L-potassium aspartate crystal form and preparation method thereof

Abstract

The invention provides a brand-new crystal form of a compound shown as a formula (I), and the crystal form is named as crystal form A. The X-ray powder diffraction pattern of the crystal form A provided by the invention has characteristic peaks when the 2 theta value is 14.6 + / -0.2 degrees, 37.6 + / -0.2 degrees and 39.0 + / -0.2 degrees. The compound is high in chemical purity, good in powder fluidity and good in crystal form stability, does not agglomerate in the storage process, does not generate degradation impurity fumaric acid, has the liquid chromatographic purity of not less than 99.9%, and has the total impurity content of not more than 0.1%. By accurately adjusting the ratio of ethanol to water and the unique crystallization mode, the polymorphic form of the compound shown in the formula (I) with high chemical purity is prepared. The powder is good in stability, not easy to degrade, not easy to cake, good in powder fluidity, not easy to generate static electricity, convenient to feed, easy to store, simple in process operation, easy to prepare and suitable for industrial production.

Description

Technical Field

[0001] The present invention belongs to the field of drug synthesis, and particularly relates to potassium L-aspartate crystals. Background Art

[0002] Potassium L-aspartate, chemical name: potassium L-2-aminobutanedioate. Aspartic acid in potassium L-aspartate participates in the tricarboxylic acid cycle to produce more ATP, directly providing energy for the cell membrane Na+-K+-ATPase to transport more K+, increasing the intracellular K+. In addition, K+ enters the cell under the action of the sodium pump, and the high-potassium environment is beneficial to intracellular material metabolism. For example, the liver is the main site for glycogen synthesis in the body, and the accelerated intake of potassium by hepatocytes can promote glycogen synthesis. Potassium L-aspartate is converted into other non-essential beneficial amino acids in the liver and brain mitochondria. At the same time, potassium L-aspartate also plays an important role in the synthesis of purines and pyrimidines. The synthesis of amino acids and nucleic acids can accelerate the cell self-repair and regeneration process, play an energy metabolism role and supplement ATP through the endoplasmic reticulum and mitochondria, reduce endoplasmic reticulum stress, inhibit endoplasmic reticulum-related apoptosis, increase the synthesis of aspartate aminotransferase, further promote the conversion of aspartic acid into oxaloacetic acid, promote ATP production, improve the activity of the sodium pump and promote the cell to synthesize proteins and nucleic acids, synergistically promoting each other. Potassium L-aspartate is a potassium supplement drug, clinically used for hypokalemia caused by various reasons, as an electrolyte supplement drug, used for hypokalemia caused by various reasons, periodic paralysis caused by hypokalemia, and arrhythmia caused by digitalis poisoning. Its chemical structure is as follows.

[0003]

[0004] Currently, Patent CN101234992A discloses a preparation method of the compound of formula (I): reacting L-aspartic acid with potassium hydroxide, concentrating the aqueous solution after the reaction to a viscous substance, and adding the viscous substance to an organic solvent for crystallization. Since the viscous substance needs to be added to the reaction kettle, the production operability is poor, the potassium L-aspartate crystals cannot be obtained, and the solid solvent residue obtained is relatively high.

[0005] Patent CN103664668A discloses a preparation method of the compound of formula (I): reacting L-aspartic acid with an inorganic base of potassium, and spray-drying the aqueous solution after the reaction to obtain the product. This method has high requirements for equipment and large investment, and the solid obtained by spray-drying is amorphous, and usually the stability of the amorphous is poor.

[0006] Patent CN103193661A discloses the polymorphs of potassium DL-aspartate. CN108546236B discloses the preparation of the amorphous form of the compound of formula (I). Amorphous potassium aspartate is usually very unstable, the powder itself has poor fluidity, and it is easy to absorb moisture and agglomerate during storage. SUMMARY OF THE INVENTION

[0007] An object of the present invention is to provide a new crystal form of the compound of formula (I) and a method for preparing the same. The structural formula of the compound of formula (I) is as follows:

[0008]

[0009] The structural formula of the new crystal form of the compound of formula (I) is as follows:

[0010]

[0011] An object of the present invention is to provide a crystal form of the compound of formula (I) named Crystal Form A.

[0012] Crystal Form A provided by the present invention is characterized in that its X-ray powder diffraction pattern has characteristic peaks at 2θ values of 14.6° ± 0.2°, 37.6° ± 0.2°, and 39.0° ± 0.2°.

[0013] Furthermore, Crystal Form A provided by the present invention is further characterized in that its X-ray powder diffraction pattern further includes one or two or three characteristic peaks at 2θ values of 22.3° ± 0.2°, 26.4° ± 0.2°, and 28.7° ± 0.2°.

[0014] Still further, Crystal Form A provided by the present invention is further characterized in that its X-ray powder diffraction pattern has characteristic peaks at 2θ values of 22.3° ± 0.2°, 26.4° ± 0.2°, and 28.7° ± 0.2°.

[0015] Furthermore, Crystal Form A of the present invention is further characterized in that its X-ray powder diffraction pattern further includes one or two or three or four characteristic peaks at 2θ values of 18.3° ± 0.2°, 21.8° ± 0.2°, 31.7° ± 0.2°, and 33.9° ± 0.2°.

[0016] Still further, Crystal Form A provided by the present invention is further characterized in that its X-ray powder diffraction pattern has characteristic peaks at 2θ values of 18.3° ± 0.2°, 21.8° ± 0.2°, 31.7° ± 0.2°, and 33.9° ± 0.2°.

[0017] Preferably, the X-ray powder diffraction pattern of Crystal Form A provided by the present invention includes characteristic peaks at 2θ values of 14.6° ± 0.2°, 37.6° ± 0.2°, 39.0° ± 0.2°, 22.3° ± 0.2°, 26.4° ± 0.2°, 28.7° ± 0.2°, 18.3° ± 0.2°, 21.8° ± 0.2°, 31.7° ± 0.2°, and 33.9° ± 0.2°.

[0018] Furthermore, the crystalline form A provided by the present invention is further characterized in that its X-ray powder diffraction pattern is substantially as Figure 1 shown.

[0019] The crystalline form A provided by the present invention is further characterized in that when differential scanning calorimetry is performed, an endothermic peak starts to appear near 43 °C during heating, and its differential scanning calorimetry pattern is substantially as Figure 2 shown.

[0020] The crystalline form A provided by the present invention is further characterized in that when thermogravimetric analysis is performed, when heated to 100 °C, it has a weight loss of about 3.1%, and when continuously heated to 215 °C, it has a weight loss of about 14.1%, and its thermogravimetric analysis pattern is substantially as Figure 3 shown.

[0021] Another object of the present invention is to provide a preparation method of crystalline form A, in which formula (III) reacts with an inorganic base of potassium, and an alcohol solvent is dropped into the reaction solution for crystallization to obtain formula (II),

[0022] The structural formula of the above formula (III) is:

[0023]

[0024] Furthermore, the inorganic base of potassium is preferably potassium hydroxide.

[0025] Furthermore, the alcohol solvent is preferably ethanol.

[0026] Furthermore, the feeding ratio of formula (III) to the base is 1.0 to 1.05.

[0027] Furthermore, the solvent ratio of alcohol to water is 1:1 to 2:1.

[0028] The present invention prepares a new crystalline form of the compound of formula (I) with high chemical purity by accurately adjusting the ratio of ethanol to water and its unique crystallization method. It has good stability, is not easily degraded, does not easily agglomerate, has good powder fluidity, does not easily generate static electricity, is convenient for feeding and easy to store, the process operation is simple and easy to prepare, and is suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] Figure 1 is the XRPD pattern of crystalline form A;

[0030] Figure 2 is the DSC pattern of crystalline form A;

[0031] Figure 3 is the TGA pattern of crystalline form A;

[0032] Figure 4 is the XRPD pattern of crystalline form A;

[0033] Figure 5 XRPD pattern of polymorph A;

[0034] Figure 6 Liquid chromatography detection spectrum of polymorph A;

[0035] Figure 7 Liquid chromatography detection spectrum of polymorph A;

[0036] Figure 8 Liquid chromatography detection spectrum of the stability of polymorph A;

[0037] Figure 9 Liquid chromatography detection spectrum of the stability of amorphous form; Detailed implementation mode

[0038] Example 1

[0039] The present invention will be further described below through specific examples, but it is not used to limit the protection scope of the present invention. Those skilled in the art can make improvements to the preparation method and the instruments used within the scope of the claims, and these improvements should also be regarded as the protection scope of the present invention. Therefore, the protection scope of this invention patent shall be subject to the appended claims.

[0040] In the present invention, unless otherwise specified, each abbreviation has the conventional meaning understood by those skilled in the art.

[0041] In the present invention, the purity or content obtained by HPLC detection refers to the purity or content (area%) calculated by the area normalization method.

[0042] In the present invention, XRPD detection method:

[0043] X-ray powder diffraction instrument: Bruker D2 Phaser X-ray powder diffractometer; Light source: Voltage: 30 kv; Current: 10 mA; Scanning range: 3 - 40°.

[0044] In the present invention, DSC detection method:

[0045] Differential scanning calorimetry (DSC) instrument: DSC250 type of TA Company, USA; In the range of 25 - 300 °C; Heating rate 10 °C / min; Nitrogen protection.

[0046] In the present invention, TGA detection method:

[0047] Thermogravimetric analysis (TGA) instrument: TGA55 type of TA Company, USA; In the range of 20 - 300 °C; Heating rate 10 °C / min; Nitrogen protection.

[0048] Preparation of polymorph A of the compound of formula (I) in Example 1

[0049] Take 31.6 g of potassium hydroxide and 200 mL of water, stir and dissolve, and add 75 g of the compound of formula (III). After adding, heat up to 55 - 60 °C and stir for 2 - 3 h. Cool down to 40 - 50 °C, distill off 100 mL of water under reduced pressure, drop 200 mL of absolute ethanol into the reaction solution, after dropping, stir at 40 - 50 °C for 5 - 6 h, add 100 mL of water, cool down to -5 - 0 °C, stir for 1 h to crystallize, let stand for 1 h, stir for 1 h to crystallize again, let stand for 1 h, and repeat this operation 5 - 6 times. Filter by suction, dry the filter cake to obtain 107.3 g of an off-white solid, HPLC: 99.9%, yield 92%, KF: 17.39%, ethanol GC: 0.063%. After detection, the obtained crystalline solid is polymorph A of the present invention, and its X-ray powder diffraction data is shown in Table 1. Its XRPD pattern is as shown in Figure 1 shown. The DSC pattern is as shown in Figure 2 shown, and an endothermic peak starts to appear near 43 °C when heated. The TGA pattern is as shown in Figure 3 shown, when heated to 100 °C, it has a weight loss of about 3.1%, and when continuously heated to 215 °C, it has a weight loss of about 14.1%. The HPLC pattern is as shown in Figure 6 shown.

[0050] Table 1

[0051]

[0052]

[0053] Preparation of polymorph A of the compound of formula (I) in Example 2

[0054] Take 66.3 g of potassium hydroxide and 210 mL of water, stir and dissolve, and add 150 g of the compound of formula (III). After adding, heat up to 55 - 60 °C and stir for 2 - 3 h. Cool down to 40 - 50 °C, distill off 105 mL of water under reduced pressure, drop 420 mL of absolute ethanol into the reaction solution, after dropping, stir at 40 - 50 °C for 5 - 6 h, add 105 mL of water, cool down to -5 - 0 °C, stir for 1 h to crystallize, let stand for 1 h, stir for 1 h to crystallize again, let stand for 1 h, and repeat this operation 5 - 6 times. Filter by suction, dry the filter cake to obtain 216.9 g of an off-white solid, HPLC: 99.9%, yield 93%, KF: 17.36%. Its HPLC pattern is as shown in Figure 7 shown.

[0055] Preparation of polymorph A of the compound of formula (I) in Example 3

[0056] Take 50.5 g of potassium hydroxide and 120 mL of water, stir to dissolve, and add 120 g of the compound of formula (III). After adding, heat up to 55 - 60 °C and stir for 2 - 3 h. Cool down to 40 - 50 °C, distill off 60 mL of water under reduced pressure, dropwise add 360 mL of absolute ethanol to the reaction solution, after dropping, stir at 40 - 50 °C for 5 - 6 h, add 60 mL of water, cool down to -5 - 0 °C, stir for 1 h to crystallize, let stand for 1 h, then stir for 1 h to crystallize again, let stand for 1 h, repeat this operation 5 - 6 times to precipitate an off-white solid.

[0057] Preparation of Crystal Form A of the Compound of Formula (I) in Example 4

[0058] Take 25.2 g of potassium hydroxide and 240 mL of water, stir to dissolve, and add 60 g of the compound of formula (III). After adding, heat up to 55 - 60 °C and stir for 2 - 3 h. Cool down to 40 - 50 °C, distill off 120 mL of water under reduced pressure, dropwise add 120 mL of absolute ethanol to the reaction solution, after dropping, stir at 40 - 50 °C for 5 - 6 h, add 120 mL of water, cool down to -5 - 0 °C, stir for 1 h to crystallize, let stand for 1 h, then stir for 1 h to crystallize again, let stand for 1 h, repeat this operation 5 - 6 times to precipitate an off-white solid.

[0059] Preparation of the Amorphous Form of the Compound of Formula (I) in Example 5

[0060] Take 20 g of Crystal Form A of the compound of formula (I), dissolve it in 200 mL of water by stirring, and lyophilize the aqueous solution to obtain an off-white amorphous solid.

[0061] Study on the fluidity of the amorphous form of the compound of formula (I) and Crystal Form A of the compound of formula (I) in Example 6. Respectively measure their bulk density, tapped density and angle of repose, and the results are shown in Table 2.

[0062] Test method for bulk density and tapped density: Select a 100 mL graduated cylinder, fill it with an appropriate volume of the material to be tested, record the initial bulk volume, and convert the bulk density. Bulk density = material weight / bulk volume; Use a ZS - 2E vibrator, select the method of 300 times per minute, measure the observed volume for 1 minute, then measure the observed volume twice for 1 minute until it remains unchanged, read the tapped volume, and convert the tapped density. Tapped density = material weight / tapped volume;

[0063] Convert the Hausner ratio: Hausner ratio = tapped density / bulk density. The closer the Hausner ratio is to 1, the better the fluidity. When the Hausner ratio is between 1.00 - 1.11, the fluidity is very good; when it is between 1.12 - 1.18, the fluidity is good; when it is between 1.19 - 1.25, the fluidity is average; when it is between 1.26 - 1.34, the fluidity is qualified; when it is between 1.35 - 1.45, the fluidity is poor; when it is between 1.46 - 1.59, the fluidity is very poor; when it is greater than 1.6, it is difficult to flow;

[0064] Angle of repose test method: Use the FBS-104 angle of repose measuring instrument. Let the material fall naturally from the triangular funnel and form a loose pile on the horizontal plane. The angle between the conical slope and the horizontal angle is the angle of repose. The smaller the angle of repose, the better the fluidity of the material. When the angle of repose is between 25° and 30°, the fluidity is very good; when it is between 31° and 35°, the fluidity is good; when it is between 36° and 40°, the fluidity is average; when it is between 41° and 45°, the fluidity is qualified; when it is between 46° and 55°, the fluidity is poor; when it is between 56° and 65°, the fluidity is very poor; when it is greater than 65°, it is difficult to flow.

[0065] Table 2

[0066]

[0067] As can be seen from Table 2, the compound of formula (I) in crystalline form A has good fluidity. When feeding, using the compound of formula (I) in crystalline form A can avoid electrostatic adsorption and is easier to operate.

[0068] Study on the stability of the compound of formula (I) in crystalline form A in Example 7

[0069] Place the compound of formula (I) in crystalline form A at 40°C ± 2°C and 75% RH ± 5% RH for 6 months. The crystalline form of the compound of formula (I) in the sample is stable, and its XRPD pattern is as Figure 4 shown.

[0070] Study on the stability of the compound of formula (I) in crystalline form A in Example 8

[0071] Place the compound of formula (I) in crystalline form A at 30°C ± 2°C and 65% RH ± 5% RH for 12 months. The crystalline form of the compound of formula (I) in the sample is stable, the chemical purity hardly changes, and no fumaric acid degradation occurs. Its XRPD pattern is as Figure 5 shown. The HPLC pattern is as Figure 8 shown.

[0072] Study on the stability of the amorphous form of the compound of formula (I) in Example 9

[0073] Place the amorphous form of the compound of formula (I) at 30°C ± 2°C and 65% RH ± 5% RH for 1 month. The chemical purity of the amorphous form of the compound of formula (I) decreases significantly, and the fumaric acid content is 1.13%. The HPLC pattern is as Figure 9 shown.

[0074] After long-term in-depth research, the inventors unexpectedly discovered a new crystalline form of the compound of formula (I). It has high chemical purity, good powder fluidity, good crystalline form stability, does not caking during storage, does not produce degradation impurities maleic acid and fumaric acid, the liquid chromatography purity is not less than 99.9%, the total impurities do not exceed 0.1%, meeting the production requirements of API GMP, ensuring the quality and safety of the drug.

[0075] It should be noted that the above preferred embodiments are only used to illustrate the technical concept and features of the present invention. The purpose is to enable those skilled in the art to understand the content of the present invention and implement it accordingly, and it should not be used to limit the protection scope of the present invention. Any equivalent changes or modifications made according to the spirit of the present invention should be covered within the protection scope of the present invention.

Claims

1. A potassium L-aspartate crystal form, characterized in that, The structural formula of the potassium L-aspartate crystal form is as follows: The X-ray powder diffraction pattern of the potassium L-aspartate crystal form has characteristic peaks at 2θ values of 14.6° ± 0.2°, 37.6° ± 0.2°, and 39.0° ± 0.2°.

2. The potassium L-aspartate crystal form according to claim 1, wherein The X-ray powder diffraction pattern of the potassium L-aspartate crystal form further includes one or two or three characteristic peaks at 2θ values of 22.3° ± 0.2°, 26.4° ± 0.2°, and 28.7° ± 0.2°.

3. The potassium L-aspartate crystal form according to claim 2, characterized in that, The X-ray powder diffraction pattern of the potassium L-aspartate crystal form further includes characteristic peaks at 2θ values of 22.3° ± 0.2°, 26.4° ± 0.2°, and 28.7° ± 0.2°.

4. The potassium L-aspartate crystal form according to claim 3, wherein, The X-ray powder diffraction pattern of the potassium L-aspartate crystal form further includes one or two or three or four characteristic peaks at 2θ values of 18.3° ± 0.2°, 21.8° ± 0.2°, 31.7° ± 0.2°, and 33.9° ± 0.2°.

5. The potassium L-aspartate crystal form according to claim 4, characterized in that, The X-ray powder diffraction pattern of the potassium L-aspartate crystal form further includes characteristic peaks at 2θ values of 18.3° ± 0.2°, 21.8° ± 0.2°, 31.7° ± 0.2°, and 33.9° ± 0.2°.

6. The potassium L-aspartate crystal form according to claim 5, wherein The X-ray powder diffraction pattern of the potassium L-aspartate crystal form further includes characteristic peaks at 2θ values of 14.6° ± 0.2°, 37.6° ± 0.2°, 39.0° ± 0.2°, 22.3° ± 0.2°, 26.4° ± 0.2°, 28.7° ± 0.2°, 18.3° ± 0.2°, 21.8° ± 0.2°, 31.7° ± 0.2°, and 33.9° ± 0.2°.

7. The preparation method of any one of the potassium L-aspartate crystal forms according to claims 1 to 6, characterized in that, The preparation method of the potassium L-aspartate crystal form is as follows: Formula (III) reacts with an inorganic base of potassium, and an alcohol solvent is dropped into the reaction solution for crystallization to obtain Formula (II). The structural formula of the said Formula (III) is as follows: The structural formula of the said Formula (II) is as follows: The inorganic base of potassium is preferably potassium hydroxide; The alcohol solvent is preferably ethanol; The feeding ratio of Formula (III) to the base is 1.0 - 1.05; The solvent ratio of the alcohol to water is 1:1 - 2:1.

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