Crystal form of alpha-ketoglutarate calcium salt and preparation method thereof

Abstract

The invention discloses a crystal form I of a compound monohydrate alpha-ketoglutarate calcium salt as shown in a formula (I). The crystal form I uses CuK alpha radiation, and an X-ray powder diffraction spectrum expressed by a 2 theta angle at least has diffraction peaks at 9.934 degrees + / -0.2 degrees, 15.468 degrees + / -0.2 degrees, 26.785 degrees + / -0.2 degrees, 32.954 degrees + / -0.2 degrees, 37.863 degrees + / -0.2 degrees and 38.650 degrees + / -0.2 degrees. The invention also discloses a preparation method of the crystal form I. Alpha-ketoglutaric acid and calcium carbonate are used as raw materials and react in an aqueous solution to obtain the crystal form I of calcium alpha-ketoglutarate monohydrate. The preparation method is simple and practical to operate, the product does not contain chloride ions, and the crystal form I has the advantages of good stability, good moisture absorption resistance and the like. # imgabs0 #

Description

Technical Field

[0001] The invention belongs to the field of fine chemicals and medicinal chemistry, and specifically relates to a crystal form of alpha-ketoglutaric acid calcium salt and a preparation method thereof. Background Art

[0002] Calcium Alpha-Ketoglutarate, referred to as Ca-AKG, is a compound that is essential to the metabolic process of human cells. It is composed of calcium and α-ketoglutaric acid. α-Ketoglutaric acid is a key intermediate metabolite in the tricarboxylic acid cycle (TCA cycle), while calcium is an essential macronutrient for the human body and plays an important role in maintaining bone strength, muscle contraction, nerve conduction, etc.

[0003] Calcium α-ketoglutarate can participate in energy metabolism in the tricarboxylic acid cycle; promote muscle growth, enhance muscle strength and muscle mass; maintain bone health and prevent osteoporosis. It can also be used as an antioxidant to fight free radicals produced in the body, help delay the aging process, and prevent cardiovascular diseases, neurodegenerative diseases, etc. It has a wide range of applications in the fields of health care products, medical fields, food fields, and cosmetics fields.

[0004]

[0005] Among the currently reported preparation processes of Ca-AKG, most use α-ketoglutaric acid as raw material, first adjust its pH value to alkaline to make sodium salt or ammonium salt, and then react with calcium chloride to obtain calcium α-ketoglutarate.

[0006] The patent document with publication number CN115974679A reports a method for preparing calcium α-ketoglutarate, wherein α-ketoglutaric acid is neutralized to pH 5-6 by stirring in steps to obtain a mixed solution, and then after exhausting carbon dioxide by means of reduced pressure concentration, ammonia water is gradually added to adjust the pH value of the mixed solution to 7-7.5, and finally calcium chloride is added to obtain calcium α-ketoglutaric acid. In addition, the patent documents with publication numbers CN112955139A and CN102976927A both report similar methods of first reacting α-ketoglutaric acid with an alkali metal salt, such as sodium hydroxide or sodium carbonate, and then reacting with calcium chloride to obtain calcium α-ketoglutaric acid.

[0007] The patent document with publication number CN112941116B uses L-glutamic acid as a raw material, and in the presence of L-glutamate oxidase and catalase, oxidizes to obtain a ketoglutaric acid intermediate solution, and then purifies and salts with calcium chloride to obtain α-ketoglutarate calcium. Although this method uses L-glutamic acid as a raw material, it is essentially oxidized to α-ketoglutaric acid by enzymes, and then salted with calcium chloride to obtain it.

[0008] In the above-reported methods, the last step is to react with calcium chloride to obtain the product calcium α-ketoglutarate. The chloride ion content in the product is relatively high, exceeding 200 ppm, and it is difficult to reduce the chloride ion content by purification methods such as washing, and the high required product quality indicators cannot be met. Summary of the invention

[0009] In order to overcome the above-mentioned defects of the α-ketoglutarate calcium product prepared by the prior art method, we have improved the production process of α-ketoglutarate calcium, avoiding the use of chemical raw materials and chemical reagents containing chlorine elements, and the obtained product does not contain residual chloride ions. In addition, our product is in the form of crystals, which is confirmed to be a monohydrated α-ketoglutarate calcium salt after testing, has good stability and anti-hygroscopic properties, is convenient for further processing into pharmaceutical compositions and solid health foods, and is conducive to long-term storage and transportation. Therefore, the present invention provides the following technical solutions.

[0010] The first aspect of the present invention provides a crystal form of α-ketoglutarate calcium salt (Ca-AKG), which is the crystal form I of the monohydrated α-ketoglutarate calcium salt of the compound represented by formula (I), and its X-ray powder diffraction spectrum using CuKα radiation and expressed in 2θ angles has diffraction peaks at least at 9.934°±0.2°, 15.468°±0.2°, 26.785°±0.2° and 32.954°±0.2°.

[0011]

[0012] Preferably, the above-mentioned crystal form I has diffraction peaks at 2θ values ​​of 9.934°±0.1°, 15.468°±0.1°, 26.785°±0.1° and 32.954°±0.1°. More preferably, the above-mentioned crystal form has diffraction peaks at 2θ values ​​of approximately 9.934°, 15.468°, 26.785° and 32.954°.

[0013] Preferably, the above-mentioned crystal form I also has diffraction peaks at 2θ values ​​of 19.675°±0.2°, 21.979°±0.2°, 37.863°±0.2° and 38.650°±0.2°; preferably, the above-mentioned crystal form I also has diffraction peaks at 2θ values ​​of 19.675°±0.1°, 21.979°±0.1°, 37.863°±0.1° and 38.650°±0.1°; more preferably, the above-mentioned crystal form also has diffraction peaks at 2θ values ​​of approximately 19.675°, 21.979°, 37.863° and 38.650°.

[0014] Furthermore, the above-mentioned crystal form I also has diffraction peaks at 2θ values ​​of 17.673°±0.2°, 26.341°±0.2° and 29.74°±0.2°; preferably, the above-mentioned crystal form I also has diffraction peaks at 2θ values ​​of 17.673°±0.1°, 26.341°±0.1° and 29.74°±0.1°; more preferably, the above-mentioned crystal form also has diffraction peaks at 2θ values ​​of approximately 17.673°, 26.341° and 29.74°.

[0015] It should be understood that when expressing numerical characteristics in this article, the terms "about", "approximately" or "around" mean that the number represented may have an error range or floating range of ±10%, ±8%, ±6%, ±4% or ±2%.

[0016] In one embodiment, in the DSC analysis, the above-mentioned Form I has no obvious endothermic peaks in its DSC thermal analysis diagram, but has exothermic peaks at 207.59°C, 344.40°C and 463.78°C; preferably, the DSC spectrum of the Form I is substantially as follows Figure 2 shown.

[0017] Furthermore, in the thermogravimetric analysis, the TGA graph of the above-mentioned Form I contains two steps, 50-259.27°C is the first step, which is caused by the loss of adsorbed water and one crystal water; 259.27-500°C is the second step, which is caused by the decomposition of the Form I of the Ca-AKG salt; preferably, the TGA spectrum of the Form I is substantially as follows Figure 3 shown.

[0018] Preferably, the above-mentioned crystal form I substantially does not contain chloride ions.

[0019] The second aspect of the present invention provides a method for preparing the crystalline form I of the calcium salt of α-ketoglutarate as described above, comprising the following steps:

[0020] (1) dissolving α-ketoglutaric acid represented by formula (II) in water to form an aqueous solution, adding calcium carbonate in batches, and performing a neutralization reaction under stirring. If necessary, insoluble matter can be filtered out, for example, by centrifugation to remove the insoluble matter. Preferably, the reaction is stirred until the solution is clear;

[0021] (2) Cooling to room temperature, slowly precipitating crystals, filtering, and drying the filter cake to obtain the crystalline form I of the monohydrated α-ketoglutaric acid calcium salt (Ca-AKG) of the compound represented by formula (I):

[0022]

[0023] Preferably, in the above step (1), the molar ratio of α-ketoglutaric acid to calcium carbonate is 0.4-1.2:1, preferably 0.8-1:1.

[0024] The neutralization reaction conditions of the above step (1) can be: after adding calcium carbonate to the aqueous solution of α-ketoglutaric acid, stirring the reaction at room temperature for 1-3 hours, preferably about 2 hours; then heating to 40-60° C., preferably 45-50° C., and continuing stirring for 3-8 hours, preferably about 5 hours, and filtering out insoluble matter if necessary, for example, removing the insoluble matter by centrifugation, preferably until a transparent solution is obtained.

[0025] Preferably, the crystallization in the above step (2) is carried out under stirring conditions, for example, stirring for more than 8 hours, or stirring for more than 10 hours, to slowly precipitate crystals.

[0026] The third aspect of the present invention provides a pharmaceutical composition, a health food or a cosmetic, which comprises the above-mentioned crystal form I as an active ingredient.

[0027] Preferably, the pharmaceutical composition, health food or cosmetics are used to promote muscle growth, prevent osteoporosis, delay the aging process, etc.

[0028] The crystal form I of the monohydrated α-ketoglutaric acid calcium salt developed by the present invention does not contain chloride ions, and has good stability and anti-hygroscopicity, which is conducive to production line processing, long-term storage and transportation. The preparation method of the crystal form I is simple and practical to operate, and is suitable for large-scale production, for example, suitable for industrial-scale production of tens of kilograms, hundreds of kilograms or even tons. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] Figure 1 The X-ray powder diffraction pattern (XPRD pattern) of the Ca-AKG salt crystalline form I of the present invention.

[0030] Figure 2 The differential scanning calorimetry diagram (DSC diagram) of the Ca-AKG salt crystal form I of the present invention is shown in Figure 1. The abscissa is temperature (°C); the ordinate is heat flow (W / g).

[0031] Figure 3 This is a thermogravimetric analysis diagram (TGA diagram) of the Ca-AKG salt crystal form I of the present invention.

[0032] Figure 4 This is the infrared spectrum (IR) of the Ca-AKG salt form I of the present invention.

[0033] Figure 5 It is the mass spectrum (MS) of the Ca-AKG salt crystalline form I of the present invention.

[0034] Figure 6 It is a liquid chromatography (HPLC) of the Ca-AKG salt form I of the present invention. DETAILED DESCRIPTION

[0035] The present invention uses α-ketoglutaric acid and calcium carbonate as reaction raw materials, and controls the feeding ratio of the two, thereby avoiding the introduction of chlorine. The product is a crystal containing one molecule of crystal water, that is, the crystal form I of monohydrated α-ketoglutaric acid calcium (Ca-AKG) salt.

[0036] Although Form I contains water of crystallization, a thermal stability test at 40°C / 75% relative humidity (RH) for two weeks and a hygroscopic resistance test of a dynamic moisture sorption (DVS) test at 30°C / 80% relative humidity confirmed that Form I has good stability and hygroscopic resistance, is not easy to deliquesce, and has stable physical and chemical properties.

[0037] An important indicator for characterizing the crystal form I of the present invention is the X-ray powder diffraction pattern (XPRD), which is represented by the diffraction peak position, i.e., the diffraction angle 2θ (°), the interplanar spacing d The diffraction peak height (cts) and diffraction peak relative intensity (I / Imax) are summarized in Table 1.

[0038] Table 1. XPRD characteristics of Ca-AKG Form I

[0039]

[0040]

[0041] The term "relative intensity" refers to the ratio of the intensity of other peaks to the intensity of the highest intensity peak among all diffraction peaks in an X-ray powder diffraction pattern when the intensity of the highest intensity peak is 100%.

[0042] In a preferred embodiment, the crystalline form I of the present invention has Figure 1 The X-ray powder diffraction spectrum shown in is essentially the same as the X-ray powder diffraction pattern.

[0043] The term "substantially the same" means that at least 70%, at least 80%, at least 90%, at least 95%, or at least 99% of the peaks in the X-ray powder diffraction pattern appear in the exemplary X-ray powder diffraction spectrum given. Figure 1 middle.

[0044] It is well known to those skilled in the art that various factors may cause Form I to differ from the above Table 1 and Figure 1There are measured data and / or differences between the X-ray powder diffraction analysis results shown in: (a) errors in sample preparation (e.g., sample height), (b) instrument errors, (c) calibration differences, (d) operator errors (including errors that occur when determining peak positions), and (e) the nature of the material (e.g., preferred orientation errors). Calibration errors and sample height errors often result in displacements of all peaks in the same direction. When a flat support is used, small differences in sample height will result in large displacements of XRPD peak positions. Systematic studies have shown that sample height differences of 1 mm can result in peak displacements of up to 1° of 2θ. These displacements can be identified from X-ray diffraction patterns and can be eliminated by compensating for the displacements (using the system calibration factor for all peak position values) or recalibrating the instrument. As described above, by applying the system calibration factor to make the peak positions consistent, measurement errors from different instruments can be corrected.

[0045] The present invention also analyzes the crystal form I by differential scanning calorimetry. When using differential scanning calorimetry for analysis, there is no obvious endothermic peak in the DSC thermal analysis diagram, but there are exothermic peaks at 207.59°C, 344.40°C, and 463.78°C. The DSC spectrum of crystal form I is basically as follows Figure 2 It should be understood that similar to the situation with X-ray powder diffraction patterns, the values ​​quoted for differential scanning calorimetry techniques may vary and should not be interpreted as absolute values.

[0046] In a preferred embodiment, the differential scanning calorimetry (DSC) spectrum of Form I of the present invention is Figure 2 Same in substance.

[0047] The preparation method of the crystal form I of the present invention is not limited to the steps (1) and (2) described above, and can be prepared by a crystallization method commonly used in the art. Generally, the solubility limit of the calcium salt of α-ketoglutarate (Ca-AKG) is exceeded by operating the solution, thereby completing the crystallization on a production scale. This can be accomplished by a variety of methods, for example, by heating, dissolving the compound at a relatively high temperature, and then cooling the solution to below the saturation limit. Alternatively, the liquid volume can be reduced by boiling, evaporation at normal pressure, vacuum drying, or by some other method. The solubility of the Ca-AKG salt can be reduced by adding an antisolvent or a solvent in which the compound has a low solubility or a mixture of such solvents. Another optional method is to adjust the pH value to reduce the solubility.

[0048] If the formation of the desired Ca-AKG salt occurs simultaneously with crystallization, the addition of an appropriate acid or base may result in direct crystallization of the desired salt if the salt is less soluble in the reaction medium than the starting materials. Likewise, completion of the synthesis reaction in a medium in which the final desired form is less soluble than the reactants may result in direct crystallization of the final product.

[0049] Optimization of crystallization can include seeding the crystallization medium with the desired form of the Ca-AKG salt Form I to induce the production of more Form I. In addition, many crystallization methods use a combination of the above strategies. One example is to dissolve the Ca-AKG salt of interest in a solvent at an elevated temperature, followed by the addition of an appropriate volume of antisolvent in a controlled manner to bring the system just below the saturation level. At this point, the desired form of seed I can be added (while maintaining the integrity of the seed), and the system is cooled to complete the crystallization.

[0050] Ca-AKG salt crystal form I can be used as an active ingredient for promoting muscle growth, preventing osteoporosis and resisting aging to prepare pharmaceutical compositions, health foods or cosmetics.

[0051] The pharmaceutical composition, health food or cosmetic contains a therapeutically effective amount of Form I and further contains pharmaceutically acceptable excipients or carriers, or excipients or carriers acceptable in health food, or excipients or carriers acceptable in cosmetics.

[0052] The term "pharmaceutically acceptable carrier" refers to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with the active ingredients of the present invention and with each other without significantly reducing the efficacy of the active ingredients. Some examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (Tween), wetting agents (such as sodium lauryl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0053] The dosage form of the pharmaceutical composition of the present invention is not particularly limited, and representative dosage forms include, but are not limited to, oral, injection (parenteral), external use such as transdermal absorption, and the like.

[0054] Oral solid dosage forms include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active ingredient Ca-AKG salt form I is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, such as microcrystalline cellulose, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, such as hydroxymethylcellulose, alginate, gelatin, polyvinyl pyrrolidone, sucrose and gum arabic; (c) humectants, such as glycerol; (d) disintegrants , for example, agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, sodium carbonate, cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethylcellulose; (e) buffering agents, such as paraffin; (f) absorption accelerators, such as quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glyceryl monostearate; (h) adsorbents, such as kaolin; and (i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage form may also contain a buffer.

[0055] Solid dosage forms such as tablets, pills, capsules, pills and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifiers, and the release of the active ingredient in such compositions can be delayed in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes. If necessary, the active ingredient Ca-AKG crystal form I can also be formed into microcapsules with one or more of the above-mentioned excipients.

[0056] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active ingredient, the liquid dosage form may contain an inert diluent conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide and oils, in particular cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances.

[0057] Besides such inert diluents, the composition may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0058] In addition to the active ingredient Ca-AKG salt form I, the suspension may contain suspending agents such as, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances and the like.

[0059] Compositions for parenteral injection may include physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

[0060] External dosage forms include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required when necessary.

[0061] The present invention is further described below by examples. It should be understood that these examples are only for illustrative purposes and are not intended to limit the present invention. Various changes or adjustments made by those skilled in the art based on the present invention should all fall within the scope of protection of the present invention.

[0062] Example

[0063] Reagents: The reactants and catalysts used in the examples of the present invention are all chemically pure / analytical pure and can be used directly or after simple purification as needed; organic solvents are all analytically pure and used directly. Reagents were purchased from Aladdin Chemical Reagent Company.

[0064] X-ray powder diffraction:

[0065] X-ray powder diffraction analysis was performed on a Thermo Fisher Scientific powder X-ray diffractometer using CuKα radiation with a test power of 45 kV×40 mA, a scanning speed of 5° / min, a step width of 0.02°, and a θ~2θ continuous scan in the scanning range of 3~40° (2θ).

[0066] Differential Scanning Calorimetry (DSC) Characterization:

[0067] The measurement was performed using a TA Q2000 / 2500 differential scanning calorimeter with nitrogen as the protective gas, a heating rate of 10°C / min, and a temperature gradually rising from 25°C to the set end point.

[0068] Thermogravimetric analysis (TGA):

[0069] The measurement was performed using a TA company's Q5000 / 5500 thermogravimetric analyzer with nitrogen as the protective gas, a heating rate of 10°C / min, and a temperature gradually rising from room temperature to a set end point.

[0070] Mass spectrometer (liquid chromatography-mass spectrometry (LC / MS)), model: Agilent 6120B, detector: DAD.

[0071] HPLC chromatographic instrument: Agilent 1260 liquid chromatograph, wavelength: 210 nm, injection volume: 20 μL

[0072] Example 1: Preparation of Ca-AKG salt crystal form I

[0073]

[0074] Add 500L of water and 50kg (342mol, 1.0eq) of α-ketoglutaric acid to a 1000L reactor, stir and dissolve; add 30.6kg (308mol, 0.9eq) of calcium carbonate in batches, a large number of bubbles emerge, cool to room temperature after addition, stir and react for 2 hours, heat to 45-50℃ and stir and react for 5 hours, filter out insoluble matter by centrifugation to obtain a transparent solution. Then cool to room temperature, stir for 10 hours, and slowly precipitate crystals. Filter, rinse the filter cake with a small amount of 45-50℃ water twice, dry in a blast oven at 50 degrees overnight to obtain 50kg of monohydrated α-ketoglutaric acid calcium, HPLC purity: 99.8%, content: 102%, calcium content: 19.5%, drying loss: 0.7%, molar yield: 72.3%, sulfate and chloride ion are not detected.

[0075] The powder X-ray diffraction pattern of Form I of Ca-AKG salt is shown in Figure 1 , the absorption peak data are listed in Table 1.

[0076] The DSC thermal analysis diagram of the crystal form I of Ca-AKG salt is shown in Figure 2 As shown. There is an exothermic peak at 207.59℃, with an enthalpy change value of 227.5J / g; there is an exothermic peak at 334.40℃, with an enthalpy change value of 50.92J / g; there is an exothermic peak at 463.78℃, with an enthalpy change value of 148.8J / g; it is caused by the decomposition of the crystalline form I of the Ca-AKG salt, and there is no obvious endothermic peak.

[0077] The TGA thermogravimetric analysis of the crystalline form I of Ca-AKG salt is shown in Figure 3 As shown, 50-259.27°C is the first step, with a weight loss of 10.63%, which is caused by the loss of adsorbed water and one crystal water. 259.27-500°C is the second step, with a weight loss of 24.83%, which is caused by the decomposition of the crystal form I of the Ca-AKG salt.

[0078] The infrared spectrum of the crystalline form I of Ca-AKG salt is shown in Figure 4 The main absorption peaks are: 3498, 1704, 1652, 1563, 1458, 651.

[0079] The mass spectrum of the crystalline form I of Ca-AKG salt is as follows Figure 5In negative ion mode, the main peak is 145.0, which is the molecular weight of the negative ion of α-ketoglutaric acid AKG minus one hydrogen [AKG-H], that is, C5H5O5 - The molecular weight of the peak with a molecular weight of 101.0 is the molecular weight of the above anion minus one carbon dioxide [AKG-CO2-H] - , namely C4H5O3 - Theoretical molecular weight: 101.02.

[0080] Liquid chromatography HPLC of Form I of Ca-AKG salt is as follows Figure 6 As shown, the purity was 99.8%.

[0081] Example 2: Preparation of Ca-AKG salt crystal form I

[0082]

[0083] Add 100mL of water and 10.0g (0.68mmol, 1.0eq) of α-ketoglutaric acid to a 500mL reactor, stir and dissolve; add 10.2g (1.02mmol, 1.5eq) of calcium carbonate in batches, a large number of bubbles emerge, cool to room temperature after addition, stir and react for 2 hours, heat to 45-50℃ and stir and react for 5 hours, filter out insoluble matter by centrifugation to obtain a transparent solution. Then cool to room temperature, stir for 10 hours, and slowly precipitate solids. Filter, rinse the filter cake with a small amount of 45-50℃ water twice, dry in a blast oven at 50 degrees overnight to obtain 12.3g of monohydrated α-ketoglutaric acid calcium, HPLC purity: 99.7%, content: 100%, calcium content: 19.8%, drying loss: 0.5%, molar yield: 89.5%, sulfate and chloride ions are not detected.

[0084] The prepared Ca-AKG salt is the crystalline form I of the monohydrated calcium salt of α-ketoglutarate, and its spectral data is basically the same as that of the product in Example 1.

[0085] The above describes the specific embodiments of the present invention. It should be understood that the present invention is not limited to the above specific embodiments, and those skilled in the art can make various modifications or variations within the scope of the claims, which do not affect the essence of the present invention and should be included in the scope of the present invention.

Claims

1. A crystalline form of α-ketoglutarate calcium salt, which is a crystalline form I of a monohydrated α-ketoglutarate calcium salt of a compound represented by formula (I), characterized in that: Its X-ray powder diffraction spectrum using CuKα radiation and expressed in 2θ angles has diffraction peaks at least at 9.934°±0.2°, 15.468°±0.2°, 26.785°±0.2° and 32.954°±0.2°:

2. The crystal form according to claim 1, characterized in that The crystal form also has diffraction peaks at 2θ values ​​of 19.675°±0.2°, 21.979°±0.2°, 37.863°±0.2° and 38.650°±0.2°.

3. The crystal form according to claim 2, characterized in that: The crystal form also has diffraction peaks at 2θ values ​​of 17.673°±0.2°, 26.341°±0.2° and 29.74°±0.2°.

4. The crystal form according to claim 1, characterized in that In the DSC analysis, the crystal form has no obvious endothermic peak in the DSC thermal analysis diagram, but has exothermic peaks at 207.59°C, 344.40°C and 463.78°C; preferably, the DSC spectrum of the crystal form I is substantially as shown in FIG2 .

5. The crystal form according to claim 1, characterized in that In thermogravimetric analysis, the crystal form contains two steps in the TGA diagram, 50-259.27°C is the first step, and 259.27-500°C is the second step; preferably, the TGA spectrum of the crystal form I is substantially as shown in FIG3 .

6. A method for preparing the crystalline form of α-ketoglutarate calcium salt according to claim 1, characterized in that: The steps include: (1) dissolving α-ketoglutaric acid represented by formula (II) in water to form an aqueous solution, adding calcium carbonate in batches, and performing a neutralization reaction under stirring. If necessary, filtering out insoluble matter until the solution is clear; (2) Cooling to room temperature, precipitating crystals, filtering, and drying the filter cake to obtain a crystalline form I of the monohydrated α-ketoglutaric acid calcium salt (Ca-AKG) of the compound represented by formula (I):

7. The method according to claim 6, characterized in that In step (1), the molar ratio of α-ketoglutaric acid to calcium carbonate is 0.4-1.2:1, preferably 0.8-1:

1.

8. The method according to claim 6, characterized in that The neutralization reaction conditions of step (1) are as follows: after adding calcium carbonate to the aqueous solution of α-ketoglutaric acid, stirring the reaction at room temperature for 1-3 hours; then heating to 40-60° C. and continuing stirring for 3-8 hours, and filtering off insoluble matter if necessary to obtain a transparent solution.

9. The method according to claim 6, characterized in that The crystallization in step (2) is to precipitate crystals under stirring.

10. A pharmaceutical composition, health food or cosmetic, characterized in that: The method comprises the crystalline form I as described in any one of claims 1 to 5 as an active ingredient.

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