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Definitions

• the invention relates to the field of chemical raw materials for medicine, health products and cosmetics, in particular to the polymorphic form of reduced ⁇ -nicotinamide mononucleotide disodium salt and its preparation method and application.
• NAD + nicotinamide adenine dinucleotide
• a growing body of research indicates that increasing NAD + equivalents significantly improves 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) .
• NAD + can use tryptophan in the de novo biosynthesis pathway, niacin (NA) in the thals-handler pathway, and nicotinamide (NAM), nicotinic acid (NAM) in the salvage pathway (salvage pathway) amide riboside (NR) and nicotinamide mononucleotide (NMN) (Canto et al., 2015; Chiarugi et al., 2012; Johnson and Imai, 2018).
• NA niacin
• NAM nicotinamide
• NAM nicotinic acid
• NR amide riboside
• NN nicotinamide mononucleotide
• NAM NAD + key intermediates
• NR NAD + NR
• NMN NAD + key intermediates
• NMN is currently considered the most suitable NAD + precursor
• NMN is currently selling in the global market, favored by consumers.
• NMNH molecular structure shown in formula (A)
• Chinese name is "reduced nicotinamide mononucleotide” or “reduced ⁇ -nicotinamide mononucleotide”, which is the reduced form of NMN and is a kind of supplement NAD
• the new precursor of + which has a better NAD + promoting effect than NMN and other biological functions such as increasing the antioxidant capacity of cells, reducing fat accumulation, reducing inflammatory reactions and inhibiting tumor cell growth, is a commercially significant Potential health promoting agent (WO2021098725A1).
• NMNH is the reduced form of NMN, which is easily oxidized by air
• NMN is easily oxidized by air
• amorphous solid needs to be obtained by freeze-drying.
• This method has no purification effect on the product, and the amorphous solid obtained by freeze-drying is Foamy, poor fluidity, easy to absorb moisture and turn into oil, and degrade quickly
• freeze-drying technology is not necessary in industry, because freeze-drying requires high energy consumption and limited production capacity; amorphous solids have higher energy and are more unstable than crystalline solids.
• the object of the present invention is to provide a new NMNH compound and its polymorph, which has the advantages of good stability, good fluidity, and suitability for industrialization, that is, the polymorph of NMNH disodium salt and its preparation method and application.
• the first aspect of the present invention provides a crystal of reduced ⁇ -nicotinamide mononucleotide disodium salt, the crystal form of which is selected from the group consisting of crystal form A, crystal form B, or crystal form C.
• the crystal of the reduced ⁇ -nicotinamide mononucleotide disodium salt is a hydrate.
• n is ⁇ 2.
• n is an integer or non-integer.
• n is a positive integer ⁇ 2, preferably 2-10, more preferably 5-9.
• the XRPD pattern of the crystal form A includes 3 or more 2 ⁇ values selected from the following group: 12.7° ⁇ 0.2°, 15.9 ⁇ 0.2°, 18.0° ⁇ 0.2°, 20.4° ⁇ 0.2°, 20.9° ⁇ 0.2°, 31.8° ⁇ 0.2°.
• the XRPD pattern of the crystal form A further includes one or more 2 ⁇ values selected from the following group: 10.5° ⁇ 0.2°, 19.8° ⁇ 0.2°, 22.6° ⁇ 0.2°, 24.0 ° ⁇ 0.2°, 26.1° ⁇ 0.2°, 28.7° ⁇ 0.2°, 30.8° ⁇ 0.2°, 33.4° ⁇ 0.2°.
• the crystal form A also has one or more characteristics selected from the following group:
• the XRPD pattern of the crystal form A includes 6 or more 2 ⁇ values selected from the following group: 5.0° ⁇ 0.2°, 10.5° ⁇ 0.2°, 12.7° ⁇ 0.2°, 13.7° ⁇ 0.2°, 14.9 ° ⁇ 0.2°, 15.9° ⁇ 0.2°, 16.1° ⁇ 0.2°, 16.6° ⁇ 0.2°, 18.0° ⁇ 0.2°, 19.8° ⁇ 0.2°, 20.4° ⁇ 0.2°, 20.9° ⁇ 0.2°, 22.6° ⁇ 0.2°, 24.0° ⁇ 0.2°, 24.7° ⁇ 0.2°, 25.2° ⁇ 0.2°, 25.7° ⁇ 0.2°, 26.1° ⁇ 0.2°, 27.8° ⁇ 0.2°, 28.7° ⁇ 0.2°, 29.3° ⁇ 0.2° , 30.3° ⁇ 0.2°, 30.8° ⁇ 0.2°, 31.8° ⁇ 0.2°, 32.7° ⁇ 0.2°, 33.4° ⁇ 0.2°, 34.2° ⁇ 0.2°, 35.8° ⁇ 0.2°, 36.4° ⁇ 0.2°, 37.4 ° ⁇ 0.2°, 39.7° ⁇ 0.2°, 41.2°
• the DSC spectrum of the crystal form A has an endothermic peak in the range of 50°C-80°C;
• the crystal form A is pentahydrate, hexahydrate, heptahydrate, octahydrate, or nonahydrate.
• the crystal form B has one or more characteristics selected from the following group:
• the XRPD pattern of the crystal form B includes 3 or more 2 ⁇ values selected from the following group: 12.0° ⁇ 0.2°, 14.5° ⁇ 0.2°, 15.3° ⁇ 0.2°, 17.5° ⁇ 0.2°, 19.9 ° ⁇ 0.2°, 21.5° ⁇ 0.2°;
• the XRPD pattern of the crystal form B also includes one or more 2 ⁇ values selected from the following group:
• the XRPD pattern of the crystal form B includes 6 or more 2 ⁇ values selected from the following group: 5.2° ⁇ 0.2°, 7.7° ⁇ 0.2°, 10.5° ⁇ 0.2°, 11.5° ⁇ 0.2°, 12.0 ° ⁇ 0.2°, 12.6° ⁇ 0.2°, 13.7° ⁇ 0.2°, 14.5° ⁇ 0.2°, 15.3° ⁇ 0.2°, 16.5° ⁇ 0.2°, 17.1° ⁇ 0.2°, 17.5° ⁇ 0.2°, 18.5° ⁇ 0.2°, 19.4° ⁇ 0.2°, 19.9° ⁇ 0.2°, 21.1° ⁇ 0.2°, 21.5° ⁇ 0.2°, 22.5° ⁇ 0.2°, 23.1° ⁇ 0.2°, 24.1° ⁇ 0.2°, 24.7° ⁇ 0.2° , 25.5° ⁇ 0.2°, 26.4° ⁇ 0.2°, 27.2° ⁇ 0.2°, 27.7° ⁇ 0.2°, 28.3° ⁇ 0.2°, 29.2° ⁇ 0.2°, 29.5° ⁇ 0.2°, 31.2° ⁇ 0.2°, 32.1 ° ⁇ 0.2°, 32.6° ⁇ 0.2°, 34.2° ⁇ 0.2°
• the DSC spectrum of the crystal form B has an endothermic peak in the range of 50°C-80°C;
• the crystal form B is trihydrate, tetrahydrate, pentahydrate, or hexahydrate.
• the crystal form C has one or more characteristics selected from the following group:
• the XRPD pattern of the crystal form C includes 3 or more 2 ⁇ values selected from the following group: 6.3° ⁇ 0.2°, 15.3° ⁇ 0.2°, 17.7° ⁇ 0.2°, 19.9° ⁇ 0.2°, 20.2 ° ⁇ 0.2°, 21.5° ⁇ 0.2°;
• the XRPD pattern of the crystal form C also includes one or more 2 ⁇ values selected from the following group: 6.3° ⁇ 0.2°, 10.0° ⁇ 0.2°, 12.1° ⁇ 0.2°, 12.3° ⁇ 0.2°, 12.8° ⁇ 0.2°, 15.3° ⁇ 0.2°, 16.6° ⁇ 0.2°, 17.7° ⁇ 0.2°, 19.9° ⁇ 0.2°, 20.2° ⁇ 0.2°, 21.5° ⁇ 0.2°, 23.3° ⁇ 0.2°, 24.9° ⁇ 0.2°, 25.6° ⁇ 0.2°, 33.7° ⁇ 0.2°;
• the DSC spectrum of the crystal form C has an endothermic peak in the range of 50°C-80°C;
• the crystal form C is dihydrate, trihydrate, or tetrahydrate.
• the second aspect of the present invention provides a method for preparing reduced ⁇ -nicotinamide mononucleotide disodium salt crystals, the method comprising the following steps:
• the first solvent and the second solvent are the same or different, and are independently selected from the group consisting of water, acetonitrile, tetrahydrofuran, methyl tert-butyl ether, 2-methyltetrahydrofuran, di Chloromethane, N,N-dimethylformamide, N,N-dimethylacetamide, N,N-diethylformamide, dimethyl sulfoxide, ethyl acetate, isopropyl acetate, ketones solvents, alcoholic solvents, or combinations thereof.
• 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 combination.
• the alcohol solvent is selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, and n-pentanol.
• the method further includes: step 3), drying the crystals.
• the drying includes: vacuum drying the obtained crystals for 2-30 hours.
• the crystal is Form A.
• step 2) further includes sub-step 2a), making crystalline form B and/or crystalline form C Placed in a moisture-containing gas to convert to Form A.
• step 2a the crystal form B and/or the crystal form C is placed in the air, so as to be converted into the crystal form A.
• the third aspect of the present invention provides a composition, said composition comprising: (a) any crystal described in the first aspect, and (b) pharmaceutically acceptable excipients or carriers, or pharmaceutically acceptable Acceptable excipients or carriers, or cosmetically acceptable excipients or carriers, or food acceptable excipients or carriers.
• the composition is selected from the group consisting of pharmaceutical composition, health product composition, cosmetic composition, or food composition.
• the pharmaceutical composition comprises: (a) any crystal described in the first aspect, and (b) pharmaceutically acceptable excipients or carriers.
• the dosage form of the pharmaceutical composition is selected from the group consisting of oral preparations, injection dosage forms, respiratory administration dosage forms, skin administration dosage forms, mucosal administration dosage forms, cavity administration dosage forms and the like.
• the health care product composition comprises: (a) any crystal described in the first aspect, and (b) an adjuvant or carrier acceptable for health care products.
• the cosmetic composition comprises: (a) any crystal described in the first aspect, and (b) cosmetically acceptable excipients or carriers.
• the cosmetic composition includes cosmetics selected from the following group of uses: skin cosmetics, hair cosmetics, cosmetic cosmetics, and cosmetics with special functions.
• the food composition comprises: (a) any crystal described in the first aspect, and (b) a food-acceptable auxiliary material or carrier.
• the fourth aspect of the present invention provides the use of a crystal for the preparation of medicines or health care products or cosmetics or food additives.
• 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/kidney disease, improve sarcopenia symptoms in the elderly, treat chronic inflammation, alleviate conditions in patients with polycystic ovary syndrome, prevent/delay glaucoma, reduce neuroinflammation, relieve anthracyclines Cardiotoxicity of chemotherapy drugs, assisting the rehabilitation of cerebral infarction, preventing and treating heart failure in the elderly, etc.
• the health product is used to slow down cell aging, delay female reproductive aging, 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 senile dementia, etc.
• the cosmetics are used to improve damaged cell function, improve skin/hair quality, prevent/treat skin photoaging, maintain skin softness and elasticity, delay skin aging, etc.
• the food additives are used to improve appetite, improve digestion, promote metabolism, promote hair/nail growth, etc., and increase nutritional value.
• Figure 1 shows the XRPD pattern of NMNH disodium salt Form A.
• Figure 2 shows the TGA spectrum of NMNH disodium salt Form A.
• Figure 3 shows the DSC spectrum of Form A of NMNH disodium salt.
• Figure 4 shows the XRPD pattern of NMNH disodium salt Form B.
• Figure 5 shows the TGA spectrum of NMNH disodium salt Form B.
• Figure 6 shows the DSC spectrum of NMNH disodium salt Form B.
• Figure 7 shows the XRPD pattern of NMNH disodium salt Form C.
• Figure 8 shows the TGA spectrum of NMNH disodium salt Form C.
• Figure 9 shows the DSC spectrum of NMNH disodium salt Form C.
• Figure 10 shows the XRPD pattern of NMNH disodium salt amorphous.
• Figure 11 shows the TGA spectrum of NMNH disodium salt amorphous.
• Figure 12 shows the DSC spectrum of NMNH disodium salt amorphous.
• Figure 13 shows the 1 H NMR spectrum of NMNH disodium salt Form A.
• Figure 14 shows the stability of Form A and amorphous solid under open storage conditions at 25°C and 65% RH.
• Figure 15 shows the stability of Form A and amorphous solid under open storage conditions at 4°C, 75% RH.
• the present inventors unexpectedly developed a specific salt of reduced NMNH for the first time, which is NMNH disodium salt.
• the research of the present invention shows that the polymorphic form (especially crystal form A) of NMNH disodium salt has excellent stability. Compared to its amorphous solid form, the amorphous form changes from solid to oily or viscous mass on standing and degrades quickly.
• the polymorphs of the present invention have the advantages of high purity, good stability, good fluidity, low hygroscopicity, etc., and are suitable for use in pharmaceutical compositions, health care products, cosmetics, food additives, and the like. On this basis, the inventors have completed the present invention.
• n in the term “ nH2O " is meant to include all possible values between 2 and 10, including Integer, non-integer; "H 2 O” is the chemical formula of water, representing water molecules or water.
• the term “about” means that the value may vary by no more than 1% from the recited specific value, for example, as used herein, the expression “about 100” includes 99 and 101 and all values in between (eg, 99.1, 99.2, 99.3, 99.4, etc.).
• the term “comprises” or “includes (comprising)” can be open, semi-closed and closed. In other words, the term also includes “consisting essentially of” or “consisting of”.
• n or more 2 ⁇ values selected from the following group refers to any positive integer including n and greater than n (such as n, n+1, 7), wherein the upper limit Nup is all 2 ⁇ values in the group the number of peaks.
• “3 or more” not only includes 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, ...
• the upper limit Nup is each positive integer, and also includes ranges such as “4 or more", “5 or more", “6 or more”.
• the salt formed by sodium ions has the structure shown in formula I. It is to be understood that the term includes hydrates and anhydrates.
• the preferred reduced NMN disodium salt is a hydrate, and its structure is shown in formula (II):
• Solids exist either in amorphous or crystalline form. In the case of crystalline forms, the molecules are positioned within three-dimensional lattice sites. When a compound crystallizes from a solution or slurry, it can crystallize in a different spatial lattice arrangement (a property known as "polymorphism"), forming crystals with different crystalline forms, which are referred to as Known as "polymorphs". Different polymorphs of a given substance may differ in one or more physical properties (e.g. solubility and rate of dissolution, true specific gravity, crystal form, packing pattern, Fluidity and/or solid state stability) are different from each other.
• physical properties e.g. solubility and rate of dissolution, true specific gravity, crystal form, packing pattern, Fluidity and/or solid state stability
• Polymorphic forms of compounds can exhibit different melting points, hygroscopicity, stability, solubility, bioavailability, bioactivity, and fluidity, which are important factors affecting druggability.
• crystal As used herein, “crystal”, “crystal of the present invention” or “polymorph” can be used interchangeably, and refers to the crystal described in the first aspect of the present invention, whose crystal form is selected from the following group: crystal form A, crystal form B, or crystal form C.
• Production-scale crystallization can be accomplished by manipulating the solution such that the solubility limit of the target compound is exceeded. This can be accomplished in a number of ways, for example, by dissolving the compound at a relatively high temperature and then cooling the solution below the saturation limit. Or reduce the volume of the liquid by boiling, atmospheric evaporation, vacuum drying, or by some other method.
• the solubility of a compound of interest 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 is to adjust the pH to reduce solubility.
• a detailed description of crystallization can be found in Crystallization, Third Edition, J.W. Mullens, Butterworth-Heineman Ltd., 1993, ISBN0750611294.
• optimization of crystallization may include seeding the crystallization medium with crystals of the desired form. Additionally, many crystallization methods use combinations of the above strategies. One implementation is to dissolve the compound of interest in a solvent at elevated temperature, followed by addition of an appropriate volume of antisolvent in a controlled manner to bring the system just below the saturation level. At this point, seeds of the desired form can be added (and the integrity of the seeds maintained) and the system cooled to complete crystallization.
• solvates Compounds that form after crystallization from a solvent are called solvates.
• the types of solvents that easily form solvates with organic compounds include water, methanol, ethanol, benzene, ether, heterocyclic aromatic hydrocarbons, and the like.
• Hydrates are a special kind of solvates.
• no matter in the synthesis of raw materials, pharmaceutical preparations, drug storage and drug activity evaluation, hydrates have the value of separate discussion because of their particularity.
• the crystal of the compound represented by formula (I) may be a non-solvate or a solvate
• the crystal form A, crystal form B and crystal form C of the compound crystal shown in formula (I) are all hydrates.
• NMNH disodium salt crystals When preparing NMNH disodium salt crystals in the present invention, temperature-controlled crystallization, decompression concentration crystallization, nitrogen purging crystallization, volatile crystallization, dissolution crystallization, temperature-controlled and humidity-controlled crystallization, vacuum drying and crystallization, etc. are used.
• the method is simple and convenient. Easy to implement and easy to industrialized production.
• NMNH disodium salt crystal including crystal form A, crystal form B, and crystal form C: the crystal has high efficiency and broad spectrum, and can be used in pharmaceutical compositions, health care products, cosmetics, food additives, and the like.
• the compound crystal of formula (I) of the present invention (including crystal form A, crystal form B, and crystal form C) has high purity, good stability, good fluidity and low hygroscopicity.
• the compound crystals of formula (I) of the present invention can be used in pharmaceutical compositions, health products, cosmetics, food additives, etc.
• the preparation method of the polymorph of the present invention is simple and suitable for industrial production.
• XRPD X-ray powder diffraction pattern determination method: Bruker D2 Phaser X-ray powder diffractometer; radiation source Generator (Generator) kv: 30kv; Generator (Generator) mA: 10mA; Initial 2 ⁇ : 2.000°; Scanning range: 2.0000 ⁇ 50.000°, scanning step size 0.02°, scanning speed 0.1s/step.
• Measurement differences associated with such X-ray powder diffraction analysis results arise from a variety of factors including Differences: (a) errors in sample preparation (e.g., sample height), (b) instrument errors, (c) calibration differences, (d) operator errors (including errors in determining peak positions), and (e ) properties of matter (such as preferred orientation errors). Calibration errors and sample height errors often cause all peaks to shift in the same direction. Small differences in sample height will result in large shifts in XRPD peak positions when using flat supports. Systematic studies have shown that a sample height difference of 1 mm can result in a peak shift in 2 ⁇ of up to 1°.
• shifts can be identified from the XRPD pattern and can be eliminated by compensating for them (using a system calibration factor for all peak position values) or recalibrating the instrument. Measurement errors from different instruments can be corrected for by applying system calibration factors to make peak positions consistent, as described above.
• TGA thermogravimetric analysis
• DSC differential scanning calorimetry
• Moisture (KF) determination method MC-2000 automatic trace moisture analyzer of Mince Instrument Equipment (Xiamen) Co., Ltd., Karl Fischer reagent (Karl fischer reagent) of Nanjing Chemical Reagent Co., Ltd.
• NMNH disodium salt Preparation of NMNH disodium salt: Add 179 mg of MnCl 2 to 2.85 liters of Tris-HCl (50 mM) solution, adjust the pH of the solution to 8.0, and control the temperature at 37°C. Add 143 mg of NAD+pyrophosphatase from Escherichia coli (EcNADD) to the solution, add 10 g of NADH, and stir for 2 hours. The NMNH solution was separated by preparative chromatography, the pH of the solution was adjusted to 10 with NaOH, and concentrated under reduced pressure to obtain 3.8 g of NMNH disodium salt solid.
• EcNADD NAD+pyrophosphatase from Escherichia coli
• the TGA spectrum of Form A is basically shown in Figure 2, and the weight loss is 19%-30% at 15°C-200°C.
• the DSC spectrum of Form A is basically shown in Figure 3, and has an endothermic peak in the range of 50°C-80°C.
• Example 2 The kilogram-level amplification and purification effect of crystal form A
• NMNH disodium salt aqueous solution add 1.7Kg ⁇ -NMN, 0.94Kg Na 2 S 2 O 4 to 10 liters of saturated sodium bicarbonate aqueous solution, stir overnight at room temperature, filter the clear liquid, adjust the pH of the clear liquid to 10 with NaOH, and obtain Aqueous solution of NMNH disodium salt (HPLC purity 95.2%).
• the obtained solid was subjected to X-ray powder diffraction test.
• the XRPD pattern of the obtained crystal form B is basically shown in Figure 4, and the diffraction angle data is basically shown in Table 3 below, wherein the error range of the 2 ⁇ value is ⁇ 0.2°.
• the TGA spectrum of Form B is basically shown in Figure 5, and the weight loss is 12%-23% at 15°C-200°C.
• the DSC spectrum of Form B is basically shown in Figure 6, and has an endothermic peak in the range of 50°C-80°C.
• the obtained solid was subjected to X-ray powder diffraction test.
• the XRPD pattern of the obtained crystal form C is basically shown in Figure 7, and the diffraction angle data is basically shown in Table 4 below, wherein the error range of 2 ⁇ value is ⁇ 0.2°.
• the TGA spectrum of Form C is basically shown in Figure 8, and the weight loss is 8%-16% at 15°C-200°C.
• the DSC spectrum of Form C is basically shown in Figure 9, and has an endothermic peak in the range of 50°C-80°C.
• Example 5 Form B absorbs water in the air and converts to Form A
• the crystal form A of the compound has a water content (KF) of 29%.
• Example 6 converts to Form A after absorbing water in the air
• the TGA spectrum of the amorphous solid is basically shown in Figure 11, and the weight loss is 1%-15% at 15°C-200°C.
• the DSC spectrum of the amorphous solid is basically shown in Figure 12, and has an endothermic peak in the range of 50°C-80°C.
• Embodiment 8 Stability comparison of crystal form A and amorphous solid
• Example 2 The product crystal (crystalline form A) in Example 2 and the product amorphous solid in Example 7 are all exposed to 25 °C, 65%RH in a stability test chamber to investigate stability, and obtain as shown in the table 5 and Figure 14 data.
• Example 2 The product crystals (crystal form A) in Example 2 and the product amorphous solid in Example 7 are all exposed and placed in a stability test box at 4° C. and 75% RH to investigate stability, and obtain as shown in the table 6 and data in Figure 15.
• the purity of Form A was 99.33% after 18 days, almost no change (still crystalline powder); and the purity of the amorphous solid dropped from 99.30% to 99.26% after 5 days (the powder solid absorbed water and changed to 99.26%). viscous into agglomerates), and the purity decreased to 99.17% on the 18th day (the color became darker). It can be seen that the crystalline form A solid of NMNH disodium salt is more stable than the amorphous solid.

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