Polymorphs of reduced beta-nicotinamide mononucleotide calcium salt, processes for their preparation and uses thereof

Abstract

The present application relates to a kind of compound NMNH calcium salt, especially to a kind of reduced beta-nicotinamide mononucleotide calcium salt Polymorph and its preparation method, and they are used as pharmaceutical ingredients, health product ingredients, cosmetic ingredients or as food additive, and preparation containing these salts, belong to medicine, health product, cosmetic, food additive field.The specific, the present application describes NMNH calcium salt Polymorph, the crystal shows long-term sustained stability, significantly better than the stability of NMNH disodium salt, anti-hygroscopicity, more conducive to long-term storage, popularization and marketing.The NMNH calcium salt crystal preparation process is simple, easy to control, suitable for large-scale production.

Description

Technical Field

[0001] This invention relates to the field of chemical raw materials for pharmaceuticals, health products, cosmetics and food additives, and specifically to the polymorphism of reduced β-nicotinamide mononucleotide calcium salt, its preparation method and uses. Background Technology

[0002] As one of the most popular molecules in the anti-aging field, nicotinamide adenine dinucleotide (NAD) + Without exception, it has become the center of anti-aging substances throughout history. NAD + It is an important coenzyme required for over 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 research indicates that increasing NAD+... + Equivalent doses can significantly improve the function of multiple organs, including liver, kidney, heart, and skeletal muscle (Canto et al., 2012; Mills et al., 2016; Rajman et al., 2018). NAD + Tryptophan can be used 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... + Key intermediates, NAM, NR, and NMN, have been extensively studied for their potential therapeutic effects in many mouse disease models (Mills et al., 2016), with NMN considered the most suitable NAD at present. + It is a precursor, and NMN is currently a hot seller in the global market, highly favored by consumers.

[0003] NMNH (molecular structure shown in formula (A)) is a reduced form of NMN and is a supplement for NAD+. Its Chinese name is "reduced nicotinamide mononucleotide" or "reduced β-nicotinamide mononucleotide". + A novel precursor with better NAD than NMN + With its promoting effects and other biological functions such as increasing cellular antioxidant capacity, reducing fat accumulation, reducing inflammatory response and inhibiting tumor cell growth, it is a health-promoting agent with significant commercial potential (WO2021098725A1).

[0004]

[0005] NMNH is a reduced form of NMN, which is sensitive to air, easily oxidized, and unstable, making it unsuitable for long-term storage and market promotion. WO2023160405(A1) reports on NMNH disodium salt compounds and their crystalline and amorphous forms. When placed in an open stability test chamber at 25°C and 65% RH, the amorphous powder of NMNH disodium salt turned into oil after one day, and its purity decreased from 99.30% to 99.02%. The purity of NMNH disodium salt crystalline form A solid decreased from 99.33% to 99.01% after five days. Such stability fails to meet the shelf life requirements of the product and is detrimental to its market promotion.

[0006] Therefore, there is still an urgent need in this field to develop new salt forms of NMNH compounds that offer advantages such as better stability, easier long-term storage, and easier marketability. Summary of the Invention

[0007] The present invention aims to provide a new salt form of NMNH compounds with better stability and easier long-term storage and market promotion, specifically involving the polymorphism of reduced β-nicotinamide mononucleotide calcium salt, its preparation method and uses.

[0008] In a first aspect, a calcium salt crystal of reduced β-nicotinamide mononucleotide as shown in Formula (I) is provided.

[0009]

[0010] The crystal is selected from the following crystal forms: crystal form A, crystal form B, crystal form C, crystal form D, or crystal form E.

[0011] In another preferred embodiment, the XRPD pattern of crystal form A includes three or more (e.g., 4, 5, 6, 7 or 8) 2θ values ​​selected from the group consisting of: 6.9°±0.2°, 9.5°±0.2°, 12.6°±0.2°, 15.6°±0.2°, 17.9°±0.2°, 21.0°±0.2°, 21.8°±0.2°, and 25.4°±0.2°.

[0012] The XRPD pattern of crystal form B includes three or more (e.g., 4, 5, 6, 7 or 8) 2θ values ​​selected from the following group: 6.5°±0.2°, 8.1°±0.2°, 11.9°±0.2°, 13.1°±0.2°, 17.6°±0.2°, 21.4°±0.2°, 23.7°±0.2°, 26.9°±0.2°;

[0013] The XRPD pattern of crystal form C includes three or more (e.g., 4, 5, 6, 7 or 8) 2θ values ​​selected from the following group: 6.2°±0.2°, 9.7°±0.2°, 12.4°±0.2°, 16.1°±0.2°, 17.1°±0.2°, 18.7°±0.2°, 20.8°±0.2°, 26.6°±0.2°.

[0014] In another preferred embodiment, the reduced β-nicotinamide mononucleotide calcium salt crystal is a hydrate, a solvate, or an organic solvent-hydrate.

[0015] In another preferred embodiment, the organic solvent-hydrate of the reduced β-nicotinamide mononucleotide calcium salt is an ethanol-hydrate or an acetone-hydrate.

[0016] In another preferred embodiment, the structural formula of the reduced β-nicotinamide mononucleotide calcium salt is shown in Formula II:

[0017]

[0018] In the formula, S represents an organic solvent and H2O is water; when x = 0 and n > 0, it is a hydrate; when x > 0 and n = 0, it is an organic solvate; when x > 0 and n > 0, it is an organic solvate-hydrate.

[0019] In another preferred embodiment, x and / or n are independently integers or non-integers.

[0020] In another preferred embodiment, the crystal form A further has one or more features selected from the group consisting of:

[0021] 1) The XRPD pattern of crystal form A includes six or more 2θ values ​​selected from the following group: 6.9°±0.2°, 9.5°±0.2°, 12.6°±0.2°, 13.9°±0.2°, 14.4°±0.2°, 15.6°±0.2°, 16.7°±0.2°, 17.2°±0.2°, 17.9°±0.2°, 18.8°±0.2°, 21.0°±0.2°, 21.8°±0.2°, 23.1°±0.2°, 25.4°±0.2°, 26.5°±0.2°, 27.3°±0.2°, 28.1°±0.2°, 31.5°±0.2°, 32.8°±0.2°, 35.6°±0.2°;

[0022] 2) The XRPD pattern of crystal form A is basically as follows: Figure 1 What it represents;

[0023] 3) The crystal form A is a hydrate with a water content of 4%wt-13%wt; preferably, the crystal form A is a 1-3 hydrate.

[0024] In another preferred embodiment, the crystal form A is a hydrate with a water content of 5%wt-12%wt.

[0025] In another preferred embodiment, the crystal form A is a hydrate with a water content of 6%wt-11%wt.

[0026] In another preferred embodiment, the crystal form B further has one or more features selected from the group consisting of:

[0027] 1) The XRPD pattern of crystal form B includes six or more 2θ values ​​selected from the following group: 6.5°±0.2°, 8.1°±0.2°, 11.9°±0.2°, 13.1°±0.2°, 13.5°±0.2°, 14.5°±0.2°, 17.6°±0.2°, 18.0°±0.2°, 18.9°±0.2°, 19.4°±0.2°, 19.7°±0.2°, 20.3°±0.2°, 21.4°±0.2°, 23.7°±0.2°, 24.3°±0.2°, 25.1°±0.2°, 2 6.4°±0.2°, 26.9°±0.2°, 27.5°±0.2°, 28.7°±0.2°, 29.3°±0.2°, 30.5°±0.2°, 30.9°±0.2°, 31.6°±0.2°, 32.4°±0.2°, 32.9°±0.2°, 34.2°±0.2°, 35.0°±0.2°, 35.4°±0.2°, 36.7°±0.2°, 37.5°±0.2°, 37.9°±0.2°, 38.2°±0.2°, 38.9°±0.2°, 40.2°±0.2°;

[0028] 2) The XRPD pattern of crystal form B is basically as follows: Figure 2 What it represents;

[0029] 3) The crystal form B is a hydrate with a water content of 4%-20% wt; preferably, the crystal form B is a 1-5 hydrate.

[0030] In another preferred embodiment, the crystal form B is a hydrate with a water content of 5%wt-19%wt.

[0031] In another preferred embodiment, the crystal form B is a hydrate with a water content of 6%wt-18%wt.

[0032] In another preferred embodiment, the crystal form C further has one or more features selected from the group consisting of:

[0033] 1) The XRPD pattern of crystal form C includes six or more 2θ values ​​selected from the following group: 6.2°±0.2°, 6.8°±0.2°, 9.7°±0.2°, 11.8°±0.2°, 12.4°±0.2°, 14.2°±0.2°, 15.5°±0.2°, 16.1°±0.2°, 17.1°±0.2°, 17.9°±0.2°, 18.7°±0.2°, 20.1°±0.2°, 20.8°±0.2°, 21.5°±0.2°, 22.9°±0.2°, 23.5°±0.2°, 24.1°±0.2°, 24.5°±0.2°. 0.2°, 25.0°±0.2°, 25.8°±0.2°, 26.6°±0.2°, 27.3°±0.2°, 27.7°±0.2°, 28.3°±0.2°, 28.5°±0.2°, 29.7°±0.2°, 30.3°±0.2°, 30.8°±0.2°, 31.4°±0.2°, 32.8°±0.2°, 33.4°±0.2°, 34.4°±0.2°, 35.3°±0.2°, 36.0°±0.2°, 37.1°±0.2°, 38.0°±0.2°, 39.0°±0.2°, 39.8°±0.2°;

[0034] 2) The XRPD pattern of crystal form C is basically as follows: Figure 3 What it represents;

[0035] 3) The crystal form C is a hydrate with a water content of 4%wt-13%wt; preferably, the crystal form C is a 1-3 hydrate.

[0036] In another preferred embodiment, the crystal form C is a hydrate with a water content of 5%wt-12%wt.

[0037] In another preferred embodiment, the crystal form C is a hydrate with a water content of 6%wt-11%wt.

[0038] In another preferred embodiment, the crystal form D has one or more features selected from the group consisting of:

[0039] 1) The XRPD pattern of the crystal form D includes three or more 2θ values ​​selected from the following group: 7.0°±0.2°, 8.0°±0.2°, 12.0°±0.2°, 17.8°±0.2°, 20.2°±0.2°, 26.9°±0.2°;

[0040] 2) The XRPD pattern of the crystal form D also includes one or more 2θ values ​​selected from the following group: 13.5°±0.2°, 14.2°±0.2°, 24.0°±0.2°;

[0041] 3) The XRPD pattern of crystal form D includes six or more 2θ values ​​selected from the following group: 7.0°±0.2°, 8.0°±0.2°, 12.0°±0.2°, 13.5°±0.2°, 14.2°±0.2°, 15.7°±0.2°, 17.8°±0.2°, 19.2°±0.2°, 20.2°±0.2°, 23.5°±0.2°, 24.0°±0.2°, 24.5°±0.2°, 26.1°±0.2°, 26.9°±0.2°, 28.7°±0.2°, 30.5°±0.2°, 33.8°±0.2°;

[0042] 4) The XRPD pattern of crystal form D is basically as follows: Figure 4 What it represents;

[0043] 5) The crystal form D 1 The basic H NMR spectrum is as follows Figure 7 What it represents;

[0044] 6) The crystal form D is an ethanol-hydrate, containing about 0.2-0.5 ethanol molecules and a water content of 16%wt-23%wt; preferably, the crystal form D is a 3-6 hydrate.

[0045] In another preferred embodiment, the crystal form D is an ethanol-hydrate with a water content of 18% wt-21% wt.

[0046] In another preferred embodiment, the crystal form E has one or more features selected from the group consisting of:

[0047] 1) The XRPD pattern of the crystal form E includes three or more 2θ values ​​selected from the following group: 6.9°±0.2°, 8.0°±0.2°, 11.9°±0.2°, 17.8°±0.2°, 20.2°±0.2°, 26.9°±0.2°;

[0048] 2) The XRPD pattern of the crystal form E also includes one or more 2θ values ​​selected from the following group: 13.5°±0.2°, 14.2°±0.2°, 24.0°±0.2°;

[0049] 3) The XRPD pattern of the crystal form E includes six or more 2θ values ​​selected from the following group: 6.9°±0.2°, 8.0°±0.2°, 11.9°±0.2°, 13.5°±0.2°, 14.2°±0.2°, 15.7°±0.2°, 17.8°±0.2°, 18.8°±0.2°, 19.2°±0.2°, 20.2°±0.2°, 24.1°±0.2°, 26.0°±0.2°, 26.9°±0.2°, 28.7°±0.2°, 30.7°±0.2°, 33.9°±0.2°;

[0050] 4) The XRPD pattern of crystal form E is basically as follows: Figure 5 What it represents;

[0051] 5) The crystal form E 1 The basic H NMR spectrum is as follows Figure 8 What it represents;

[0052] 6) The crystal form E is acetone-hydrate, containing about 0.2-0.5 acetone molecules and a water content of 16%wt-23%wt; preferably, the crystal form E is 3-6 hydrate.

[0053] In another preferred embodiment, the crystal form E is acetone-hydrate with a water content of 18%wt-21%wt.

[0054] In a second aspect of the invention, a method for preparing a crystal as described in the first aspect is provided, the method comprising the following steps:

[0055] (I) Preparation of crystal form A:

[0056] I-1) provides a solution containing a calcium salt of reduced β-nicotinamide mononucleotide in a first solvent;

[0057] I-2) At 40-50°C, a second solvent is added dropwise to the reduced β-nicotinamide mononucleotide calcium salt solution described in step I-1), followed by crystallization, filtration, and drying at 40-50°C to obtain crystal form A of the reduced β-nicotinamide mononucleotide calcium salt. The first solvent is selected from water; the second solvent is selected from water, methanol, ethanol, n-propanol, isopropanol, acetone, acetonitrile, tetrahydrofuran, or mixtures thereof.

[0058] (II) Preparation of crystal form B:

[0059] II-1) Provides a solution containing a calcium salt of reduced β-nicotinamide mononucleotide formed in a first solvent;

[0060] II-2) At 20-30°C, a second solvent is added dropwise to the reduced β-nicotinamide mononucleotide calcium salt solution described in step II-1) above, followed by crystallization, filtration, and drying at 20-30°C to obtain crystal form B of the reduced β-nicotinamide mononucleotide calcium salt, wherein the first solvent is selected from water; the second solvent is selected from water, methanol, or a mixture thereof.

[0061] (III) Preparation of crystal form C:

[0062] III-1) Provide a solution containing a calcium salt of reduced β-nicotinamide mononucleotide formed in a first solvent;

[0063] III-2) At 20-30°C, a second solvent is added dropwise to the reduced β-nicotinamide mononucleotide calcium salt solution described in step III) above, followed by crystallization and filtration, and then drying at 40-50°C to obtain crystal form C of the reduced β-nicotinamide mononucleotide calcium salt, wherein the first solvent is selected from water; the second solvent is selected from water, methanol, or a mixture thereof.

[0064] (IV) Preparation of crystal form D:

[0065] IV-1) provides a solution containing a calcium salt of reduced β-nicotinamide mononucleotide formed in a first solvent;

[0066] IV-2) At 20-30°C, a second solvent is added dropwise to the reduced β-nicotinamide mononucleotide calcium salt solution described in step IV-1) above, followed by crystallization and filtration, and then drying at 30-40°C to obtain the crystal form D of the reduced β-nicotinamide mononucleotide calcium salt, wherein the first solvent is selected from water; the second solvent is selected from water, ethanol, or a mixture thereof.

[0067] (V) Preparation of crystal form E:

[0068] V-1) provides a solution containing a calcium salt of reduced β-nicotinamide mononucleotide formed in a first solvent;

[0069] V-2) At 20-30°C, a second solvent is added dropwise to the reduced β-nicotinamide mononucleotide calcium salt solution described in step V-1), followed by crystallization and filtration, and then drying at 30-40°C to obtain the crystal form E of the reduced β-nicotinamide mononucleotide calcium salt, wherein the first solvent is selected from water; the second solvent is selected from water, acetone, or a mixture thereof.

[0070] In another preferred embodiment, the solution containing reduced β-nicotinamide mononucleotide calcium salt is provided by adding reduced β-nicotinamide mononucleotide calcium salt to a first solvent to obtain a solution containing reduced β-nicotinamide mononucleotide calcium salt, or by generating a solution of reduced β-nicotinamide mononucleotide calcium salt in situ in a reaction solution.

[0071] In another preferred embodiment, the method for preparing the crystal form includes the steps of:

[0072] 1) Provide a solution containing a calcium salt of reduced β-nicotinamide mononucleotide formed in a first solvent;

[0073] 2) Under stirring conditions, a second solvent is added dropwise to the reduced β-nicotinamide mononucleotide calcium salt solution described in step 1) above, and crystallization is performed to obtain reduced β-nicotinamide mononucleotide calcium salt crystals.

[0074] In another preferred embodiment, the first solvent and the second solvent may be the same or different, and are independently selected from the group consisting of: 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 combinations thereof.

[0075] In another preferred embodiment, the ketone solvent is selected from the group consisting of acetone, 2-butanone, methyl isobutyl ketone, methyl tert-butyl ketone, 3-methyl-2-butanone, or combinations thereof.

[0076] 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 combinations thereof.

[0077] In a third aspect of the invention, a composition is provided comprising: (a) crystals as described in the first aspect, and (b) a pharmaceutically acceptable excipient or carrier, or a health product acceptable excipient or carrier, or a cosmetic acceptable excipient or carrier, or a food acceptable excipient or carrier.

[0078] In another preferred embodiment, the composition is selected from the group consisting of: pharmaceutical compositions, health product compositions, cosmetic compositions, or food compositions.

[0079] In another preferred embodiment, the pharmaceutical composition comprises: (a) any of the crystals described in the first aspect, and (b) a pharmaceutically acceptable excipient or carrier.

[0080] In another preferred embodiment, the dosage form of the pharmaceutical composition is selected from the group consisting of oral preparations, injectable preparations, respiratory preparations, skin preparations, mucosal preparations, cavity preparations, etc.

[0081] In another preferred embodiment, the health supplement composition comprises: (a) any of the crystals described in the first aspect, and (b) excipients or carriers acceptable for health supplements.

[0082] In another preferred embodiment, the cosmetic composition comprises: (a) any of the crystals described in the first aspect, and (b) cosmetically acceptable excipients or carriers.

[0083] In another preferred embodiment, the cosmetic composition includes cosmetics selected from the group consisting of skin cosmetics, hair cosmetics, beauty cosmetics, and special function cosmetics.

[0084] In another preferred embodiment, the food composition comprises: (a) any of the crystals described in the first aspect, and (b) a food-acceptable excipient or carrier.

[0085] In a fourth aspect of the invention, a use is provided for the crystal described in the first aspect in the preparation of pharmaceuticals, health products, cosmetics, or food additives.

[0086] 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 diabetic / 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 cardiotoxicity of anthracycline chemotherapy drugs, assist in cerebral infarction rehabilitation, and prevent and treat heart failure in the elderly.

[0087] In another preferred embodiment, the health product is used to slow down cell aging, delay female reproductive aging, improve fertility, improve menopause, enhance male sexual function, improve sleep, soothe emotions, boost energy, improve cardiovascular function, improve cardiovascular health, enhance immunity, improve sub-health, prevent tumors, and prevent Alzheimer's disease.

[0088] In another preferred embodiment, the cosmetic is used to improve the function of damaged cells, improve skin / hair quality, prevent / treat photoaging of the skin, maintain skin softness and elasticity, and delay skin aging.

[0089] In another preferred embodiment, the food additive is used to improve appetite, improve digestive function, promote metabolism, promote hair / nail growth, etc., thereby increasing nutritional value.

[0090] It should be understood that, within the scope of this invention, the above-described technical features of this invention and the technical features specifically described below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be described in detail here. Attached Figure Description

[0091] Figure 1 The XRPD pattern of NMNH calcium salt crystal form A is shown.

[0092] Figure 2 The XRPD pattern of NMNH calcium salt crystal form B is shown.

[0093] Figure 3 The XRPD pattern of NMNH calcium salt crystal form C is shown.

[0094] Figure 4 The XRPD pattern of NMNH calcium salt crystal form D is shown.

[0095] Figure 5 The XRPD pattern of NMNH calcium salt crystal form E is shown.

[0096] Figure 6 The crystal forms A, B, and C of NMNH calcium salt hydrate are shown. 1 H NMR spectrum.

[0097] Figure 7 The crystal form D of NMNH calcium salt ethanol-hydrate was shown. 1 H NMR spectrum.

[0098] Figure 8 The crystal form E of NMNH calcium salt acetone-hydrate is shown. 1 H NMR spectrum. Detailed Implementation

[0099] Through extensive and in-depth research, the inventors have unexpectedly developed a specific salt of NMNH, namely, the calcium salt of NMNH. This invention demonstrates that the polymorphs of the calcium salt of NMNH exhibit excellent stability. Compared to the crystalline and amorphous forms of disodium NMNH, the polymorphs of the calcium salt of NMNH (crystal form A, crystal form B, crystal form C, crystal form D, and crystal form E) exhibit long-term stability and moisture resistance, making them more suitable for long-term storage and marketing. Furthermore, the polymorphs of this invention meet the shelf life requirements of products and are suitable for use in pharmaceutical compositions, health products, cosmetics, food additives, etc. Based on these findings, the inventors completed this invention.

[0100] Terminology Explanation

[0101] Unless otherwise defined, 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 pertains.

[0102] As used herein, in the term "nH2O", n refers to all possible values ​​between 0 and 6, including integers and non-integers; "H2O" is the chemical formula for water, representing a water molecule or water. In "xS", x refers to all possible values ​​between 0 and 6, including integers and non-integers; "S" in this document refers to an organic solvent molecule, which can be any organic solvent.

[0103] As used herein, when referring to a specific enumerated value, the term “about” means that the value can vary by no more than 1% from the enumerated value. For example, as used herein, the expression “about 100” includes all values ​​between 99 and 101 (e.g., 99.1, 99.2, 99.3, 99.4, etc.).

[0104] As used herein, the terms “containing” or “including (comprise)” can be open-ended, semi-closed, or closed. In other words, the terms also include “consistently made of” or “made of”.

[0105] As used in this article, the term "n or more 2θ values ​​selected from the following group" refers to any positive integer including n and greater than n (e.g., n, n+1, ...), where the upper limit Nup is the number of all 2θ peaks in the group. For example, "3 or more" includes not only the positive integers of the upper limit Nup (3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, ...), but also ranges such as "4 or more", "5 or more", and "6 or more".

[0106] NMNH calcium salts

[0107] 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,” and “NMNH-Ca” are used interchangeably and all refer 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 this term includes amorphous, hydrated, solvate, solvent-hydrated, and anhydrous forms.

[0108]

[0109] In this invention, the preferred reduced NMNH calcium salt is a hydrate, the structure of which is shown in formula (II):

[0110]

[0111] Polymorphs

[0112] Solids exist either in an amorphous form or in a crystalline form. In the crystalline form, molecules are located within three-dimensional lattice sites. When a compound crystallizes from a solution or slurry, it can crystallize using different spatial lattice arrangements (a property known as "polymorphism"), forming crystals with different crystalline forms, which are called "polymorphs." Different polymorphs of a given substance can differ from each other in one or more physical properties (such as solubility and dissolution rate, true specific gravity, crystal form, packing order, fluidity, and / or solid-state stability).

[0113] Polymorphic forms of compounds can exhibit different melting points, hygroscopicity, stability, solubility, bioavailability, biological activity, and flowability, which are important factors affecting drug properties.

[0114] As used herein, “crystal,” “crystal of the present invention,” or “polymorph” are used interchangeably to refer to the crystal described in the first aspect of the present invention, wherein the crystal form is selected from the group consisting of crystal form A, crystal form B, crystal form C, crystal form D, or crystal form E.

[0115] crystallization

[0116] Production-scale crystallization can be achieved by manipulating the solution to exceed the solubility limit of the target compound. This can be done in several ways, such as dissolving the compound at a relatively high temperature and then cooling the solution below its saturation limit. Alternatively, it can be done by reducing the liquid volume through boiling, evaporation at atmospheric pressure, vacuum drying, or other methods. The solubility of the target compound can be reduced by adding an antisolvent or a solvent in which the compound has low solubility, or a mixture of such solvents. Another alternative method is to adjust the pH value to reduce solubility. For a detailed description of crystallization, see Crystallization, 3rd Edition, J.W. Mullens, Butterworth-Heineman Ltd., 1993, ISBN 0750611294.

[0117] If it is desired that salt formation and crystallization occur simultaneously, and if the salt is less soluble than the reactants in the reaction medium, then adding an appropriate acid or base can lead to the direct crystallization of the desired salt. Similarly, in a medium where the final desired form is less soluble than the reactants, the completion of the synthesis reaction can allow the final product to crystallize directly.

[0118] Optimization of crystallization may include seeding the crystals in the desired form into the crystallization medium. Additionally, many crystallization methods utilize combinations of the strategies described above. One implementation involves dissolving the target compound in a solvent at high temperature, followed by controlled addition of an appropriate volume of antisolvent to bring the system just below saturation. At this point, seed crystals in the desired form can be added (while maintaining their integrity), and the system is cooled to complete crystallization.

[0119] solvates

[0120] During the contact between compound or drug molecules and solvent molecules, it is difficult to avoid the formation of eutectic residues of solvent and compound molecules in the solid substance due to external and internal factors. The substance formed after the crystallization of the compound and solvent is called a solvate. Solvents that readily form solvates with organic compounds include water, methanol, ethanol, benzene, ethers, and heterocyclic aromatic hydrocarbons.

[0121] hydrates

[0122] Hydrates are a special type of solvate. In the pharmaceutical industry, hydrates are worthy of separate discussion due to their unique characteristics, whether in the synthesis of active pharmaceutical ingredients, drug formulations, drug storage, or evaluation of drug activity.

[0123] In this invention, the crystal of the compound shown in formula (I) can be a non-solvent or a solvate; the crystal forms A, B and C of the compound shown in formula (I) are all hydrates, crystal form D is an ethanol-hydrate, and crystal form E is an acetone-hydrate.

[0124] use

[0125] This invention provides the uses of NMNH calcium salt crystals (including crystal form A, crystal form B, crystal form C, crystal form D, and crystal form E): the crystals are highly efficient and broad-spectrum, and can be used in pharmaceutical compositions, health products, cosmetics, food additives, etc.

[0126] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0127] (1) The compound crystals of formula (I) of the present invention (including crystal form A, crystal form B, crystal form C, crystal form D and crystal form E) have better stability, lower hygroscopicity and are more conducive to long-term storage and market promotion compared with NMNH disodium salt crystal form and amorphous solid.

[0128] (2) The preparation method of the compound crystal of formula (I) of the present invention (including crystal form A, crystal form B, crystal form C, crystal form D and crystal form E) is simple and suitable for industrial production.

[0129] (3) The compound crystals of formula (I) of the present invention (including crystal form A, crystal form B, crystal form C, crystal form D, and crystal form E) can be used in pharmaceutical compositions, health products, cosmetics, food additives, etc.

[0130] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions or as recommended by the manufacturer. Percentages and parts are by weight unless otherwise stated.

[0131] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as are familiar to those skilled in the art. Furthermore, any methods and materials similar to or equivalent to those described herein may be used in the methods of this invention.

[0132] Test method:

[0133] XRPD (X-ray Powder Diffraction) pattern determination method: Bruker D2 Phaser X-ray powder diffractometer; radiation source

[0134] Measurement discrepancies associated with these X-ray powder diffraction (XPD) analysis results are caused by a variety of factors, including: (a) errors in sample preparation (e.g., sample height), (b) instrument errors, (c) calibration discrepancies, (d) operator errors (including errors occurring when determining peak positions), and (e) the properties of the material (e.g., preferred orientation errors). Calibration errors and sample height errors often result in shifts in the same direction for all peaks. When using a flat support, small differences in sample height can lead to large shifts in XRPD peak positions. Systematic studies have shown that a 1 mm sample height difference can result in peak shifts as high as 1° 2θ. These shifts can be identified from the XRPD spectra and can be eliminated by compensating for the shifts (applying a systematic calibration factor to all peak position values) or by recalibrating the instrument. As mentioned above, measurement errors from different instruments can be corrected by applying a systematic calibration factor to ensure consistent peak positions.

[0135] The following examples illustrate the invention without limiting it.

[0136] Example 1. Preparation of NMNH calcium salt aqueous solution

[0137] Add 1.7 kg β-NMN and 0.94 kg sodium dithionite to 10 L of saturated sodium bicarbonate aqueous solution, stir overnight at room temperature, filter to obtain a clear solution, and adjust the pH of the clear solution to 3-4 with 37% hydrochloric acid. Desalinate 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; to obtain an aqueous solution of NMNH calcium salt, containing approximately 1.71 kg of NMNH calcium salt (the purity of the solution was 94.5% as determined by HPLC).

[0138] Example 2. Preparation of NMNH calcium salt crystal form A

[0139] Take 500 ml of NMNH calcium salt aqueous solution and stir it in an oil bath at 40-50℃. Slowly add 2 L of methanol dropwise over a period of more than 1 hour. After the addition is complete, stir at 40-50℃ for 1-2 hours, filter, and dry at 40-50℃ to obtain 79.5 g of NMNH calcium salt crystals. The obtained crystals are of crystal form A, with a yield of 84.2% and a purity of 99.83%.

[0140] X-ray powder diffraction (XRPD) was performed on the obtained solid, and the XRPD pattern of crystal form A was basically as follows: Figure 1 As shown, 1 HNMR spectra as follows Figure 6 As shown in Table 1, the diffraction angle data are basically as follows, with the 2θ value having an error range of ±0.2°. Crystal form A is a hydrate with a water content of 9.2% wt.

[0141] Table 1 XRPD data for crystal form A

[0142]

[0143]

[0144] Example 3. Preparation of NMNH calcium salt crystal form B

[0145] Take 500 ml of NMNH calcium salt aqueous solution and stir it in an oil bath at 20-30℃. Add 2 L of methanol at once and stir at 20-30℃ for 1-2 h. Filter and dry at 20-30℃ to obtain 80.3 g of NMNH calcium salt crystals. The obtained crystals are of crystal form B, with a yield of 85.0% and a purity of 99.75%.

[0146] X-ray powder diffraction (XRPD) was performed on the obtained solid, and the XRPD pattern of crystal form B was basically as follows: Figure 2 As shown, 1 HNMR spectra as follows Figure 6 As shown in Table 2, the diffraction angle data are basically as follows, with the 2θ value having an error range of ±0.2°. Crystal form B is a hydrate with a water content of 13.3% wt.

[0147] Table 2 XRPD data for crystal form B

[0148]

[0149]

[0150] Example 4. Preparation of NMNH calcium salt crystal form C

[0151] Take 500 ml of NMNH calcium salt aqueous solution and stir it in an oil bath at 20-30℃. Slowly add 2 L of methanol dropwise over a period of more than 1 hour. After the addition is complete, stir for 1-2 hours, filter, and dry at 40-50℃ to obtain 80.1 g of NMNH calcium salt crystals. The obtained crystals are of crystal form C, with a yield of 84.8% and a purity of 99.78%.

[0152] X-ray powder diffraction (XRPD) was performed on the obtained solid, and the XRPD pattern of the obtained crystal form C was basically as follows: Figure 3 As shown, 1 HNMR spectra as follows Figure 6 As shown in Table 3, the diffraction angle data are basically as follows, with the 2θ value having an error range of ±0.2°. Crystal form C is a hydrate with a water content of 9.5% wt.

[0153] Table 3 XRPD data for crystal form C

[0154]

[0155]

[0156] Example 5. Preparation of NMNH calcium salt crystal form D

[0157] Take 500 ml of NMNH calcium salt aqueous solution and stir it in an oil bath at 20-30℃. Slowly add 2 L of ethanol dropwise over a period of more than 1 hour. After the addition is complete, stir for 1-2 hours, filter, and dry at 30-40℃ to obtain 80.7 g of NMNH calcium salt crystals. The obtained crystals are of crystal form D, with a yield of 85.5% and a purity of 99.64%.

[0158] X-ray powder diffraction (XRPD) was performed on the obtained solid, and the XRPD pattern of the obtained crystal form C was basically as follows: Figure 4 As shown in Table 4, the basic diffraction angle data are as follows, with the error range of 2θ value being ±0.2°.

[0159] Crystal form D is ethanol-hydrate with a water content of 18.4% wt. 1 H NMR spectrum as follows Figure 7 As shown, each molecule of NMNH calcium salt contains approximately 0.33 ethanol molecules.

[0160] Table 4 XRPD data for crystal form D

[0161]

[0162] Example 6. Preparation of NMNH calcium salt crystal form E

[0163] Take 500 ml of NMNH calcium salt aqueous solution and stir it in an oil bath at 20-30℃. Slowly add 2 L of acetone dropwise over a period of more than 1 hour. After the addition is complete, stir for 1-2 hours, filter, and dry at 30-40℃ to obtain 80.8 g of NMNH calcium salt crystals. The obtained crystals are of crystal form E, with a yield of 85.6% and a purity of 99.60%.

[0164] X-ray powder diffraction (XRPD) was performed on the obtained solid, and the XRPD pattern of the obtained crystal form C was basically as follows: Figure 5 As shown in Table 5, the basic diffraction angle data are as follows, with the error range of 2θ value being ±0.2°.

[0165] Crystal form E is acetone-hydrate with a water content of 20.3% wt. 1 H NMR spectrum as follows Figure 8 As shown, each molecule of NMNH calcium salt contains approximately 0.33 acetone molecules.

[0166] Table 5 XRPD data for crystal form E

[0167]

[0168] Example 7. Crystal forms A, B, C, D, and E of NMNH calcium salt and NMNH disodium salt crystal form A and amorphous Comparison of the stability and hygroscopicity of solids

[0169] The stability and hygroscopicity of NMNH calcium salt crystal forms A, B, C, D, and E were investigated by placing them in an open stability test chamber at 25°C and 65% RH. The data are shown in Tables 6 and 7.

[0170] Table 6. Stability comparison of NMNH calcium salt crystal forms A, B, C, D, and E with NMNH disodium salt crystal form A and amorphous solid (25℃, 65% RH)

[0171]

[0172]

[0173] Table 7. Study on the hygroscopic properties of NMNH calcium salt crystal forms A, B, C, D, and E (25℃, 65% RH)

[0174]

[0175] After being stored for 60 days, the purity and moisture content of NMNH calcium salt crystal forms A, B, C, D, and E remained almost unchanged. This means that NMNH calcium salt crystal forms A, B, C, D, and E can be stored openly at 25°C and 65% RH for at least 60 days with stable purity and moisture content.

[0176] According to WO2023160405(A1), when NMNH disodium salt is stored in the air, both crystal forms B and C will absorb water and transform into crystal form A. After absorbing water, crystal form A has a water content of 19%-30% (high water content), and its purity drops from 99.33% to 99.01% after 5 days. The amorphous solid of NMNH disodium salt is even more unstable in the air. After being left for 1 day, it absorbs water from the powder and turns into oil, and its purity drops from 99.30% to 99.02%.

[0177] Therefore, it is evident that both the crystalline and amorphous forms of NMNH disodium salt are unstable and easily absorb moisture, which is extremely detrimental to storage, fails to meet shelf life requirements, and hinders market promotion. In contrast, the solid forms of NMNH calcium salt (crystalline A, B, C, D, and E) exhibit significantly improved stability and moisture resistance, facilitating long-term stable storage and making them easier to market.

[0178] All documents mentioned in this invention are incorporated herein by reference as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the foregoing teachings of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. A crystalline form of reduced β-nicotinamide mononucleotide calcium salt of formula (I), ###0001### (I) said crystalline form is a crystalline form selected from the group consisting of: Form A, Form B, Form C, Form D, or Form E; characterized in that wherein said Form A is a hydrate having an XRPD pattern comprising 5 or more 2Θ values selected from the group consisting of: 6.9°±0.2°, 9.5°±0.2°, 12.6°±0.2°, 15.6°±0.2°, 17.9°±0.2°, 21.0°±0.2°, 21.8°±0.2°, 25.4°±0.2°; said Form B is a hydrate having an XRPD pattern comprising 5 or more 2Θ values selected from the group consisting of: 6.5°±0.2°, 8.1°±0.2°, 11.9°±0.2°, 13.1°±0.2°, 17.6°±0.2°, 21.4°±0.2°, 23.7°±0.2°, 26.9°±0.2°; said Form C is a hydrate having an XRPD pattern comprising 5 or more 2Θ values selected from the group consisting of: 6.2°±0.2°, 9.7°±0.2°, 12.4°±0.2°, 16.1°±0.2°, 17.1°±0.2°, 18.7°±0.2°, 20.8°±0.2°, 26.6°±0.2°; said Form D is an ethanol-water hydrate having an XRPD pattern comprising 5 or more 2Θ values selected from the group consisting of: 7.0°±0.2°, 8.0°±0.2°, 12.0°±0.2°, 17.8°±0.2°, 20.2°±0.2°, 26.9°±0.2°; said Form E is an acetone-water hydrate having an XRPD pattern comprising 5 or more 2Θ values selected from the group consisting of: 6.9°±0.2°, 8.0°±0.2°, 11.9°±0.2°, 17.8°±0.2°, 20.2°±0.2°, 26.9°±0.2°. said Form A further has one or more characteristics selected from the group consisting of:

2. The crystal of claim 1, wherein 1) the XRPD pattern of said Form A comprises 2Θ values selected from the group consisting of: 6.9°±0.2°, 9.5°±0.2°, 12.6°±0.2°, 13.9°±0.2°, 14.4°±0.2°, 15.6°±0.2°, 16.7°±0.2°, 17.2°±0.2°, 17.9°±0.2°, 18.8°±0.2°, 21.0°±0.2°, 21.8°±0.2°, 23.1°±0.2°, 25.4°±0.2°, 26.5°±0.2°, 27.3°±0.2°, 28.1°±0.2°, 31.5°±0.2°, 32.8°±0.2°, 35.6°±0.2°; 2) the XRPD pattern of said Form A is substantially as characterized in Figure 1; 3) said Form A is a hydrate having a water content of 4%wt to 13%wt. said Form A is a mono-hydrate.

3. The crystal of claim 2, wherein said Form B further has one or more characteristics selected from the group consisting of:

4. The crystal of claim 1, wherein ​ 1) the XRPD pattern of said crystalline Form B comprises the 2Θ values selected from the group consisting of: 6.5°±0.2°, 8.1°±0.2°, 11.9°±0.2°, 13.1°±0.2°, 13.5°±0.2°, 14.5°±0.2°, 17.6°±0.2°, 18.0°±0.2°, 18.9°±0.2°, 19.4°±0.2°, 19.7°±0.2°, 20.3°±0.2°, 21.4°±0.2°, 23.7°±0.2°, 24.3°±0.2°, 25.1°±0.2°, 26.4°±0.2°, 26.9°±0.2°, 27.5°±0.2°, 28.7°±0.2°, 29.3°±0.2°, 30.5°±0.2°, 30.9°±0.2°, 31.6°±0.2°, 32.4°±0.2°, 32.9°±0.2°, 34.2°±0.2°, 35.0°±0.2°, 35.4°±0.2°, 36.7°±0.2°, 37.5°±0.2°, 37.9°±0.2°, 38.2°±0.2°, 38.9°±0.2°, 40.2°±0.2°; 2) the XRPD pattern of said crystalline Form B is substantially as characterized in Figure 2; 3) said crystalline Form B is a hydrate, having a water content comprised between 4%wt and 20%wt.

5. The crystal of claim 4, wherein Said crystalline Form B is a 1-5 hydrate.

6. The crystal of claim 1, wherein Said crystalline Form C further has one or more characteristics selected from the group consisting of: 1) the XRPD pattern of said crystalline Form C comprises the 2Θ values selected from the group consisting of: 6.2°±0.2°, 6.8°±0.2°, 9.7°±0.2°, 11.8°±0.2°, 12.4°±0.2°, 14.2°±0.2°, 15.5°±0.2°, 16.1°±0.2°, 17.1°±0.2°, 17.9°±0.2°, 18.7°±0.2°, 20.1°±0.2°, 20.8°±0.2°, 21.5°±0.2°, 22.9°±0.2°, 23.5°±0.2°, 24.1°±0.2°, 24.5°±0.2°, 25.0°±0.2°, 25.8°±0.2°, 26.6°±0.2°, 27.3°±0.2°, 27.7°±0.2°, 28.3°±0.2°, 28.5°±0.2°, 29.7°±0.2°, 30.3°±0.2°, 30.8°±0.2°, 31.4°±0.2°, 32.8°±0.2°, 33.4°±0.2°, 34.4°±0.2°, 35.3°±0.2°, 36.0°±0.2°, 37.1°±0.2°, 38.0°±0.2°, 39.0°±0.2°, 39.8°±0.2°; 2) the XRPD pattern of said crystalline Form C is substantially as characterized in Figure 3; 3) said crystalline Form C is a hydrate, having a water content comprised between 4%wt and 13%wt.

7. The crystal of claim 6, wherein Said crystalline Form C is a 1-3 hydrate.

8. The crystal of claim 1, wherein The crystal form D has one or more characteristics selected from the group consisting of: 1) The XRPD pattern of the crystal form D further comprises one or more 2Θ values selected from the group consisting of: 13.5°±0.2°, 14.2°±0.2°, 24.0°±0.2°; 2) The XRPD pattern of the crystal form D comprises 2Θ values selected from the group consisting of: 7.0°±0.2°, 8.0°±0.2°, 12.0°±0.2°, 13.5°±0.2°, 14.2°±0.2°, 15.7°±0.2°, 17.8°±0.2°, 19.2°±0.2°, 20.2°±0.2°, 23.5°±0.2°, 24.0°±0.2°, 24.5°±0.2°, 26.1°±0.2°, 26.9°±0.2°, 28.7°±0.2°, 30.5°±0.2°, 33.8°±0.2°; 3) The XRPD pattern of the crystal form D is substantially as characterized in Figure 4; 4) the crystalline Form D of 1 The H NMR pattern is substantially as characterized in Figure 7; 5) The crystal form D is ethanol-hydrate, containing 0.2-0.5 ethanol, and the water content is 16%wt-23%wt.

9. The crystal of claim 8, wherein The crystal form D is ethanol-hydrate, containing 3-6 water molecules.

10. The crystal of claim 1, wherein The crystal form E has one or more characteristics selected from the group consisting of: 1) The XRPD pattern of the crystal form E further comprises one or more 2Θ values selected from the group consisting of: 13.5°±0.2°, 14.2°±0.2°, 24.0°±0.2°; 2) The XRPD pattern of the crystal form E comprises 2Θ values selected from the group consisting of: 6.9°±0.2°, 8.0°±0.2°, 11.9°±0.2°, 13.5°±0.2°, 14.2°±0.2°, 15.7°±0.2°, 17.8°±0.2°, 18.8°±0.2°, 19.2°±0.2°, 20.2°±0.2°, 24.1°±0.2°, 26.0°±0.2°, 26.9°±0.2°, 28.7°±0.2°, 30.7°±0.2°, 33.9°±0.2°; 3) The XRPD pattern of the crystal form E is substantially as characterized in Figure 5; 4) the crystalline Form E of 1 The H NMR pattern is substantially as characterized in Figure 8; 5) The crystal form E is acetone-hydrate, containing 0.2-0.5 acetone, and the water content is 16%wt-23%wt.

11. The crystal of claim 10, wherein The crystal form E is acetone-hydrate, containing 3-6 water molecules.

12. A method of preparing the crystal of claim 1, wherein, The method comprises the following steps: (I) Preparation of crystal form A: I-1) providing a solution containing reduced β-nicotinamide mononucleotide calcium salt formed in a first solvent; I-2) adding a second solvent dropwise to the solution of reduced β-nicotinamide mononucleotide calcium salt in step I-1) at 40-50°C, filtering and drying at 40-50°C to obtain crystal form A of reduced β-nicotinamide mononucleotide calcium salt, wherein the first solvent is selected from: water; the second solvent is selected from: methanol, ethanol, n-propanol, isopropanol, acetone, acetonitrile, tetrahydrofuran; (II) Preparation of crystal form B: II-1) providing a solution containing reduced β-nicotinamide mononucleotide calcium salt formed in a first solvent; II-2) adding a second solvent dropwise to the solution of reduced β-nicotinamide mononucleotide calcium salt in step II-1) at 40-50°C, filtering and drying at 40-50°C to obtain crystal form B of reduced β-nicotinamide mononucleotide calcium salt, wherein the first solvent is selected from: water; the second solvent is selected from: methanol, ethanol, n-propanol, isopropanol, acetone, acetonitrile, tetrahydrofuran. II-2) adding a second solvent to the solution of the reduced β-nicotinamide mononucleotide calcium salt as described in step II-1) at 20-30°C, crystallizing, filtering and drying at 20-30°C to obtain the crystal form B of the reduced β-nicotinamide mononucleotide calcium salt, wherein the first solvent is selected from: water; and the second solvent is selected from: methanol, or an aqueous solution of methanol; (III) Preparation of the crystal form C: III-1) providing a solution containing the reduced β-nicotinamide mononucleotide calcium salt in a first solvent; III-2) adding a second solvent to the solution of the reduced β-nicotinamide mononucleotide calcium salt as described in step III) at 20-30°C, crystallizing, filtering and drying at 40-50°C to obtain the crystal form C of the reduced β-nicotinamide mononucleotide calcium salt, wherein the first solvent is selected from: water; and the second solvent is selected from: methanol, or an aqueous solution of methanol; (IV) Preparation of the crystal form D: IV-1) providing a solution containing the reduced β-nicotinamide mononucleotide calcium salt in a first solvent; IV-2) adding a second solvent to the solution of the reduced β-nicotinamide mononucleotide calcium salt as described in step IV-1) at 20-30°C, crystallizing, filtering and drying at 30-40°C to obtain the crystal form D of the reduced β-nicotinamide mononucleotide calcium salt, wherein the first solvent is selected from: water; and the second solvent is selected from: ethanol, or an aqueous solution of ethanol; (V) Preparation of the crystal form E: V-1) providing a solution containing the reduced β-nicotinamide mononucleotide calcium salt in a first solvent; V-2) adding a second solvent to the solution of the reduced β-nicotinamide mononucleotide calcium salt as described in step V-1) at 20-30°C, crystallizing, filtering and drying at 30-40°C to obtain the crystal form E of the reduced β-nicotinamide mononucleotide calcium salt, wherein the first solvent is selected from: water; and the second solvent is selected from: acetone, or an aqueous solution of acetone.

13. The method of claim 12, wherein, The solution containing the reduced β-nicotinamide mononucleotide calcium salt is provided by adding the reduced β-nicotinamide mononucleotide calcium salt to a first solvent to obtain a solution containing the reduced β-nicotinamide mononucleotide calcium salt, or generating the solution of the reduced β-nicotinamide mononucleotide calcium salt in situ in a reaction mixture.

14. A composition characterized in that, The composition comprises: (a) the crystal as claimed in any one of claims 1-11, and (b) a pharmaceutically acceptable excipient or a cosmetically acceptable excipient.

15. The composition of claim 14, wherein The composition is a pharmaceutical composition, and the dosage form is selected from the group consisting of oral preparations, injection dosage forms, respiratory tract administration dosage forms, skin administration dosage forms, mucosal administration dosage forms, and cavity administration dosage forms.

16. The composition of claim 14, wherein The composition is a cosmetic composition, and the cosmetic is selected from the group consisting of skin cosmetics, hair cosmetics, and beauty cosmetics.

17. The composition of claim 14, wherein The composition is a special functional cosmetic.

18. Use of a crystal according to any one of claims 1 to 11, characterized in that The composition is used for preparing a medicine or a cosmetic. The composition is used for preparing a medicine or a cosmetic.

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