CN106995397B - R-amisulpride medicinal salt, preparation method, crystal form and application thereof - Google Patents

Abstract

The present invention relates to R -amisulpride medicinal salt, preparation method, crystal form and its use in preparing medicine for treating diabetes, the preparation method is as follows: 2-aminomethyl- N -ethylpyrrolidine Be raw material, adopt L -tartaric acid to split, obtain ( R )-2-aminomethyl- N -ethyl pyrrolidine; Amic acid is directly with ( R )-2 under isopropyl chloroformate, triethylamine catalysis -aminomethyl- N -ethylpyrrolidine condensation to obtain R -amisulpride; R-amisulpride obtained in step (2) is reacted with acid to obtain R - amisulpride medicinal salt, this preparation method It has the advantages of simple operation, high safety, good product quality and low cost, which is convenient for large-scale production.

Description

R-amisulpride medicinal salt, preparation method, crystal form and use thereof

technical field

The invention relates to the field of medicine, in particular to a pharmaceutical salt of R -amisulpride, a preparation method, a crystal form and use thereof.

Background technique

Amisulpride, English name: Amisulpride, chemical name: 4-amino- N -[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxy benzamide. It is a new non-classical antipsychotic drug developed by Sanofi-Synthelabo in France with significant advantages for negative symptoms. It was first marketed in Portugal in 1986, in the United States in January 1997 and in 2001 Listed in China, the domestic market is currently in wide demand and has far-reaching economic and social significance. However, compared with traditional antipsychotics, amisulpride has a lower risk of inducing weight gain, diabetes and extrapyramidal side effects. At present, the clinical drug form of amisulpride is the racemate administration.

Studies have shown that S -amisulpride, the active isomeric form of racemic amisulpride, is two times more potent than the racemic form, and has an increased ability to bind to dopamine D2 and dopamine _{D3 receptors} 19 to 38 times larger than R -amisulpride. R -amisulpride is considered to have no antipsychotic activity due to its weak affinity for dopamine D2 and dopamine _{D3 receptors} . At present, there are few researches on R-amisulpride, and there is no research on the medicinal salt of R-amisulpride in the prior art.

SUMMARY OF THE INVENTION

The technical problem to be solved by the present invention is to provide R -amisulpride medicinal salt, and simultaneously provide the preparation method of the salt to be used, and the use of the crystal form and the R-amisulpride medicinal salt in the preparation of a medicine for treating diabetes.

For solving the above problems, the technical scheme of the present invention is as follows:

One aspect of the present invention provides the pharmaceutically acceptable salt of R -amisulpride shown in formula 1:

1

Wherein: n is 1/2 or 1; X is acid radical, and described acid radical is selected from hydrochloric acid, sulfuric acid, nitric acid, methanesulfonic acid, benzenesulfonic acid, oxalic acid, formic acid, benzoic acid, maleic acid, fumaric acid, Acid radicals of malic acid, tartaric acid, dibenzoyltartaric acid or citric acid.

Preferably, the acid group is selected from tartaric acid, hydrochloric acid, sulfuric acid or fumaric acid.

Preferably, the acid group is selected from L -tartaric acid, hydrochloric acid or sulfuric acid.

Another aspect of the present invention provides the preparation method shown in formula 1, which specifically comprises the following steps:

(1) take 2-aminomethyl- N -ethylpyrrolidine as raw material, adopt L -tartaric acid to split, obtain ( R )-2-aminomethyl- N -ethylpyrrolidine;

(2) Amic acid is directly condensed with ( R )-2-aminomethyl- N -ethylpyrrolidine obtained in step (1) under the catalysis of isopropyl chloroformate and triethylamine to obtain R -amisulfuridine profit;

(3) Formula 1 is obtained by reacting the R -amisulpride obtained in step (2) with an acid.

The synthetic route is shown in formula I:

Preferably, the step (1) is specifically as follows: using 2-aminomethyl- N -ethylpyrrolidine as a raw material, adding L -tartaric acid, reacting at a temperature of 25-30° C. for 1-3 hours, and then adding NaOH, obtained by hydrolysis.

Preferably, the molar ratio of L -tartaric acid and 2-aminomethyl- N -ethylpyrrolidine is 0.5-1.3:1.

Preferably, the molar ratio of L -tartaric acid and 2-aminomethyl- N -ethylpyrrolidine is 0.6~0.9:1

Preferably, it is recrystallized from methanol before adding NaOH.

Preferably, the volume-to-mass ratio of the L -tartaric acid to methanol is 1:5 to 1:7, the crystallization temperature is 10 to 15°C, and the crystallization time is 1 to 2 hours.

Preferably, the mass percentage of the sodium hydroxide is 25-40%, the hydrolysis temperature is 25-30°C, and the volume-to-mass ratio of sodium hydroxide to 2-aminomethyl-N-ethylpyrrolidine is 1:0.5～ 0.9.

Preferably, the hydrolysis time is 1 to 3 hours.

Preferably, in the step (2), the molar ratio of amidic acid, triethylamine, isopropyl chloroformate and R -2-aminomethyl-N-ethylpyrrolidine is 1:1.0～2.0:1.2～ 1.6:1.1~1.7.

Preferably, in the step (2), the molar ratio of amidic acid, triethylamine, isopropyl chloroformate and R -2-aminomethyl-N-ethylpyrrolidine is 1:1.27～1.8:1.34～ 1.5:1.30~1.5.

Preferably, in the step (2), the reaction temperature is 10-15° C., the reaction time is 0.5-1 hour, and then moved to room temperature and stirred for 1-3 hours.

Preferably, the step (3) is the reaction of R -amisulpride and an acid in an organic solvent, cooling and stirring for crystallization to obtain a medicinal salt of R -amisulpride.

Preferably, the mol ratio of R -amisulpride and acid described in the step (3) is 1:1～1.5.

Preferably, the organic solvent is selected from methanol/diethyl ether mixed solvent, methanol/acetone mixed solvent or methanol.

Preferably, in the step (3), the crystallization temperature is 0 to 5° C., and the crystallization time is 3 to 5 hours.

Preferably, in the step (3), the crystallization temperature is -10~-20°C, and the crystallization time is 0.5~1.5 hours.

Yet another aspect of the present invention provides a crystalline or amorphous form of the pharmaceutically acceptable salt of formula 1.

Preferably, the crystalline or amorphous form of the pharmaceutically acceptable salt of formula 1 is selected from:

Crystal form A of R -amisulpride- L -tartrate;

R - the amorphous form of amisulpride hydrochloride;

Amorphous form of R -amisulpride sulfate.

The crystal form A of the R -amisulpride L -tartrate salt, using Cu-Ka radiation, has characteristic peaks in the X-ray powder diffraction pattern expressed in 2θ at the following positions: 10.25±0.2, 12.69±0.2, 13.70 ±0.2, 13.95±0.2, 15.49±0.2, 15.84±0.2, 16.06±0.2, 16.32±0.2, 19.13±0.2, 19.36±0.2, 21.42±0.2, 22.08±0.2, 22.48±0.2; preferably, expressed in degrees 2θ The X-ray powder diffraction pattern has characteristic peaks at the following positions: 10.25±0.2, 12.69±0.2, 13.70±0.2, 13.95±0.2, 15.49±0.2, 15.84±0.2, 16.06±0.2, 16.32±0.2, 17.11±0.2, 17.54 ±0.2, 17.77±0.2, 19.13±0.2, 19.36±0.2, 21.42±0.2, 22.08±0.2, 22.48±0.2, 23.07±0.2, 24.36±0.2, 25.22±0.2, 26.92±0.2.

The powder X-ray diffraction pattern of the crystal form A of the R -amisulpride- L -tartrate is shown in FIG. 1 .

The powder X-ray diffraction pattern of the amorphous form of the R -amisulpride hydrochloride is shown in FIG. 2 .

The powder X-ray diffraction pattern of the amorphous form of the R -amisulpride sulfate is shown in FIG. 3 .

The crystalline or amorphous preparation method of described R -amisulpride medicinal salt is as follows: adding R -amisulpride medicinal salt into methanol, dissolving by heating up, hot filtration, cooling and crystallization, thermal insulation stirring , filtered and dried, and the volume-to-mass ratio of the R-amisulpride medicinal salt and methanol is 1g:4-6ml.

The heating and dissolving system is heated to 55~60°C for dissolving.

The heat preservation stirring system is stirred at 10~15°C for 1.5-2.5h.

The last aspect of the present invention provides the use of the pharmaceutically acceptable salt represented by formula 1 in the preparation of a medicament for treating diabetes.

The use of the pharmaceutically acceptable salt represented by the formula 1 in the preparation of a medicine for treating diabetes is to use it as an active ingredient and add pharmaceutically acceptable adjuvants or auxiliary ingredients to prepare a preparation.

The mode of administration of the compounds or pharmaceutical compositions of the present invention is not particularly limited, and representative modes of administration include, but are not limited to, oral, parenteral, or topical administration. For oral administration, it includes, but is not limited to, capsules, tablets, pills, powders, granules, emulsions, solutions, suspensions, syrups or tinctures. For parenteral administration, including but not limited to injection solutions, dispersions or powders. For topical administration, include but are not limited to ointments, powders, patches, sprays and inhalants.

The beneficial effects produced by the above technical solutions are:

The medicinal salt of R -amisulpride provided by the invention can significantly reduce blood sugar and has a good curative effect on treating diabetes.

The preparation method of the R -amisulpride medicinal salt of the present invention solves the problem of avoiding the use of a large number of expensive hand-type reagents in the preparation process of the R-amisulpride-medicinal salt, and has the advantages of simple operation, high safety, and high product quality. The advantages of good quality, high optical purity and low cost are convenient for large-scale production.

The crystal form or amorphous form of the R -amisulpride pharmaceutical salt provided by the invention has the characteristics of stable properties and good solubility, and can be conveniently used in various dosage forms in pharmacy.

Description of drawings

Accompanying drawing 1 is the powder X-ray diffraction pattern of the crystal form A of R -amisulpride- L -tartrate;

Accompanying drawing 2 is the powder X-ray diffraction pattern of the amorphous form of R -amisulpride hydrochloride;

Accompanying drawing 3 is the powder X-ray diffraction pattern of the amorphous form of R -amisulpride sulfate;

Accompanying drawing 4 is R, S -amisulpride optical purity determination high performance liquid chromatogram;

Accompanying drawing 5 is S -amisulpride- D -tartrate optical purity determination high performance liquid chromatogram;

Accompanying drawing 6 is R -amisulpride- L -tartrate optical purity determination high performance liquid chromatogram.

Detailed ways

In order to make the objectives, technical solutions and advantages of the present invention clearer, the invention will be clearly and completely described below with reference to specific embodiments.

Example 1 Synthesis of R -2-aminomethyl- N -ethylpyrrolidine- L -tartrate

Add 45.6 g of L -tartaric acid to 60 mL of distilled water, stir until it is completely dissolved, slowly add 30 g of 2-aminomethyl-N-ethylpyrrolidine dropwise, and keep the temperature between 25°C and 30°C during the dropwise addition. After adding, stir at room temperature for 1 h, then add 260 ml of methanol to the reaction flask, stir at 12±2 °C for 2 h, filter, and wash the filter cake with 20 ml of methanol once. Filter, add the filter cake to 190 ml of 75% methanol, heat to clarification, naturally cool to 20±2 °C, stir for 1 h, suction filtration, rinse with 15 ml of methanol, and dry to obtain a colorless solid.

Dissolve 11 g of R -2-aminomethyl- N -ethylpyrrolidine- L -tartrate in 60 ml of distilled water, add 36 g of 30% sodium hydroxide solution dropwise, after the dripping is completed, at 20±2℃ Stir for 1 h, extract with dichloromethane (30 ml × 3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and rotate to dryness.

Example 2 Synthesis of R -amisulpride

Dissolve 10 g of ampic acid and 4.96 g of triethylamine in 50 ml of acetone, cool down to 5 °C, slowly add 5.6 g of isopropyl chloroformate dropwise, keep stirring for 0.5 h after dropping, and then slowly dropwise add Example 1 25 mL of an acetone solution of 6.42 g of prepared R -2-aminomethyl- N -ethylpyrrolidine was dripped, stirred at 12 °C for 0.5 h, and then moved to room temperature and stirred for 1 h. Rotary-evaporated, added water and extracted with dichloromethane (25 ml × 3), combined organic phases, dried over anhydrous sodium sulfate, filtered, and rotary-evaporated to dryness to obtain a yellow-brown oil.

Example 3 Synthesis of R -amisulpride maleic acid

10 g of R -amisulpride prepared in Example 2 and 35 ml of methanol were heated to dissolve, 15 ml of a methanol solution of 4.06 g of maleic acid was added, stirred at 45 °C for 5 h, cooled to 3 °C and stirred for 3 h, and precipitated. A large amount of crystals were filtered and dried to obtain 10.9 g of the product with a yield of 83% and an optical purity of ee%=100%.

Example 4 Synthesis of R -amisulpride L -tartaric acid

Add R-amisulpride (50g, 0.135mol) and 190ml methanol prepared in Example 2 to a 500ml reaction flask, heat up and stir, and dropwise add a mixture of L-tartaric acid (21.3g, 0.142mol) and 90ml methanol under temperature control at 40~50°C. The mixture was added dropwise, kept stirring for 2 hours, cooled to -10~-20 °C and stirred for 1 hour, filtered, washed with a small amount of cold methanol, and dried by blasting at 45 °C to obtain 61.11 g of the product with a yield of 87% and an optical purity of ee %=100%.

Example 5 Synthesis of R -amisulpride hydrochloride

Add R-amisulpride (5g, 0.0135mol) prepared in Example 2 into a 50ml reaction flask, dissolve it in 2ml methanol and dilute with 10ml ether, stir at room temperature, and dropwise add a mixture of 2g saturated hydrogen chloride ether solution and 10ml ether at controlled temperature. After adding, keep stirring for 2h, cool down to -10~-20℃ and stir for 1h, filter, wash the filter cake with a small amount of cold ether, and blow dry at 45℃ to obtain 4.12g of product, yield 75%, optical purity ee%=100% .

Example 6 Synthesis of R -amisulpride sulfate

Add R-amisulpride (5g, 0.0135mol) prepared in Example 2 into a 50ml reaction flask, dilute with 2ml methanol and 10ml diethyl ether, stir at 0~5°C, and dropwise add 9g 15% sulfuric acid ether ether solution and 5ml diethyl ether under temperature control The mixture was added dropwise, kept stirring for 2 hours, cooled to -10~-20°C, stirred for 1 hour, filtered, washed with a small amount of cold ether, and dried by blowing at 45°C to obtain 5.43 g of the product, yield 86%, optical purity ee %=100%.

Example 7 Crystal form A of R -amisulpride- L -tartrate

10 g of R -amisulpride L-tartrate obtained in Example 4 was added to 50 mL of methanol, and the temperature was raised to 55-60 °C, the solid was dissolved, filtered, the filtrate was cooled for crystallization, stirred at 10-15 °C for 2 h, filtered, methanol The filter cake was washed and dried by blowing at 45°C to obtain 9.23 g of R -amisulpride- L -tartrate with a yield of 92.3%.

The X-ray powder diffraction pattern obtained by measuring the obtained R -amisulpride sulfate using Cu-Kα rays is shown in FIG. 1 .

Example 8 Amorphous form of R -amisulpride hydrochloride

1 g of R -amisulpride hydrochloride obtained in Example 5 was added to 5 mL of methanol, the temperature was raised to 55-60 °C, the solid was dissolved, filtered, the filtrate was cooled for crystallization, stirred at 10-15 °C for 2 h, filtered, and washed with methanol The filter cake was dried by blasting at 45°C to obtain 0.8 g of R-amisulpride hydrochloride in a yield of 80%.

The X-ray powder diffraction pattern obtained by measuring the obtained R-amisulpride hydrochloride using Cu-Kα rays is shown in FIG. 2 .

Example 9 Amorphous form of R -amisulpride sulfate

1 g of R -amisulpride sulfate obtained in Example 6 was added to 5 mL of methanol, and the temperature was raised to 55-60 °C, the solid was dissolved, filtered, the filtrate was cooled for crystallization, stirred at 10-15 °C for 2 h, filtered, washed with methanol and filtered. The cake was air-dried at 45°C to obtain 0.65 g of R -amisulpride sulfate in a yield of 65%.

The X-ray powder diffraction pattern obtained by measuring the obtained R-amisulpride sulfate using Cu-Kα rays is shown in FIG. 2 .

Test Example 1 Optical Purity Measurement

Instrument: High Performance Liquid Chromatograph

Reagents and solvents: diethylamine AR, chromatography n-hexane, chromatography ethanol

Chromatographic conditions:

Column: ChiralpakAD-H (250mm×4.6mm, 5um)

Detection wavelength: 224nm

Flow rate: 0.6ml/min

Column temperature: 23℃

Mobile phase preparation: n-hexane solution (add 0.05 ml of diethylamine to 650 ml of n-hexane solution) - ethanol (65:35:0.05).

R,S -Amisulpride reference solution: Precisely weigh 10 mg of R,S -Amisulpride sample and place it in a 10ml volumetric flask, dissolve in ethanol, make up to volume with ethanol, and use it as a stock solution, take 2ml of the stock solution in a 10ml volumetric flask In a 10ml volumetric flask, make up to a volume of 200μg/ml of the test solution.

S -amisulpride- D -tartrate reference solution: Weigh 10 mg of the sample and place it in a 10 ml volumetric flask, dissolve in ethanol, and make up to volume with ethanol as a stock solution. Take 2 ml of the stock solution in a 10 ml volumetric flask, dilute to volume, and prepare a 200 μg/ml test solution.

The R -amisulpride- L -tartaric acid test solution prepared in Example 4: Weigh 10 mg of the sample and place it in a 10 ml volumetric flask, dissolve in ethanol, and make the volume with ethanol as a stock solution. Take 2 ml of the stock solution in a 10 ml volumetric flask, dilute to volume, and prepare a 200 μg/ml test solution.

The R,S -amisulpride reference solution was measured and analyzed using the above measurement conditions and instruments, and the retention time and optical purity were analyzed.

The S -amisulpride- D -tartrate reference substance solution was measured and analyzed using the above measurement conditions and instruments, and the retention time and optical purity were analyzed, and its map was shown in accompanying drawing 5.

The R -amisulpride- L -tartaric acid need testing solution was measured and analyzed using the above measurement conditions and instruments, and the retention time and optical purity were analyzed. is 100%.

R,S -Amisulpride achieved baseline separation, and the resolution was greater than 1.5. Compared with the chromatogram of S -Amisulpride- D -tartrate reference substance, it was determined that RT=8.237 was S configuration, and RT=9.471 was R. structure.

Test Example 2 Stability Study of R -Amisulpride- L -Tartaric Acid

1. Illumination experiment

Take the solid R -amisulpride- L -tartaric acid obtained in Example 4 and the R -amisulpride- L -tartaric acid crystal form A prepared in Example 7 and spread them in a petri dish (about 2mm thickness) in an appropriate amount. Place under 4500Lx±500Lx strong light irradiation conditions for 10 days, take samples for testing on the 5th and 10th days, and use high performance liquid phase to detect the content and optical purity.

Table 1 Illumination test results

2. High temperature experiment

Take the solid R -amisulpride- L -tartaric acid obtained in Example 4 and the R -amisulpride- L -tartaric acid crystal form A prepared in Example 7 and spread them in a petri dish (about 2mm thickness) in an appropriate amount. Place in a 60°C incubator for 10 days, take samples for testing on the 5th and 10th days, and use high performance liquid phase to detect the content and optical purity.

Table 2 High temperature experimental results

3. High humidity experiment

Take the solid R -amisulpride- L -tartaric acid obtained in Example 4 and the R -amisulpride- L -tartaric acid crystal form A prepared in Example 7 and spread them in a petri dish (about 2mm thickness) in an appropriate amount. It was placed for 10 days under the conditions of room temperature 25℃±2℃ and relative humidity RH90±5%, and sampling was carried out on the 5th and 10th days, and the content and optical purity were detected by high performance liquid phase.

Table 3 High humidity experimental results

4. Accelerated experiments

Take an appropriate amount of the solid R -amisulpride- L -tartaric acid obtained in Example 4 and the R -amisulpride- L -tartaric acid crystal form A prepared in Example 7, and place them at 40°C and 75% RH for 6 Months, samples were taken at the end of the first, second, third, and June months, and the content and optical purity were detected by high-performance liquid chromatography.

Table 4 Accelerated experimental results

From the experimental data, it can be known that the R -amisulpride- L -tartaric acid crystal form A of the present invention has better stability than the crystallization stability of Example 4 under the conditions of illumination, high temperature, high humidity and accelerated experimental conditions.

Test Example 3 Solubility of R -amisulpride- L -tartaric acid

According to the provisions of Chinese Pharmacopoeia 2005 Edition II General Example Seven (2), the solubility of R -amisulpride- L -tartaric acid crystal form A in water is determined to be greater than the R -amisulpride- L -tartaric acid obtained in Example 4.

Test Example 4 Stability Study of R -Amisulpride Hydrochloride

1. Illumination experiment

Take the solid R -amisulpride hydrochloride obtained in Example 5 and the amorphous form of R -amisulpride hydrochloride prepared in Example 8, and spread them in a petri dish (about 2mm thickness), and place them in a petri dish. Place under 4500Lx±500Lx strong light irradiation conditions for 10 days, take samples for detection on the 5th and 10th days, and use high performance liquid phase to detect the content and optical purity.

Table 5 Illumination test results

2. High temperature experiment

Take the solid R -amisulpride hydrochloride obtained in Example 5 and the amorphous form of R -amisulpride hydrochloride prepared in Example 8, and spread them in a petri dish (about 2mm thickness), and place them in a petri dish. Place in a 60°C incubator for 10 days, take samples for testing on the 5th and 10th days, and use high performance liquid phase to detect the content and optical purity.

Table 6 High temperature experimental results

3. High humidity experiment

Take the solid R -amisulpride hydrochloride obtained in Example 5 and the amorphous form of R -amisulpride hydrochloride prepared in Example 8, and spread them in a petri dish (about 2mm thickness), and place them in a petri dish. Place for 10 days under the conditions of room temperature 25℃±2℃ and relative humidity RH90±5%, take samples for detection on the 5th and 10th days, and use high performance liquid phase to detect the content and optical purity.

Table 7 High humidity experimental results

4. Accelerated experiments

Take an appropriate amount of the amorphous form of the solid R -amisulpride hydrochloride obtained in Example 5 and the R -amisulpride hydrochloride prepared in Example 8, and place 6 pieces under the conditions of 40° C. and 75% RH. The samples were taken at the end of the first, second, third, and June months, and the content and optical purity were detected by high performance liquid phase.

Table 8 Accelerated experimental results

It can be seen from the experimental data that the amorphous form of R -amisulpride hydrochloride prepared by the present invention has better stability than the crystal stability of Example 5 under the conditions of illumination, high temperature, high humidity and accelerated experimental conditions.

Test Example 5 Solubility of R -amisulpride hydrochloride

According to the provisions of Chinese Pharmacopoeia 2005 Edition II General Example Seven (2), the solubility of the amorphous form of R -amisulpride hydrochloride in water is determined to be greater than the R -amisulpride hydrochloride obtained in Example 5.

Test Example 6 Stability Study of R -Amisulpride Sulfate

1. Illumination experiment

Take the solid R -amisulpride sulfate obtained in Example 6 and the amorphous form of the R -amisulpride sulfate prepared in Example 9, and lay them flat in a petri dish (about 2mm thickness), and place them at 4500Lx± It was placed under 500Lx strong light irradiation for 10 days, and samples were taken on the 5th and 10th days for detection, and the content and optical purity were detected by high performance liquid phase.

Table 9 Illumination test results

2. High temperature experiment

Take the solid R -amisulpride sulfate obtained in Example 6 and the amorphous form of R -amisulpride sulfate prepared in Example 9, and spread them in a petri dish (about 2mm thickness), and place them at 60°C. It was placed in an incubator for 10 days, and samples were taken on the 5th and 10th days for detection, and the content and optical purity were detected by high performance liquid phase.

Table 10 High temperature experimental results

3. High humidity experiment

Take the solid R -amisulpride sulfate obtained in Example 6 and the amorphous form of the R -amisulpride sulfate prepared in Example 9 and spread them in a petri dish (about 2mm thickness), and place them at room temperature for 25 minutes. ℃±2℃, relative humidity RH90±5% for 10 days, sampling and testing on the 5th and 10th days, using high performance liquid phase to detect the content and optical purity.

Table 11 High humidity test results

4. Accelerated experiments

Take an appropriate amount of the amorphous form of the solid R -amisulpride sulfate obtained in Example 6 and the R -amisulpride sulfate prepared in Example 9, and place them at 40 ° C and 75% RH for 6 months, At the end of 1st, 2nd, 3rd and 6th months, samples were taken for testing, and the content and optical purity were detected by high performance liquid phase.

Table 12 Accelerated experimental results

It can be seen from the experimental data that the amorphous form of R -amisulpride sulfate prepared by the present invention has better stability than the crystal stability of Example 6 under the conditions of illumination, high temperature, high humidity and accelerated experimental conditions.

Test Example 7 Solubility of R -amisulpride sulfate

According to the provisions of Chinese Pharmacopoeia 2005 edition two general examples seven (2), measure the solubility of R -amisulpride sulfate amorphous form in water greater than the R -amisulpride sulfate obtained in Example 6.

Test Example 8 Oral glucose tolerance test in normal mice

Eight-week-old Kunming mice, male, were randomly divided into 4 groups, 10 mice in each group, and their body weights were recorded. They are blank control group: given 1.5ml of normal saline orally; test group 1: given R -amisulpride- L -tartrate (3.0μmol/kg) prepared in Example 4, dissolved with 1.5ml of normal saline; Test group 2: R -amisulpride hydrochloride (3.0 μmol/kg) prepared in Example 5 was administered, dissolved in 1.5 ml of normal saline orally; Test group 3: R -amisulpride prepared in Example 5 was administered Lisulfate (3.0 μmol/kg) was dissolved in 1.5 ml of normal saline orally.

Before the experiment, the mice were fasted for 12 hours, and each group was given oral gavage. Then 4 groups of mice were given normal saline, R -amisulpride L-tartrate, R -amisulpride hydrochloride and R -amisulpride sulfate by gavage, respectively, and the blood glucose value was measured after 30 minutes and recorded as 30 minutes , and then immediately give 3g/10ml glucose solution by gavage at 10ml/kg, and after 15min (denoted as 45min), 30min (denoted as 60min), 45min (denoted as 75min), after 60min (denoted as 60min) 90min), and after 120min (recorded as 150min), the blood glucose level (mmol/L) was measured. The results are shown in Table 13.

Table 13 Changes in blood glucose levels

According to the oral glucose tolerance test in mice, the compounds of test groups 1-3 can obviously improve the glucose tolerance of mice, and show a significant hypoglycemic effect.

It should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, but not to limit them; although the present invention has been described in detail with reference to the foregoing embodiments, those of ordinary skill in the art should understand: it can still be Modifications are made to the technical solutions described in the foregoing embodiments, or some technical features thereof are equivalently replaced; and these modifications or replacements do not make the essence of the corresponding technical solutions depart from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims (4)

1. An amorphous form of a pharmaceutically acceptable salt of R-amisulpride, characterized by the amorphous form of R-amisulpride hydrochloride having an X-ray powder diffraction pattern as shown in figure 2.

2. An amorphous form of a pharmaceutically acceptable salt of R-amisulpride, characterised by being an amorphous form of R-amisulpride sulphate having an X-ray powder diffraction pattern as shown in figure 3.

3. An amorphous form of a pharmaceutically acceptable salt of R-amisulpride according to claim 1 or 2, prepared by a process comprising:

the amorphous preparation method of the R-amisulpride medicinal salt comprises the steps of adding the R-amisulpride medicinal salt into methanol, heating to 55 ~ 60 ℃ for dissolution, carrying out heat filtration, cooling for crystallization, stirring at 10 ~ 15 ℃ for 1.5-2.5h, filtering, and drying to obtain the R-amisulpride medicinal salt and the methanol in a volume-mass ratio of 1g to 4-6 ml.

4. Use of a pharmaceutically acceptable salt of R-amisulpride, as claimed in claim 1 or 2, in the manufacture of a medicament for the treatment of diabetes.

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