Amorphous form of reduced beta-nicotinamide mononucleotide calcium salt and preparation method and application thereof

Abstract

The invention relates to a compound NMNH calcium salt, in particular to an amorphous form of a reduced beta-nicotinamide mononucleotide calcium salt, a preparation method of the reduced beta-nicotinamide mononucleotide calcium salt, application of the reduced beta-nicotinamide mononucleotide calcium salt as a pharmaceutical ingredient, a health care product ingredient, a cosmetic ingredient or a food additive, and a preparation containing the reduced beta-nicotinamide mononucleotide calcium salt, and belongs to the field of medicines, health care products, cosmetics and food additives. Specifically, the invention describes an amorphous compound of NMNH calcium salt, the compound shows long-term continuous stability, the oxidation resistance, the stability and the moisture absorption resistance of the compound are obviously superior to those of NMNH disodium salt, and the compound is more beneficial to long-term storage, popularization and marketing. The preparation process of the NMNH calcium salt amorphous compound is simple, easy to control and suitable for large-scale production.

Description

Technical Field

[0001] The present invention relates to the field of chemical raw materials for medicines, health products, cosmetics and food additives, and in particular to an amorphous reduced beta-nicotinamide mononucleotide calcium salt and a preparation method and use thereof. Background Art

[0002] As one of the most popular molecules in the field of anti-aging, nicotinamide adenine dinucleotide (NAD + ) has become the core of anti-aging substances in all generations. + It is an important coenzyme required for more than 500 enzymatic reactions and is well known for its role in oxidation and reduction (Ansari and Raghava, 2010; Rajman et al., 2018; Stein and Imai, 2012). More and more studies indicate that increasing NAD + Equivalent amounts can significantly improve multiple organ functions, including liver function, kidney function, cardiac function, and skeletal muscle function (Canto et al., 2012; Mills et al., 2016; Rajman et al., 2018). + It can be synthesized using tryptophan in the de novo biosynthesis pathway, nicotinic acid (NA) in the preiss-handler pathway, and nicotinamide (NAM), nicotinamide riboside (NR), and nicotinamide mononucleotide (NMN) in the salvage pathway (Canto et al., 2015; Chiarugi et al., 2012; Johnson and Imai, 2018). In particular, as NAD + The key intermediates, NAM, NR, and NMN, have been extensively studied for their potential therapeutic effects in many mouse disease models (Mills et al., 2016), among which NMN is currently considered the most suitable NAD + Precursor, and currently NMN is hot-selling in the global market and is highly favored by consumers.

[0003] NMNH (molecular structure as shown in formula (A)) is called "reduced nicotinamide mononucleotide" or "reduced β-nicotinamide mononucleotide" in Chinese. It is the reduced form of NMN and is a supplement to NAD. + A new precursor of NAD with better NMN properties + The promoting effect and other biological functions such as increasing cellular antioxidant capacity, reducing fat accumulation, reducing inflammatory response and inhibiting tumor cell growth are health-promoting agents with significant commercial potential (WO2021098725A1).

[0004]

[0005] NMNH is the reduced form of NMN, which is sensitive to air, easily oxidized, and unstable, making it unfavorable for long-term storage and market promotion. WO2023160405 (A1) reports NMNH disodium salt compounds and their crystal forms and amorphous forms. When left open in a stability test chamber at 25°C and 65% RH, the amorphous powder of NMNH disodium salt turned into oil after one day and the purity dropped from 99.30% to 99.02%. The purity of NMNH disodium salt crystal form A solid dropped from 99.33% to 99.01% after 5 days. Such stability cannot meet the shelf life of the product and is not conducive to the market promotion of the product.

[0006] Therefore, there is still an urgent need in this field to develop new salt forms of NMNH compounds with better stability, better suitability for long-term storage and market promotion. Summary of the invention

[0007] The present invention aims to provide a new salt form of NMNH compounds with better stability and better long-term storage, and specifically relates to an amorphous reduced β-nicotinamide mononucleotide calcium salt, a preparation method and uses thereof.

[0008] In a first aspect of the present invention, there is provided an amorphous compound of a reduced β-nicotinamide mononucleotide calcium salt as shown in formula (I),

[0009]

[0010] The amorphous is selected from the group consisting of amorphous A, amorphous B, amorphous C, or amorphous D.

[0011] In another preferred embodiment, the XRPD spectrum of the amorphous form A is substantially as follows Figure 1 Characterized by.

[0012] In another preferred embodiment, the amorphous A 1 The H NMR spectrum is basically Figure 5 Characterized by.

[0013] In another preferred embodiment, the XRPD spectrum of the amorphous form B is substantially as follows Figure 2 Characterized by.

[0014] In another preferred embodiment, the amorphous B 1 The H NMR spectrum is basically Figure 5 Characterized by.

[0015] In another preferred embodiment, the XRPD spectrum of the amorphous C is substantially as follows Figure 3 Characterized by.

[0016] In another preferred embodiment, the amorphous C 1 The H NMR spectrum is basically Figure 5 Characterized by.

[0017] In another preferred embodiment, the XRPD spectrum of the amorphous D is substantially as follows Figure 4 Characterized by.

[0018] In another preferred embodiment, the amorphous D 1 The H NMR spectrum is basically Figure 5 Characterized by.

[0019] In a second aspect of the present invention, a method for preparing the amorphous compound according to the first aspect is provided, the method comprising the following steps:

[0020] 1) adding reduced β-nicotinamide mononucleotide calcium salt to a first solvent to obtain a solution containing reduced β-nicotinamide mononucleotide calcium salt, or generating a reduced β-nicotinamide mononucleotide calcium salt solution in situ in the reaction solution;

[0021] 2) adding the solution obtained in 1) above to a second solvent to precipitate a solid to obtain a reduced β-nicotinamide mononucleotide calcium salt amorphous compound; or freeze-drying or spray-drying the solution obtained in 1) above to obtain a reduced β-nicotinamide mononucleotide calcium salt amorphous compound; or slurrying the reduced β-nicotinamide mononucleotide calcium salt solid in a second solvent to obtain the reduced β-nicotinamide mononucleotide calcium salt amorphous compound as described in the first aspect.

[0022] In another preferred embodiment, the method is prepared by any one of the following methods (I) to (IV):

[0023] (I) Preparation of Amorphous Form A

[0024] I-1) providing a solution of reduced β-nicotinamide mononucleotide calcium salt in a first solvent;

[0025] I-2) adding the solution obtained in I-1) above to a second solvent, and drying the precipitated solid at 30-45° C. to obtain amorphous form A;

[0026] Wherein, the first solvent is selected from: water; the second solvent is selected from: methanol, or a mixed solvent of methanol and water;

[0027] (II) Preparation of Amorphous Form B

[0028] II-1) providing a solution of reduced β-nicotinamide mononucleotide calcium salt in a first solvent;

[0029] II-2) adding the solution obtained in II-1) above to a second solvent, and drying the precipitated solid at 30-45° C. to obtain amorphous B;

[0030] Wherein, the first solvent is selected from: water; the second solvent is selected from: ethanol, or a mixed solvent of ethanol and water;

[0031] (III) Preparation of Amorphous C

[0032] III-1) providing a solution of reduced β-nicotinamide mononucleotide calcium salt in a first solvent;

[0033] III-2) adding the solution obtained in the above III-1) to a second solvent, and drying the precipitated solid at 30-45° C. to obtain amorphous C;

[0034] Wherein, the first solvent is selected from: water; the second solvent is selected from: acetone, or a mixed solvent of acetone and water;

[0035] (IV) Preparation of Amorphous Form D

[0036] IV-1) providing a solution of reduced β-nicotinamide mononucleotide calcium salt in a first solvent;

[0037] IV-2) drying the solution obtained in IV-1) to obtain amorphous D;

[0038] The drying process includes freeze drying, spray drying, reduced pressure vacuum drying, rotary evaporation drying, etc.

[0039] In another preferred embodiment, the first solvent and the second solvent are the same or different, and are independently selected from the following groups: water, acetonitrile, tetrahydrofuran, methyl tert-butyl ether, 2-methyltetrahydrofuran, dichloromethane, N,N-dimethylformamide, N,N-dimethylacetamide, N,N-diethylformamide, dimethyl sulfoxide, ethyl acetate, isopropyl acetate, ketone solvents, alcohol solvents, or a combination thereof.

[0040] In another preferred embodiment, the ketone solvent is selected from the following group: acetone, 2-butanone, methyl isobutyl ketone, methyl tert-butyl ketone, 3-methyl-2-butanone, or a combination thereof.

[0041] In another preferred embodiment, the alcohol solvent is selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, n-pentanol, or a combination thereof.

[0042] In another preferred embodiment, the solution of the reduced β-nicotinamide mononucleotide calcium salt in the first solvent is provided by the following method: adding the reduced β-nicotinamide mononucleotide calcium salt to the first solvent to obtain a solution containing the reduced β-nicotinamide mononucleotide calcium salt, or generating the reduced β-nicotinamide mononucleotide calcium salt solution in situ in the reaction solution.

[0043] In the third aspect of the present invention, a composition is provided, comprising: (a) the amorphous compound as described in the first aspect, and (b) a pharmaceutically acceptable excipient or carrier, or an excipient or carrier acceptable for health products, or an excipient or carrier acceptable for cosmetics, or an excipient or carrier acceptable for food.

[0044] In another preferred embodiment, the composition is selected from the following group: a pharmaceutical composition, a health product composition, a cosmetic composition, or a food composition.

[0045] In another preferred embodiment, the pharmaceutical composition comprises: (a) the amorphous compound described in the first aspect, and (b) a pharmaceutically acceptable excipient or carrier.

[0046] In another preferred embodiment, the dosage form of the pharmaceutical composition is selected from the following group: oral preparations, injection dosage forms, respiratory tract administration dosage forms, skin administration dosage forms, mucosal administration dosage forms, cavity administration dosage forms, etc.

[0047] In another preferred embodiment, the health care product composition comprises: (a) the amorphous compound described in the first aspect, and (b) an auxiliary material or carrier acceptable for health care products.

[0048] In another preferred embodiment, the cosmetic composition comprises: (a) the amorphous compound described in the first aspect, and (b) a cosmetically acceptable auxiliary material or carrier.

[0049] In another preferred embodiment, the cosmetic composition includes cosmetics selected from the following groups: skin cosmetics, hair cosmetics, beauty cosmetics, and special function cosmetics.

[0050] In another preferred embodiment, the food composition comprises: (a) the amorphous compound described in the first aspect, and (b) a food-acceptable auxiliary material or carrier.

[0051] In the fourth aspect of the present invention, there is provided a use of the amorphous compound described in the first aspect for preparing medicines, health products, cosmetics or food additives.

[0052] In another preferred embodiment, the drug is used to protect the optic nerve, improve retinal damage, prevent / treat hair loss, prevent / improve cardiovascular and cerebrovascular diseases, inhibit renal tubular damage and aging, prevent liver fibrosis, improve fatty liver disease, improve dry eye symptoms, repair kidney damage, prevent diabetes / nephropathy, improve sarcopenia symptoms in the elderly, treat chronic inflammation, alleviate the condition of patients with polycystic ovary syndrome, prevent / delay glaucoma, reduce neuroinflammation, reduce the cardiac toxicity of anthracycline chemotherapy drugs, assist in cerebral infarction recovery, prevent and treat heart failure in the elderly, etc.

[0053] In another preferred embodiment, the health care products are used to slow down cell aging, delay reproductive aging in women, improve fertility, improve menopause, enhance male sexual function, improve sleep, relieve mood, increase energy, improve cardiovascular function, improve cardiovascular health, improve immunity, improve sub-health, prevent tumors, prevent Alzheimer's disease, etc.

[0054] In another preferred embodiment, the cosmetics are used to improve the function of damaged cells, improve skin quality / hair quality, prevent / treat skin photoaging, maintain skin softness and elasticity, delay skin aging, etc.

[0055] In another preferred embodiment, the food additive is used to improve appetite, improve digestive function, promote metabolism, promote hair / nail growth, etc., and improve nutritional value.

[0056] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (such as embodiments) can be combined with each other to form a new or preferred technical solution. Due to space limitations, they will not be described one by one here. BRIEF DESCRIPTION OF THE DRAWINGS

[0057] Figure 1 The XRPD pattern of NMNH calcium salt amorphous form A is shown.

[0058] Figure 2 The XRPD pattern of NMNH calcium salt amorphous form B is shown.

[0059] Figure 3 The XRPD pattern of NMNH calcium salt amorphous form C is shown.

[0060] Figure 4 The XRPD pattern of NMNH calcium salt amorphous form D is shown.

[0061] Figure 5 The amorphous NMNH calcium salt is shown 1 H NMR spectrum. DETAILED DESCRIPTION

[0062] Through extensive and in-depth research, the inventors unexpectedly developed a specific salt of NMNH for the first time, which is NMNH calcium salt. The present invention shows that the amorphous compound of NMNH calcium salt has excellent stability. Compared with the crystalline form and amorphous form of NMNH disodium salt, the amorphous form of NMNH calcium salt shows long-term stability and anti-hygroscopicity, which is more conducive to long-term storage and market promotion. In addition, the amorphous compound of the present invention meets the shelf life of the commodity and is suitable for pharmaceutical compositions, health products, cosmetics, food additives, etc. On this basis, the inventors completed the present invention.

[0063] Terminology

[0064] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0065] NMNH calcium salt

[0066] As used herein, the terms "reduced β-nicotinamide mononucleotide calcium salt", "β-dihydronicotinamide mononucleotide calcium salt", "dihydronicotinamide mononucleotide calcium salt", "reduced nicotinamide mononucleotide calcium salt", "reduced NMN calcium salt", "NMNH calcium salt", "NMNH-Ca" are used interchangeably, all referring to the salt formed by reduced β-nicotinamide mononucleotide and calcium ions, the structure of which is shown in formula (I). It should be understood that the term includes amorphous, hydrates, solvates, solvent-hydrates and anhydrates.

[0067]

[0068] Use of the reduced β-nicotinamide mononucleotide calcium salt of the present invention

[0069] The present invention provides the use of an amorphous NMNH calcium salt compound, which has high efficiency and broad spectrum and can be used in pharmaceutical compositions, health products, cosmetics, food additives, and the like.

[0070] Compared with the prior art, the present invention has the following beneficial effects:

[0071] (1) The amorphous solid of the compound of formula (I) of the present invention has better antioxidant properties and stability, lower hygroscopicity, and is more conducive to subsequent formulation process operation, long-term storage and market promotion than the NMNH disodium salt crystal form and amorphous solid.

[0072] (2) The preparation method of the amorphous solid compound of formula (I) of the present invention is simple and suitable for industrial production.

[0073] (3) The amorphous solid of the compound of formula (I) of the present invention can be used in pharmaceutical compositions, health products, cosmetics, food additives, etc.

[0074] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. The experimental methods in the following examples without specifying specific conditions are usually based on conventional conditions or the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are by weight.

[0075] Unless otherwise defined, all professional and scientific terms used herein have the same meaning as those familiar to those skilled in the art. In addition, any method and material similar or equivalent to the described content can be applied to the method of the present invention.

[0076] Unless otherwise specified, the experimental materials and reagents used in the following examples can be obtained from commercial channels.

[0077] Test method:

[0078] XRPD (X-ray powder diffraction) pattern determination method: Bruker D2 Phaser X-ray powder diffractometer; radiation source

[0079] The measurement differences associated with such X-ray powder diffraction analysis results are caused by a variety of factors including: (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 the XRPD spectrum and can be eliminated by compensating for the displacements (applying the system calibration factor to 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.

[0080] Example 1. Preparation of NMNH calcium salt aqueous solution

[0081] Add 1.7 kg β-NMN and 0.94 kg sodium dithionite to 10 liters of saturated sodium bicarbonate aqueous solution, stir at room temperature overnight, filter to obtain a clear solution, and adjust the pH of the clear solution to 3-4 with 37% hydrochloric acid. Desalt the solution by electrodialysis until the conductivity of the solution drops to 50-100 μS. Adjust the pH of the solution to 10 with calcium hydroxide; or add 0.57 kg calcium chloride and adjust the pH of the solution to 10 with sodium hydroxide; obtain an aqueous solution of NMNH calcium salt, containing about 1.71 kg NMNH calcium salt (the purity of the solution is 94.5% as measured by HPLC).

[0082] Example 2. Preparation of NMNH calcium salt amorphous solid A

[0083] Take 500 ml of NMNH calcium salt aqueous solution and add it dropwise to 2 L of stirring methanol. After the addition is complete, stir for 1 hour, filter, and dry at 30-45°C to obtain 80.3 g of NMNH calcium salt amorphous A product with a yield of 85.0% and a purity of 99.5%.

[0084] The obtained solid was subjected to X-ray powder diffraction test, and the XRPD pattern of the obtained NMNH calcium salt amorphous form A was basically as follows: Figure 1 As shown, 1 The H NMR spectrum is basically Figure 5 shown.

[0085] Example 3. Preparation of NMNH calcium salt amorphous solid B

[0086] Take 500 ml of NMNH calcium salt aqueous solution and add it dropwise to 2 L of ethanol under stirring. After the addition is complete, stir for 1 hour, filter, and dry at 30-45°C to obtain 82.6 g of NMNH calcium salt amorphous B product with a yield of 87.5% and a purity of 99.2%.

[0087] The obtained solid was subjected to X-ray powder diffraction test, and the XRPD pattern of the obtained NMNH calcium salt amorphous form B was basically as follows: Figure 2 As shown, 1 The H NMR spectrum is basically Figure 5 shown.

[0088] Example 4. Preparation of NMNH calcium salt amorphous C solid

[0089] Take 500 ml of NMNH calcium salt aqueous solution and add it dropwise to 2 L of acetone under stirring. After the addition is complete, stir for 1 hour, filter, and dry at 30-45°C to obtain 83.5 g of NMNH calcium salt amorphous C product with a yield of 88.4% and a purity of 99.1%.

[0090] The obtained solid was subjected to X-ray powder diffraction test, and the XRPD pattern of the obtained NMNH calcium salt amorphous C was basically as follows: Figure 3 As shown, 1 The H NMR spectrum is basically Figure 5 shown.

[0091] Example 5. Preparation of NMNH calcium salt amorphous D solid

[0092] 10.0 g of NMNH calcium salt amorphous A solid was dissolved in 100 ml of purified water and freeze-dried to obtain 9.8 g of NMNH calcium salt amorphous D product with a yield of 98% and a purity of 99.5%.

[0093] The obtained solid was subjected to X-ray powder diffraction test, and the XRPD pattern of the obtained NMNH calcium salt amorphous form D was basically as follows: Figure 4 As shown, 1 The H NMR spectrum is basically Figure 5 shown.

[0094] Example 6. Preparation of NMNH calcium salt amorphous D solid

[0095] 10.0 g of NMNH calcium salt amorphous A solid was dissolved in 100 ml of purified water and spray-dried to obtain 9.0 g of NMNH calcium salt amorphous D product with a yield of 90% and a purity of 99.5%.

[0096] The obtained solid was subjected to X-ray powder diffraction test, and the XRPD pattern of the obtained NMNH calcium salt amorphous form D was basically as follows: Figure 4 As shown, 1 The H NMR spectrum is basically Figure 5 shown.

[0097] Example 7. Stability of NMNH calcium salt amorphous solids A / B / C / D and NMNH disodium salt crystalline form A and amorphous solids contrast

[0098] The NMNH calcium salt amorphous solids A / B / C / D were respectively placed in an open state in a stability test box at 25°C and 65% RH to examine the stability, and the data shown in Tables 1 and 2 were obtained.

[0099] Table 1 Comparison of the stability of NMNH calcium salt amorphous solid and NMNH disodium salt crystal form A and amorphous solid (25°C, 65% RH)

[0100]

[0101] Table 2 Study on hygroscopicity of amorphous solid NMNH calcium salt (25°C, 65% RH)

[0102]

[0103] According to WO2023160405 (A1), when NMNH disodium salt is stored in the air, both crystal forms B and C absorb water and transform into crystal form A. After saturation with water, the moisture content of crystal form A is 19%-30% (high water content), and the purity drops from 99.33% to 99.01% after 5 days. The amorphous solid of NMNH disodium salt is more unstable in the air. After being placed for 1 day, it absorbs water from powder to oil, and the purity drops from 99.30% to 99.02%.

[0104] It can be seen from Tables 1 and 2 that after being placed for 60 days, the amorphous solid of NMNH calcium salt is still a solid powder, and the purity and moisture content are almost unchanged, that is, the amorphous solid of NMNH calcium salt can be placed in the open at 25°C and 65% RH for not less than 60 days, and the purity and moisture content can be continuously stable. However, both the crystalline form A and the amorphous form of NMNH disodium salt are unstable and easily absorb water, which is extremely unfavorable for storage, cannot meet the shelf life of the product, and is difficult to market and promote. It can be seen that the stability and hygroscopicity resistance of the amorphous solid of NMNH calcium salt are significantly improved, which is conducive to the subsequent preparation process operation and long-term continuous and stable storage, and is convenient for market promotion.

[0105] All documents mentioned in the present invention are cited as references in this application, just as each document is cited as reference individually. In addition, it should be understood that after reading the above teachings of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the claims attached to this application.

Claims

1. An amorphous compound of reduced β-nicotinamide mononucleotide calcium salt as shown in formula (I), It is characterized in that The amorphous is selected from the group consisting of amorphous A, amorphous B, amorphous C, or amorphous D.

2. The amorphous material according to claim 1, characterized in that The XRPD spectrum of the amorphous form A is basically shown in FIG1 .

3. The amorphous material according to claim 1, characterized in that: The XRPD spectrum of the amorphous form B is basically represented as shown in FIG2 .

4. The amorphous material according to claim 1, characterized in that: The XRPD spectrum of the amorphous C is basically represented by FIG3 .

5. The amorphous material according to claim 1, wherein: The XRPD spectrum of the amorphous form D is basically represented by FIG4 .

6. A method for preparing an amorphous compound as claimed in claim 1, characterized in that: The method comprises the following steps: 1) adding reduced β-nicotinamide mononucleotide calcium salt to a first solvent to obtain a solution containing reduced β-nicotinamide mononucleotide calcium salt, or generating a reduced β-nicotinamide mononucleotide calcium salt solution in situ in the reaction solution; 2) adding the solution obtained in 1) above to a second solvent to precipitate a solid to obtain a reduced β-nicotinamide mononucleotide calcium salt amorphous compound; or freeze-drying or spray-drying the solution obtained in 1) above to obtain a reduced β-nicotinamide mononucleotide calcium salt amorphous compound; or slurrying the reduced β-nicotinamide mononucleotide calcium salt solid in a second solvent to obtain the reduced β-nicotinamide mononucleotide calcium salt amorphous compound as claimed in claim 1.

7. The method according to claim 6, characterized in that The method is prepared by any one of the following methods (I) to (IV): (I) Preparation of Amorphous Form A I-1) providing a solution of reduced β-nicotinamide mononucleotide calcium salt in a first solvent; I-2) adding the solution obtained in I-1) above to a second solvent, and drying the precipitated solid at 30-45° C. to obtain amorphous form A; Wherein, the first solvent is selected from: water; the second solvent is selected from: methanol, or a mixed solvent of methanol and water; (II) Preparation of Amorphous Form B II-1) providing a solution of reduced β-nicotinamide mononucleotide calcium salt in a first solvent; II-2) adding the solution obtained in II-1) above to a second solvent, and drying the precipitated solid at 30-45° C. to obtain amorphous B; Wherein, the first solvent is selected from: water; the second solvent is selected from: ethanol, or a mixed solvent of ethanol and water; (III) Preparation of Amorphous C III-1) providing a solution of reduced β-nicotinamide mononucleotide calcium salt in a first solvent; III-2) adding the solution obtained in the above III-1) to a second solvent, and drying the precipitated solid at 30-45° C. to obtain amorphous C; Wherein, the first solvent is selected from: water; the second solvent is selected from: acetone, or a mixed solvent of acetone and water; (IV) Preparation of Amorphous Form D IV-1) providing a solution of reduced β-nicotinamide mononucleotide calcium salt in a first solvent; IV-2) drying the solution obtained in IV-1) to obtain amorphous D; The drying process includes freeze drying, spray drying, reduced pressure vacuum drying, rotary evaporation drying, etc.

8. The method according to claim 6, characterized in that The first solvent and the second solvent are the same or different, and are independently selected from the following groups: water, acetonitrile, tetrahydrofuran, methyl tert-butyl ether, 2-methyltetrahydrofuran, dichloromethane, N,N-dimethylformamide, N,N-dimethylacetamide, N,N-diethylformamide, dimethyl sulfoxide, ethyl acetate, isopropyl acetate, ketone solvents, alcohol solvents, or a combination thereof.

9. A composition, characterized in that The composition comprises: (a) the amorphous compound according to claim 1, and (b) a pharmaceutically acceptable excipient or carrier, or an excipient or carrier acceptable for health products, or an excipient or carrier acceptable for cosmetics, or an excipient or carrier acceptable for food.

10. Use of the amorphous compound according to claim 1, characterized in that: Used for preparing medicines, health products, cosmetics or food additives.

Images