WO2022033589A1 - NOUVELLE FORME CRISTALLINE DE β-NICOTINAMIDE MONONUCLÉOTIDE, SON PROCÉDÉ DE PRÉPARATION ET SON UTILISATION - Google Patents

NOUVELLE FORME CRISTALLINE DE β-NICOTINAMIDE MONONUCLÉOTIDE, SON PROCÉDÉ DE PRÉPARATION ET SON UTILISATION Download PDF

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WO2022033589A1
WO2022033589A1 PCT/CN2021/112598 CN2021112598W WO2022033589A1 WO 2022033589 A1 WO2022033589 A1 WO 2022033589A1 CN 2021112598 W CN2021112598 W CN 2021112598W WO 2022033589 A1 WO2022033589 A1 WO 2022033589A1
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present
formula
polymorphic form
ethanol
compound represented
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李强
陈宣福
刘向群
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常州博海威医药科技股份有限公司
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    • 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
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A61P39/06—Free radical scavengers or antioxidants
    • 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
    • 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

Definitions

  • the present invention belongs to the field of medicine. Specifically, the present invention relates to a new crystal form of beta nicotinamide mononucleotide and its preparation method and use.
  • Beta-nicotinamide mononucleotide is an inherent substance in the human body. In the human body, NMN is the most direct precursor of NAD+, and its function is reflected by NAD+. NAD+ is also called coenzyme I, the full name of nicotinamide adenine dinucleotide, exists in every cell and participates in thousands of reactions. NAD+ has a fundamental impact on human health, but with age, the content of NAD+ in the human body gradually decreases, the communication between mitochondria and nucleus is impaired, and the reduction of NAD+ also impairs the ability of cells to generate energy, resulting in Aging and disease.
  • ⁇ -nicotinamide mononucleotide can effectively and rapidly increase the level of NAD+ in the human body, thereby greatly delaying aging and preventing various neuronal degenerative diseases such as Alzheimer's, and fundamentally conditioning and improving various aging diseases. symptom.
  • ⁇ -nicotinamide mononucleotide NPN
  • Currently, the recommended daily dose of ⁇ -nicotinamide mononucleotide (NMN) is 300mg.
  • the final crystallization solvent of the product must be non-toxic and harmless, otherwise the residual solvent will have adverse health effects.
  • NMN The crystallization method of NMN has been reported, such as CN108697722A (PCT/US2016/054776, 2016.09.30, American Metro Biotechnology Co., Ltd.); WO2018/047715 A1 (Japan Kyowa Bio-Fermentation Co., Ltd.) and WO2018/047715 A1 (The Queen's University of Harbor and ChromaDex. Inc).
  • methanol or methanol-water mixed solvent is mainly selected as the crystallization solvent among these three methods. Since methanol is a toxic and harmful solvent, many countries restrict methanol as the final crystallization solvent as a food supplement. In addition, these methods are complicated to operate and time-consuming, which is not conducive to production.
  • the purpose of the present invention is to provide a new ⁇ -nicotinamide mononucleotide crystal form.
  • the present invention also aims to provide a new crystallization method of beta nicotinamide mononucleotide, which does not utilize toxic and harmful organic solvents such as methanol and is simple to operate.
  • the present invention provides a polymorph of the compound represented by formula (I),
  • the X-ray powder diffraction pattern of the polymorph has characteristic peaks at the following 2 ⁇ angles ( ⁇ 0.2°): 20.42; 21.65; 22.75 and 24.98.
  • the polymorph is unsolvated, anhydrous or substantially anhydrous.
  • the polymorphic X-ray powder diffraction pattern further has characteristic peaks at the following 2 ⁇ angles ( ⁇ 0.2°): 21.21; 22.26; 23.99; 24.69; and 27.21.
  • the polymorphic X-ray powder diffraction pattern further has characteristic peaks at the following 2 ⁇ angles ( ⁇ 0.2°): 7.70; 11.33; 12.43; 16.32; 17.78; 19.06; and 19.93.
  • the polymorphic X-ray powder diffraction pattern further has characteristic peaks at the following 2 ⁇ angles ( ⁇ 0.2°): 10.18; 15.25; 19.26; 22.75; 23.34; 25.69; 26.24; 26.70; 27.61; 28.08; 29.88; 31.78; and 38.00.
  • the polymorph is characterized in that the polymorph has an XRPD pattern substantially as shown in FIG. 1 .
  • the purity of the polymorph is above 99.7%, preferably above 99.8%, more preferably above 99.9%.
  • the content of the degraded impurity nicotinamide in the polymorph is less than 0.05%, preferably less than 0.03%, more preferably less than 0.01%.
  • the decrease in purity is less than 0.1% compared with the purity at the 0th time; preferably less than 0.07%; More preferably less than 0.05%.
  • the decrease in purity is less than 0.15%, preferably less than 0.13%, compared with the purity at the 0th time; More preferably less than 0.12%.
  • the decrease in purity is less than 0.5% compared with the purity at the 0th time; preferably less than 0.4% ; more preferably less than 0.33%.
  • the purity of the polymorph of the present invention is greater than 99.5% after being placed under the condition of 25° C. for more than 2 years.
  • the present invention provides a method for preparing the polymorphic form of the first aspect, the method comprising the steps of:
  • step b An anti-solvent is added to the aqueous solution of the compound represented by formula (I) obtained in step a, so that crystals of the compound represented by formula (I) are precipitated from the solution.
  • the anti-solvent is ethanol, acetone, isopropanol or a mixed solvent thereof.
  • the mass percentage concentration of the aqueous solution of the compound represented by the formula (I) obtained in step a is 5%-25%, preferably 8%-20%.
  • the anti-solvent in step b such as ethanol, is added in an amount (volume) that is 1-3 times the volume of water in step a.
  • an anti-solvent is added in step b, for example, the temperature of ethanol is 20°C-40°C, preferably 25°C-35°C.
  • the anti-solvent in step b such as ethanol
  • the anti-solvent in step b is added in an amount such that after the addition of ethanol, the solution is still clear, and then crystallization is induced by stirring to form crystal nuclei or adding seed crystals.
  • the temperature is appropriately lowered.
  • the present invention provides the use of the polymorphic form of the first aspect in the preparation of a medicament for delaying aging and treating or preventing neuronal degenerative diseases.
  • the neuron degenerative diseases include but are not limited to Alzheimer's disease, ALS, Parkinson's disease and other diseases.
  • the present invention provides a pharmaceutical composition comprising the polymorphic form of the first aspect and optionally a pharmaceutically acceptable excipient.
  • Fig. 1 is the XRPD spectrum of ⁇ -nicotinamide mononucleotide (NMN) obtained in the embodiment of the present invention, namely the crystalline compound of formula (I).
  • Fig. 2 is the HNMR spectrum of the crystalline compound of formula (I) obtained in the example of the present invention.
  • Fig. 3 is an XRPD pattern of the crystalline compound of formula (I) obtained in Reference Example of the present invention.
  • Fig. 5 is a comparison of the infrared spectrograms of the crystalline compound (I) obtained in the Example of the present invention and the crystalline compound of the formula (I) obtained in the Reference Example.
  • Fig. 6 is the HPLC detection pattern of the crystalline compound of (I) obtained in the example of the present invention.
  • FIG. 7 is an XRPD pattern of the crystalline compound of FIG. 1 after one year of stability testing at 25 ⁇ 2°C.
  • FIG. 8 is an XRPD pattern of the crystalline compound of FIG. 1 after 1 year stability test at 40 ⁇ 2°C.
  • Fig. 9 is an XRPD pattern of the crystalline compound of Fig. 1 stored at 5 ⁇ 3°C for 1 year.
  • ⁇ -nicotinamide mononucleotide a new crystal form of ⁇ -nicotinamide mononucleotide obtained by using this method.
  • ⁇ -nicotinamide mononucleotide crystals can be obtained without using toxic and harmful organic solvents such as methanol.
  • the polymorphic form of the present invention not only exhibits significant improvement in stability, but also exhibits significant improvement in bioavailability, pharmacokinetics, pharmacodynamics, and the like. The present invention has been completed on this basis.
  • the crystalline compound of formula (I) is unsolvated, anhydrous or substantially anhydrous.
  • polymorphic forms of crystalline compounds are characterized by powder X-ray diffraction (XRD).
  • XRD powder X-ray diffraction
  • ⁇ represents the diffraction angle in degrees.
  • a diffraction angle that is twice the diffraction angle ⁇ is measured with an XRD diffractometer.
  • the diffraction patterns described herein refer to the X-ray intensities measured against the angle 2 ⁇ .
  • the X-ray powder diffraction pattern of the crystalline compound of formula (I) has characteristic peaks at the following 2 ⁇ angles ( ⁇ 0.2°): 20.42; 21.65; 22.75 and 24.98; further, at the following 2 ⁇ angles Characteristic peaks at ( ⁇ 0.2°): 21.21; 22.26; 23.99; 24.69; and 27.21; further, characteristic peaks at the following 2 ⁇ angles ( ⁇ 0.2°): 7.70; and 19.93; and further, characteristic peaks at the following 2 ⁇ angles ( ⁇ 0.2°): 10.18; 15.25; 19.26; 22.75; 23.34; 25.69; 26.24; 26.70; 27.61; In a preferred embodiment, the crystalline compound of formula (I) has an XRD pattern as shown in FIG. 1 .
  • the compound represented by formula (I) will degrade, and its degradation product is nicotinamide. Therefore, the content of nicotinamide in the polymorphic form of the compound represented by formula (I) can not only reflect the purity of the polymorphic form itself, but also measure the stability of the polymorphic form.
  • the polymorphic form of the present invention can have excellent purity.
  • the purity of the polymorph of the present invention is more than 99.7%, preferably more than 99.8%, more preferably more than 99.9%; wherein the content of degraded impurity nicotinamide is less than 0.05%; preferably less than 0.03%; more It is preferably less than 0.01%.
  • the polymorphic form of the present invention can not only have excellent purity, but also can have excellent stability.
  • the polymorph of the present invention has a decrease in purity of less than 0.1%; preferably less than 0.07% compared to the purity at time 0 after being placed at 25°C and 0% RH for 12 weeks ; more preferably less than 0.05%; or
  • the decrease in purity is less than 0.15%; preferably less than 0.13%; more preferably less than 0.12% compared to the purity at time 0 ;or
  • the decrease in purity is less than 0.5%; preferably less than 0.4%; more preferably less than 0.33% compared to the purity at time 0 %.
  • the polymorphs of the present invention are prepared by a method comprising supersaturating the resulting solution by adding an antisolvent to an aqueous solution of a compound of formula (I) to cause the compound of formula (I) to precipitate out of solution.
  • the anti-solvent is ethanol, acetone, isopropanol or a mixed solvent thereof.
  • the mass percentage concentration of the aqueous solution of the compound of formula (I) is 5%-25%, preferably 8%-20%.
  • the anti-solvent eg, ethanol, is added in an amount (by volume) 1-3 times the volume of water added to the aqueous solution of the compound of formula (I).
  • the amount of anti-solvent such as ethanol
  • the amount of anti-solvent can be the same or different depending on the concentration of the compound of formula (I) in the aqueous solution.
  • the specific principle is that the amount of anti-solvent, such as ethanol, is initially added. To ensure that after the addition is completed, the solution is still clear and no oil droplets are precipitated; after adding the primary anti-solvent, such as ethanol, crystallization is induced by stirring to form crystal nuclei or adding the seed crystal obtained in the embodiment of the present invention.
  • a clear solution is obtained, and crystallization is induced by stirring to form crystal nuclei or by adding the seed crystal obtained in the embodiment of the present invention, and after a large amount of solid is precipitated after stirring, That is, the solution becomes slurried visually, and a part of the anti-solvent, such as ethanol, is continuously added, which will not affect the crystal form of the compound of formula (I) obtained, and can appropriately increase the recovery rate.
  • the primary anti-solvent such as ethanol
  • the temperature at which the anti-solvent, eg ethanol, is added is 20°C to 40°C, preferably 25°C to 35°C.
  • crystallization After adding an anti-solvent, such as ethanol, additional heating or cooling is not required to promote crystallization, and crystallization can be induced by stirring to form a crystal nucleus or adding the seed crystal obtained in the embodiment of the present invention.
  • an anti-solvent such as ethanol
  • an antisolvent such as ethanol
  • an aqueous solution of a compound of formula (I) with stirring is exothermic.
  • Aqueous solution of 20°C-25°C, without cooling, adding anti-solvent, for example, ethanol will be heated to 30°C-35°C; It is also possible to naturally raise the temperature to 30°C-35°C without controlling the temperature, and keep the temperature at 30°C-35°C to precipitate crystals, and the crystal form of the compound of formula (I) obtained will not change.
  • the anti-solvent of the compound of formula (I), such as an aqueous ethanol solution precipitates a large amount of crystalline solid at 20°C-40°C, and then lowers the temperature, such as 0°C-5°C, without changing the obtained formula (I). ), the crystalline form of the compound can also appropriately improve the recovery rate.
  • the polymorphic forms of the present invention can be prepared into medicines for delaying aging and preventing senile dementia and other neuronal degenerative diseases. Accordingly, the present invention also provides a pharmaceutical composition comprising a polymorph of the present invention and optionally a pharmaceutically acceptable excipient.
  • the specific excipients in the pharmaceutical composition and the specific dosage form of the pharmaceutical composition can be manufactured by those skilled in the art in a known manner according to specific needs.
  • the polymorphic forms of the present invention can be made into oral formulations, such as tablets, by conventional mixing, granulating, tableting, dissolving, or freeze-drying processes.
  • Suitable excipients may include fillers such as sugars such as lactose or sucrose, mannitol or sorbitol; cellulosic preparations or calcium phosphates such as tricalcium phosphate or dicalcium phosphate; and binders such as starch pastes including Corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methylcellulose, hydroxypropylmethylcellulose, sodium hydroxymethylcellulose, or polyvinylpyrrolidone.
  • fillers such as sugars such as lactose or sucrose, mannitol or sorbitol
  • cellulosic preparations or calcium phosphates such as tricalcium phosphate or dicalcium phosphate
  • binders such as starch pastes including Corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methylcellulose, hydroxypropylmethylcellulose, sodium hydroxymethylcellulose, or polyvinylpyrrolidone
  • disintegrants such as the starches mentioned above, can be added, as well as carboxymethyl starch, cross-linked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate.
  • Adjuvants are especially flow conditioners and lubricants, for example, silica, talc, stearates, such as magnesium calcium stearate, stearic acid or polyethylene glycols.
  • tablet cores can be provided with a suitable coating that is resistant to gastric juices. For this purpose, concentrated sugar solutions can be used.
  • This solution may contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/titanium dioxide, a lacquer solution and a suitable organic solvent or solvent mixture.
  • suitable cellulose solutions such as cellulose acetate phthalate or hydroxypropyl methylcellulose phthalate can be used.
  • Dyestuffs or pigments may be added to the coatings of the tablets or dragee cores. For example, for identification or to characterize combinations of active ingredient doses.
  • the present invention also provides a method for delaying aging and treating various neuronal degenerative diseases such as senile dementia, the method comprising adding a therapeutically effective amount of the polymorph or pharmaceutical composition of the present invention Give to those who need it.
  • the crystallization method of the present invention does not need to use toxic and harmful organic solvents, such as methanol etc.;
  • the crystallization method of the present invention is easy to operate, thereby being conducive to large-scale production
  • the crystallization method of the present invention is safe for production personnel and friendly to the environment;
  • the crystallization method of the present invention can obtain higher product purity, and the purity of the obtained product crystal can reach more than 99.9%, and the purity is better than the prior art, such as the crystallization purity (99.52%) reported in CN108697722A.
  • the stability of the crystal obtained by the present invention is better, which is better than that of the prior art, such as the crystalline form 1 reported by CN108697722A.
  • Machine model Bruker D8 Advance diffractometer, using Cu K ⁇ radiation (40kV, 40Ma);
  • Step size 0.02 degrees 2 ⁇
  • ⁇ -nicotinamide mononucleotide (NMN) (98.65% pure) and 90.0 ml of water were added to a 500 ml reaction flask. After stirring and dissolving, the mass percentage of the aqueous solution was 10.0%. The aqueous solution was stirred at 24 °C, and 180 ml of ethanol was added, and the temperature was raised to 32 °C. It started to be a clear solution. After stirring for 5 minutes, a white solid gradually precipitated. Constant weight yielded 8.8 g of a white solid.
  • NPN ⁇ -nicotinamide mononucleotide
  • ⁇ -nicotinamide mononucleotide NPN
  • 40.0 ml of water 10.0 g were added to a 250 ml reaction flask. After stirring and dissolving, the mass percentage of the aqueous solution was 20.0%. The aqueous solution was at 24°C, and 60 ml of ethanol was added dropwise with stirring, and the temperature was raised to 30°C. After the dropwise addition, it began to be a clear solution. After stirring for 3 minutes, a white solid gradually precipitated. After continuing to stir for 2 hours, the white solid was obtained by filtration. Washed and dried under vacuum at 25°C to constant weight to obtain 8.8 g of crystals.
  • NPN ⁇ -nicotinamide mononucleotide
  • ⁇ -nicotinamide mononucleotide NPN
  • 115.0 ml of water 10.0 g were added to a 250 ml reaction flask. After stirring and dissolving, the mass percentage of the aqueous solution was 8.0%. The aqueous solution was at 24°C, and 250 ml of ethanol was added dropwise with stirring, and the temperature was raised to 32°C. After the dropwise addition, the solution began to be a clear solution, and a solid was gradually precipitated under stirring. At constant weight, 8.6 g of a white solid was obtained.
  • NPN ⁇ -nicotinamide mononucleotide
  • Example 1 ⁇ -nicotinamide mononucleotide (NMN) and 30 mL of water to a 250-mL reaction flask. After stirring and dissolving, the mass percentage of the aqueous solution was 25.0%. The aqueous solution was added dropwise with 30 ml of ethanol at 25°C under stirring, and the temperature was raised to 30°C. After the dropwise addition, it began to be a clear solution. The solid obtained in Example 1 was added as a seed crystal, and a white solid was gradually precipitated under stirring. Continue to stir for 2 hours. After that, the white solid was obtained by filtration, rinsed with ethanol, and dried under vacuum at 25°C to constant weight to obtain 8.9 g.
  • NPN ⁇ -nicotinamide mononucleotide
  • Example 1 of the present invention was added as a seed crystal, and more white solids were precipitated. Continue to drip 60 ml of acetone, stirred for 1 hour, filtered at 25°C, rinsed with acetone, and vacuum dried to constant weight at 25°C to obtain 7.8 g of a white solid.
  • NPN ⁇ -nicotinamide mononucleotide
  • Example 1 of the present invention was added as a seed crystal, and the stirring was continued, and more white solids were precipitated.
  • Stir for 1 After one hour, at 25°C, filter, rinse with isopropanol, and vacuum dry to constant weight at 25°C to obtain 7.6 g of a white solid.
  • NNN ⁇ -nicotinamide mononucleotide
  • the stability data list of the crystal form obtained by the present invention is as follows:
  • the data in the left table is: the data of the crystalline form 1 described in CN108697722 at the stability test point at week 0, wherein the impurity of RRT 1.74 is a known impurity (nicotinamide), and at week 0, the impurity is 0.12%.
  • the data in the right table is: the test data of the crystalline form 1 described in CN108697722 placed at 25°C, 0% RH for 12 weeks
  • the known impurity "nicotinamide” of crystalline form 1 described in CN108697722 increased from 0.12% at 0 to 0.38% over 12 weeks (3 months), and nicotinamide increased 0.26%, the total purity decreased from 99.52% at 0 to 98.90%; while the known impurity "nicotinamide” of the crystal form of the present invention increased from 0.01% at 0 to 0.05% after 12 weeks (3 months) placement , nicotinamide only increased by 0.04%, and the total purity decreased from 99.91% at 0 to 99.86%; it can be concluded that the stability of the crystal form obtained by the present invention is far better than the crystal form described in CN108697722A.
  • the crystal form of the present invention was placed at 25°C and 0% RH for 1 year, the total purity was 99.79%, and the known impurity "nicotinamide” increased to 0.07%; the crystal form of the present invention was placed at 40°C and 0% RH for 6 times. Month time, the total purity was 99.58%, the known impurity "nicotinamide” increased to 0.28%. From the above data, it can be predicted that the crystal form of the present invention can be stored stably for more than 2 years at room temperature of 25°C, and within 2 years, the purity of the crystal form of the present invention can still be greater than 99.5%.

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Abstract

La présente invention concerne une nouvelle forme cristalline de β-nicotinamide mononucléotide représentée par la formule (I) et son procédé de préparation. Le procédé selon la présente invention n'utilise pas de solvants organiques toxiques et nocifs tels que le méthanol, est simple à mettre en œuvre, est sûr pour le personnel de production, et est respectueux de l'environnement. La nouvelle forme cristalline selon la présente invention a une pureté cristalline élevée et une bonne stabilité. (I)
PCT/CN2021/112598 2020-08-13 2021-08-13 NOUVELLE FORME CRISTALLINE DE β-NICOTINAMIDE MONONUCLÉOTIDE, SON PROCÉDÉ DE PRÉPARATION ET SON UTILISATION WO2022033589A1 (fr)

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CN112538101A (zh) * 2020-08-13 2021-03-23 常州博海威医药科技股份有限公司 一种β烟酰胺单核苷酸的新晶型及其制备方法和用途
CN113402570A (zh) * 2021-05-25 2021-09-17 天尔生物医药(湖北)有限公司 一种烟酰胺单核苷酸的结晶方法
CN113912653B (zh) * 2021-06-04 2024-04-23 天津大学 一种提高β-烟酰胺单核苷酸结晶粉末松堆密度的方法
CN113292619B (zh) * 2021-06-18 2022-04-22 邦泰生物工程(深圳)有限公司 烟酰胺单核苷酸-异烟碱共晶体及其组合物
CN113402575B (zh) * 2021-06-18 2022-04-22 邦泰生物工程(深圳)有限公司 一种制备烟酰胺单核苷酸共晶体的方法
CN115368423A (zh) * 2022-02-23 2022-11-22 音芙医药科技(上海)有限公司 还原型β-烟酰胺单核苷酸二钠盐的多晶型及其制法和用途

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