074 of the patent WO2009/089365.

In the present invention, each of the above preferred conditions can be arbitrarily combined on the basis of common knowledge in the art, and preferred embodiments of the present invention can be obtained.

In the present invention, the reagents and raw materials used are commercially available.

The positive effects of the present invention are:

1. The present invention provides crystal forms of two new asiatic acid tromethamine salts which are more versatile than the amorphous asiatic acid tromethamine salt and the semi-crystalline asiatic acid tromethamine salt. Good stability, better able to meet the needs of pharmaceuticals.

2. The preparation method of the crystal form of asiatic acid tromethamine salt of the present invention is simple in operation and easy to realize industrial production. DRAWINGS

Figure 1 is a PXRD pattern of crystal form A of asiatic acid tromethamine salt.

Figure 2 is a PXRD pattern of crystal form B of asiatic acid tromethamine salt.

Figure 3 is a PXRD pattern of semi-crystalline asiatic acid tromethamine salt.

Figure 4 is a PXRD pattern of amorphous stearic acid tromethamine salt

Figure 5 is a DSC spectrum of crystal form A of asiatic acid tromethamine salt.

Figure 6 is a DSC spectrum of crystal form B of asiatic acid tromethamine salt. BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be further illustrated by the examples, but the invention is not limited thereto.

The semi-crystals of asiatic acid tromethamine in the following examples were prepared according to the description of paragraph 0074 of the patent WO2009/089365.

The specific preparation method of amorphous stearoxylic acid tromethamine salt is as follows: lg (2.046 mmol) of asiatic acid is mixed with 100 ml of absolute ethanol at room temperature, heated to 60 ° C until completely dissolved, and 0.31 g is added thereto. (2.559 mmol) tromethamine, after stirring at this temperature for 0.5 h, a clear solution was obtained, and the solvent was removed by evaporation at 60 ° C under normal pressure, and the product was dried in a vacuum oven at 50 ° C to obtain an amorphous type. Snow oxalate tromethamine salt.

Example 1-15 Preparation of crystal form A of asiatic acid tromethamine salt

Example 1

The lg amorphous asiatic acid tromethamine salt was placed in a stirred vessel, 100 ml of acetonitrile was added thereto at 20 ° C, and the mixture was stirred for 72 hours, and then the suspension was suction filtered, and the filter cake was dried and tested. The product is crystal form A of asiatic acid tromethamine salt.

Example 2

The lg amorphous asiatic acid tromethamine salt was placed in a stirred vessel, 100 ml of methyl ethyl ketone was added thereto at 20 ° C, and the mixture was stirred for 72 hours, the suspension was suction filtered, and the filter cake was dried and tested. This product is crystal form A of asiatic acid tromethamine salt.

Example 3

2 g of amorphous asiatic acid tromethamine salt was placed in a stirred vessel, and a mixture of 80 ml of acetonitrile and 20 ml of methanol was added thereto at 30 ° C, and the mixture was stirred for 72 hours. The suspension was suction filtered, and the filter cake was dried. Upon testing, the product was crystal form A of asiatic acid tromethamine salt.

Example 4

2 g of the semicrystalline volume of glacial acid tromethamine salt was placed in a stirred vessel, and a mixture of 80 ml of acetonitrile and 20 ml of isopropyl alcohol was added thereto at 40 ° C, and the mixture was stirred for 48 hours, and then the suspension was suction filtered. The filter cake was dried and tested to be the crystal form A of asiatic acid tromethamine salt.

Example 5

2 g of amorphous asiatic acid tromethamine salt was placed in a stirred vessel, and a mixture of 80 ml of methyl ethyl ketone and 20 ml of methanol was added thereto at 30 ° C, and the mixture was stirred for 72 hours, and then the suspension was filtered with suction. The cake is dried and tested to be the crystal form A of asiatic acid tromethamine salt.

Example 6

2 g of amorphous asiatic acid tromethamine salt was placed in a stirred vessel, and a mixture of 80 ml of acetonitrile and 20 ml of methanol was added thereto at 40 ° C, and the mixture was stirred for 24 hours, and then the suspension was suction filtered to filter cake. Dry, after testing, the product is crystal form A of asiatic acid tromethamine salt.

Example 7

2 g of a half-crystalline volume of glacial acid tromethamine salt was placed in a stirred vessel, and a mixture of 40 ml of methanol and 40 ml of ethyl acetate was added thereto at 40 ° C, and stirring was started to dissolve the solute at 40 ° C. The solvent was evaporated under a pressure of 0.08 MPa, and the obtained solid was dried to find crystals of succinic acid tromethamine salt.

Example 8

2 g of amorphous asiatic acid tromethamine salt was placed in a stirred vessel, and a mixture of 40 ml of methanol and 40 ml of acetonitrile was added thereto at 20 ° C, and stirring was started to dissolve the solute at 20 ° C at 0.05 MPa. The solvent is evaporated under pressure, and the obtained solid is dried and detected to be ammonia sulphate. Dicitol salt crystal form A.

Example 9

2 g of the semicrystalline volume of glacial acid tromethamine salt was placed in a stirred vessel, and a mixture of 40 ml of ethanol and 40 ml of methyl ethyl ketone was added thereto at 40 ° C, and stirring was started to dissolve the solute at 40 ° C, at 0.05. The solvent was evaporated under a pressure of MPa, and the obtained solid was dried to find crystal form A of asiatic acid tromethamine salt.

Example 10

3 g of amorphous asiatic acid tromethamine salt was placed in a stirred vessel, and a mixture of 80 ml of ethanol and 80 ml of butyl acetate was added thereto at 30 ° C, and stirring was started to dissolve the solute at 30 ° C. The solvent was evaporated under a pressure of 0.05 MPa, and the obtained solid was dried to find crystal form of succinic acid tromethamine salt.

Example 11

The lg semi-crystalline volume of glacial acid tromethamine salt was placed in a stirred vessel, and a mixture of 100 ml of ethyl acetate was added thereto at 50 ° C, and stirring was started to dissolve the solute at 50 ° C at 0.05 MPa. The solvent was removed by evaporation under pressure, and the obtained solid was dried to afford crystals of succinic acid tromethamine salt.

Example 12

The lg amorphous asiatic acid tromethamine salt was dissolved in 20 ml of methanol at room temperature, and 20 ml of ethyl acetate was added dropwise thereto under stirring to precipitate a solid, which was filtered, and the filter cake was dried and detected to be asiatic acid. The tromethamine salt crystal form A.

Example 13

The lg semi-crystalline volume of glacial acid tromethamine salt was dissolved in 20 ml of methanol at room temperature, and 60 ml of acetonitrile was added dropwise thereto under stirring to precipitate a solid, which was filtered, and the filter cake was dried and then detected as chlorpyrifos Triol salt crystal form A.

Example 14

At room temperature, lg amorphous asiatic acid tromethamine salt is dissolved in 20 ml of ethanol, stirring Under the conditions, 40 ml of butyl acetate was added dropwise thereto, a solid was precipitated, and the mixture was filtered, and the filter cake was dried and then detected as the crystal form A of asiatic acid tromethamine salt.

Example 15

At room temperature, lg amorphous asiatic acid tromethamine salt was dissolved in 20 ml of ethanol, and 80 ml of methyl ethyl ketone was added dropwise thereto under stirring to precipitate a solid, which was filtered, and the filter cake was dried to be detected as snow oxalic acid ammonia. Dicitol salt crystal form A.

Example 16-19 Preparation of crystal form of asiatic acid tromethamine salt B

Example 16

2 g of the semicrystalline volume of succinic acid tromethamine salt was placed in a stirred vessel, and a mixture of 80 ml of acetonitrile and 20 ml of n-propanol was added thereto at 40 ° C, and the mixture was stirred for 24 hours, and then the suspension was suction filtered. The filter cake was dried and tested to be the crystal form B of asiatic acid tromethamine salt.

Example 17

2 g of amorphous asiatic acid tromethamine salt was placed in a stirred vessel, and a mixture of 80 ml of acetone and 20 ml of n-butanol was added thereto at 30 ° C, and the mixture was stirred for 72 hours, and then the suspension was suction filtered. The filter cake was dried and tested to be the crystal form B of asiatic acid tromethamine salt.

Example 18

2 g of the semicrystalline volume of glacial acid tromethamine salt was placed in a stirred vessel, and a mixture of 80 ml of methyl ethyl ketone and 20 ml of n-propanol was added thereto at 20 ° C, and the mixture was stirred for 72 hours, and then the suspension was suction filtered. The filter cake was dried and tested to be the crystal form B of asiatic acid tromethamine salt.

Example 19

The lg amorphous stearoxylic acid tromethamine salt was placed in a stirred vessel, 100 ml of acetone was added thereto at 40 ° C, and the mixture was stirred for 72 hours, and then the suspension was suction filtered, and the filter cake was dried and tested. The product is crystal form B of asiatic acid tromethamine salt.

Effect embodiment 1

For the crystal form A of the asiatic acid tromethamine salt of Examples 1-15, the crystal form B of the asiatic acid tromethamine salt of Example 16-19, the semi-crystalline asiatic acid tromethamine salt and the absence Stigtamine The butyl triolate was subjected to powder X-ray diffraction, and the radiation source was Cu-Κα. The spectra are shown in Figure 1 - Figure 4, respectively. The specific peaks of Form A and Form B are shown in Tables 1 and 2.

Table 1 PXRD characteristic peak of crystal form of asiatic acid tromethamine salt A No. 2 Θ angle (°) Height 1% Area Relative intensity (1%)

1 3.44 429 4.1 2513 1.6

2 5.98 1220 11.7 18079 11.2

3 6.87 2560 24.6 40960 25.3

4 9.12 2795 26.9 46223 28.6

5 10.38 2498 24 42279 26.2

6 12.00 6506 62.6 114303 70.7

7 12.47 3471 33.4 69725 43.1

8 12.93 1723 16.6 16362 10.1

9 13.42 6110 58.8 78080 48.3

10 13.87 972 9.4 9022 5.6

11 14.72 10394 100 161651 100

12 15.10 3828 36.8 119298 73.8

13 15.89 1284 12.4 14395 8.9

14 17.01 3049 29.3 46375 28.7

15 18.14 2655 25.5 67493 41.8

16 19.04 813 7.8 10188 6.3

17 19.64 437 4.2 5949 3.7

18 20.17 1012 9.7 11484 7.1

19 20.94 447 4.3 9603 5.9

20 21.75 1028 9.9 22630 14

21 22.56 542 5.2 10855 6.7

22 23.33 257 2.5 2316 1.4 24.18 1307 12.6 27534 17

26.38 785 7.6 11868 7.3

26.98 448 4.3 6373 3.9

27.75 603 5.8 10218 6.3 Table 2 PXRD characteristic peak of crystal form of asiatic acid tromethamine salt B

21 25.20 327 6.2 6814 7.7

22 26.86 546 10.4 4686 5.3

23 27.73 214 4.1 1544 1.7

24 28.30 351 6.7 3874 4.4

25 28.85 235 4.5 2666 3

26 30.43 262 5 6314 7.1

27 30.83 202 3.8 1402 1.6

28 33.93 324 6.2 2251 2.5 Effect example 2

The crystal form A of asiatic acid tromethamine in Example 6 was detected by differential scanning calorimetry (DSC), and the temperature was raised to 300 ° C at a rate of 10 ° C/min from 30 ° C. It has an endothermic peak at 162 ° C ± 5 ° C, as shown in Figure 5. The melting points of the other examples are the same as those of Example 6.

The crystal form B of the asiatic acid tromethamine salt of Example 16 was detected by differential scanning calorimetry (DSC), and the temperature was raised to 300 ° C at a rate of 10 ° C/min from 30 ° C. It has an endothermic peak at 153 ° C ± 5 ° C, as shown in Figure 6. The melting points of the other examples are the same as those of Example 16.

Effect Example 3 Stability Experiment

Take 10 mg of amorphous asiatic acid tromethamine salt, add 1 ml of acetonitrile, suspend it at 25 ° C for 48 h, and drain the solvent to obtain a solid, which is detected as the crystal form of asiatic acid tromethamine salt. A, it can be seen that Form A is more stable than the amorphous asiatic acid tromethamine salt.

40 mg of amorphous asiatic acid tromethamine salt was added thereto, and a mixture of 1.6 ml of acetonitrile and 0.4 ml of n-propanol was added thereto, and suspended at 25 ° C for 72 hours, and the solid was filtered off, and after drying, it was detected as snow. As the crystal form B of oxalic acid tromethamine salt, it can be seen that the B crystal form is more stable than the amorphous stearoxylate tromethamine salt.

Crystallized Form A, B crystal form and amorphous stearoxylic acid tromethamine salt were placed in an environment of 80 ° C for one week. After detection, A and B crystal forms of triclosolic acid tromethamine were found. The salt did not change, and the amorphous asiatic acid tromethamine salt was partially decomposed. The crystal forms of A and B were placed in a condition of 40 ° C and a relative humidity of 75% for one week. After the detection, the crystal form A was not changed, and the B crystal form was partially converted into the crystal form A. This proves that the B crystal form is not as stable as the crystal form A under this condition.

From the above experiments, it is concluded that the stability of the three crystal forms is A>B>no stereotype.

Claims

Rights request

1. A crystal form A of asiatic acid tromethamine salt, which is in a powder X-ray diffraction spectrum using a radiation source of Cu- Κα at diffraction angles 2Θ = 5.98, 6.87, 9.12, 10.38, 12.00, 12.47, There are main peaks at 12.93, 13.42, 14.72, 15.10, 17.01 and 18.14 degrees; there are times at 2Θ=3.44, 13.87, 15.89, 19.04, 19.64, 20.17, 20.94, 21.75, 22.56, 23.33, 24.18, 26.38, 26.98 and 27.75 degrees For the peak, the 2Θ error range is ±0.2.

The asiatic acid tromethamine salt crystal form according to claim 1, which has a melting point of 162 ° C ± 5 ° C.

A method for producing a crystal form A of asiatic acid tromethamine salt according to claim 1 or 2, which employs any one of the following schemes:

Scheme 1: The method comprises the steps of: suspending the raw material asiatic acid tromethamine in an organic solvent to form a paddle under stirring; separating the crystal form A of asiatic acid tromethamine salt, and drying; Wherein, the organic solvent is a single solvent or a mixed solvent of two or more solvents; when the organic solvent is a single solvent, the solvent is acetonitrile and/or butanone; When the solvent is mixed, the mixed solvent includes an alcohol solvent and a non-alcohol solvent, and the alcohol solvent includes one or more of methanol, ethanol, and isopropyl alcohol, and the non-alcohol solvent includes acetonitrile. And one or more of acetone and methyl ethyl ketone; the volume ratio of the non-alcoholic solvent to the alcohol solvent is 4:1 or more; Scheme 2: the following steps are included: the raw material is concentrated The triol salt is dissolved in an organic solvent; the organic solvent is removed to obtain the crystal form A of the asiatic acid tromethamine salt; wherein the organic solvent is a single solvent or a mixed solvent of two or more solvents; When the organic solvent is a single solvent The solvent is ethyl acetate and/or butyl acetate; when the organic solvent is a mixed solvent, the mixed solvent includes an alcohol solvent and a non-alcohol solvent, and the alcohol solvent includes methanol and And / or ethanol, the non-alcohol solvent comprises one or more of acetonitrile, acetone, ethyl acetate, butyl acetate and methyl ethyl ketone; the volume ratio of the alcohol solvent to the non-alcohol solvent is 1 : 1 to 4: 1; Scheme 3: It comprises the following steps: dissolving the raw material, asiatic acid, tromethamine salt, in an alcohol solvent a suspension obtained by adding an anti-solvent of asiatic acid tromethamine salt; filtering the obtained suspension to dry the filter cake; wherein the alcohol solvent comprises methanol and/or ethanol; One or more of ethyl acetate, butyl acetate, acetonitrile, and methyl ethyl ketone are included.

4. The preparation method according to claim 3, wherein:

In the first embodiment, when the organic solvent is a mixed solvent, the mixed solvent is methanol and acetonitrile, methanol and methyl ethyl ketone, or isopropanol and acetonitrile;

In the second embodiment, when the organic solvent is a mixed solvent, the mixed solvent is methanol and ethyl acetate, methanol and acetonitrile, ethanol and methyl ethyl ketone, or ethanol and butyl acetate;

In the third embodiment, when the alcohol solvent is methanol, the anti-solvent is ethyl acetate or acetonitrile; and when the alcohol solvent is ethanol, the anti-solvent is butyl acetate or methyl ethyl ketone.

5. The preparation method according to claim 4, wherein:

In the first scheme, the volume ratio of acetonitrile to methanol, the volume ratio of methyl ethyl ketone to methanol, or the volume ratio of acetonitrile to isopropyl alcohol is 4:1 or more;

In the second embodiment, the volume ratio of methanol to ethyl acetate, the volume ratio of methanol to acetonitrile, the volume ratio of ethanol to methyl ethyl ketone, or the volume ratio of ethanol to butyl acetate is 1: 1 to 4: 1;

In the third embodiment, the anti-solvent is used in an amount of 1 to 4 times the volume of the alcohol solvent.

6. The preparation method according to any one of claims 3-5, characterized in that:

In the first embodiment, the organic solvent is used in an amount of 50 to 100 ml/g of asiatic acid tromethamine; the time for the paddle is 24 hours or more, preferably 24 to 72 hours; The temperature is 20 to 40 ° C _; the separation is suction filtration; the drying is vacuum drying at room temperature;

In the second embodiment, the organic solvent is used in an amount of 40 to 100 ml/g of asiatic acid tromethamine; the dissolution temperature is 20 to 40 ° C _{; and} the method for removing the organic solvent is 0.05 to 0.1. Evaporating under pressure of MP, the temperature of the evaporation is preferably 20 to 50 ° C _;

In the third embodiment, the alcohol solvent is used in an amount of 10 to 20 ml/g of asiatic acid tromethamine; the dissolution temperature is 20 to 30 ° C _{; and} the drying is vacuum and atmospheric drying.

7. A crystal form of asiatic acid tromethamine salt B, which is a powder of Cu- Κα using a radiation source

15 In the X-ray diffraction spectrum, there are main peaks at diffraction angles of 2Θ=3.54, 7.05, 10.04, 11.88, 13.38, 14.29 and 15.18 degrees; at 2Θ=9.28, 9.59, 12.43, 16.68, 17.03, 17.57, 18.16, 18.91, 19.24, There are secondary peaks at 20.07, 20.68, 22.46, 24.84, 25.20, 26.86, 27.73, 28.30, 28.85, 30.43, 30.83 and 33.93 degrees, with a 2-value error range of ± 0.2.

The asiatic acid tromethamine salt crystal form according to claim 7, which has a melting point of 153 ° C ± 5 ° C.

The method for preparing the crystal form B of the asiatic acid tromethamine salt according to claim 7 or 8, comprising the steps of: suspending the raw material squalinaric acid tromethamine in an organic state under stirring; Forming a paddle in a solvent; separating the crystal form B of the asiatic acid tromethamine salt, and drying; wherein the organic solvent is a single solvent or a mixed solvent of two or more solvents, when the organic solvent is a single In the case of a solvent, the solvent is acetone; when the organic solvent is a mixed solvent, the mixed solvent includes an alcohol solvent and a non-alcohol solvent, and the alcohol solvent includes n-butanol and/or positive The propanol, the non-alcohol solvent includes one or more of acetonitrile, acetone and methyl ethyl ketone; and the volume of the non-alcohol solvent and the alcohol solvent is preferably 4:1 or more.

The preparation method according to claim 9, wherein the organic solvent is used in an amount of 40 to 60 ml/g of asiatic acid tromethamine; the mixed solvent is acetone and n-butanol and butanone. And n-propanol, or acetonitrile and n-propanol, wherein the volume of acetone and n-butanol, butanone and n-propanol, or acetonitrile and n-propanol is preferably 4:1 or more; the time for the paddle is 24 hours or more. Preferably, it is 24 to 72 hours; the temperature of the paddle is 20 to 40 ° C; the separation is suction filtration; and the drying is vacuum drying at room temperature.

16