CN112538101A - Novel crystal form of beta nicotinamide mononucleotide, preparation method and application thereof - Google Patents
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Abstract
The invention relates to a novel crystal form of beta nicotinamide mononucleotide shown in a formula (I) and a preparation method thereof. The method does not use toxic and harmful organic solvents such as methanol and the like, is simple and convenient to operate, is safe to production personnel, and is environment-friendly.
Description
Technical Field
The invention belongs to the field of medicine. In particular, the invention relates to a novel crystal form of beta nicotinamide mononucleotide, a preparation method and application thereof.
Background
beta-Nicotinamide Mononucleotide (NMN) is an inherent substance in the human body. In humans, NMN is the most direct precursor of NAD +, whose function is represented by NAD +. NAD + is also called coenzyme I, and is known as nicotinamide adenine dinucleotide, and is present in every cell and participates in thousands of reactions. NAD + exerts fundamental effects on human health, but as the content of NAD + in the human body gradually decreases with age, communication between mitochondria and nucleus is impaired, and the decrease in NAD + also impairs the ability of cells to generate energy, resulting in aging and disease.
The supplementation of beta-Nicotinamide Mononucleotide (NMN) can effectively and rapidly increase the level of NAD + in human bodies, thereby greatly delaying senility, preventing various neuronal degeneration diseases such as senile dementia and the like, and fundamentally conditioning and improving various symptoms of senility. At present, beta-Nicotinamide Mononucleotide (NMN) is approved to be on the market in countries such as Canada, Japan and the like as a food supplement with anti-aging function. At present, the recommended daily dosage of beta-Nicotinamide Mononucleotide (NMN) is 300mg, and as a food supplement, the final crystallization solvent of the product must be non-toxic and harmless, otherwise the residual solvent can have adverse effects on health.
The crystallization method of NMN has been reported, for example, CN108697722A (PCT/US2016/054776, 2016.09.30, McSt. McClont, McClont., USA); WO 2018/047715A 1 (Nippon Biofermentation Co., Ltd.) and WO 2018/047715A 1(The Queen's University of Belfast and ChromaDex. Inc.). However, methanol or a methanol-water mixed solvent is mainly selected as the crystallization solvent in these three methods. Since methanol is a toxic and harmful solvent, many countries as food supplements restrict methanol as the last crystallization solvent. In addition, these methods are complicated and time-consuming to operate, which is disadvantageous for production.
Therefore, there is a need in the art for novel crystallization methods of β -nicotinamide mononucleotide and novel crystalline forms of β -nicotinamide mononucleotide.
Disclosure of Invention
The invention aims to provide a novel beta nicotinamide mononucleotide crystal form.
The present invention also aims to provide a novel crystallization method of β nicotinamide mononucleotide, which does not use toxic and harmful organic solvents such as methanol and is simple to operate.
In a first aspect, the present invention provides a polymorph of a compound of formula (I),
the polymorphic form has an X-ray powder diffraction pattern having characteristic peaks at the following 2 theta angles (± 0.2 °): 20.42; 21.65; 22.75 and 24.98.
In preferred embodiments, the polymorph is non-solvated, anhydrous, or substantially anhydrous.
In a specific embodiment, the polymorphic form further has an X-ray powder diffraction pattern having characteristic peaks at the following 2 Θ angles (± 0.2 °): 21.21; 22.26; 23.99; 24.69; and 27.21.
In a specific embodiment, the polymorphic form further has an X-ray powder diffraction pattern having characteristic peaks at the following 2 Θ angles (± 0.2 °): 7.70 of; 11.33; 12.43; 16.32 of; 17.78; 19.06; and 19.93.
In a specific embodiment, the polymorphic form further has an X-ray powder diffraction pattern having characteristic peaks at the following 2 Θ angles (± 0.2 °): 10.18 of; 15.25; 19.26; 22.75; 23.34; 25.69; 26.24; 26.70, respectively; 27.61; 28.08 of; 29.88, respectively; 31.78; and 38.00.
In a specific embodiment, the polymorph has an XRPD pattern substantially as shown in figure 1.
In a second aspect, the present invention provides a process for preparing a polymorph according to the first aspect, the process comprising the steps of:
a. dissolving a compound of formula (I) in water to obtain an aqueous solution of the compound of formula (I); and
b. adding an antisolvent to the aqueous solution of the compound of formula (I) obtained in step a, thereby causing crystals of the compound of formula (I) to precipitate out of solution.
In a specific embodiment, the anti-solvent is ethanol.
In a preferred embodiment, the concentration of the aqueous solution of the compound represented by the formula (I) obtained in the step a is 5 to 25 percent by mass, and preferably 8 to 20 percent by mass.
In a preferred embodiment, the amount (volume) of ethanol added in step b is 1-3 times the volume of water in step a.
In a preferred embodiment, the temperature of the ethanol added in step b is from 20 ℃ to 40 ℃, preferably from 25 ℃ to 35 ℃.
In a specific embodiment, the ethanol is added in step b in an amount such that after the addition of ethanol is completed, the solution is still clear, and then crystallization is induced by stirring to form crystal nuclei or adding seed crystals.
In a preferred embodiment, after the crystals of the compound represented by formula (I) have precipitated from the solution, ethanol is further added.
In a preferred embodiment, the temperature is suitably lowered after crystals of the compound represented by formula (I) are precipitated from the solution.
In a third aspect, the present invention provides the use of a polymorph according to the first aspect in the manufacture of a medicament for the delay of ageing and for the treatment or prevention of a neurodegenerative disease.
In preferred embodiments, the neuronal degeneration disorders include, but are not limited to, senile dementia, and parkinson's disease.
In a fourth aspect, the present invention provides a pharmaceutical composition comprising a polymorph according to the first aspect and optionally a pharmaceutically acceptable excipient.
It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Not to be reiterated herein, but to the extent of space.
Drawings
Figure 1 is an XRPD pattern of crystalline compound of formula (I), a β -Nicotinamide Mononucleotide (NMN) obtained by an example of the invention.
FIG. 2 is a HNMR map of a crystalline compound of formula (I) obtained in an example of the present invention.
FIG. 3 is an XRPD pattern of a crystalline compound of formula (I) obtained in reference example of the present invention.
FIG. 4 is an XRPD comparison pattern of the crystalline compound of formula (I) obtained in the inventive example and the crystalline compound of formula (I) obtained in the reference example.
FIG. 5 is a comparison of the infrared spectroscopic spectra of the crystalline compound of formula (I) obtained in the inventive example and the crystalline compound of formula (I) obtained in the reference example.
FIG. 6 is an HPLC chromatogram of the crystalline compound of (I) obtained in the example of the present invention.
Detailed Description
The inventors have extensively and intensively studied and unexpectedly found a novel crystallization method of beta nicotinamide mononucleotide and a novel crystal form of beta nicotinamide mononucleotide obtained by the method. The method can obtain the beta nicotinamide mononucleotide crystal without using toxic and harmful organic solvents such as methanol and the like. The polymorph of the present invention shows significant improvements not only in stability, but also in bioavailability, pharmacokinetics, pharmacodynamics, etc. The present invention has been completed based on this finding.
Polymorphs of the present invention and methods of making the same
As used herein, the terms "crystal of the present invention", "polymorph of the present invention", "crystalline compound of formula (I)" and the like have the same meaning, and refer to a crystalline compound of the compound represented by formula (I),
in particular embodiments, the crystalline compound of formula (I) is non-solvated, anhydrous, or substantially anhydrous.
In certain embodiments, the polymorphic form of the crystalline compound is characterized by powder X-ray diffraction (XRD). θ represents the diffraction angle in degrees. In certain embodiments, the diffraction angle of twice the diffraction angle θ is measured with a diffractometer for XRD. Thus, the diffraction pattern described herein refers to the X-ray intensity measured for an angle 2 θ.
In a specific embodiment, the crystalline compound of formula (I) has an X-ray powder diffraction pattern with characteristic peaks at the following 2 Θ angles (± 0.2 °): 20.42; 21.65; 22.75 and 24.98; further, there are characteristic peaks at the following 2 θ angles (± 0.2 °): 21.21; 22.26; 23.99; 24.69; and 27.21; further, there are characteristic peaks at the following 2 θ angles (± 0.2 °): 7.70 of; 11.33; 12.43; 16.32 of; 17.78; 19.06; and 19.93; still further, there are characteristic peaks at the following 2 θ angles (± 0.2 °): 10.18 of; 15.25; 19.26; 22.75; 23.34; 25.69; 26.24; 26.70, respectively; 27.61; 28.08 of; 29.88, respectively; 31.78; and 38.00. In a preferred embodiment, the crystalline compound of formula (I) has an XRD pattern as shown in figure 1.
The polymorph of the invention is prepared by a process comprising: the addition of an anti-solvent to an aqueous solution of the compound of formula (I) supersaturates the resulting solution to cause the compound of formula (I) to precipitate out of solution. In a specific embodiment, the anti-solvent is ethanol. In a particular embodiment, the aqueous solution of the compound of formula (I) has a concentration by mass of between 5% and 25%, preferably between 8% and 20%. In a specific embodiment, ethanol is added in an amount (volume) of 1 to 3 times the volume of water added to the aqueous solution of the compound of formula (I).
The inventors have found, in particular, that to obtain the polymorph of the invention, the amount of ethanol added may be the same or different depending on the concentration of the aqueous solution of the compound of formula (I), with the specific principle that the amount of ethanol added for the first time is such as to ensure that, after the end of the addition, the solution is still clear and no oily droplets are precipitated; after the primary ethanol addition is finished, crystal nuclei are formed by stirring or crystal seeds obtained in the embodiment of the invention are added to induce crystallization.
In some embodiments of the present invention, after the initial ethanol addition is completed, a clear solution is obtained, crystallization is induced by stirring to form crystal nuclei or adding the seed crystals obtained in the embodiments of the present invention, and after a large amount of solids are precipitated after stirring, i.e., the solution becomes slurry by visual observation, a part of ethanol is continuously added, which does not affect the crystal form of the obtained compound of formula (I), and the recovery rate can be properly increased.
In an embodiment of the invention, the temperature of the addition of ethanol is from 20 ℃ to 40 ℃, preferably from 25 ℃ to 35 ℃.
After the ethanol is added, extra heating or refrigeration is not needed to promote crystallization, and crystal nuclei are formed by stirring or crystal seeds obtained by the embodiment of the invention are added to induce crystallization.
In certain embodiments of the invention, the addition of ethanol to an aqueous solution of the compound of formula (I) with stirring, will be exothermic. The temperature of the aqueous solution at 20-25 ℃ is raised to 30-35 ℃ after the ethanol is added without cooling; in some embodiments of the invention, the temperature can be controlled and maintained at 20 ℃ to 25 ℃ to precipitate crystals, or the temperature can be naturally raised to 30 ℃ to 35 ℃ without controlling the temperature, and the crystals can be precipitated while the temperature is maintained at 30 ℃ to 35 ℃, so that the crystal form of the obtained compound of the formula (I) is not changed.
In an embodiment of the invention, after the ethanol aqueous solution of the compound of formula (I) precipitates a large amount of crystalline solids at 20 ℃ to 40 ℃, the temperature is lowered, for example, 0 ℃ to 5 ℃, without changing the crystal form of the obtained compound of formula (I), and the recovery rate can be improved appropriately.
On the basis of the polymorphic form provided by the invention, a person skilled in the art can understand that the polymorphic form can be prepared into a medicament for delaying senility and preventing various neuronal degenerative diseases such as senile dementia and the like. Accordingly, the present invention also provides a pharmaceutical composition comprising the polymorph of the present invention and optionally a pharmaceutically acceptable excipient.
The particular excipients in the pharmaceutical composition and the particular dosage form of the pharmaceutical composition may be manufactured by those skilled in the art in a manner known per se according to the particular needs. The polymorph of the invention can be manufactured, for example, by means of conventional mixing, granulating, dragee-making, dissolving or lyophilizing processes to form oral formulations, such as tablets. Suitable excipients may include fillers, for example sugars such as lactose or sucrose, mannitol or sorbitol; cellulose preparations or calcium phosphates, such as tricalcium phosphate or calcium hydrogen phosphate; and binders, such as starch pastes, including corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium hydroxymethylcellulose, or polyvinylpyrrolidone. If desired, disintegrating agents such as the starches mentioned above, as well as carboxymethyl starch, cross-linked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate may be added. Adjuvants are, in particular, flow regulators and lubricants, for example silica, talc, stearates, such as calcium magnesium stearate, stearic acid or polyethylene glycol. If desired, the lozenge cores may be provided with a suitable coating which is resistant to gastric juices. For this purpose, concentrated saccharide solutions can be used. This solution may contain gum arabic, talc, polyvinyl pyrrolidone, polyethylene glycol and/or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures. For the preparation of coatings resistant to gastric juices, suitable cellulose solutions can be used, for example cellulose acetate phthalate or hydroxypropylmethyl cellulose phthalate. Dyes or pigments may be added to the coating of the tablet or lozenge core. For example, for identifying or for characterizing combinations of active ingredient doses.
On the basis of the polymorph, the invention also provides a method for delaying aging and treating various neuronal degenerative diseases such as senile dementia, which comprises administering a therapeutically effective amount of the polymorph or the pharmaceutical composition of the invention to a subject in need thereof.
The main advantages of the invention are:
1. the crystallization method of the invention does not need to use toxic and harmful organic solvents, such as methanol and the like;
2. the crystallization method of the invention is simple and convenient to operate, thereby being beneficial to large-scale production;
3. the crystallization method is safe for production personnel and environment-friendly;
4. the crystallization method can obtain higher product purity, and the obtained crystal has better stability.
The technical solution of the present invention will be further described with reference to the following specific embodiments, but the following embodiments are not intended to limit the present invention, and all of the various application methods adopted according to the principles and technical means of the present invention belong to the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out under conventional conditions or conditions recommended by the manufacturers. Unless otherwise indicated, percentages and parts are by weight.
Materials and methods
The analytical methods used in the examples and reference examples of the present invention are as follows:
x-ray powder diffraction method
The machine model is as follows: bruker D8 Advance diffractometer using Cu ka radiation (40kV,40 Ma);
angle range: 3-45 degrees 2 θ;
step length: 0.02 degrees 2 θ;
collecting speed: 8 degrees/min;
HPLC
LC2030C 3D high performance liquid chromatograph, PDA detector, and Labsolution workstation
Chromatographic conditions are as follows:
a chromatographic column: thermo Hypersil gold 4.6X 250mm 5 um; (part No 25005-254630)
Flow rate: 1.0 ml/min;
column temperature: 30 ℃;
sample temperature: 5 ℃;
detection wavelength: 265 nm;
sample introduction amount: 5 ul;
mobile phase: a: 0.005mol/L ammonium acetate aqueous solution (pH adjusted to 3.0. + -. 0.1 with acetic acid); b: methanol
Gradient:
| time (minutes) | 0 | 5 | 10 | 15 | 15.1 | 25 |
| Mobile phase A (%) | 100 | 100 | 0 | 0 | 100 | 100 |
| Mobile phase B (%) | 0 | 0 | 100 | 100 | 0 | 0 |
Infrared analysis (IR)
RAffinty-1S infrared spectrometer of Shimadzu, workstation: labsolution IR Potassium bromide pellets.
Example 1.
10.0 g of beta-Nicotinamide Mononucleotide (NMN) (98.65% purity) and 90.0 ml of water were added to a 500 ml reaction flask. After stirring and dissolving, the mass percent of the aqueous solution is 10.0%. Adding 180 ml of ethanol into the water solution at 24 ℃ under stirring, heating to 32 ℃, starting to be a clear solution, stirring for 5 minutes, gradually separating out white solids, continuing stirring for 3 hours, filtering at 25 ℃, leaching with ethanol, and drying at 25 ℃ in vacuum to constant weight to obtain 8.8 g of white solids.
After XRPD analysis, the resulting crystal has an XRPD pattern as shown in figure 1;
purity by HPLC was 99.91%, as shown in fig. 6;
the HNMR nuclear magnetic spectrum is shown in figure 2;
loss on drying: drying under reduced pressure at 60 deg.C (drying agent: phosphorus pentoxide) to a loss on drying of 0.05%, the resulting solid was anhydrous.
Example 2.
Add 10.0 g of beta-Nicotinamide Mononucleotide (NMN) and 90.0 ml of water to a 500 ml reaction flask. After stirring and dissolving, the mass percent of the aqueous solution is 10.0%. Adding 180 milliliters of ethanol into the aqueous solution at 24 ℃ under stirring, heating to 32 ℃, starting to be a clear solution, stirring for 5 minutes, gradually separating out white solids, continuing to stir for 3 hours, continuing to dropwise add 90 milliliters of ethanol, continuing to stir for 2 hours, filtering at 25 ℃, leaching with ethanol, and drying at 25 ℃ in vacuum to constant weight to obtain 9.1 grams of white solids.
After XRPD analysis, the XRPD pattern of the resulting crystals is shown in figure 1.
Example 3.
Add 10.0 g of beta-Nicotinamide Mononucleotide (NMN) and 40.0 ml of water to a 250ml reaction flask. After stirring and dissolving, the mass percent of the aqueous solution is 20.0%. Adding 60ml of ethanol into the water solution at 24 ℃ while stirring, heating to 30 ℃, starting to be a clear solution after the dropwise addition, gradually separating out white solids after stirring for 3 minutes, filtering to obtain white solids after continuously stirring for 2 hours, leaching with ethanol, and drying in vacuum at 25 ℃ to constant weight to obtain 8.8 g of crystals.
After XRPD analysis, the XRPD pattern of the resulting crystals is shown in figure 1.
Example 4.
Add 10.0 g of beta-Nicotinamide Mononucleotide (NMN) and 60.0 ml of water to a 250ml reaction flask. After stirring and dissolving, the mass percent of the aqueous solution is 14.3%. And dropwise adding 100ml of ethanol into the aqueous solution at 24 ℃ under stirring, heating to 31 ℃, starting to be a clear solution after dropwise adding, gradually precipitating solids under stirring, continuously stirring for 1 hour, filtering, leaching with ethanol, and drying at 25 ℃ in vacuum to constant weight to obtain 8.6 g of white solids.
After XRPD analysis, the XRPD pattern of the resulting crystals is shown in figure 1.
Example 5.
Add 10.0 g of beta-Nicotinamide Mononucleotide (NMN) and 60.0 ml of water to a 250ml reaction flask. After stirring and dissolving, the mass percent of the aqueous solution is 14.3%. And dropwise adding 100ml of ethanol into the aqueous solution at 24 ℃ under stirring, heating to 31 ℃, starting to be a clear solution after dropwise adding, gradually precipitating a solid under stirring, continuously stirring for 1 hour, cooling to 0-5 ℃ in an ice bath, continuously stirring for 1 hour, filtering, leaching with ethanol, and drying in vacuum at 25 ℃ to constant weight to obtain 8.9 g of a white solid.
After XRPD analysis, the XRPD pattern of the resulting crystals is shown in figure 1.
Example 6.
Add 10.0 g of beta-Nicotinamide Mononucleotide (NMN) and 115.0 ml of water to a 250ml reaction flask. After stirring and dissolving, the mass percent of the aqueous solution is 8.0%. And dropwise adding 250ml of ethanol into the aqueous solution at 24 ℃ under stirring, heating to 32 ℃, starting to be a clear solution after dropwise adding, gradually precipitating solids under stirring, continuously stirring for 2 hours, filtering, leaching with ethanol, and drying at 25 ℃ in vacuum to constant weight to obtain 8.6 g of white solids.
After XRPD analysis, the XRPD pattern of the resulting crystals is shown in figure 1.
Example 7.
Add 10.0 g of beta-Nicotinamide Mononucleotide (NMN) and 30ml of water to a 250ml reaction flask. After stirring and dissolving, the mass percent of the aqueous solution is 25.0%. Adding 30ml of ethanol into the aqueous solution dropwise at 25 ℃ under stirring, heating to 30 ℃, starting to be a clear solution after the dropwise addition, adding the solid obtained in the example 1 as a seed crystal, gradually separating out white solid under stirring, continuously stirring for 2 hours, filtering to obtain white solid, leaching with ethanol, and drying in vacuum at 25 ℃ to constant weight to obtain 8.9 g.
After XRPD analysis, the XRPD pattern of the resulting crystals is shown in figure 1.
Comparative example
Referring to the methods of CN108697722A and WO2018/047715, 50.0 g of β -Nicotinamide Mononucleotide (NMN) is dissolved in 150 ml of water, 300 ml of methanol is added with stirring to precipitate a white solid, stirring is continued for 2 hours, then filtration is performed, and vacuum drying at 25 ℃ is performed to obtain 46.0 g of a white solid.
After XRPD analysis, the XRPD pattern of the resulting crystals is shown in figure 3. Compared with the crystal form 1 reported in CN108697722A, the crystal form is substantially the same.
All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.
Claims (10)
1. A polymorph of a compound of formula (I),
the polymorphic form has an X-ray powder diffraction pattern having characteristic peaks at the following 2 theta angles (± 0.2 °): 20.42; 21.65; 22.75 and 24.98.
2. The polymorph of claim 1, wherein the polymorph has an X-ray powder diffraction pattern further comprising characteristic peaks at the following 2 θ angles (± 0.2 °): 21.21; 22.26; 23.99; 24.69; and 27.21.
3. The polymorph of claim 2, wherein the polymorph has an X-ray powder diffraction pattern further comprising characteristic peaks at the following 2 θ angles (± 0.2 °): 7.70 of; 11.33; 12.43; 16.32 of; 17.78; 19.06; and 19.93.
4. The polymorph of claim 3, wherein the polymorph has an X-ray powder diffraction pattern further comprising characteristic peaks at the following 2 θ angles (± 0.2 °): 10.18 of; 15.25; 19.26; 22.75; 23.34; 25.69; 26.24; 26.70, respectively; 27.61; 28.08 of; 29.88, respectively; 31.78; and 38.00.
5. The polymorph of any one of claims 1 to 4, wherein the polymorph has an XRPD pattern substantially as shown in figure 1.
6. A process for preparing the polymorph of any one of claims 1 to 5, comprising the steps of:
a. dissolving a compound of formula (I) in water to obtain an aqueous solution of the compound of formula (I); and
b. adding an antisolvent to the aqueous solution of the compound of formula (I) obtained in step a, thereby causing crystals of the compound of formula (I) to precipitate out of solution.
7. The method of claim 6, wherein the anti-solvent is ethanol.
8. The process of claim 7, wherein ethanol is added in step b in an amount such that after the addition of ethanol is complete, the solution remains clear, and crystallization is induced by stirring to form crystal nuclei or by adding seed crystals.
9. Use of the polymorph of any one of claims 1 to 5 in the manufacture of a medicament for the delay of aging and the treatment or prevention of a neurodegenerative disease.
10. A pharmaceutical composition comprising the polymorph of any one of claims 1 to 5 and optionally a pharmaceutically acceptable excipient.
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| Application Number | Priority Date | Filing Date | Title |
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| CN202010814293.2A CN112538101A (en) | 2020-08-13 | 2020-08-13 | Novel crystal form of beta nicotinamide mononucleotide, preparation method and application thereof |
| PCT/CN2021/112598 WO2022033589A1 (en) | 2020-08-13 | 2021-08-13 | NEW CRYSTAL FORM OF β-NICOTINAMIDE MONONUCLEOTIDE, PREPARATION METHOD THEREFOR AND USE THEREOF |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113292619A (en) * | 2021-06-18 | 2021-08-24 | 邦泰生物工程(深圳)有限公司 | Nicotinamide mononucleotide-isonicotinine cocrystal and composition thereof |
| CN113402570A (en) * | 2021-05-25 | 2021-09-17 | 天尔生物医药(湖北)有限公司 | Crystallization method of nicotinamide mononucleotide |
| CN113402575A (en) * | 2021-06-18 | 2021-09-17 | 邦泰生物工程(深圳)有限公司 | Method for preparing nicotinamide mononucleotide eutectic |
| CN113912653A (en) * | 2021-06-04 | 2022-01-11 | 天津大学 | Method for improving bulk density of beta-nicotinamide mononucleotide crystal powder |
| WO2022033589A1 (en) * | 2020-08-13 | 2022-02-17 | 常州博海威医药科技股份有限公司 | NEW CRYSTAL FORM OF β-NICOTINAMIDE MONONUCLEOTIDE, PREPARATION METHOD THEREFOR AND USE THEREOF |
| CN115368423A (en) * | 2022-02-23 | 2022-11-22 | 音芙医药科技(上海)有限公司 | Polymorphism of reduced beta-nicotinamide mononucleotide disodium salt and preparation method and application thereof |
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| GB2542881B (en) * | 2015-10-02 | 2020-01-01 | Carr Andrew | Crystal forms of ß-nicotinamide mononucleotide |
| WO2018047715A1 (en) * | 2016-09-06 | 2018-03-15 | 協和発酵バイオ株式会社 | CRYSTALS OF β-NICOTINAMIDE MONONUCLEOTIDE AND PRODUCTION PROCESS THEREFOR |
| NZ803738A (en) * | 2016-11-11 | 2024-05-31 | Chromadex Inc | Efficient and scalable syntheses of nicotinoyl ribosides and reduced nicotinoyl ribosides, modified derivatives thereof, phosphorylated analogs thereof, adenylyl dinucleotide conjugates thereof, and novel crystalline forms thereof |
| CN110195089A (en) * | 2019-06-13 | 2019-09-03 | 叁爻生物科技(上海)有限公司 | Nicotinamide mononucleotide and preparation method thereof |
| CN113121628A (en) * | 2019-12-30 | 2021-07-16 | 尚科生物医药（上海）有限公司 | Preparation method of amorphous nicotinamide mononucleotide |
| CN111377983B (en) * | 2020-03-26 | 2023-05-16 | 音芙医药科技(上海)有限公司 | Preparation method of beta-nicotinamide mononucleotide |
| CN111705096A (en) * | 2020-06-29 | 2020-09-25 | 上海舒泽生物科技研究所 | Method for producing beta-nicotinamide mononucleotide by enzyme conversion method |
| CN112538101A (en) * | 2020-08-13 | 2021-03-23 | 常州博海威医药科技股份有限公司 | Novel crystal form of beta nicotinamide mononucleotide, preparation method and application thereof |
| CN112694505A (en) * | 2020-12-30 | 2021-04-23 | 音芙医药科技(上海)有限公司 | Preparation method of high-density NMN |
| CN113402570A (en) * | 2021-05-25 | 2021-09-17 | 天尔生物医药(湖北)有限公司 | Crystallization method of nicotinamide mononucleotide |
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2020
- 2020-08-13 CN CN202010814293.2A patent/CN112538101A/en active Pending
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Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2022033589A1 (en) * | 2020-08-13 | 2022-02-17 | 常州博海威医药科技股份有限公司 | NEW CRYSTAL FORM OF β-NICOTINAMIDE MONONUCLEOTIDE, PREPARATION METHOD THEREFOR AND USE THEREOF |
| CN113402570A (en) * | 2021-05-25 | 2021-09-17 | 天尔生物医药(湖北)有限公司 | Crystallization method of nicotinamide mononucleotide |
| CN113912653A (en) * | 2021-06-04 | 2022-01-11 | 天津大学 | Method for improving bulk density of beta-nicotinamide mononucleotide crystal powder |
| CN113912653B (en) * | 2021-06-04 | 2024-04-23 | 天津大学 | Method for improving bulk density of beta-nicotinamide mononucleotide crystalline powder |
| CN113292619A (en) * | 2021-06-18 | 2021-08-24 | 邦泰生物工程(深圳)有限公司 | Nicotinamide mononucleotide-isonicotinine cocrystal and composition thereof |
| CN113402575A (en) * | 2021-06-18 | 2021-09-17 | 邦泰生物工程(深圳)有限公司 | Method for preparing nicotinamide mononucleotide eutectic |
| CN113292619B (en) * | 2021-06-18 | 2022-04-22 | 邦泰生物工程(深圳)有限公司 | Nicotinamide mononucleotide-isonicotinine cocrystal and composition thereof |
| CN113402575B (en) * | 2021-06-18 | 2022-04-22 | 邦泰生物工程(深圳)有限公司 | Method for preparing nicotinamide mononucleotide eutectic |
| US11932602B2 (en) | 2021-06-18 | 2024-03-19 | Bontac Bio-Engineering(Shenzhen) Co., Ltd | Method for preparing nicotinamide mononucleotide cocrystal |
| CN115368423A (en) * | 2022-02-23 | 2022-11-22 | 音芙医药科技(上海)有限公司 | Polymorphism of reduced beta-nicotinamide mononucleotide disodium salt and preparation method and application thereof |
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