WO2022033589A1 - 一种β烟酰胺单核苷酸的新晶型及其制备方法和用途 - Google Patents

一种β烟酰胺单核苷酸的新晶型及其制备方法和用途 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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formula
polymorphic form
ethanol
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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

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  • 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%.

Abstract

本发明涉及式(I)所示β烟酰胺单核苷酸的新晶型及其制备方法。本发明的方法不利用甲醇等有毒有害的有机溶剂，操作简便，对生产人员安全，对环境友好。本发明的新晶型的结晶纯度高、稳定性好。(I)

Description

一种β烟酰胺单核苷酸的新晶型及其制备方法和用途 技术领域
本发明属于医药领域。具体地说，本发明涉及β烟酰胺单核苷酸的新晶型及其制备方法和用途。
背景技术
β-烟酰胺单核苷酸(NMN)是人体内固有的物质。在人体中，NMN是NAD+最直接的前体，其功能是通过NAD+体现。NAD+又叫辅酶Ⅰ，全称烟酰胺腺嘌呤二核苷酸，存在每一个细胞中，参与上千项反应。NAD+对人体健康发挥着根本性的影响，但随着年龄的增长NAD+在人体内的含量逐渐降低，线粒体和细胞核之间的交流受损，NAD+的减少也损害了细胞产生能量的能力，从而导致衰老与疾病。
补充β-烟酰胺单核苷酸(NMN)可有效快速地增加人体内NAD+的水平，从而大幅延缓衰老和防止老年痴呆等多种神经元退化疾病，并且从根本上调理和改善衰老的各种症状。目前β-烟酰胺单核苷酸(NMN)做为抗衰老等功能的食品补充剂已在加拿大，日本等国家批准上市。目前，β-烟酰胺单核苷酸(NMN)的日推荐剂量为300mg，作为食品补充剂，产品最后的结晶溶剂必须无毒无害，否则残留溶剂会对健康产生不良影响。
NMN的结晶方法已见诸报道，例如CN108697722A(PCT/US2016/054776，2016.09.30，美国麦德龙生物科技有限公司)；WO2018/047715 A1(日本协和生物发酵株式会社)和WO2018/047715 A1(The Queen’s University of Belfast及ChromaDex.Inc)。然而，这三种方法中主要选择甲醇或甲醇水混合溶剂作为结晶溶剂。由于甲醇是有毒有害溶剂，作为食品补充剂很多国家是限制甲醇作为最后的结晶溶剂。此外，这几种方法操作复杂，耗时久，不利于生产。
因此，本领域急需全新的β烟酰胺单核苷酸结晶方法以及新的的β烟酰胺单核苷酸晶型。
发明内容
本发明的目的在于提供一种全新的β烟酰胺单核苷酸晶型。
本发明的目的还在于提供一种β烟酰胺单核苷酸的新结晶方法，该方法不利用甲醇等有毒有害的有机溶剂并且操作简单。
在第一方面，本发明提供式(I)所示化合物的多晶型，
Figure PCTCN2021112598-appb-000001
所述多晶型的X-射线粉末衍射图在以下2θ角(±0.2°)处有特征峰：20.42；21.65；22.75和24.98。
在优选的实施方式中，所述多晶型是非溶剂化的、无水的或大致无水的。
在具体的实施方式中，所述多晶型的X-射线粉末衍射图进一步在以下2θ角(±0.2°)处有特征峰：21.21；22.26；23.99；24.69；和27.21。
在具体的实施方式中，所述多晶型的X-射线粉末衍射图进一步在以下2θ角(±0.2°)处有特征峰：7.70；11.33；12.43；16.32；17.78；19.06；和19.93。
在具体的实施方式中，所述多晶型的X-射线粉末衍射图进一步在以下2θ角(±0.2°)处有特征峰：10.18；15.25；19.26；22.75；23.34；25.69；26.24；26.70；27.61；28.08；29.88；31.78；和38.00。
在具体的实施方式中，其特征在于，所述多晶型具有大体上如图1所示的XRPD图谱。
在一优选例中，所述多晶型的纯度在99.7％以上，优选99.8％以上，更优选99.9％以上。
在一优选例中，所述多晶型中降解杂质烟酰胺的含量低于0.05％，优选低于0.03％，更优选低于0.01％。
在一优选例中，本发明的多晶型在25℃，0％RH的条件下放置12周后，与第0时的纯度相比，纯度的降低少于0.1％；优选少于0.07％；更优选少于0.05％。
在一优选例中，本发明的多晶型在25℃，0％RH的条件下放置1年后，与第0时的纯度相比，纯度的降低少于0.15％；优选少于0.13％；更优选少于0.12％。
在一优选例中，本发明的多晶型在40℃，0％RH的条件下放置6个月后，与第0时的纯度相比，纯度的降低少于0.5％；优选少于0.4％；更优选少于0.33％。
在一优选例中，在25℃的条件下放置2年以上，本发明的多晶型的纯度大于99.5％。
在第二方面，本发明提供一种制备第一方面所述多晶型的方法，所述方法包括以下步骤：
a.将式(I)所示化合物溶解于水中，从而得到式(I)所示化合物的水溶液；和
b.向步骤a中得到的式(I)所示化合物的水溶液中加入反溶剂，从而使得式(I)所示化合物的晶体从溶液中沉淀析出。
在具体的实施方式中，所述反溶剂为乙醇、丙酮、异丙醇或它们的混合溶剂。
在优选的实施方式中，步骤a得到的式(I)所示化合物的水溶液的质量百分浓度为5％-25％，优选为8％-20％。
在优选的实施方式中，步骤b中反溶剂，例如乙醇的加入量(体积)为步骤a中水的体积的1-3倍。
在优选的实施方式中，步骤b中加入反溶剂，例如乙醇的温度为20℃-40℃，优选为25℃-35℃。
在具体的实施方式中，步骤b中反溶剂，例如乙醇的加入量使得乙醇加入结束后，溶液仍然是澄清的，随后通过搅拌形成晶核或者添加晶种来诱导析晶。
在优选的实施方式中，在式(I)所示化合物的晶体从溶液中析出后，继续添加乙醇。
在优选的实施方式中，在式(I)所示化合物的晶体从溶液中析出后，适当降低温度。
在第三方面，本发明提供第一方面所述多晶型在制备延缓衰老和治疗或预防神经元退化疾病的药物中的用途。
在优选的实施方式中，所述神经元退化疾病包括但不限于老年痴呆、渐冻症及帕金森等疾病。
在第四方面，本发明提供一种药物组合物，所述药物组合物包含第一方面所述多晶型和任选的药学上可接受的赋形剂。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
附图说明
图1是本发明实施例得到的β-烟酰胺单核苷酸(NMN)，即式(I)的结晶化合物XRPD图谱。
图2是本发明实施例得到的式(I)的结晶化合物的HNMR图谱。
图3是本发明中参考例得到的式(I)的结晶化合物的XRPD图谱。
图4是本发明实施例得到的(I)的结晶化合物与参考例得到的式(I)的结晶化合物的XRPD比较图谱。
图5是本发明实施例得到的(I)的结晶化合物与参考例得到的式(I)的结晶化合物的红外分光图谱的比较。
图6是本发明实施例得到的(I)的结晶化合物的HPLC检测图谱。
图7是图1的结晶化合物25±2℃稳定性试验1年以后的XRPD图。
图8是图1的结晶化合物40±2℃稳定性试验1年后的XRPD图。
图9是图1的结晶化合物5±3℃保存1年后的XRPD图。
具体实施方式
发明人经过广泛而深入的研究，出乎意料地发现了一种全新的β烟酰胺单核苷酸的结晶方法以及利用该方法得到的β烟酰胺单核苷酸新晶型。采用本发明的方法可以在不利用甲醇等有毒有害有机溶剂的前提下得到β烟酰胺单核苷酸晶体。本发明的多晶型不仅在稳定性方面表现出显著改善，在生物利用度、药代动力学、药效学等方面也表现出显著改善。在此基础上完成了本发明。
本发明的多晶型及其制备方法
在本文中，“本发明的晶体”、“本发明的多晶型”、“本发明的结晶化合物”、“式(I)的结晶化合物”等术语具有相同的含义，其是指式(I)所示化合物的结晶化合物，
Figure PCTCN2021112598-appb-000002
在具体的实施方式中，式(I)的结晶化合物是非溶剂化的、无水的或大体无水的。
在某些实施方式中，结晶化合物的多晶型通过粉末X射线衍射(XRD)表征。θ表示按度数计量的衍射角。在某些实施方案中，用XRD的衍射仪测量衍射角θ的两倍的衍射角。因此，本文中所描述的的衍射图谱指针对角度2θ测量的X射线强度。
在具体的实施方式中，式(I)的结晶化合物的X-射线粉末衍射图在以下2θ角(±0.2°)处有特征峰：20.42；21.65；22.75和24.98；进一步地，在以下2θ角(±0.2°)处有特征峰：21.21；22.26；23.99；24.69；和27.21；更进一步地，在以下2θ角(±0.2°)处有特征峰：7.70；11.33；12.43；16.32；17.78；19.06；和19.93；再进一步地，在以下2θ角(±0.2°)处有特征峰：10.18；15.25；19.26；22.75；23.34；25.69；26.24；26.70；27.61；28.08；29.88；31.78；和38.00。在优选的实施方式中，式(I)的结晶化合物具有如图1所示的XRD图谱。
本领域技术人员知晓，式(I)所示化合物会降解，其降解产物是烟酰胺。因此，式(I)所示化合物的多晶型中烟酰胺的含量既可以体现该多晶型本身的纯度，又可以衡量该多晶型的稳定性。
相比于现有技术中的式(I)所示化合物的多晶型的纯度，本发明的多晶型能够具备优异的纯度。在具体的实施方式中，本发明的多晶型的纯度在99.7％以上，优选99.8％以上，更优选99.9％以上；其中降解杂质烟酰胺的含量低于0.05％；优选低于0.03％；更优选低于0.01％。
相比于现有技术中的式(I)所示化合物的多晶型，本发明的多晶型不仅能够具备优 异的纯度，还能够具备优异的稳定性。在具体的实施方式中，本发明的多晶型在25℃，0％RH的条件下放置12周后，与第0时的纯度相比，纯度的降低少于0.1％；优选少于0.07％；更优选少于0.05％；或者
本发明的多晶型在25℃，0％RH的条件下放置1年后，与第0时的纯度相比，纯度的降低少于0.15％；优选少于0.13％；更优选少于0.12％；或者
本发明的多晶型在40℃，0％RH的条件下放置6个月后，与第0时的纯度相比，纯度的降低少于0.5％；优选少于0.4％；更优选少于0.33％。
本发明的多晶型通过以下方法制备得到，所述方法包括：在式(I)化合物的水溶液中添加反溶剂使所得溶液过饱和，以引起式(I)化合物从溶液中沉淀析出。在具体的实施方式中，所述反溶剂为乙醇、丙酮、异丙醇或它们的混合溶剂。在具体的实施方式中，式(I)化合物的水溶液的质量百分浓度为5％-25％，优选为8％-20％。在具体的实施方式中，添加反溶剂，例如乙醇的量(体积)为式(I)化合物水溶液中添加水的体积的1-3倍。
本发明人尤其发现，为获得本发明的多晶型，反溶剂，例如乙醇的添加量根据式(I)化合物水溶液浓度不同可以相同也可以不同，具体原则是初次添加反溶剂，例如乙醇的量要保证添加结束后，溶液仍然是澄清的，没有油滴状物析出；添加初次反溶剂，例如乙醇结束后，通过搅拌形成晶核或者添加本发明实施例得到的晶种来诱导析晶。
本发明的某些实施方式中，添加初次反溶剂，例如乙醇结束后，得到澄清溶液，通过搅拌形成晶核或者添加本发明实施例得到的晶种来诱导析晶，搅拌后析出大量固体后，即目视溶液变浆状，继续添加一部分反溶剂，例如乙醇，不会影响所得式(I)化合物的晶型，还能适当提高回收率。
本发明的实施方案中，添加反溶剂，例如乙醇的温度为20℃-40℃，优选为25℃-35℃。
添加反溶剂，例如乙醇结束后，不需要额外的加热或制冷来促进结晶，通过搅拌形成晶核或者添加本发明实施例得到的晶种来诱导析晶即可。
本发明的某些实施方案中，式(I)化合物的水溶液搅拌下加入反溶剂，例如乙醇，会放热。20℃-25℃的水溶液，不冷却加完反溶剂，例如乙醇后会升温至30℃-35℃；本发明的某些实施方案中，可以控制温度，保持20℃-25℃下析出晶体，也可以不控温自然升至30℃-35℃，保持30℃-35℃下析出晶体，得到的式(I)化合物的晶型不会改变。
本发明的实施方案中，式(I)化合物的反溶剂，例如乙醇水溶液在20℃-40℃下析出大量结晶固体后，再降低温度，例如0℃-5℃，不改变得到的式(I)的化合物的晶型，还能适当提高回收率。
在本发明提供的多晶型的基础上，本领域技术人员会理解，可以将本发明的多晶 型制备成延缓衰老和防止老年痴呆等多种神经元退化疾病的药物。因此，本发明还提供了这样一种药物组合物，所述组合物包含本发明的多晶型和任选的药学上可接受的赋形剂。
药物组合物中具体赋形剂以及药物组合物的具体剂型可以由本领域技术人员根据具体需求，采用已知的方式制造。例如可以通过传统的混合、制粒、制锭、溶解或冷冻干燥过程制造将本发明的多晶型制成口服制剂，例如片剂。合适的赋形剂可以包括填料，例如糖类如乳糖或蔗糖，甘露醇或山梨醇；纤维素制剂或钙磷酸盐，例如磷酸三钙或磷酸氢钙；以及粘结剂，例如淀粉糊，包括玉米淀粉，小麦淀粉，大米淀粉，马铃薯淀粉，明胶，黄芪胶，甲基纤维素，羟丙基甲基纤维素，羟甲基纤维素钠，或聚乙烯吡咯烷酮。如果需要，可增加崩解剂，比如上面提到的淀粉，以及羧甲基淀粉，交联聚乙烯吡咯烷酮，琼脂，或褐藻酸或其盐，如海藻酸钠。辅助剂特别是流动调节剂和润滑剂，例如，硅石，滑石，硬脂酸盐类，如镁硬脂酸钙，硬脂酸或聚乙二醇。如果需要，可以给锭剂核心提供可以抵抗胃液的合适包衣。为此，可以应用浓缩糖类溶液。这个溶液可以含有***树胶，滑石，聚乙烯吡咯烷酮，聚乙二醇和/二氧化钛，漆溶液和合适的有机溶剂或溶剂混合物。为了制备耐胃液的包衣，可使用适当的纤维素溶液，例如醋酸纤维素邻苯二甲酸或羟丙基甲基纤维素邻苯二甲酸。可向药片或锭剂核心的包衣加入染料或色素。例如，用于识别或为了表征活性成分剂量的组合。
在所述多晶型的基础上，本发明还提供一种延缓衰老和治疗老年痴呆等多种神经元退化疾病的方法，该方法包括将治疗有效量的本发明的多晶型或药物组合物给予有此需要的对象。
本发明的主要优点在于：
1.本发明的结晶方法无需使用有毒有害的有机溶剂，例如甲醇等；
2.本发明的结晶方法操作简便，从而有利于大规模生产；
3.本发明的结晶方法对生产人员安全，对环境友好；
4.本发明的结晶方法可以获得更高的产品纯度，所得产品结晶的纯度可达99.9％以上，纯度优于现有技术，例如CN108697722A中报道的结晶纯度(99.52％)。
5.本发明所得晶体的稳定性更好，优于现有技术，例如CN108697722A报道的结晶形式1。
以下结合具体实施案例对本发明的技术方案进一步描述，但以下实施案例不构成对本发明的限制，所有依据本发明的原理和技术手段采用的各种施用方法，均属于本发明范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。
材料与方法
用于本发明中实施例和参考例的分析方法如下所述：
X射线粉末衍射法
机器型号：Bruker D8 Advance衍射仪，使用Cu Kα辐射(40kV,40Ma)；
角度范围：3-45度2θ；
步长：0.02度2θ；
收集速度：8度/min；
HPLC
岛津制作所LC2030C 3D高效液相色谱仪，PDA检测器，Labsolution工作站
色谱条件：
色谱柱：Thermo Hypersil gold 4.6×250mm 5um；(part No 25005-254630)
流速：1.0ml/min；
柱温：30℃；
样品温度：5℃；
检测波长：265nm；
进样量：5ul；
流动相：A：0.005mol/L乙酸铵水溶液(乙酸调pH＝3.0±0.1)；B：甲醇
梯度:
时间(分) 0 5 10 15 15.1 25
流动相A(％) 100 100 0 0 100 100
流动相B(％) 0 0 100 100 0 0
红外分析(IR)
岛津制作所RAffinty-1S红外光谱仪，工作站：Labsolution IR溴化钾压片。
实施例1.
将10.0克β-烟酰胺单核苷酸(NMN)(纯度为98.65％)和90.0毫升水加入500毫升反应瓶。搅拌溶解后，水溶液质量百分比为10.0％。水溶液在24℃，搅拌下加入乙醇180毫升，升温至32℃，开始为澄清溶液，搅拌5分钟后有白色固体逐渐析出，继续搅拌3小时，25℃过滤，乙醇淋洗，25℃真空干燥至恒重，得到8.8克白色固体。
XRPD分析后，所得结晶的XRPD图谱如图1所示；
HPLC测得纯度为99.91％，如图6所示；
HNMR核磁图谱如图2所示；
干燥失重：60℃减压干燥(干燥剂：五氧化二磷)，干燥失重0.05％，得到的固体是无水物。
实施例2.
将10.0克β-烟酰胺单核苷酸(NMN)和90.0毫升水加入500毫升反应瓶。搅拌溶解后，水溶液质量百分比为10.0％。水溶液在24℃，搅拌下加入乙醇180毫升，升温至32℃，开始为澄清溶液，搅拌5分钟后有白色固体逐渐析出，继续搅拌3小时，继续滴加90毫升乙醇，再继续搅拌2小时，25℃，过滤，乙醇淋洗，25℃真空干燥至恒重，得到9.1克白色固体。
XRPD分析后，所得结晶形式与实施例1得到的结晶形式相同。
实施例3.
将10.0克β-烟酰胺单核苷酸(NMN)和40.0毫升水加入250毫升反应瓶。搅拌溶解后，水溶液质量百分比为20.0％。水溶液在24℃，搅拌下滴加入乙醇60ml，升温至30℃，滴加完后，开始为澄清溶液，搅拌3分钟后有白色固体逐渐析出，继续搅拌2小时后，过滤得到白色固体，乙醇淋洗，25℃真空干燥至恒重，得8.8克晶体。
XRPD分析后，所得结晶形式与实施例1得到的结晶形式相同
实施例4.
将10.0克β-烟酰胺单核苷酸(NMN)和60.0毫升水加入250毫升反应瓶。搅拌溶解后，水溶液质量百分比为14.3％。水溶液在24℃，搅拌下滴加入乙醇100ml，升温至31℃，滴加完后，开始为澄清溶液，搅拌下逐渐析出固体，继续搅拌1小时后，过滤，乙醇淋洗，25℃真空干燥至恒重，得到白色固体8.6克。
XRPD分析后，所得结晶与实施例1得到的结晶相同。
实施例5.
将10.0克β-烟酰胺单核苷酸(NMN)和60.0毫升水加入250毫升反应瓶。搅拌溶解后，水溶液质量百分比为14.3％。水溶液在24℃，搅拌下滴加入乙醇100ml，升温至31℃，滴加完后，开始为澄清溶液，搅拌下逐渐析出固体，继续搅拌1小时后，冰浴冷却至0℃-5℃，继续搅拌1小时后，过滤，乙醇淋洗，25℃真空干燥至恒重，得到白色固体8.9克。
XRPD分析后，所得结晶形式与实施例1形式得到的结晶相同。
实施例6.
将10.0克β-烟酰胺单核苷酸(NMN)和115.0毫升水加入250毫升反应瓶。搅拌溶解后，水溶液质量百分比为8.0％。水溶液在24℃，搅拌下滴加入乙醇250ml，升温至32℃，滴加完后，开始为澄清溶液，搅拌下逐渐析出固体，继续搅拌2小时后，过滤，乙醇淋洗，25℃真空干燥至恒重，得到白色固体8.6克。
XRPD分析后，所得结晶形式与实施例1得到的结晶形式相同。
实施例7.
将10.0克β-烟酰胺单核苷酸(NMN)和30毫升水加入250毫升反应瓶。搅拌溶解后，水溶液质量百分比为25.0％。水溶液在25℃，搅拌下滴加入乙醇30ml，升温至30℃，滴加完后，开始为澄清溶液，加入实施例1得到的固体作为晶种，搅拌下有白 色固体逐渐析出，继续搅拌2小时后，过滤得到白色固体，乙醇淋洗，25℃真空干燥至恒重，得8.9克。
XRPD分析后，所得结晶形式与实施例1得到的结晶形式相同。
实施例8
将10.0克β-烟酰胺单核苷酸(NMN)和90.0毫升水加入500毫升反应瓶。搅拌溶解后，水溶液质量百分比为10.0％。水溶液在25℃，搅拌下加滴加入丙酮120毫升，升温至31℃，开始为澄清溶液，加入本发明实施例1得到的晶体作为晶种，继续搅拌，析出较多白色固体，继续滴加60毫升丙酮，搅拌1小时后，25℃，过滤，丙酮淋洗，25℃真空干燥至恒重，得到7.8克白色固体。
XRPD分析后，所得结晶形式与实施例1得到的结晶形式相同。
实施例9
将10.0克β-烟酰胺单核苷酸(NMN)和90.0毫升水加入500毫升反应瓶。搅拌溶解后，水溶液质量百分比为10.0％。水溶液在26℃，搅拌下加滴加入异丙醇160毫升，升温至31℃，开始为澄清溶液，加入本发明实施例1得到的晶体作为晶种，继续搅拌，析出较多白色固体，搅拌1小时后，25℃，过滤，异丙醇淋洗，25℃真空干燥至恒重，得到7.6克白色固体。
XRPD分析后，所得结晶形式与实施例1得到的结晶形式相同。
对比例
参考CN108697722A和WO2018/047715的方法，将50.0克β-烟酰胺单核苷酸(NMN)溶于150毫升水，搅拌下加入300毫升甲醇，析出白色固体，继续搅拌2小时后过滤，25℃真空干燥，得到46.0克白色固体。
XRPD分析后，所得结晶的XRPD图谱如图3所示。与CN108697722A报道的结晶形式1比较，大体相同。
实施例10.本发明所得结晶形式的稳定性研究
稳定性试验描述：将本发明所得结晶以市售包装(双层聚乙烯塑料袋+铝箔袋密封)形态分别放置于25±2℃、40±2℃、5±3℃三个条件下，考察其在不同条件下的稳定性。
本发明得到的晶型的稳定性数据列表如下：
Figure PCTCN2021112598-appb-000003
Figure PCTCN2021112598-appb-000004
*已知杂质：烟酰胺
CN108697722A中描述的结晶形式1的稳定性数据列表如下：
左表格数据为：CN108697722描述的结晶形式1在稳定性测试点0周的数据，其中RRT 1.74的杂质为已知杂质(烟酰胺)，0周时，该杂质为0.12％。
右表格数据为：CN108697722描述的结晶形式1在25℃，0％RH条件下放置12周的测试数据
Figure PCTCN2021112598-appb-000005
比较本发明晶型与CN108697722所描述的晶型稳定性实验数据可以看出：
在25℃，0％RH的条件下，CN108697722所描述的结晶形式1的已知杂质“烟酰胺”由0时的0.12％经12周(3个月)放置，增加到0.38％，烟酰胺增加了0.26％，总纯度由0时的99.52％下降至98.90％；而本发明晶型的已知杂质“烟酰胺”由0时的0.01％经12周(3个月)放置，增加到0.05％，烟酰胺仅增加0.04％，总纯度由0时的99.91％下降至99.86％；可以得出结论，本发明得到的晶型稳定性远优于CN108697722A描述的晶型。
同时本发明的晶型在25℃，0％RH放置1年时间，总纯度为99.79％，已知杂质“烟酰胺”增加至0.07％；本发明晶型在40℃，0％RH放置6个月时间，总纯度为99.58％，已知杂质“烟酰胺”增加至0.28％。从以上数据可以预测，本发明晶型在室温25℃的条件可以稳定保存2年以上，在2年内，本发明晶型的纯度仍可以大于99.5％。
比较图7与图1，可以知晓在25±2℃下放置1年，本发明得到的晶型是稳定的，没有发生结晶形态的改变。
比较图8与图1，可以知晓在40±2℃下放置1年，本发明得到的晶型是稳定的，没有发生结晶形态的改变。
比较图9与图1，可以知晓在5±3℃下放置1年，本发明得到的结晶是稳定的，没有发生结晶形态的改变。
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (10)

  1. 式(I)所示化合物的多晶型，
    Figure PCTCN2021112598-appb-100001
    所述多晶型的X-射线粉末衍射图在以下2θ角(±0.2°)处有特征峰：20.42；21.65；22.75和24.98。
  2. 如权利要求1所述的多晶型，其特征在于，所述多晶型的X-射线粉末衍射图进一步在以下2θ角(±0.2°)处有特征峰：21.21；22.26；23.99；24.69；和27.21。
  3. 如权利要求2所述的多晶型，其特征在于，所述多晶型的X-射线粉末衍射图进一步在以下2θ角(±0.2°)处有特征峰：7.70；11.33；12.43；16.32；17.78；19.06；和19.93。
  4. 如权利要求3所述的多晶型，其特征在于，所述多晶型的X-射线粉末衍射图进一步在以下2θ角(±0.2°)处有特征峰：10.18；15.25；19.26；22.75；23.34；25.69；26.24；26.70；27.61；28.08；29.88；31.78；和38.00。
  5. 如权利要求1-4中任一项所述的多晶型，其特征在于，所述多晶型具有大体上如图1所示的XRPD图谱。
  6. 一种制备权利要求1-5中任一项所述多晶型的方法，所述方法包括以下步骤：
    a.将式(I)所示化合物溶解于水中，从而得到式(I)所示化合物的水溶液；和
    b.向步骤a中得到的式(I)所示化合物的水溶液中加入反溶剂，从而使得式(I)所示化合物的晶体从溶液中沉淀析出。
  7. 如权利要求6所述的方法，其特征在于，所述反溶剂为乙醇。
  8. 如权利要求7所述的方法，其特征在于，步骤b中乙醇的加入量要保证乙醇加入结束后，溶液仍然是澄清的，随后通过搅拌形成晶核或者添加晶种来诱导析晶。
  9. 权利要求1-5中任一项所述多晶型在制备延缓衰老和治疗或预防神经元退化疾病的药物中的用途。
  10. 一种药物组合物，所述药物组合物包含权利要求1-5中任一项所述多晶型和任选的药学上可接受的赋形剂。
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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
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Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018047715A1 (ja) * 2016-09-06 2018-03-15 協和発酵バイオ株式会社 β－ニコチンアミドモノヌクレオチドの結晶及びその製造方法
US20180134742A1 (en) * 2016-11-11 2018-05-17 The Queen's University Of Belfast Crystalline forms of nicotinoyl ribosides, modified derivatives thereof, and phosphorylated analogs thereof, and methods of preparation thereof
CN108697722A (zh) * 2015-10-02 2018-10-23 麦德龙国际生物科技有限责任公司 β-烟酰胺单核苷酸的晶体形式
CN110195089A (zh) * 2019-06-13 2019-09-03 叁爻生物科技(上海)有限公司 烟酰胺单核苷酸及其制备方法
CN111377983A (zh) * 2020-03-26 2020-07-07 音芙医药科技(上海)有限公司 一种β-烟酰胺单核苷酸的制备方法
CN111705096A (zh) * 2020-06-29 2020-09-25 上海舒泽生物科技研究所 一种酶转化法生产β-烟酰胺单核苷酸的方法
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
CN112694505A (zh) * 2020-12-30 2021-04-23 音芙医药科技(上海)有限公司 一种高密度的nmn的制备方法
CN113121628A (zh) * 2019-12-30 2021-07-16 尚科生物医药（上海）有限公司 一种无定型烟酰胺单核苷酸的制备方法
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

Patent Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108697722A (zh) * 2015-10-02 2018-10-23 麦德龙国际生物科技有限责任公司 β-烟酰胺单核苷酸的晶体形式
WO2018047715A1 (ja) * 2016-09-06 2018-03-15 協和発酵バイオ株式会社 β－ニコチンアミドモノヌクレオチドの結晶及びその製造方法
US20180134742A1 (en) * 2016-11-11 2018-05-17 The Queen's University Of Belfast Crystalline forms of nicotinoyl ribosides, modified derivatives thereof, and phosphorylated analogs thereof, and methods of preparation thereof
CN110195089A (zh) * 2019-06-13 2019-09-03 叁爻生物科技(上海)有限公司 烟酰胺单核苷酸及其制备方法
CN113121628A (zh) * 2019-12-30 2021-07-16 尚科生物医药（上海）有限公司 一种无定型烟酰胺单核苷酸的制备方法
CN111377983A (zh) * 2020-03-26 2020-07-07 音芙医药科技(上海)有限公司 一种β-烟酰胺单核苷酸的制备方法
CN111705096A (zh) * 2020-06-29 2020-09-25 上海舒泽生物科技研究所 一种酶转化法生产β-烟酰胺单核苷酸的方法
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
CN112694505A (zh) * 2020-12-30 2021-04-23 音芙医药科技(上海)有限公司 一种高密度的nmn的制备方法
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

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
DENG, JUN ET AL.: "Clinical Research and Chemical Preparation Progress of Nicotinamide Nucleotide", GUANGDONG CHEMICAL INDUSTRY, vol. 48, no. 12, 25 June 2021 (2021-06-25), pages 98 - 100,88, XP055900260 *

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