CN106995397B - R-amisulpride medicinal salt, preparation method, crystal form and application thereof - Google Patents
R-amisulpride medicinal salt, preparation method, crystal form and application thereof Download PDFInfo
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- CN106995397B CN106995397B CN201710354473.5A CN201710354473A CN106995397B CN 106995397 B CN106995397 B CN 106995397B CN 201710354473 A CN201710354473 A CN 201710354473A CN 106995397 B CN106995397 B CN 106995397B
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- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
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Abstract
The invention relates to a toolBody relates toR-amisulpride pharmaceutical salt, preparation method, crystal form and use thereof in preparing medicament for treating diabetes, the preparation method is as follows: by 2-aminomethyl-N-ethyl pyrrolidine as a raw material, usingLResolution of tartaric acid to giveR) -2-aminomethyl-N-ethyl pyrrolidine; the amiaric acid is directly reacted with (A) under the catalysis of isopropyl chloride and triethylamineR) -2-aminomethyl-N-ethyl pyrrolidine to obtainR-amisulpride; subjecting the product obtained in step (2)RReaction of amisulpride with an acid to giveRThe preparation method has the advantages of simple operation, high safety, good product quality, low cost and the like, and is convenient for large-scale production.
Description
Technical Field
The invention relates to the field of medicines, in particular toR-amisulpride pharmaceutical salts, processes for their preparation, crystalline forms and uses thereof.
Background
Amisulpride, english name: amisulpride, chemical name: 4-amino-N- [ (1-ethyl-2-pyrrolidinyl) methyl]-5- (ethylsulfonyl) -2-methoxybenzamide. Is prepared by Sanofi-Synthe, St.Dreher, Senoffie, Francelabo) was first marketed in grapevine in 1986, in the united states in 1 month 1997, in china in 2001, with wide domestic market requirements and profound economic and social implications at present, but amisulpride has a lower risk of inducing weight gain, diabetes and extrapyramidal side effects than traditional antipsychotics. Currently, amisulpride is clinically administered in the form of racemate.
The research shows that the compound has the advantages of high purity,Samisulpride is the active isomeric form of racemic amisulpride, which is twice as potent as the racemic form and is in contact with dopamine D2And dopamine D3Ratio of receptor binding capacityR-amisulpride 19 to 38 times greater. Because R-amisulpride is used for dopamine D2And dopamine D3The receptor has a weak affinity and is thereforeRAmisulpride is considered to have no antipsychotic activity. There are few studies on R-amisulpride currently, and no studies on pharmaceutically acceptable salts of R-amisulpride have been conducted in the prior art.
Disclosure of Invention
The technical problem to be solved by the invention is to provideR-amisulpride pharmaceutical salts, a preparation method of the salts and the use of the crystal form and the R-amisulpride pharmaceutical salts in the preparation of medicaments for treating diabetes are also provided.
In order to solve the problems, the technical scheme of the invention is as follows:
in one aspect of the present invention, there is provided a compound represented by formula 1R-a pharmaceutically acceptable salt of amisulpride:
1
wherein: n is 1/2 or 1; x is acid radical, and the 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, malic acid, tartaric acid, dibenzoyltartaric acid or citric acid.
Preferably, the acid radical is selected from tartaric acid, hydrochloric acid, sulfuric acid or fumaric acid.
Preferably, the acid radical is selected fromLTartaric acid, hydrochloric acid or sulfuric acid.
The invention also provides a preparation method shown in the formula 1, which specifically comprises the following steps:
(1) by 2-aminomethyl-N-ethyl pyrrolidine as a raw material, usingLResolution of tartaric acid to giveR) -2-aminomethyl-N-ethyl pyrrolidine;
(2) the amiaric acid is directly reacted with the (1) obtained in the step (1) under the catalysis of isopropyl chloride and triethylamineR) -2-aminomethyl-N-ethyl pyrrolidine to obtainR-amisulpride;
(3) subjecting the product obtained in step (2)R-reacting amisulpride with an acid to give formula 1.
The synthetic route is shown as formula I:
preferably, the step (1) is specifically: by 2-aminomethyl-N-ethyl pyrrolidine as a raw material, addingLTartaric acid, at a temperature of 25 ~ 30 ℃ for 1 ~ 3 hours, then NaOH, hydrolyzed.
Preferably, the first and second electrodes are formed of a metal,Ltartaric acid and 2-aminomethyl-N-ethyl pyrrolidine in a molar ratio of 0.5 ~ 1.3.3: 1.
Preferably, the first and second electrodes are formed of a metal,Ltartaric acid and 2-aminomethyl-NMolar ratio of-ethylpyrrolidine of 0.6 ~ 0.9.0.9: 1
Preferably, recrystallization from methanol is carried out before the addition of NaOH.
Preferably, theLThe volume mass ratio of tartaric acid to methanol is 1: 5 ~ 1:1, the crystallization temperature is 10 ~ 15 ℃, and the crystallization time is 1 ~ 2 hours.
Preferably, the mass percent of the sodium hydroxide is 25 ~ 40%, the hydrolysis temperature is 25 ~ 30 ℃, and the volume mass ratio of the sodium hydroxide to the 2-aminomethyl-N-ethylpyrrolidine is 1: 0.5 ~ 0.9.9.
Preferably, the hydrolysis time is 1 ~ 3 hours.
Preferably, the step (2) is carried out by using amiric acid, triethylamine,Isopropyl chloroformate andRthe molar ratio of (E) -2-aminomethyl-N-ethylpyrrolidine is 1:1.0 ~ 2.0.0: 1.2 ~ 1.6.6: 1.1 ~ 1.7.7.
Preferably, the step (2) comprises amiric acid, triethylamine, isopropyl chloride andRthe molar ratio of (E) -2-aminomethyl-N-ethylpyrrolidine is 1:1.27 ~ 1.8:1.34 ~ 1.5.5: 1.30 ~ 1.5.5.
Preferably, in the step (2), the reaction temperature is 10 ~ 15 ℃, the reaction time is 0.5 ~ 1 hours, and the mixture is moved to room temperature and stirred for 1 ~ 3 hours.
Preferably, the step (3) isRReacting amisulpride and acid in an organic solvent, cooling, stirring and crystallizing to obtainR-a pharmaceutically acceptable salt of amisulpride.
Preferably, said step (3) is performedR-the molar ratio of amisulpride to acid is 1:1 ~ 1.5.5.
Preferably, the organic solvent is selected from a mixed solvent of methanol/diethyl ether, a mixed solvent of methanol/acetone or methanol.
Preferably, the crystallization temperature in the step (3) is 0 ~ 5 ℃, and the crystallization time is 3 ~ 5 hours.
Preferably, the crystallization temperature in the step (3) is-10 ~ -20 ℃, and the crystallization time is 0.5 ~ 1.5.5 hours.
In a further aspect, the present invention provides a crystalline or amorphous form of a pharmaceutically acceptable salt represented by formula 1.
Preferably, the crystalline or amorphous form of the pharmaceutically acceptable salt represented by formula 1 is selected from:
Ramisulpride-L-crystalline form a of the tartrate salt;
R-amorphous form of amisulpride hydrochloride;
Ramorphous form of amisulpride sulphate.
SaidR-amisulprideL-a crystalline form a of the tartrate salt, having characteristic peaks in the following positions in an X-ray powder diffraction pattern expressed in 2 Θ using Cu-Ka radiation: 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 and 22.48 +/-0.2; preferably, X-ray powder derivatives in degrees 2 θThe mapping pattern has characteristic peaks at the following positions: 10.25 plus or minus 0.2, 12.69 plus or minus 0.2, 13.70 plus or minus 0.2, 13.95 plus or minus 0.2, 15.49 plus or minus 0.2, 15.84 plus or minus 0.2, 16.06 plus or minus 0.2, 16.32 plus or minus 0.2, 17.11 plus or minus 0.2, 17.54 plus or minus 0.2, 17.77 plus or minus 0.2, 19.13 plus or minus 0.2, 19.36 plus or minus 0.2, 21.42 plus or minus 0.2, 22.08 plus or minus 0.2, 22.48 plus or minus 0.2, 23.07 plus or minus 0.2, 24.36 plus or minus 0.2, 25.22 plus or minus 0.2 and 26.92 plus or minus 0.2.
SaidRAmisulpride-L-the powder X-ray diffraction pattern of the crystalline form a of the tartrate salt is shown in figure 1.
SaidRThe amorphous form of amisulpride hydrochloride has a powder X-ray diffraction pattern as shown in figure 2.
SaidRThe amorphous form of amisulpride sulphate has a powder X-ray diffraction pattern as shown in figure 3.
SaidR-the crystalline or amorphous form of a pharmaceutically acceptable salt of amisulpride is prepared as follows: will be provided withRAdding the pharmaceutical salt of amisulpride into methanol, heating to dissolve, carrying out hot filtration, cooling to crystallize, keeping the temperature, stirring, filtering and drying to obtain the R-amisulpride pharmaceutical salt and the methanol in a volume-mass ratio of 1g to 4-6 ml.
The temperature-rising dissolution is carried out by heating to 55 ~ 60 ℃ for dissolution.
The heat preservation stirring system is used for stirring for 1.5-2.5h at the temperature of 10 ~ 15 ℃.
In a final aspect of the invention, the invention provides an application of a medicinal salt shown in formula 1 in preparing a medicament for treating diabetes.
The medicinal salt shown in the formula 1 is used for preparing the medicament for treating diabetes, and is prepared into a preparation by taking the medicinal salt as an active ingredient and adding pharmaceutically acceptable auxiliary materials or auxiliary ingredients.
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, including, but 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, it includes, but is not limited to, ointments, powders, patches, sprays, and inhalants.
Adopt the produced beneficial effect of above-mentioned technical scheme to lie in:
provided by the inventionRThe pharmaceutical salt of amisulpride can obviously reduce blood sugar and has better curative effect on treating diabetes.
According to the inventionRThe preparation method of the amisulpride medicinal salt solves the problem that a large amount of expensive hand reagents are not used in the preparation process of the R-amisulpride medicinal salt, has the advantages of simple operation, high safety, good product quality, high optical purity, low cost and the like, and is convenient for large-scale production.
The invention providesRThe crystalline form or amorphous form of the amisulpride medicinal salt has the characteristics of stable property and good solubility, and can be conveniently applied to various dosage forms in pharmacy.
Drawings
FIG. 1 is a drawing ofRAmisulpride-L-a powder X-ray diffraction pattern of crystalline form a of the tartrate salt;
FIG. 2 isR-a powder X-ray diffraction pattern of an amorphous form of amisulpride hydrochloride;
FIG. 3 isR-a powder X-ray diffraction pattern of amorphous form of amisulpride sulphate;
FIG. 4 is a drawing ofR,S-amisulpride optical purity determination high performance liquid chromatogram;
FIG. 5 is a drawing ofSAmisulpride-D-high performance liquid chromatogram for optical purity determination of tartrate;
FIG. 6 is a drawing ofRAmisulpride-L-high performance liquid chromatogram for determination of optical purity of tartrate.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention will be described in detail and fully with reference to the following embodiments.
Example 1R-2-aminomethyl-N-ethylpyrrolidine-LSynthesis of tartrate
Will be provided withL45.6 g of tartaric acid 60 mL of distilled waterAnd stirring until the mixture is completely dissolved, slowly dropwise adding 30 g of 2-aminomethyl-N-ethylpyrrolidine, keeping the temperature between 25 ℃ and ~ 30 ℃ in the dropwise adding process, stirring for 1h at room temperature after the dropwise adding is finished, then adding 260 ml of methanol into a reaction bottle, stirring for 2h at 12 +/-2 ℃, filtering, washing a filter cake once with 20 ml of methanol, filtering, adding the filter cake into 190ml of 75% methanol, heating to be clear, naturally cooling to 20 +/-2 ℃, stirring for 1h, performing suction filtration, leaching with 15ml of methanol, and drying to obtain a colorless solid.
Will be provided withR-2-aminomethyl-N-ethylpyrrolidine-L11g of tartrate is dissolved in 60 ml of distilled water, 36 g of 30% sodium hydroxide solution is added dropwise, after addition, the mixture is stirred at 20. + -. 2 ℃ for 1h, extracted with dichloromethane (30 ml. times.3), the organic phases are combined, dried over anhydrous sodium sulfate, filtered and rotary evaporated to dryness.
Example 2RSynthesis of amisulpride
Dissolving 10g of amiric acid and 4.96 g of triethylamine in 50ml of acetone, cooling to 5 ℃, slowly dropwise adding 5.6 g of isopropyl chloride, stirring for 0.5 h under heat preservation after dropwise adding, and then slowly dropwise adding the solution prepared in the example 1R-2-aminomethyl-N25 mL of an acetone solution of 6.42 g of ethyl pyrrolidine, after dropwise addition, was stirred at 12 ℃ for 0.5 h, and then moved to room temperature and stirred for 1 h. Rotary evaporation, addition of water and extraction with dichloromethane (25 ml × 3), combination of organic phases, drying over anhydrous sodium sulfate, filtration and rotary evaporation to dryness gave a yellowish brown oil.
Example 3RSynthesis of amisulpride maleic acid
Prepared in example 2RHeating and dissolving 10g of amisulpride and 35 ml of methanol, adding 15ml of methanol solution of 4.06 g of maleic acid, stirring at 45 ℃ for 5h, cooling to 3 ℃ and stirring for 3h, separating out a large amount of crystals, performing suction filtration and drying to obtain a product with the yield of 10.9g of 83% and the optical purity of ee% = 100%.
Example 4R-amisulprideLSynthesis of tartaric acid
Adding 50g of R-amisulpride (prepared in example 2) and 190ml of methanol into a 500ml reaction bottle, heating and stirring, controlling the temperature to be 40 ~ 50 ℃ and dropping a mixed solution of L-tartaric acid (21.3 g and 0.142 mol) and 90ml of methanol at 40 ℃ to 50 ℃, preserving heat and stirring for 2h after dropping, cooling to-10 ~ -20 ℃, stirring for 1h, filtering, washing a filter cake with a small amount of cold methanol, and drying by blowing at 45 ℃ to obtain the product with yield of 61.11g being 87%, and optical purity being ee% = 100%.
Example 5RSynthesis of amisulpride hydrochloride
Adding 5g of R-amisulpride (0.0135 mol) prepared in example 2 into a 50ml reaction bottle, dissolving 10ml of diethyl ether in 2ml of methanol for dilution, stirring at room temperature, dropwise adding a mixed solution of 2g of saturated hydrogen chloride diethyl ether solution and 10ml of diethyl ether at controlled temperature, preserving heat and stirring for 2h after dropwise adding is finished, cooling to-10 ~ -20 ℃, stirring for 1h, filtering, washing a filter cake with a small amount of cold diethyl ether, and drying by blowing at 45 ℃ to obtain a product with the yield of 4.12g and the optical purity ee% = 100%.
Example 6RSynthesis of amisulpride sulfate
Adding 5g of R-amisulpride (0.0135 mol) prepared in example 2 into a 50ml reaction bottle, diluting the R-amisulpride with 10ml of ethyl ether in 2ml of methanol, stirring at 0 ~ 5 ℃, dropwise adding 9g of 15% ether sulfate solution and 5ml of ethyl ether mixed solution at controlled temperature, keeping the temperature and stirring for 2h after dropwise adding, cooling to-10 ~ -20 ℃, stirring for 1h, filtering, washing a filter cake with a small amount of cold ethyl ether, and drying by blowing at 45 ℃ to obtain a product with the yield of 5.43g of 86% and the optical purity of ee% = 100%.
Example 7RAmisulpride-L-crystalline form A of the tartrate salt
Obtained in example 4RAdding 10g of amisulpride L-tartrate into 50mL of methanol, heating to 55 ~ 60 ℃, dissolving the solid, filtering, cooling the filtrate for crystallization, stirring for 2h at 10 ~ 15 ℃, filtering, washing the filter cake with methanol, and drying by blowing at 45 ℃ to obtain the amisulpride L-tartrateRAmisulpride-LTartrate 9.23g yield 92.3%.
Will obtainRAmisulpride sulphate X-ray powder diffraction pattern measured using Cu-ka radiation, as shown in figure 1.
Example 8RAmorphous form of amisulpride hydrochloride
Obtained in example 5R1g of amisulpride hydrochloride is added into 5mL of methanol, the temperature is raised to 55 ~ 60 ℃, the solid is dissolved and filtered, the filtrate is cooled and crystallized, the mixture is stirred for 2 hours at 10 ~ 15 ℃, filtered, the filter cake is washed by the methanol, and the mixture is dried by air blowing at 45 ℃ to obtain R-Amisulpride hydrochloride 0.8g yield 80%.
The obtained R-amisulpride hydrochloride has X-ray powder diffraction pattern measured by Cu-Kalpha ray, as shown in figure 2.
Example 9RAmorphous form of amisulpride sulphate
Obtained in example 6RAdding 1g of amisulpride sulfate into 5mL of methanol, heating to 55 ~ 60 ℃, dissolving solids, filtering, cooling the filtrate for crystallization, stirring at 10 ~ 15 ℃ for 2h, filtering, washing a filter cake with methanol, and drying by blowing at 45 ℃ to obtain the amisulpride sulfateR0.65g of amisulpride sulfate, 65% yield.
The obtained R-amisulpride sulfate has X-ray powder diffraction pattern measured by Cu-Kalpha ray, as shown in figure 2.
Test example 1 optical purity measurement
The instrument comprises the following steps: high performance liquid chromatograph
Reagents and solvents: diethylamine AR, chromatographic n-hexane, chromatographic ethanol
Chromatographic conditions are as follows:
a chromatographic column: ChiralpakAD-H (250 mm X4.6 mm, 5 um)
Detection wavelength: 224nm
Flow rate: 0.6ml/min
Column temperature: 23 deg.C
Preparing a mobile phase: n-hexane solution (0.05 ml of diethylamine added to 650 ml of n-hexane solution) -ethanol (65: 35: 0.05).
R,S-amisulpride control solution: precision weighingR,SPutting a 10 mg sample of amisulpride into a 10ml volumetric flask, dissolving the sample in ethanol, fixing the volume with the ethanol to obtain a stock solution, putting 2ml of the stock solution into the 10ml volumetric flask, fixing the volume and preparing a sample solution of 200 mu g/ml.
SAmisulpride-DTartrate control solution: weighing 10 mg of sample, placing the sample in a 10ml volumetric flask, dissolving the sample in ethanol, and determining the volume of the ethanol to obtain a stock solution. Taking 2ml of the stock solution, putting the stock solution into a 10ml volumetric flask, fixing the volume and preparing a sample solution of 200 mug/ml.
Prepared in example 4RAmisulpride-LTartaric acid test solution: weighing 10 mg of sample, placing the sample in a 10ml volumetric flask, dissolving the sample in ethanol, and determining the volume of the ethanol to obtain a stock solution. Taking 2ml of the stock solution, putting the stock solution into a 10ml volumetric flask, fixing the volume and preparing a sample solution of 200 mug/ml.
Using the above-described assay conditions and instrument pairsR,S-amisulpride reference solutions were subjected to assay analysis, retention time and optical purity analysis, the spectrum of which is shown in figure 4.
Using the above-described assay conditions and instrument pairsSAmisulpride-DThe tartrate control solution was subjected to assay analysis, retention time and optical purity analysis, and its spectrum is shown in FIG. 5.
Using the above-described assay conditions and instrument pairsRAmisulpride-LThe tartaric acid test solution is subjected to determination analysis, retention time analysis and optical purity analysis, the spectrum is shown in figure 6, and the optical purity of the sample is 100% by area normalization.
R,SAmisulpride achieves a baseline separation with a degree of separation of greater than 1.5, withSAmisulpride-DComparison of the tartrate control chromatograms determined RT =8.237 for the S configuration and RT =9.471 for the R configuration.
Test example 2RAmisulpride-LStability study of tartaric acid
1. Illumination experiment
The solid obtained in example 4 was takenRAmisulpride-LTartaric acid and prepared as in example 7RAmisulpride-LAn appropriate amount of tartaric acid crystal form A is spread in a culture dish (about 2mm in thickness), placed under the strong light irradiation condition of 4500Lx +/-500 Lx for 10 days, sampled and detected on the 5 th day and the 10 th day, and the content and the optical purity are detected by using a high performance liquid phase.
TABLE 1 illumination test results
2. High temperature experiment
The solid obtained in example 4 was takenRAmisulpride-LTartaric acid and prepared as in example 7RAmisulpride-LAn appropriate amount of tartaric acid crystal form a was spread in a petri dish (about 2mm in thickness), placed in a 60 ℃ incubator for 10 days, sampled and detected on days 5 and 10, and the content and optical purity were detected by using a high performance liquid chromatography.
TABLE 2 high temperature test results
3. High humidity experiment
The solid obtained in example 4 was takenRAmisulpride-LTartaric acid and prepared as in example 7RAmisulpride-LAn appropriate amount of tartaric acid crystal form A is spread in a culture dish (about 2mm in thickness), placed under the conditions of room temperature 25 +/-2 ℃ and relative humidity RH90 +/-5% for 10 days, sampled and detected on the 5 th day and the 10 th day, and the content and the optical purity are detected by using a high performance liquid phase.
TABLE 3 high humidity test results
4. Accelerated test
The solid obtained in example 4 was takenRAmisulpride-LTartaric acid and prepared as in example 7RAmisulpride-LAn appropriate amount of tartaric acid crystal form A, placing at 40 deg.C and 75% R.H for 6 months, sampling at the end of 1, 2, 3, 6 months, and detecting content and optical purity by high performance liquid chromatography.
TABLE 4 accelerated test results
As can be seen from the above experimental data, the inventionRAmisulpride-LThe stability of tartaric acid crystal form a under light, high temperature, high humidity and accelerated test conditions was superior to the crystallization stability of example 4.
Test example 3RAmisulpride-LSolubility of tartaric acid
Measured according to the regulation of the second part of the radix et rhizoma Parthenocissi Hemsl (2) of the Chinese pharmacopoeia 2005 editionRAmisulpride-LThe solubility in water of the tartaric acid crystalline form A is greater than that obtained in example 4RAmisulpride-L-tartaric acid.
Test example 4RStability study of amisulpride hydrochloride
1. Illumination experiment
The solid obtained in example 5 was takenRAmisulpride hydrochloride and prepared as in example 8RAppropriate amount of amorphous amisulpride hydrochloride is spread in a culture dish (about 2mm in thickness), placed under strong light irradiation of 4500Lx +/-500 Lx for 10 days, sampled and detected on 5 days and 10 days, and content and optical purity are detected by using high performance liquid phase.
TABLE 5 illumination test results
2. High temperature experiment
The solid obtained in example 5 was takenRAmisulpride hydrochloride and prepared as in example 8RAppropriate amount of amorphous amisulpride hydrochloride was spread in a petri dish (about 2mm in thickness), placed in a 60 ℃ incubator for 10 days, sampled and tested on days 5 and 10, and the content and optical purity were tested by high performance liquid chromatography.
TABLE 6 high temperature test results
3. High humidity experiment
The solid obtained in example 5 was takenRAmisulpride hydrochloride and prepared as in example 8RAn appropriate amount of amorphous amisulpride hydrochloride was spread in a petri dish (about 2mm in thickness), placed at room temperature of 25 ℃. + -. 2 ℃ and relative humidity of RH 90. + -. 5% for 10 days, sampled and tested on days 5 and 10, and the content and optical purity were determined using high performance liquid chromatography.
Table 7 high humidity test results
4. Accelerated test
The solid obtained in example 5 was takenRAmisulpride hydrochloride and prepared as in example 8RProper amorphous form of amisulpride hydrochloride, placing at 40 ℃ and 75% R.H for 6 months, sampling and detecting at the end of 1, 2, 3 and 6 months, and detecting content and optical purity by using a high performance liquid phase.
TABLE 8 accelerated test results
As can be seen from the experimental data, the product prepared by the inventionRThe amorphous form of amisulpride hydrochloride has better stability than the crystalline stability of example 5 under the conditions of illumination, high temperature, high humidity and accelerated test.
Test example 5RSolubility of amisulpride hydrochloride
Measured according to the regulation of the second part of the radix et rhizoma Parthenocissi Hemsl (2) of the Chinese pharmacopoeia 2005 editionRThe solubility in water of the amorphous form of amisulpride hydrochloride is greater than that obtained in example 5R-amisulpride hydrochloride.
Test example 6RStability Studies of amisulpride sulfate
1. Illumination experiment
The solid obtained in example 6 was takenRAmisulpride sulphate and prepared as in example 9RAn appropriate amount of amorphous amisulpride sulfate is spread in a culture dish (about 2mm in thickness), placed under the strong light irradiation condition of 4500Lx +/-500 Lx for 10 days, sampled and detected on the 5 th day and the 10 th day, and the content and the optical purity are detected by using a high performance liquid phase.
TABLE 9 illumination test results
2. High temperature experiment
Taking example 6The obtained solidRAmisulpride sulphate and prepared as in example 9RAn appropriate amount of amorphous amisulpride sulfate was spread in a petri dish (about 2mm in thickness), placed in a 60 ℃ incubator for 10 days, sampled and detected on days 5 and 10, and the content and optical purity were detected by using a high performance liquid chromatography.
TABLE 10 high temperature test results
3. High humidity experiment
The solid obtained in example 6 was takenRAmisulpride sulphate and prepared as in example 9RAn appropriate amount of amorphous amisulpride sulfate is spread in a culture dish (about 2mm in thickness), placed under the conditions of room temperature of 25 +/-2 ℃ and relative humidity of RH90 +/-5% for 10 days, sampled and detected on the 5 th day and the 10 th day, and the content and the optical purity are detected by using a high performance liquid phase.
TABLE 11 high humidity test results
4. Accelerated test
The solid obtained in example 6 was takenRAmisulpride sulphate and prepared as in example 9RProper amorphous form of amisulpride sulfate, placing at 40 ℃ and 75% R.H for 6 months, sampling and detecting at the end of 1, 2, 3 and 6 months, and detecting content and optical purity by using a high performance liquid phase.
TABLE 12 accelerated test results
As can be seen from the experimental data, the product prepared by the inventionRThe amorphous form of amisulpride sulphate is more stable than the crystalline form of example 6 under light, high temperature, high humidity and accelerated test conditions.
Test example 7RSolubility of amisulpride sulphate
Measured according to the regulation of the second part of the radix et rhizoma Parthenocissi Hemsl (2) of the Chinese pharmacopoeia 2005 editionRThe solubility in water of the amorphous form of amisulpride sulphate is greater than that obtained in example 6R-amisulpride sulphate.
Test example 8 oral glucose tolerance test in Normal mice
The weight was recorded using 8 week-old Kunming mice, male, randomly divided into 4 groups of 10 mice each. Blank control groups were used: 1.5ml of physiological saline is given orally; test group 1: to the preparation of example 4RAmisulpride-LTartrate (3.0. mu. mol/kg), dissolved in 1.5ml of physiological saline; test group 2: to the preparation of example 5RAmisulpride hydrochloride (3.0. mu. mol/kg), dissolved in 1.5ml of physiological saline for oral administration; test group 3: to the preparation of example 5RAmisulpride sulphate (3.0. mu. mol/kg), dissolved in 1.5ml of physiological saline for oral administration.
Before the experiment, mice are fasted for 12 hours without water prohibition, and all groups are orally administrated by gastric lavage, blood is taken from tail vein, and the blood sugar value is measured (recorded as 0 min). Then 4 groups of mice are respectively gavaged and given with physiological saline,R-amisulpride L-tartrate,RAmisulpride hydrochloride andRamisulpride sulfate, measuring the blood glucose value after 30min and recording for 30min, then immediately administering a glucose solution with the concentration of 3g/10ml by intragastric administration according to 10ml/kg, and measuring the blood glucose value (mmol/L) after 15min (recording for 45 min), 30min (recording for 60 min), 45min (recording for 75 min), 60min (recording for 90 min) and 120min (recording for 150 min). The results are shown in Table 13.
TABLE 13 blood glucose value variation
According to the oral glucose tolerance test of mice, the compounds of the tested groups 1-3 can obviously improve the glucose tolerance of the mice and show a more obvious hypoglycemic effect.
What should be noted later is: the above examples are only intended to illustrate the technical solution of the present invention, but not to limit it; although the present invention has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: the technical solutions described in the foregoing embodiments may still be modified, or some technical features may be equivalently replaced; and such modifications or substitutions do not depart from the spirit and scope of the corresponding 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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| CN103906514A (en) * | 2011-09-13 | 2014-07-02 | 拜奥迈德瓦利探索有限公司 | Compositions and methods for treating metabolic disorders |
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