CN116621898A - Organic acid salt of nicotinamide riboside and crystal form, preparation method and application thereof - Google Patents
Organic acid salt of nicotinamide riboside and crystal form, preparation method and application thereof Download PDFInfo
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- CN116621898A CN116621898A CN202310595345.5A CN202310595345A CN116621898A CN 116621898 A CN116621898 A CN 116621898A CN 202310595345 A CN202310595345 A CN 202310595345A CN 116621898 A CN116621898 A CN 116621898A
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- Prior art keywords
- nicotinamide riboside
- organic acid
- acid salt
- crystalline form
- tartrate
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- 235000020956 nicotinamide riboside Nutrition 0.000 title claims abstract description 172
- 239000011618 nicotinamide riboside Substances 0.000 title claims abstract description 172
- JLEBZPBDRKPWTD-TURQNECASA-O N-ribosylnicotinamide Chemical group NC(=O)C1=CC=C[N+]([C@H]2[C@@H]([C@H](O)[C@@H](CO)O2)O)=C1 JLEBZPBDRKPWTD-TURQNECASA-O 0.000 title claims abstract description 139
- -1 Organic acid salt Chemical class 0.000 title claims abstract description 64
- 239000013078 crystal Chemical group 0.000 title claims abstract description 32
- 238000002360 preparation method Methods 0.000 title abstract description 16
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims abstract description 60
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims abstract description 51
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims abstract description 49
- 239000007787 solid Substances 0.000 claims abstract description 26
- 239000002537 cosmetic Substances 0.000 claims abstract description 17
- 150000007524 organic acids Chemical class 0.000 claims abstract description 11
- 239000001530 fumaric acid Substances 0.000 claims abstract description 9
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims abstract description 8
- 235000002906 tartaric acid Nutrition 0.000 claims abstract description 8
- 239000011975 tartaric acid Substances 0.000 claims abstract description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 14
- 238000010521 absorption reaction Methods 0.000 claims description 11
- 238000002441 X-ray diffraction Methods 0.000 claims description 8
- 238000001914 filtration Methods 0.000 claims description 8
- 235000013305 food Nutrition 0.000 claims description 8
- 238000003756 stirring Methods 0.000 claims description 8
- 230000004580 weight loss Effects 0.000 claims description 8
- 239000011259 mixed solution Substances 0.000 claims description 5
- 230000005855 radiation Effects 0.000 claims description 4
- 238000005979 thermal decomposition reaction Methods 0.000 claims description 4
- 238000005406 washing Methods 0.000 claims description 4
- 238000004108 freeze drying Methods 0.000 claims description 3
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 229940095064 tartrate Drugs 0.000 abstract description 42
- 239000003814 drug Substances 0.000 abstract description 9
- 239000002552 dosage form Substances 0.000 abstract description 8
- 229940079593 drug Drugs 0.000 abstract description 4
- 239000000126 substance Substances 0.000 abstract description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 39
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 25
- XUMBMVFBXHLACL-UHFFFAOYSA-N Melanin Chemical compound O=C1C(=O)C(C2=CNC3=C(C(C(=O)C4=C32)=O)C)=C2C4=CNC2=C1C XUMBMVFBXHLACL-UHFFFAOYSA-N 0.000 description 16
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 239000000047 product Substances 0.000 description 12
- 210000004027 cell Anatomy 0.000 description 11
- 238000004949 mass spectrometry Methods 0.000 description 10
- 238000000034 method Methods 0.000 description 10
- 239000000243 solution Substances 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 238000004128 high performance liquid chromatography Methods 0.000 description 9
- 239000000843 powder Substances 0.000 description 9
- 238000000354 decomposition reaction Methods 0.000 description 8
- 238000001228 spectrum Methods 0.000 description 8
- 238000005303 weighing Methods 0.000 description 8
- 230000036564 melanin content Effects 0.000 description 7
- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 6
- 238000009472 formulation Methods 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 239000002775 capsule Substances 0.000 description 5
- 150000001793 charged compounds Chemical class 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 4
- DFPAKSUCGFBDDF-ZQBYOMGUSA-N [14c]-nicotinamide Chemical compound N[14C](=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-ZQBYOMGUSA-N 0.000 description 4
- 235000009508 confectionery Nutrition 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 235000013373 food additive Nutrition 0.000 description 4
- 239000002778 food additive Substances 0.000 description 4
- 150000002500 ions Chemical class 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- 235000013336 milk Nutrition 0.000 description 4
- 239000008267 milk Substances 0.000 description 4
- 210000004080 milk Anatomy 0.000 description 4
- 238000012545 processing Methods 0.000 description 4
- 150000003839 salts Chemical class 0.000 description 4
- 238000013112 stability test Methods 0.000 description 4
- 238000003860 storage Methods 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 238000004090 dissolution Methods 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000008176 lyophilized powder Substances 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- 229960003966 nicotinamide Drugs 0.000 description 3
- 235000005152 nicotinamide Nutrition 0.000 description 3
- 239000011570 nicotinamide Substances 0.000 description 3
- 230000002087 whitening effect Effects 0.000 description 3
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 150000001450 anions Chemical class 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 235000013361 beverage Nutrition 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 150000001768 cations Chemical class 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- OKKJLVBELUTLKV-VMNATFBRSA-N methanol-d1 Chemical compound [2H]OC OKKJLVBELUTLKV-VMNATFBRSA-N 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 238000000634 powder X-ray diffraction Methods 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- YABIFCKURFRPPO-IVOJBTPCSA-N 1-[(2r,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]pyridin-1-ium-3-carboxamide;chloride Chemical group [Cl-].NC(=O)C1=CC=C[N+]([C@H]2[C@@H]([C@H](O)[C@@H](CO)O2)O)=C1 YABIFCKURFRPPO-IVOJBTPCSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- ZZZCUOFIHGPKAK-UHFFFAOYSA-N D-erythro-ascorbic acid Natural products OCC1OC(=O)C(O)=C1O ZZZCUOFIHGPKAK-UHFFFAOYSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 229930003268 Vitamin C Natural products 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000003698 anagen phase Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 239000013592 cell lysate Substances 0.000 description 1
- 150000003841 chloride salts Chemical class 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 230000019771 cognition Effects 0.000 description 1
- 238000005056 compaction Methods 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 210000004748 cultured cell Anatomy 0.000 description 1
- 230000009089 cytolysis Effects 0.000 description 1
- 230000006866 deterioration Effects 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 239000000428 dust Substances 0.000 description 1
- 238000005538 encapsulation Methods 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 238000010829 isocratic elution Methods 0.000 description 1
- 239000012931 lyophilized formulation Substances 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-O pyridinium Chemical compound C1=CC=[NH+]C=C1 JUJWROOIHBZHMG-UHFFFAOYSA-O 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000005871 repellent Substances 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 210000004243 sweat Anatomy 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 238000009210 therapy by ultrasound Methods 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 235000019154 vitamin C Nutrition 0.000 description 1
- 239000011718 vitamin C Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/048—Pyridine radicals
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23C—DAIRY PRODUCTS, e.g. MILK, BUTTER OR CHEESE; MILK OR CHEESE SUBSTITUTES; MAKING THEREOF
- A23C9/00—Milk preparations; Milk powder or milk powder preparations
- A23C9/152—Milk preparations; Milk powder or milk powder preparations containing additives
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23G—COCOA; COCOA PRODUCTS, e.g. CHOCOLATE; SUBSTITUTES FOR COCOA OR COCOA PRODUCTS; CONFECTIONERY; CHEWING GUM; ICE-CREAM; PREPARATION THEREOF
- A23G3/00—Sweetmeats; Confectionery; Marzipan; Coated or filled products
- A23G3/34—Sweetmeats, confectionery or marzipan; Processes for the preparation thereof
- A23G3/36—Sweetmeats, confectionery or marzipan; Processes for the preparation thereof characterised by the composition containing organic or inorganic compounds
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L2/00—Non-alcoholic beverages; Dry compositions or concentrates therefor; Their preparation
- A23L2/385—Concentrates of non-alcoholic beverages
- A23L2/39—Dry compositions
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/60—Sugars; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q19/00—Preparations for care of the skin
- A61Q19/02—Preparations for care of the skin for chemically bleaching or whitening the skin
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/41—Preparation of salts of carboxylic acids
- C07C51/412—Preparation of salts of carboxylic acids by conversion of the acids, their salts, esters or anhydrides with the same carboxylic acid part
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
- C07C57/02—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms with only carbon-to-carbon double bonds as unsaturation
- C07C57/13—Dicarboxylic acids
- C07C57/15—Fumaric acid
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C59/235—Saturated compounds containing more than one carboxyl group
- C07C59/245—Saturated compounds containing more than one carboxyl group containing hydroxy or O-metal groups
- C07C59/255—Tartaric acid
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
- C07H1/06—Separation; Purification
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The application 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 application also discloses crystal forms of nicotinamide riboside tartrate and nicotinamide riboside fumarate and a preparation method thereof. The nicotinamide riboside tartrate and the nicotinamide riboside fumarate have low hygroscopicity, good chemical stability in an air environment, basically no change in color, and keep a solid shape; the heat stability is high, the hygroscopicity and the stability (air stability and heat stability) of the crystal form are further improved compared with the non-crystal form, and the preparation has better pharmaceutical performance and wider application scene, thereby laying a foundation for developing various dosage forms of cosmetics and medicines.
Description
The application relates to an organic acid salt of nicotinamide riboside, which has the application number of 2022103896294, the application date of 2022, 4 and 13, and the application name of nicotinamide riboside, and a crystal form, a preparation method and application thereof.
Technical Field
The application belongs to the field of biological medicine, and in particular relates to an organic acid salt of nicotinamide riboside and a crystal form and a preparation method thereof.
Background
Nicotinamide Riboside (NR) exists as a pyridinium cation that forms a relatively stable structure by virtue of ion pairing with an anion. According to the structural characteristics, the organic salt is water-repellent, easy to decompose, poor in stability and easy to change color, and the organic salt brings serious challenges to the preparation, storage, processing and application of products. At present, the nicotinamide riboside is commercially applied in the field of health-care foods, is matched with a hydrophobic drug carrier to increase the hydrophobicity, and the dosage form is mainly a capsule, and is sealed in the capsule to avoid exposure to air, avoid the contact of the product with air and water in the storage process and avoid the contact with water before entering the stomach for absorption. At present, the commercial capsule is nicotinamide riboside chloride salt, and no report on nicotinamide riboside organic acid salt is seen. However, not all dosage forms are suitable for being enclosed in capsules, and in the cosmetic field, two aspects are unavoidable: 1. water is ubiquitous in cosmetics, even if oil solution is slightly water, the freeze-dried dosage form needs to be dissolved in water firstly, sweat exists on the skin surface in the application process, and therefore, the maintenance of certain stability in water is a precondition that the product can be applied; 2. during the storage and use of the cosmetics, the surface of the cosmetics is exposed to the air, and the stability, the color consistency and the like of the cosmetics become standards for whether the products can be applied. In other fields of application, such as candy, milk powder and other solid formulations, the same demands are made on color, thermal stability, moisture resistance during processing and application. The reported NR organic acid salt and NR chlorine salt have poor water resistance and stability, and change color when exposed to air, so that the application and processing of the NR organic acid salt and NR chlorine salt in the fields of medicines, cosmetics and food additives are generally limited. Therefore, it is necessary to develop NR organic acid salts stable to water and air, and to apply NR organic acid salts to fields having higher demands on physicochemical properties.
Disclosure of Invention
In a first aspect of the application, 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 application, there is provided a crystalline form of an organic acid salt of nicotinamide riboside with improved stability, wherein the organic acid is tartaric acid, and an X-ray diffraction pattern expressed in terms of 2θ using Cu-kα 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 present application, there is provided a crystalline form of an organic acid salt of nicotinamide riboside with improved stability, wherein the organic acid is fumaric acid, and an X-ray diffraction pattern expressed in terms of 2θ using Cu-kα 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 is substantially in accordance with fig. 2.
Further, the thermal decomposition temperature of the crystalline form was 147 ℃ calculated as 5% weight loss.
In another aspect of the present application, there is provided a method for preparing a crystalline form of an organic acid salt of nicotinamide riboside, comprising the steps of:
s1, dissolving a crude organic acid salt of 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 to 99.9): (0.1-10).
Further, the steps S1 and S2 are carried out at a temperature of between-30 ℃ and-10 ℃.
In another aspect of the present application, the organic acid salt of nicotinamide riboside is used in the fields of medicine, cosmetics, and food, such as lyophilized powder formulation of cosmetics, oil, gel formulation, candy, milk powder, solid preparation, solid beverage, etc., which are inevitably exposed to air or in the fields where water contact is required.
In another aspect of the present application, the crystalline form of organic acid salt of nicotinamide riboside is used in the pharmaceutical, cosmetic, food fields, such as lyophilized powder formulation of cosmetics, oil, gel formulation, candy, milk powder, solid formulation, solid beverage, etc., which are inevitably exposed to air or in the fields where contact with water is required.
The application has the following beneficial effects:
1. the application adopts specific organic acid (fumaric acid and tartaric acid) to form salt with nicotinamide ribose, has low hygroscopicity and is superior to the existing NR organic acid salt (including chloride salt); the chemical stability in the air environment is good, the color is basically unchanged, and the solid shape is maintained; high thermal stability.
2. Compared with the amorphous form, the crystalline forms of the nicotinamide riboside fumarate and the nicotinamide riboside tartrate have the advantages of further improved hygroscopicity and stability (air stability and thermal stability), better proprietary medicine performance and wider application scene, and lay a foundation for developing various dosage forms of cosmetics, foods, health-care products, food additives and medicines.
3. The existing NR organic acid salt has the problem of moisture absorption and color change, which is generally determined by the physicochemical properties of the NR organic acid salt, however, the nicotinamide riboside fumarate, the nicotinamide riboside tartrate and the crystal forms thereof break the inherent cognition, have no change of color in the air for a long time, and obtain unexpected technical effects.
4. The nicotinamide riboside fumarate, the nicotinamide riboside tartrate and the crystal forms thereof are not limited to closed systems, are suitable for dosage forms (including oil, gel, freeze-dried powder injection, tablets and solid preparations added into milk powder and the like as food additives) exposed in the storage and application processes, can be widely applied to the fields of cosmetics, foods, health-care products, food additives and medicines, such as the processing of candies has requirements on the thermal stability of the products, and further such as the field of cosmetics, the color consistency is a precondition for determining whether raw materials can be applied or not, and the products of the application can be well applied to the fields.
Drawings
FIG. 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 riboside fumarate of example 2;
FIG. 3 is a TGA spectrum of nicotinamide riboside citrate of example 3;
FIG. 4 is a TGA spectrum of nicotinamide riboside fumarate of example 3;
FIG. 5 is a TGA spectrum of the crystalline form of nicotinamide riboside fumarate of example 3;
FIG. 6 is a TGA spectrum of nicotinamide riboside tartrate of example 3;
FIG. 7 is a TGA spectrum of a crystalline form of nicotinamide riboside tartrate of example 3;
FIG. 8 is a photograph of NR chloride salt of example 6 left for 0 day;
FIG. 9 is a photograph of NR chloride salt of example 6 left for 15 days;
fig. 10 is a photograph of NR citrate of example 6 placed for 0 day;
FIG. 11 is a photograph of NR citrate of example 6 placed for 15 days;
FIG. 12 is a photograph of NR tartrate of example 6 on standing for 0 day;
FIG. 13 is a photograph of NR tartrate of example 6 after 15 days of standing;
FIG. 14 is a photograph of NR tartrate crystals of example 6, left for 0 days;
FIG. 15 is a photograph of NR tartrate crystals of example 6, placed for 15 days;
FIG. 16 is a photograph of NR fumarate of example 6 after 0 days of standing;
fig. 17 is a photograph of NR fumarate of example 6 on standing for 15 days;
FIG. 18 is a photograph of NR fumarate crystals of example 6 left standing for 0 days;
FIG. 19 is a photograph of NR fumarate crystals of example 6 left standing for 15 days;
FIG. 20 is a bar graph showing the results of melanin content detection of nicotinamide in example 9;
FIG. 21 is a bar graph showing the results of melanin content measurement of NR tartrate of example 9;
FIG. 22 is a bar graph showing the melanin content assay results for the NR tartrate form of example 9;
FIG. 23 is a bar graph showing the results of melanin content detection of NR fumarate of example 9;
FIG. 24 is a bar graph showing the results of melanin content assay for NR fumarate crystalline form of example 9;
fig. 25 is a color picture of the lyophilized formulation of example 10.
Detailed Description
The application will be further illustrated with reference to specific examples.
Example 1
Preparation of nicotinamide riboside tartrate (1:2)
Under the protection of nitrogen, 150ml of anhydrous methanol is added into a 500ml three-neck flask, cooled to-5-0 ℃, 0.1568mol NR is added, a methanol solution of tartaric acid (0.3115 mol of tartaric acid is dissolved in 250ml of methanol) is added while stirring, the reaction is continued for 6 hours at-5-0 ℃, 20ml of anhydrous ethyl acetate is added, the solid is obtained after filtration, the solid is rinsed with anhydrous ethyl acetate, and light yellow solid 53.38g and 0.1391mol are obtained after drying. The molar yield is: 88.72%, HPLC:96.213%.
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 being the molecular weight of NR tartrate (1:2).
Crystal preparation of nicotinamide riboside tartrate
Into a 250ml three-necked flask, 100ml of a methanol solution (methanol: water=95:5, volume ratio) was added, cooled to-20 ℃, 50g of a crude NR tartrate was added, and after stirring for 1 hour, 50ml of absolute ethanol was added, stirring was continued for 1 hour, a solid was precipitated, and filtration and washing with absolute ethanol were carried out. The solid was then added to a 250ml three-necked flask at room temperature, 150ml of absolute ethanol was added, stirred for 2h, filtered and lyophilized to give 45g of pale yellow solid, HPLC:97.885%.
IR(KBr)νmax3409,2940,1698,1580,1411,1293,1181,1098,1028,658cm -1 。
The XRD of the crystal was: 12.68 17.14, 22.88, 29.75, 36.84, the spectra are shown in fig. 1.
Example 2
Preparation of nicotinamide riboside fumarate (1:2)
Under the protection of nitrogen, 100ml of anhydrous methanol is added into a 500ml three-neck flask, cooled to-5-0 ℃, 0.0784mol NR is added, a methanol solution of fumaric acid (0.1138 mol of fumaric acid is dissolved in 60ml of methanol) is added while stirring, the reaction is continued for 5 hours after the addition, 10ml of anhydrous ethyl acetate is added, the solid is obtained after filtration, the solid is rinsed and filtered by the anhydrous ethyl acetate, and the pale yellow and pale yellow solid is obtained after drying, namely 23.5g and 0.0484mol. The molar yield is: 61.74%, HPLC:94.713%.
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 riboside fumarate
Into a 100ml three-necked flask, 30ml of a methanol solution (methanol: water=98:2, volume ratio) was added, cooled to-20 ℃, 20g of a crude NR fumarate was added, and after stirring for 1 hour, 30ml of absolute ethanol was added, stirring was continued for 1 hour, a solid was precipitated, and filtration and washing with absolute ethanol were carried out. The solid was then added to a 100ml three-necked flask at room temperature, 50ml of absolute ethanol was added, stirred for 2h, filtered and lyophilized to give 18.4g of pale yellow solid, which was subjected to HPLC:96.150%.
IR(KBr)νmax3409,2940,1698,1580,1411,1293,1181,1098,1028,658cm-1。
The XRD of the crystal was: 11.2 17.98, 22.28, 27.94, 29.44, 37.5, the spectra are shown in fig. 2.
Example 3
TGA stability test
Figures 3 to 7 are TGA spectra of nicotinamide riboside citrate, nicotinamide riboside fumarate (prepared in example 2), nicotinamide riboside tartrate (prepared in example 1), and nicotinamide riboside tartrate (prepared in example 1), respectively; the decomposition temperature is 80 ℃, 143 ℃, 147 ℃, 153 ℃ and 155 ℃ in turn calculated by weight loss of 5 percent, the weight loss of nicotinamide riboside citrate along with the temperature rise is obvious before the decomposition temperature, the weight loss of nicotinamide riboside fumarate and nicotinamide riboside tartrate along with the temperature rise is obvious, the weight loss of the crystal forms of nicotinamide riboside fumarate and nicotinamide riboside tartrate along with the temperature rise is not obvious relative to the amorphous form of the nicotinamide riboside fumarate, and the platform shape is basically maintained, which shows that the thermal stability of the nicotinamide riboside fumarate and the nicotinamide riboside tartrate is better than that of the nicotinamide riboside citrate, and the thermal stability of the crystal forms of nicotinamide riboside fumarate and the nicotinamide riboside tartrate is the best, and the thermal stability of the crystal forms of the nicotinamide riboside fumarate is better than that of the amorphous form.
Example 4
Mass spectrometry stability analysis
Stability analysis was performed based on data from Mass Spectrometry (MS) using ESI source, NR chloride salt commercially available, NR citrate salt prepared with reference to CN111454311a, NR fumarate salt prepared as example 2, and NR tartrate salt prepared as example 1, with the results shown in the following table:
ESI is an ionization technique that converts ions in solution into gas phase ions for MS analysis. The transfer of ions from solution to gas phase is a strongly endothermic process requiring high energy, so for such ionic structures the molecular ion peaks of mass spectra are generally those of cations. The molecular ion peaks of the reported NR citrate and NR chloride salts, as well as NR fumarate, NR tartrate, MS (ESI+) are all NR cation peaks.
As a result of MS (ESI), NR citrate, NR chloride and NR fumarate do not have molecular ion peaks of the whole compound, only NR tartrate shows molecular ion peaks of the whole compound, and in combination with the principle and experimental result of ESI, NR tartrate is the only NR organic acid salt which can show molecular ion peaks of the whole compound and is found at present, which indicates that NR tartrate can endure the condition of electric spraying which cannot be endured by other NR salt compounds, and also proves that the cations and anions of NR tartrate form very compact ion pairs, have very high stability and have better chemical stability than all reported NR salts.
Example 5
Accelerated stability test
HPLC test method
Each sample was separated into 7 bottles, sealed from air and protected from light, placed in a constant temperature bath at 40℃and tested, one bottle of sample was taken each time (day) and 5mL or 10mL of solution was prepared with a 5mL or 10mL volumetric flask, filtered, HPLC was prepared to test the purity of the sample, the results were as shown in the following table, and the decomposition rate was calculated.
Mobile phase: isocratic elution 5% water (0.1% formic acid) +95% methanol (0.1% formic acid)
Wavelength: 254nm
Humiture: 23.0 ℃,54% RH
Sample dissolution: methanol dissolution
Chromatographic column: ODS-2, 4.6X105 mm,5 μm, pressure constant at 12-13 MPa
Flow rate: 1.0mL/min
Sample injection amount: 5 mu L
Run time: not less than 15min
After the sample was placed in a constant temperature bath at 40 ℃ for 6 days, the decomposition rates of both NR tartrate and NR fumarate exceeded 10% (10.47% and 11.17%). The corresponding crystalline forms, with a decomposition rate of only 1.17% and 1.53%, demonstrate that the crystalline forms of NR tartrate and NR fumarate have a better thermal stability than the amorphous forms.
Example 6
Air stability test
Weighing 5g of the sample respectively, placing in a weighing bottle, opening the cover of the weighing bottle, placing for 15 days, and comparing the color change before and after the comparison, wherein the average temperature is 20 ℃, and the average relative humidity/RH%: 66; the results were as follows:
after 15 days, the sample turns red brown in color and becomes liquid from solid because the sample has high hygroscopicity, absorbs water in the air and becomes liquid, and the two salts are not suitable for application in the field of exposing air and dosage forms.
The sample surface portion became darker and remained solid after 15 days of exposure to air, indicating that the hygroscopicity was lower than that of NR chloride and NR citrate, and the stability to air was better than that of NR chloride and NR citrate.
The crystals of NR tartrate and NR fumarate were exposed to air and after 15 days the sample did not change, indicating that they were very stable to both water and air, very low hygroscopicity and better stability than the amorphous form.
The compound keeps the color consistent in the air, which is the precondition and the property of the compound for cosmetics, foods and additives, otherwise, the compound can only isolate the air by encapsulation such as capsules. Therefore, NR tartrate and NR fumarate are satisfactory compared to the previously reported NR salts, and their crystalline forms are more prominent than amorphous forms.
Example 7
Hygroscopicity test
Weighing the sample bottles respectively, weighing again after adding the samples, exposing the samples to air for 15 days, weighing again, and calculating the water absorption rate: w% = (M3-M2)/(M2-M1) ×100%. Experimental conditions: average temperature 20 ℃, average relative humidity/rh%: 66. the results were as follows:
the water absorption rates of the NR chloride salt and the NR citrate salt were 15.11% and 3.5%, respectively, whereas the water absorption rates of the NR tartrate salt and the NR fumarate salt were less than 1% (0.40% and 0.57%), the crystallization 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 hygroscopicity of the NR tartrate salt and the NR fumarate salt was far lower than that of the NR salt reported in the prior art (such as NR citrate salt and NR chloride salt), and the crystal form thereof was lower in hygroscopicity as compared with the amorphous state, and exhibited very excellent hydrophobicity.
Example 8
Purity detection
1g of the sample was weighed separately, placed in a weighing flask, spread flat, opened lid of the weighing flask, left open for days 1 and 15, and purity was measured by HPLC, respectively. Experimental conditions: average temperature 20 ℃, average relative humidity/rh%: 66. the results were as follows:
sample of | HPLC/day 1 | HPLC/day 15 |
NR tartrate | 96.213% | 84.555% |
NR tartrate crystals | 97.885% | 97.853% |
NR fumarate salt | 94.713% | 78.553% |
Crystalline NR fumarate salt | 96.150% | 96.281% |
After 15 days of NR tartrate and NR fumarate, decomposition occurred; the purities of the NR tartrate crystals and the NR fumarate crystals are basically unchanged, no obvious decomposition occurs, and the crystalline form is better in stability in air than the amorphous form, which is consistent with the rules of color change, form change and water absorption.
Example 9
Cell whitening comparative experiment
Cell experiment steps: parallel inoculation of B16F10 cells in exponential growth phase into 60mm cell culture dishes with DMEM medium containing 10% FBS at 37deg.C, 5% CO 2 The cells were incubated in an incubator for 24 hours, and the samples (nicotinamide, NR tartrate, NR fumarate) were added thereto at different concentrations, respectively, and replaced with DMEM medium containing 2.5% FBS, and allowed to act on the cells for 72 hours. The cultured cells were discarded in medium, washed 3 times with PBS, placed on ice plates, 100. Mu.L of non-denatured cell lysate was added to each dish, lysed for 20min at 4℃and the cells were collected. Centrifuging at 4deg.C and 13000r/min for 10min, and determining the content of melanin by NaOH method.
Determination of melanin content by NaOH cleavage: 330. Mu.L NaOH (10% DMSO) was added, vortexed to facilitate sufficient lysis, and placed in a metal bath at 80℃for 2h to allow sufficient dissolution of the melanin precipitate. Vortex mixing, adding 100 μl of melanin solution into each well of 96-well plate, setting 3 multiple wells, and measuring OD value at 405 nm.
Fig. 20 to 24 are bar charts of melanin content detection results of nicotinamide, NR tartrate crystals, NR fumarate, and NR fumarate crystals, respectively. Compared with nicotinamide, the nicotinamide has no obvious effect on B16F10 cell melanin generation, the NR tartrate crystal form can slightly reduce the cell melanin formation, but the NR tartrate has insignificant effect, no statistical difference, the NR fumarate and the NR fumarate crystal form reduce the cell melanin formation and content, and the nicotinamide has better whitening effect, so that the effect of reducing the cell melanin by the NR fumarate and the NR fumarate crystal form is not realized by completely relying on decomposition into nicotinamide, and the specific organic acid salt of nicotinamide ribose, namely the fumarate, has better whitening effect, and can reduce the cell melanin.
Example 10
Preparation of lyophilized preparation
The lyophilized powder is prepared by dissolving and dispersing effective active ingredient or effective active ingredient with excipient, etc. in water, vacuum-treating at low temperature, and filling N 2 Sealing, fixing the components, and directly preparing a solution when in use, so the freeze-dried powder has the following advantages: (1) improving preservability; (2) Good re-solubility, and can be dissolved rapidly after adding water and restore the original characteristics of the liquid medicine; (3) accurate product dosage and good appearance; (4) ease of aseptic manipulation; (5) improving the production environment and avoiding harmful dust; (6) solving the problem of moisture absorption and deterioration of the product in the split charging process; and (7) solving the problem that the product is easy to oxidize when exposed to air. In order to solve the problem that the product is exposed to the air, the freeze-dried powder can be prepared into a dosage form, so that the freeze-dried powder can be conveniently and accurately used and stored.
The preparation process comprises the following steps: adding 0.5g mannitol, 0.5g vitamin C into 3mL water, performing ultrasonic treatment for 5min, cooling at 0-5 ℃, and adding 1g NR salt separately, wherein the NR salt is respectively as follows: NR chloride salt, NR citrate, NR tartrate and NR fumarate are stirred uniformly in ice water bath, and the mixed solution is prepared successfully.
Setting freeze-drying process parameters
Color comparison as shown in fig. 25, NR tartrate (NRJSS) and NR fumarate (NRFMS) freeze-dried powder was uniform pale yellow; and 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, the stability of NR tartrate and NR fumaric acid is good, the color is lighter, and the NR chloride salt and the NR citrate are not waterproof and the color is darker.
The foregoing is merely illustrative embodiments of the present application, and the present application is not limited thereto, and any changes or substitutions that may be easily contemplated by those skilled in the art within the scope of the present application should be included in the scope of the present application. Therefore, the protection scope of the present application should be subject to the protection scope of the claims.
Claims (10)
1. An organic acid salt of nicotinamide riboside, characterized in that the organic acid is tartaric acid or fumaric acid; the molar ratio of nicotinamide riboside to organic acid is 1:2.
2. the crystalline form of an organic acid salt of nicotinamide riboside of claim 1, wherein the organic acid is tartaric acid and the X-ray diffraction pattern, expressed in terms of 2Θ angles, using Cu-ka radiation has the following characteristic absorption peaks: 12.68, 17.14, 22.88, 29.75, 36.84.
3. A crystalline form of an organic acid salt of nicotinamide riboside according to claim 2, wherein the X-ray diffraction pattern of the crystalline form is substantially in accordance with figure 1.
4. A crystalline form of an organic acid salt of nicotinamide riboside according to claim 2, wherein the thermal decomposition temperature of the crystalline form is 155 ℃ calculated as weight loss 5%.
5. A crystalline form of an organic acid salt of nicotinamide riboside of claim 1, wherein the organic acid is fumaric acid and the X-ray diffraction pattern expressed in terms of 2Θ angles using Cu-ka radiation has the following characteristic absorption peaks: 11.2, 17.98, 22.28, 27.94, 29.44, 37.5.
6. A crystalline form of an organic acid salt of nicotinamide riboside according to claim 5, wherein the X-ray diffraction pattern of the crystalline form is substantially in accordance with figure 2.
7. A crystalline form of an organic acid salt of nicotinamide riboside according to claim 5, wherein the thermal decomposition temperature of the crystalline form is 147 ℃ calculated as weight loss 5%.
8. The process for preparing a crystalline form of an organic acid salt of nicotinamide riboside according to any one of claims 2 to 7, comprising the steps of:
s1, dissolving a crude organic acid salt of 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.
9. Use of an organic acid salt of nicotinamide riboside in the pharmaceutical, cosmetic, food fields, said organic acid salt of nicotinamide riboside being as defined in claim 1.
10. Use of a crystalline form of an organic acid salt of nicotinamide riboside in the pharmaceutical, cosmetic, food fields, said crystalline form of an organic acid salt of nicotinamide riboside being as claimed in any one of claims 2 to 7.
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