CN114933621A - Organic acid salt of nicotinamide ribose, and crystal form, preparation method and application thereof - Google Patents

Organic acid salt of nicotinamide ribose, and crystal form, preparation method and application thereof Download PDF

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CN114933621A
CN114933621A CN202210389629.4A CN202210389629A CN114933621A CN 114933621 A CN114933621 A CN 114933621A CN 202210389629 A CN202210389629 A CN 202210389629A CN 114933621 A CN114933621 A CN 114933621A
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organic acid
nicotinamide
acid salt
crystalline form
salt
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杨超文
符定良
宋家良
叶柳
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Shenzhen Dieckmann Technology Development Co ltd
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Shenzhen Dikeman Biotechnology Co ltd
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    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
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Abstract

The invention belongs to the field of biological medicine, and discloses an organic acid salt of nicotinamide riboside, wherein the organic acid is tartaric acid or fumaric acid, and the molar ratio of the nicotinamide riboside to the organic acid is 1: 2; the invention also discloses the crystal forms of the nicotinamide ribosyl tartrate and the nicotinamide ribosyl fumarate and the preparation methods thereof. The nicotinamide ribotartrate and the nicotinamide ribofumarate have low hygroscopicity, good chemical stability in air environment, basically no change in color and solid shape maintenance; the thermal stability is high, compared with the amorphous form, the crystalline form of the compound has the advantages of further improving the hygroscopicity and the stability (air stability and thermal stability), having better pharmaceutical performance and wider application scenes, and laying a foundation for the development of various formulations of cosmetics and medicines.

Description

Organic acid salt of nicotinamide riboside, and crystal form, preparation method and application thereof
Technical Field
The invention belongs to the field of biological medicine, and particularly relates to an organic acid salt of nicotinamide riboside, a crystal form and a preparation method thereof.
Background
Nicotinamide Riboside (NR) exists as a pyridinium cation, forming a relatively stable structure by virtue of forming an ion pair with an anion. According to the structural characteristics of the organic salt, the organic salt is waterproof, easy to decompose, poor in stability and easy to discolor, and therefore the organic salt brings serious challenges to preparation, storage, processing and application of products. At present, nicotinamide riboside is commercially applied to the field of health-care foods, and is matched with a hydrophobic drug carrier to increase the hydrophobicity of the nicotinamide riboside, and the nicotinamide riboside is mainly in a capsule form, is sealed in the capsule to avoid exposure to air, avoids air and water contact of products in the storage process and avoids water contact of the products before the products enter the stomach for absorption. The current commercialized capsule is nicotinamide ribosyl chloride salt, and no report of nicotinamide ribosyl organic acid salt is found. Not all dosage forms are suitable for encapsulation in capsules, which is unavoidable in the cosmetic field in two respects: 1. water, which is ubiquitous in cosmetics, even though a small amount of water exists in an oil agent, the freeze-dried preparation formulation needs to be dissolved in water firstly, and sweat exists on the surface of skin in the application process, so that the condition that a certain stability is kept in water is a prerequisite for the application of the product; 2. the air and the surface of the cosmetics are exposed to the air in the storage and use processes, and the stability, the color consistency and the like of the cosmetics become the standards whether the products can be applied or not. In other fields of application, such as confectionery, milk powder and other solid formulations, the same requirements are placed on colour, heat stability and moisture resistance during processing and application. The currently reported organic acid salts and chloride salts of NR have poor water resistance and stability, and the color of the organic acid salts and chloride salts of NR can change when the organic acid salts and chloride salts of NR are exposed in the air, so that the application and processing of the organic acid salts and chloride salts of NR in the fields of medicines, cosmetics and food additives are generally limited. Therefore, it is necessary to research and develop a NR organic acid salt that is stable to water and air, and to actually apply the NR organic acid salt to a field having higher requirements for its physicochemical properties.
Disclosure of Invention
In a first aspect of the present invention, a class of organic acid salts of nicotinamide riboside with good stability is provided, wherein the organic acid is tartaric acid or fumaric acid.
Further, the molar ratio of nicotinamide riboside to organic acid is 1: 2.
in another aspect of the present invention, a crystalline form of an organic acid salt of nicotinamide riboside with better stability is provided, wherein the organic acid is tartaric acid, and an X-ray diffraction pattern expressed by a 2 θ angle using Cu-K α radiation has the following characteristic absorption peaks: 12.68, 17.14, 22.88, 29.75, 36.84.
Further, the X-ray diffraction pattern of the crystalline form is substantially in accordance with fig. 1.
Further, the thermal decomposition temperature of the crystalline form was 155 ℃ calculated as 5% weight loss.
In another aspect of the invention, a crystal form of an organic acid salt of nicotinamide riboside with better stability is provided, wherein the organic acid is fumaric acid, and an X-ray diffraction pattern expressed by a 2 theta angle by using Cu-Ka radiation has the following characteristic absorption peaks: 11.2, 17.98, 22.28, 27.94, 29.44, 37.5.
Further, the X-ray diffraction pattern of the crystalline form substantially corresponds to that of fig. 2.
Further, the thermal decomposition temperature of the crystalline form was 147 ℃ calculated as 5% weight loss.
In another aspect of the present invention, a method for preparing a crystalline form of an organic acid salt of nicotinamide riboside is provided, which comprises the following steps:
s1, dissolving the crude product of the organic acid salt of the nicotinamide riboside by using a methanol-water mixed solution;
s2, adding ethanol, and filtering and washing the precipitated solid;
s3, dissolving the obtained solid in ethanol, stirring, filtering and freeze-drying to obtain crystals.
Further, the volume ratio of the methanol-water mixed solution is methanol: water (90-99.9): (0.1-10).
Further, steps S1 and S2 are performed at-30 to-10 ℃.
In another aspect of the present invention, the organic acid salt of nicotinamide riboside is used in the fields of medicine, cosmetics, and food, such as lyophilized powder, oil, gel, candy, milk powder, solid preparation, solid beverage, etc. which are inevitably exposed to air or require contact with water.
In another aspect of the present invention, the crystalline form of the organic acid salt of nicotinamide riboside is applied to the fields of medicines, cosmetics and foods, such as freeze-dried powder, oil, gel of cosmetics, candy, milk powder, solid preparation, solid beverage and the like, which are inevitably exposed to air or need to be contacted with water.
The invention has the following beneficial effects:
1. the invention adopts specific organic acid (fumaric acid and tartaric acid) and nicotinamide ribose to form salt, has low hygroscopicity, and is superior to the prior NR organic acid salt (including chloride salt); the chemical stability in the air environment is good, the color basically does not change, and the solid shape is kept; the thermal stability is high.
2. The invention prepares the crystal forms of the nicotinamide ribofumarate and the nicotinamide ribotartrate, compared with the non-crystal forms, the hygroscopicity and the stability (air stability and thermal stability) are further improved, the nicotinamide ribofumarate and the nicotinamide ribotartrate have better pharmaceutical performance and wider application scenes, and lay the foundation for the development of various dosage forms of cosmetics, foods, health products, food additives and medicines.
3. The prior NR organic acid salt has the problem of moisture absorption and discoloration, which is generally considered to be determined by the physicochemical properties of the NR organic acid salt, however, the nicotinamide ribofumarate, the nicotinamide ribotartrate and the crystal form thereof break the inherent cognition, the color is not changed in the air for a long time, and unexpected technical effects are obtained.
4. The nicotinamide ribofumarate and the nicotinamide ribotartrate and the crystal forms thereof are not limited to closed systems, are suitable for formulations (including oil agents, gels, freeze-dried powder formulations, tablets and solid formulations added into milk powder and the like as food additives) exposed in the air in the storage and application processes, can be widely applied to the fields of cosmetics, foods, health care products, food additives and medicines, for example, the processing of candies has requirements on the heat stability of products, for example, the field of cosmetics, the consistent color is a precondition for determining whether raw materials can be applied, and the products can be well applied to the fields.
Drawings
Figure 1 is an X-ray powder diffraction pattern of the crystalline form of nicotinamide riboside tartrate of example 1;
FIG. 2 is an X-ray powder diffraction pattern of the crystalline form of nicotinamide ribofumarate of example 2;
FIG. 3 is a TGA spectrum of nicotinamide riboside citrate of example 3;
FIG. 4 is a TGA spectrum of nicotinamide ribofumarate of example 3;
figure 5 is a TGA profile of the crystalline form of nicotinamide ribofumarate of example 3;
FIG. 6 is a TGA spectrum of nicotinamide ribotartrate of example 3;
figure 7 is a TGA profile of the crystalline form of nicotinamide ribotartrate of example 3;
FIG. 8 is a picture of the NR chloride salt of example 6 left for 0 days;
FIG. 9 is a picture of the NR chloride salt of example 6 left for 15 days;
fig. 10 is a picture of NR citrate of example 6 left for 0 days;
fig. 11 is a picture of NR citrate of example 6 left for 15 days;
fig. 12 is a picture of NR tartrate of example 6 left for 0 day;
fig. 13 is a picture of NR tartrate of example 6 left for 15 days;
fig. 14 is a picture of the NR tartrate crystals of example 6 left for 0 day;
fig. 15 is a picture of the NR tartrate crystals of example 6 left for 15 days;
fig. 16 is a picture of the NR fumarate of example 6 left for 0 days;
fig. 17 is a picture of NR fumarate of example 6 left for 15 days;
fig. 18 is a picture of the NR fumarate crystal of example 6 left for 0 day;
fig. 19 is a picture of NR fumarate crystals of example 6 left for 15 days;
FIG. 20 is a bar graph of melanin content measurements of nicotinamide of example 9;
FIG. 21 is a bar graph showing the results of measuring the melanin content of NR tartrate in example 9;
FIG. 22 is a bar graph of the results of measuring melanin content of the crystalline form of NR tartrate of example 9;
FIG. 23 is a bar graph showing the results of measuring the melanin content of NR fumarate according to example 9;
FIG. 24 is a bar graph of the results of measuring melanin content of the crystalline form of NR fumarate of example 9;
fig. 25 is a color picture of the lyophilized formulation of example 10.
Detailed Description
The present invention will be further described with reference to the following specific examples.
Example 1
Preparation of nicotinamide ribotartrate (1: 2)
Under the protection of nitrogen, 150ml of anhydrous methanol is added into a 500ml three-neck flask, the flask is cooled to-5-0 ℃, 0.1568mol of NR is added, methanol solution of tartaric acid (0.3115mol of tartaric acid is dissolved in 250ml of methanol) is added while stirring, after the addition is finished, the reaction is continued for 6 hours at-5-0 ℃, 20ml of anhydrous ethyl acetate is added, the solid is obtained by filtration, the solid is rinsed by anhydrous ethyl acetate, and the light yellow solid 53.38g and 0.1391mol are obtained by drying. The molar yield is: 88.72%, HPLC: 96.213 percent.
HNMR(400MHz,MeOD):δ9.59(s,1H),9.25-9.27(d,1H),8.96-8.98(d,1H),8.25-8.29(t,1H),6.24-6.25(d,1H),4.49-4.50(d,4H),4.45-4.48(q,1H),4.34-4.36(t,1H)，4.02-4.05(dd,1H),3.87-3.97(dd,1H)。
IR(KBr)ν max 3331，1693，1620，1408，1307，1263，1215,1134，1068，680，484cm -1 。
MS: MS (ESI +): 255.09 [ M ], M being the molecular weight of the NR cation; MS (ESI-):553.11 [ M-1 ], M is the molecular weight of NR tartrate (1: 2).
Crystalline preparation of nicotinamide ribotartrate
100ml of a methanol solution (methanol: water: 95:5, volume ratio) was added to a 250ml three-necked flask, cooled to-20 ℃, and 50g of the crude NR tartrate was added thereto, stirred for 1 hour, then 50ml of absolute ethanol was added thereto, and further stirred for 1 hour to precipitate a solid, which was then filtered and washed with absolute ethanol. Adding the solid into a 250ml three-necked bottle at room temperature, adding 150ml of absolute ethanol, stirring for 2h, filtering, and freeze-drying to obtain 45g of pale yellow white solid, and performing HPLC: 97.885 percent.
IR(KBr)νmax3409，2940，1698，1580，1411，1293，1181，1098，1028，658cm -1 。
The XRD of the crystals is: 12.68, 17.14, 22.88, 29.75 and 36.84, and the spectrum is shown in figure 1.
Example 2
Preparation of nicotinamide ribofumarate (1: 2)
Adding 100ml of anhydrous methanol into a 500ml three-neck flask under the protection of nitrogen, cooling to-5-0 ℃, adding 0.0784mol of NR, stirring while adding a methanol solution of fumaric acid (0.1138mol of fumaric acid is dissolved in 60ml of methanol), continuing to react for 5 hours after the addition is finished, adding 10ml of anhydrous ethyl acetate, filtering to obtain a solid, rinsing with the anhydrous ethyl acetate, filtering, and drying to obtain 23.5g of a light yellowish whitish solid, namely 0.0484mol of the light yellowish whitish solid. The molar yield is: 61.74%, HPLC: 94.713 percent.
HNMR(400MHz,MeOD):δ9.61(s,1H),9.27-9.29(d,1H),8.97-8.99(d,1H),8.26-8.30(t,1H),6.67(d,4H)6.25-6.26(d,1H),4.47-4.53(m,2H),4.35-4.38(t,1H),4.03-4.07(dd,1H)，3.88-3.92(dd,1H)。
IR(KBr)ν max 3394，2937，1687,1614，1184，1097，983，650，503cm -1 。
MS: MS (ESI +): 255.09 [ M ], M being the molecular weight of the NR cation.
Crystal preparation of nicotinamide ribofumarate
In a 100ml three-necked flask, 30ml of methanol solution (methanol: water 98:2 by volume) was added, cooled to-20 ℃, 20g of the crude NR fumarate was added, stirred for 1 hour, then 30ml of absolute ethanol was added, and stirring was continued for 1 hour to precipitate a solid, filtered, and washed with absolute ethanol. The solid was then added to a 100ml three-necked flask at room temperature, 50ml absolute ethanol was added, stirred for 2h, filtered and lyophilized to give 18.4g of a pale yellow whitish solid, HPLC: 96.150 percent.
IR(KBr)νmax3409，2940，1698，1580，1411，1293，1181，1098，1028，658cm-1。
The XRD of the crystals is: 11.2, 17.98, 22.28, 27.94, 29.44 and 37.5, and the spectrum is shown in figure 2.
Example 3
TGA stability test
FIGS. 3 to 7 are TGA spectra of nicotinamide ribocitrate, nicotinamide ribofumarate (prepared in example 2), nicotinamide ribofumarate crystal form (prepared in example 2), nicotinamide ribotartrate (prepared in example 1), and nicotinamide ribotartrate crystal form (prepared in example 1), respectively; calculated by 5% of weight loss, the decomposition temperature is 80 ℃, 143 ℃, 147 ℃, 153 ℃ and 155 ℃ in sequence, before the decomposition temperature, the nicotinamide ribose citrate has obvious weight loss along with the temperature rise, the nicotinamide ribose fumarate and the nicotinamide ribose tartrate have obvious weight loss along with the temperature rise, the crystal forms of the nicotinamide ribose fumarate and the nicotinamide ribose tartrate have insignificant weight loss along with the temperature rise compared with the amorphous forms thereof, and the platform shape is basically maintained, which shows that the thermal stability of the fumarate and tartrate of the nicotinamide ribose is superior to that of the nicotinamide ribose citrate, and the thermal stability of the crystal forms of the nicotinamide ribose fumarate and the nicotinamide ribose tartrate is the best and superior to that of the amorphous forms.
Example 4
Mass spectrometric stability analysis
Stability analyses were performed on the basis of Mass Spectrometry (MS) using ESI source, NR chloride salt commercially available, NR citrate prepared with reference to CN111454311A, NR fumarate prepared as example 2, NR tartrate prepared as example 1, with the results shown in the following table:
Figure BDA0003595101010000051
ESI is an ionization technique that converts ions in solution into gas phase ions for MS analysis. The process in which the transfer of ions from solution to the gas phase is strongly endothermic and requires higher energy, so for such ionic structures the molecular ion peaks of the mass spectrum are generally cationic molecular ion peaks. Molecular ion peaks for NR citrate and NR chloride, as well as NR fumarate, NR tartrate, MS (ESI +), have been reported to be NR cation peaks.
The results of MS (ESI-), NR citrate, NR chloride and NR fumarate, all have no molecular ion peak of the whole compound, only NR tartrate shows the molecular ion peak of the whole compound, and combining the principle and experimental results of ESI, NR tartrate is the only one NR organic acid salt which is found at present and can show the molecular ion peak of the whole compound, which shows that NR tartrate can endure the electrospray conditions that other NR salt compounds can not endure, and also proves that the cation and anion of NR tartrate form a very compact ion pair, has very high stability and chemical stability better than all reported NR salts.
Example 5
Accelerated stability testing
HPLC test method
Each sample was divided into 7 bottles, sealed from the air and dark, placed in a constant temperature bath at 40 ℃, one bottle of sample was taken each time (day) at the time of the test, 5mL or 10mL solution was prepared using a 5mL or 10mL volumetric flask, and the HPLC test sample purity was prepared by filtration, and the results were as shown in the table below, and the decomposition rate was calculated.
Mobile phase: isocratic elution 5% water (0.1% formic acid) + 95% methanol (0.1% formic acid)
Wavelength: 254nm
Temperature and humidity: 23.0 ℃ and 54% RH
Sample dissolution: dissolving with methanol
A chromatographic column: ODS-2, 4.6X 250mm, 5 μm, constant pressure of 12-13 MPa
Flow rate: 1.0mL/min
Sample introduction amount: 5 μ L
Operating time: not less than 15min
Figure BDA0003595101010000061
Figure BDA0003595101010000071
The decomposition rates of the NR tartrate and NR fumarate each exceeded 10% (10.47% and 11.17%) after the sample was left in a constant temperature bath at 40 ℃ for 6 days. The corresponding crystal forms have the decomposition rates of only 1.17% and 1.53%, which shows that the crystal forms of NR tartrate and NR fumarate have more excellent thermal stability than the amorphous forms.
Example 6
Air stability test
Respectively weighing 5g of sample, placing the sample in a weighing bottle, opening the cover of the weighing bottle, placing for 15 days, comparing the color changes before and after the comparison, wherein the average temperature is 20 ℃, and the average relative humidity/RH%: 66; the results were as follows:
Figure BDA0003595101010000072
the NR chloride salt and NR citrate salt are exposed to air, and the color of the sample turns into reddish brown after 15 days, and the form changes from solid to liquid because the sample has high hygroscopicity, absorbs moisture in the air, and becomes liquid, and the two salts are not suitable for the fields and dosage forms of exposed air.
The NR tartrate and NR fumarate were exposed to air, and the surface portions of the samples became dark in color after 15 days and maintained solid shapes, indicating that they were less hygroscopic than the NR chloride and NR citrate and more stable to air than the NR chloride and NR citrate.
The crystals of NR tartrate and NR fumarate were exposed to air and the samples did not change after 15 days, indicating that they are very stable to both water and air, have very low hygroscopicity and are more stable than the amorphous form.
The compound keeps consistent color in the air, which is a precondition and a necessary property for the compound to be used for cosmetics, foods and additives, otherwise, the compound can only be used for isolating the air by a packaging mode such as capsules. Therefore, compared with the prior reported NR salts, the NR tartrate and the NR fumarate are satisfactory, and the crystal form of the NR tartrate and the NR fumarate is more outstanding than the amorphous form.
Example 7
Moisture absorption test
Respectively weighing the sample bottles, weighing again after adding the samples, exposing the samples in the air for 15 days, weighing again, and calculating the water absorption: w% (M3-M2)/(M2-M1) × 100%. The experimental conditions are as follows: average temperature 20 ℃, average relative humidity/RH%: 66. the results were as follows:
Figure BDA0003595101010000081
the water absorption rates of the NR chloride salt and the NR citrate salt were 15.11% and 3.5%, respectively, while the water absorption rates of the NR tartrate salt and the NR fumarate salt were less than 1% (0.40% and 0.57%), and the crystals of the NR tartrate salt and the NR fumarate salt hardly absorbed water, which is consistent with the results of the air stability test, that is, the NR tartrate salt and the NR fumarate salt are much less hygroscopic than the currently reported NR salts (such as the NR citrate salt and the NR chloride salt), and the crystal forms thereof are much less hygroscopic than the amorphous forms, exhibiting very excellent hydrophobicity.
Example 8
Purity detection
1g of each sample is weighed and placed in a weighing bottle, laid flat, the cover of the weighing bottle is opened, the bottle is placed on the 1 st day and the 15 th day in an open manner, and the purity is detected by HPLC respectively. The experimental conditions are as follows: average temperature 20 ℃, average relative humidity/RH%: 66. the results are as follows:
sample (I) HPLC/day 1 HPLC/day 15
NR tartrate salt 96.213％ 84.555％
NR tartrate crystal 97.885％ 97.853％
NR fumarate salt 94.713％ 78.553％
NR fumarate salt crystal 96.150％ 96.281％
Decomposition occurred after 15 days of standing for NR tartrate and NR fumarate; the purities of the NR tartrate crystals and the NR fumarate crystals are basically unchanged, and no obvious decomposition occurs, which shows that the stability of the crystal forms in the air is better than that of the amorphous forms, and the stability is consistent with the color change, the form change and the water absorption rule.
Example 9
Comparative cell whitening experiment
Cell experiment steps: the B16F10 cells in exponential growth phase were inoculated in parallel into 60mm cell culture dishes and maintained at 37 ℃ in DMEM medium containing 10% FBS and 5% CO 2 Culturing in an incubator for 24h, adding test substances (nicotinamide, NR tartrate crystal form, NR fumarate, and NR fumarate crystal form) with different concentrations, respectively, replacing with DMEM medium containing 2.5% FBS, and acting on cells for 72 h. Removing the culture medium from the cultured cells, washing with PBS for 3 times, placing the cell culture dish on an ice plate, adding 100. mu.L of non-denatured cell lysate into each dish, lysing at 4 ℃ for 20min, and collecting the cells. Centrifuging at 13000r/min for 10min at 4 ℃, obtaining black precipitate as melanin, and measuring the melanin content by using a NaOH method.
Determination of melanin content by NaOH cracking method: add 330. mu.L NaOH (containing 10% DMSO), vortex for sufficient lysis, place in 80 ℃ metal bath for 2h to dissolve the melanin precipitate sufficiently. Vortex and mix evenly, add 100 μ L melanin dissolving solution into each well of 96-well plate, set 3 multiple wells, determine OD value at 405 nm.
FIGS. 20 to 24 are histograms of melanin content detection results of nicotinamide, NR tartrate, NR fumarate, and NR fumarate crystal forms, respectively. By taking nicotinamide as a comparison, the nicotinamide does not obviously influence the generation of B16F10 cell melanin, the NR tartrate crystal form can slightly reduce the formation of the cell melanin, but the NR tartrate effect is not obvious, and no statistical difference exists, the NR fumarate and the NR fumarate crystal form reduce the formation and the content of the cell melanin, so that the nicotinamide riboside has a better whitening effect, and the effect of the NR fumarate and the crystal form on reducing the cell melanin is shown, and the nicotinamide riboside specific organic acid salt, namely the fumarate, does not completely depend on decomposition into nicotinamide, has a better whitening effect, and can reduce the cell melanin.
Example 10
Preparation of lyophilized preparation
The lyophilized powder is a common preparation for health products, cosmetics and medicines, and is prepared by dissolving or dispersing functional active ingredient or functional active ingredient added with excipient and other adjuvants in water, vacuum-cooling at low temperature, and adding N 2 Sealed, and the weight is fixed, directly prepare the solution during the use can, so the freeze-dried powder has following advantage: (1) improving the storage property; (2) good re-solubility, and can be quickly dissolved after being added with water and restore the original characteristics of the liquid medicine; (3) the product has accurate dosage and good appearance; (4) the aseptic operation is easy to realize; (5) the production environment is improved, and harmful dust is avoided; (6) the problem of moisture absorption and deterioration of products in the subpackaging process is solved; (7) the problem that the product is easy to oxidize when exposed in the air is solved. In order to solve the problem that the product is exposed in the air, the freeze-dried powder can be prepared into a dosage form so as to be convenient and accurate to use and store.
The preparation process comprises the following steps: adding 0.5g of mannitol and 0.5g of vitamin C into 3mL of water, carrying out ultrasonic treatment for 5min by using ultrasonic waves, cooling at 0-5 ℃, and independently adding 1g of NR salt, wherein the NR salt is as follows: and (3) uniformly stirring NR chloride salt, NR citrate, NR tartrate and NR fumarate in an ice-water bath, and successfully preparing a mixed solution.
Setting the parameters of the freeze-drying process
Figure BDA0003595101010000101
Color comparison as shown in fig. 25, NR tartrate (NRJSS), NR fumarate (NRFMS) salt lyophilized powder was uniform pale yellow; while NR chloride (NRCl) and NR citrate (NRNMS) are reddish. In the process of preparing the mixed solution, the tolerance of different NR organic acid salts in water is inconsistent, and the NR tartrate and the NR fumarate have better stability and lighter color, and the NR chloride salt and the NR citrate have no water resistance and darker color.
The above description is only an embodiment of the present invention, but the scope of the present invention is not limited thereto, and any changes or substitutions that can be easily conceived by those skilled in the art within the technical scope of the present invention are included in the scope of the present invention. Therefore, the protection scope of the present invention should be subject to the protection scope of the claims.

Claims (11)

1. An organic acid salt of nicotinamide riboside, characterized in that the organic acid is tartaric acid or fumaric acid.
2. The organic acid salt of nicotinamide ribose according to claim 1, wherein the molar ratio of nicotinamide ribose to organic acid is 1: 2.
3. the crystalline form of an organic acid salt of nicotinamide riboside, according to claim 2, characterized in that the organic acid is tartaric acid and the X-ray diffraction pattern expressed in 2 Θ angles using Cu-ka radiation has the following characteristic absorption peaks: 12.68, 17.14, 22.88, 29.75, 36.84.
4. The crystalline form of an organic acid salt of nicotinamide ribose of claim 3, characterized in that the crystalline form has an X-ray diffraction pattern substantially in accordance with figure 1.
5. A crystalline form of an organic acid salt of nicotinamide ribose according to claim 3, characterized in that the thermal decomposition temperature of the crystalline form is 155 ℃ calculated as 5% weight loss.
6. The crystalline form of an organic acid salt of nicotinamide riboside of claim 2, characterized in that the organic acid is fumaric acid and the X-ray diffraction pattern expressed in 2 Θ degrees using Cu-ka radiation has the following characteristic absorption peaks: 11.2, 17.98, 22.28, 27.94, 29.44, 37.5.
7. The crystalline form of an organic acid salt of nicotinamide ribose of claim 6, characterized in that the crystalline form has an X-ray diffraction pattern substantially in accordance with figure 2.
8. A crystalline form of an organic acid salt of nicotinamide ribose according to claim 6, characterized in that the thermal decomposition temperature of the crystalline form is 147 ℃ calculated as 5% weight loss.
9. The method for preparing a crystalline form of an organic acid salt of nicotinamide riboside of any one of claims 3 to 8, comprising the steps of:
s1, dissolving the crude product of the organic acid salt of the nicotinamide riboside by using a methanol-water mixed solution;
s2, adding ethanol, and filtering and washing the precipitated solid;
s3, dissolving the solid in ethanol, stirring, filtering and freeze-drying to obtain the crystal.
10. Use of an organic acid salt of nicotinamide riboside in the fields of pharmaceuticals, cosmetics, and foods, wherein the crystalline form of the organic acid salt of nicotinamide riboside is as defined in claim 1 or 2.
11. The application of the crystal form of the organic acid salt of nicotinamide riboside in the fields of medicines, cosmetics and foods is as claimed in any one of claims 3-8.
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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105873937A (en) * 2013-10-30 2016-08-17 可劳迈戴斯有限公司 Nicotinamide riboside compositions for topical use in treating skin conditions
CN106536535A (en) * 2014-06-02 2017-03-22 葛兰素史密斯克莱知识产权（第2 号）有限公司 Preparation and use of crystalline beta-d-nicotinamide riboside
US20180030079A1 (en) * 2015-03-09 2018-02-01 W. R. Grace & Co.-Conn. Crystalline Form Of Nicotinamide Riboside
CN108774278A (en) * 2018-09-10 2018-11-09 张洪喜 A method of preparing niacinamide nucleosides salt
CN111377983A (en) * 2020-03-26 2020-07-07 音芙医药科技(上海)有限公司 Preparation method of β -nicotinamide mononucleotide

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105873937A (en) * 2013-10-30 2016-08-17 可劳迈戴斯有限公司 Nicotinamide riboside compositions for topical use in treating skin conditions
CN106536535A (en) * 2014-06-02 2017-03-22 葛兰素史密斯克莱知识产权（第2 号）有限公司 Preparation and use of crystalline beta-d-nicotinamide riboside
US20180030079A1 (en) * 2015-03-09 2018-02-01 W. R. Grace & Co.-Conn. Crystalline Form Of Nicotinamide Riboside
CN108774278A (en) * 2018-09-10 2018-11-09 张洪喜 A method of preparing niacinamide nucleosides salt
CN111377983A (en) * 2020-03-26 2020-07-07 音芙医药科技(上海)有限公司 Preparation method of β -nicotinamide mononucleotide

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