CN111808156A - Beta-nicotinamide riboside chloride crystal form 1A and crystal form 1B and preparation method thereof - Google Patents

Abstract

The invention discloses a beta-nicotinamide riboside chloride crystal form 1A, a crystal form 1B and a preparation method thereof, wherein the crystal form 1A has diffraction peaks of 13.0 degrees +/-0.2 degrees, 14.0 degrees +/-0.2 degrees, 23.8 degrees +/-0.2 degrees, 24.5 degrees +/-0.2 degrees and 25.4 degrees +/-0.2 degrees in an X-ray powder diffraction pattern. Form 1B having diffraction peaks, in an X-ray powder diffraction pattern, at 2 Θ ═ 5.0 ° ± 0.2 °, 15.6 ° ± 0.2 °, 21.6 ° ± 0.2 °, 26.4 ° ± 0.2 °. The two crystalline forms of nicotinamide riboside have more favorable properties including morphology of the substance, stability (e.g., low solvent residue, low hygroscopicity, storage stability, stability of polymorphic conversion), solubility, chemical purity, and the like. The change of the properties is more beneficial to the industrial production of high-purity nicotinamide ribose, and provides wide space for the development of the dosage form of the nicotinamide ribose.

Description

Beta-nicotinamide riboside chloride crystal form 1A and crystal form 1B and preparation method thereof

Technical Field

The invention particularly relates to a crystal form 1A and a crystal form 1B of beta-nicotinamide riboside chloride and a preparation method thereof.

Background

The information in this background section is only for enhancement of understanding of the general background of the invention and is not necessarily to be construed as an admission or any form of suggestion that this information forms the prior art that is already known to a person of ordinary skill in the art.

Nicotinamide ribochloride (3-carbamoyl-1- [ (2R,3R,4S,5R) -3, 4-dihydroxy-5-hydroxymethyloxolane-2-yl ] -pyridin-1-ium chloride; also known as 1- (. beta. -D-ribofuranosyl) nicotinamide chloride) is a known salt form of nicotinamide riboside, having the following structure (I):

nicotinamide ribose is Nicotinamide Adenine Dinucleotide (NAD)⁺) Is a vitamin B3 with effects of promoting energy metabolism and protecting nerve^[1]Nicotinamide riboside, which expresses NAD via the NrK and Urh1/Pnp1/Meu1 pathways⁺Promoting Sir2 silencing and prolonging life span. A large number of researches show that the uptake of a certain amount of nicotinamide riboside can enhance the metabolism of organisms, has important effects on the aspects of preventing cell aging, maintaining the functions of stem cells and the like, and has important significance for the field of regenerative medicine. Secondly, it can enhance oxidative metabolism and prevent obesity caused by high fat diet. In the aspect of liver cancer research, the result shows that the development of liver cancer of mice can be inhibited and tumor regression can be induced by supplementing nicotinamide riboside with diet. Other researches show that nicotinamide riboside has a neuroprotective effect and also has a certain value in the research of Alzheimer's disease.

Different crystalline forms of a molecule may have advantageous properties relative to non-crystalline forms of such molecules. For example, crystalline forms generally have better stability, are easier to store, and are easier to purify. The crystal form of the useful compound can improve the pharmaceutical characteristics of the compound, and the same drug has different physical properties and different biological activities due to different crystal forms, thereby interfering the clinical application of the drug. The good crystal form is obtained, which is not only beneficial to the optimization of the preparation, but also can better play the role of the medicine.

The inventors found that, although studies on methods for synthesizing nicotinamide ribose have been increased in recent years, nicotinamide ribose and chloride salts thereof are mainly involved in amorphous forms, and nicotinamide ribose and chloride salts thereof in crystalline forms are of fewer kinds. In addition, the conventional crystalline nicotinamide riboside and chloride thereof require an instrument such as ion exchange chromatography during the synthesis process, and thus it is difficult to carry out industrial mass production.

Disclosure of Invention

In order to solve the technical problems in the prior art, the invention aims to provide a beta-nicotinamide riboside chloride crystal form 1A and a crystal form 1B and a preparation method thereof.

To solve the above technical problem, one or more of the following embodiments of the present invention provide the following technical solutions:

in a first aspect, the present invention provides a crystalline form 1A of β -nicotinamide ribochloride, which crystalline form 1A has diffraction peaks, in an X-ray powder diffraction pattern, of 2 θ ═ 13.0 ° ± 0.2 °, 14.0 ° ± 0.2 °, 23.8 ° ± 0.2 °, 24.5 ° ± 0.2 °, 25.4 ° ± 0.2 °.

In a second aspect, the present invention provides a crystalline form 1B of β -nicotinamide ribochloride, which crystalline form 1B has diffraction peaks, in an X-ray powder diffraction pattern, at 2 θ ═ 5.0 ° ± 0.2 °, 15.6 ° ± 0.2 °, 21.6 ° ± 0.2 °, and 26.4 ° ± 0.2 °.

In a third aspect, a process for preparing crystalline form 1A of β -nicotinamide ribochloride is provided, comprising the steps of:

carrying out condensation and deacetylation reactions on beta-tetraacetyl ribose and nicotinamide under the catalytic action of a catalyst, quenching the reaction after the reaction is finished, and treating the reaction product by using organic alkali to obtain a nicotinamide ribose crude product;

and (3) introducing hydrogen chloride gas into the nicotinamide ribose crude product solution to carry out chlorination, wherein the temperature of the chlorination reaction is 0-30 ℃, and the time of the chlorination reaction is 8-16h, so as to prepare the crystal form 1A of the beta-nicotinamide ribose chloride.

In a fourth aspect, a method for preparing crystalline form 1B of β -nicotinamide ribochloride is provided, comprising the steps of:

under the protection of inert gas, dissolving the prepared crystal form 1A of the beta-nicotinamide riboside chloride by using a solvent, stirring and cooling for 2-48h at the temperature of-30-25 ℃, and directly performing suction filtration or performing suction filtration after adding an anti-solvent to obtain the beta-nicotinamide riboside chloride with a crystal structure.

Compared with the prior art, one or more technical schemes of the invention have the following beneficial effects:

beta-nicotinamide riboside chloride in crystal form 1A and crystal form 1B has more favorable properties including substance form, good stability (such as low solvent residue, low hygroscopicity, storage stability and polymorphic transformation stability), high solubility, high chemical purity and the like. The change of the properties is more beneficial to the industrial production of high-purity nicotinamide ribose, and provides wide space for the development of the dosage form of the nicotinamide ribose.

The crystal form 1A of the beta-nicotinamide riboside chloride can be converted simply to obtain the crystal form 1B, and the crystal form 1B of the nicotinamide riboside chloride has the advantages of good stability and higher purity and is easy to prepare.

The preparation method of the crystal form 1A and the crystal form 1B of the beta-nicotinamide riboside chloride is simple, and the prepared product has high purity and high yield, and is beneficial to industrial production.

Drawings

The accompanying drawings, which are incorporated in and constitute a part of this specification, are included to provide a further understanding of the invention, and are incorporated in and constitute a part of this specification, illustrate exemplary embodiments of the invention and together with the description serve to explain the invention and not to limit the invention.

Figure 1 provides the nmr hydrogen spectra of a sample of crystalline nicotinamide riboside crystalline form 1A.

Figure 2 provides the nmr hydrogen spectra of the crystalline nicotinamide ribose crystalline form 1B sample.

FIG. 3 provides an X-ray powder diffraction pattern of a sample of crystalline nicotinamide riboside crystalline form 1A

FIG. 4 provides an X-ray powder diffraction pattern of a sample of crystalline nicotinamide riboside crystalline form 1B

FIG. 5 provides a DSC thermogram of a sample of nicotinamide riboside crystalline form 1A with a heating rate of 10 deg.C/min.

FIG. 6 provides a DSC thermogram of a sample of nicotinamide riboside crystalline form 1B with a heating rate of 10 deg.C/min.

Detailed Description

It is to be understood that the following detailed description is exemplary and is intended to provide further explanation of the invention as claimed. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

It is noted that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of exemplary embodiments according to the invention. As used herein, the singular forms "a", "an" and "the" are intended to include the plural forms as well, and it should be understood that when the terms "comprises" and/or "comprising" are used in this specification, they specify the presence of stated features, steps, operations, devices, components, and/or combinations thereof, unless the context clearly indicates otherwise.

In a first aspect, the present invention provides a crystalline form 1A of β -nicotinamide ribochloride, which crystalline form 1A has diffraction peaks, in an X-ray powder diffraction pattern, of 2 θ ═ 13.0 ° ± 0.2 °, 14.0 ° ± 0.2 °, 23.8 ° ± 0.2 °, 24.5 ° ± 0.2 °, 25.4 ° ± 0.2 °.

In some embodiments, the crystalline form 1A has an absorption peak at 80 ± 3 ℃ and 111 ± 3 ℃ in a DSC profile.

Further, the temperature rise rate in the range of 30 to 200 ℃ is 10 ℃ when analyzed by differential scanning calorimetry.

In a second aspect, the present invention provides a crystalline form 1B of β -nicotinamide ribochloride, which crystalline form 1B has diffraction peaks, in an X-ray powder diffraction pattern, at 2 θ ═ 5.0 ° ± 0.2 °, 15.6 ° ± 0.2 °, 21.6 ° ± 0.2 °, and 26.4 ° ± 0.2 °.

In some embodiments, the crystalline form 1B has an absorption peak at 122 ± 3 ℃ in a DSC profile.

Further, the temperature rise rate in the range of 30 to 200 ℃ is 10 ℃ when analyzed by differential scanning calorimetry.

In a third aspect, a process for preparing crystalline form 1A of β -nicotinamide ribochloride is provided, comprising the steps of:

carrying out condensation and deacetylation reactions on beta-tetraacetyl ribose and nicotinamide under the catalytic action of a catalyst, quenching the reaction after the reaction is finished, and treating the reaction product by using organic alkali to obtain a nicotinamide ribose crude product;

and (3) introducing hydrogen chloride gas into the nicotinamide ribose crude product solution to carry out chlorination, wherein the temperature of the chlorination reaction is 0-30 ℃, and the time of the chlorination reaction is 8-16h, so as to prepare the crystal form 1A of the beta-nicotinamide ribose chloride.

In some embodiments, the catalyst is TMSOTf, TESOTf, or TMSCl.

In some embodiments, the molar ratio of β -tetraacetyl ribose, nicotinamide, and catalyst is 1:0.2 to 1: 5.

In some embodiments, the condensation and deacetylation reaction temperature is 20-45 ℃; the reaction time is 2-3 h.

In some embodiments, the solvent system for the condensation, deacetylation reaction is dichloromethane, chloroform, dichloroethane, tetrahydrofuran, 1, 4-dioxane, or acetonitrile.

In some embodiments, quenching is accomplished by controlling the temperature of the reaction system and adding water to the reaction system.

In some embodiments, the organic base is potassium carbonate, sodium carbonate, potassium bicarbonate, sodium ethoxide, sodium methoxide, or potassium tert-butoxide.

In some embodiments, the temperature of the chlorination reaction is 0-30 ℃ and the time of the chlorination reaction is 8-16 h.

In some embodiments, the solvent for the chlorination reaction is ethyl acetate, dichloromethane, chloroform, methanol, or ethanol.

In a fourth aspect, a method for preparing crystalline form 1B of β -nicotinamide ribochloride is provided, comprising the steps of:

under the protection of inert gas, dissolving the prepared crystal form 1A of the beta-nicotinamide riboside chloride by using a solvent, stirring and cooling for 2-48h at the temperature of-30-25 ℃, and directly performing suction filtration or performing suction filtration after adding an anti-solvent to obtain the beta-nicotinamide riboside chloride with a crystal structure.

In some embodiments, the prepared β -nicotinamide ribochloride is dissolved with methanol, ethanol, isopropanol, N-butanol, glycerol, ethylene glycol, t-butanol, 1-butanol, 2-butanol, ethylene glycol dimethyl ether, acetone, acetonitrile, N-Dimethylformamide (DMF), 1, 2-Dimethoxyethane (DME), dimethyl sulfoxide (DMSO), Hexamethylphosphoramide (HMPA), hexamethylortho triamide (HMPT), N-methyl-2-pyrrolidone (NMP), pyridine, water, dichloromethane, or chloroform.

In some embodiments, the anti-solvent is methyl tert-butyl ether (MTBE).

By anti-solvent is herein meant a solvent which assists in the precipitation of the crystalline product from solution.

In some embodiments, after adding the anti-solvent to the cooled solution, an additional cooling step is included for a set time.

Further, the temperature of the additional cooling is 25 ℃, 20 ℃, 15 ℃, 10 ℃, 0 ℃, 10 ℃, 15 ℃, 20 ℃ or 30 ℃, and the time of the additional cooling is 2h, 4h, 8h, 12h, 20h, 24h, 30h, 36h or 48 h.

The crystalline forms referred to herein, as depicted in the figures, of graphical data comprising: x-ray powder diffractogram and DSC thermogram. The data may undergo small changes in the plot due to certain factors (changes in sample concentration and purity, changes in instrument response) such as in terms of peak relative intensity and position, as is well known to the skilled person. Nevertheless, the skilled person is readily able to compare the data from the figures herein with data generated from other crystal forms and to confirm whether the two sets of data are indicative of two substances having the same crystal form or different crystal forms.

The present disclosure relates to 2 crystalline forms of nicotinamide riboside, including nicotinamide riboside crystalline form 1A and nicotinamide riboside chloride crystalline form 1B of formula II.

Example 1: preparation of beta-nicotinamide riboside chloride

The following examples illustrate the synthesis of nicotinamide ribochloride according to embodiments of the invention. Feed ii may be obtained from commercial sources.

Step a: condensation and deacetylation reaction: adding beta-tetraacetyl ribose (125g,393mmol) and 500mL of dichloromethane into a 1L reaction bottle in sequence, stirring for dissolving, adding nicotinamide (52.5kg,430mmol), stirring and heating to 30 ℃, dropwise adding trimethylsilyl trifluoromethanesulfonate (TMSOTf,135g,607mmol) diluted by dichloromethane, releasing heat in the dropwise adding process, controlling the temperature below 40 ℃, completing the addition within about 1h, after the dropwise addition is completed, continuing to stir for 10-30min, and completely reacting (TLC monitoring). The reaction was stopped, the reaction mixture was cooled to 15 ℃ or lower, 300mL of water was added to the reaction mixture, and the reaction was quenched by stirring for 30 min. The solution was used directly in the next step without further work-up.

Controlling the temperature to be below 15 ℃, dropwise adding about 130mL of potassium carbonate solution (30%) into the solution, releasing heat in the dropwise adding process, controlling the temperature to be below 15 ℃, adjusting the pH to be neutral after dropwise adding for about 1h, stirring for 0.5h, standing for layering, discarding an aqueous layer, washing an organic layer with water (300L multiplied by 3), drying with anhydrous magnesium sulfate, filtering, and concentrating the filtrate under reduced pressure to obtain 100.0g of a nicotinamide ribose crude product.

Step b: chlorination: adding 100.0g of the nicotinamide ribose crude product into a 1L dry reaction bottle, adding 300mL of methanol, controlling the temperature below 10 ℃, introducing hydrogen chloride gas, stirring overnight at 10-15 ℃, precipitating a large amount of white solid, and performing suction filtration to obtain 1A93.5g of nicotinamide ribose chloride crystal form.

Step c: preparation of nicotinamide riboside crystalline form 1B: under the protection of argon, dissolving the obtained nicotinamide riboside chloride crystal form 1A93.5g in 2L of dichloromethane solution, stirring for 2h at 10-12 ℃, carrying out suction filtration, pulping the solid for 2h by using dichloromethane, standing, carrying out suction filtration, and carrying out vacuum drying on the obtained solid at 20 ℃ to obtain nicotinamide riboside chloride crystal form 1B and white powder 92.6 g. The purity of the nicotinamide riboside chloride prepared by the method is more than 98.0 percent, and the total yield of the route is 81.2 percent.

¹HNMR(MeOD,400MHz):9.64(s,1H),9.31(d,J＝8.8Hz,1H),9.02(d,J＝8.0Hz,1H),8.32(t,J＝6.4Hz),6.29(d,J＝4.4Hz,1H),4.52(t,J＝10.2Hz,1H),4.51(d,J＝3.2Hz,1H),4.10(d,J＝10.0Hz,1H),3.96(dd,J＝13.2，3.6Hz,1H),3.92(dd,J＝13.2，3.6Hz,1H)。

Solid forms 1A and 1B of beta-nicotinamide riboside chloride, free of crystalline water component, when analyzed by powder X-ray diffraction using CuK_αDiffraction peak position 2-Theta value (degree) or d value under irradiation experiment condition

The diffraction peak relative intensity peak Height values (Height%) are shown in table 1, fig. 3, table 2, and fig. 4 below.

TABLE 1 powder X-ray diffraction peaks for Nicotinamide ribose crystalline form 1A material samples

TABLE 2 powder X-ray diffraction peaks for Nicotinamide riboside chloride crystalline form 1B material samples

When analyzed by differential scanning calorimetry, it shows a DSC thermogram as shown in FIGS. 5 and 6 at a temperature rise rate of 10 ℃ per minute in the range of 30 to 200 ℃.

Wherein the DSC thermogram of crystalline form 1A of nicotinamide riboside has 2 endothermic peaks at 80 + -3 deg.C, 111 + -3 deg.C.

Wherein the DSC thermogram obtained for crystalline form 1B of nicotinamide riboside has 1 endothermic peak at 122. + -. 3 ℃.

Example 2:

the following examples illustrate the synthesis of nicotinamide ribochloride according to embodiments of the invention. Feed ii may be obtained from commercial sources.

Step a: condensation and deacetylation reaction: adding beta-tetraacetyl ribose (12.5kg,39.3mol) and 48L of dichloromethane into a 100L reaction kettle in sequence, stirring to dissolve, adding nicotinamide (5.25kg,43.0mol), stirring and heating to 30 ℃, dropwise adding trimethylsilyl trifluoromethanesulfonate (TMSOTf,13.5kg,60.7mol) diluted by dichloromethane, releasing heat in the dropwise adding process, controlling the temperature to be below 40 ℃, completing the addition within about 3 hours, continuing to stir for 10-30min, and completely reacting (TLC monitoring). The reaction was stopped, the reaction solution was cooled to 15 ℃ or lower, 5L of water was added to the reaction solution, and the reaction was quenched by stirring for 30 min. The solution was used directly in the next step without further work-up.

Controlling the temperature to be below 15 ℃, dropwise adding about 13L of potassium carbonate solution (30%) into the solution, releasing heat in the dropwise adding process, controlling the temperature to be below 15 ℃, completing dropwise adding for about 2 hours, adjusting the pH to be neutral, stirring for 1 hour, standing for layering, discarding an aqueous layer, washing an organic layer (1L multiplied by 3), drying with anhydrous magnesium sulfate, filtering, and concentrating the filtrate under reduced pressure to obtain 10.5kg of a nicotinamide ribose crude product.

Step b, chlorination: adding 10.5kg of the nicotinamide ribose crude product into a 100L dry reaction kettle, adding 33L of methanol, controlling the temperature below 10 ℃, introducing hydrogen chloride gas, stirring overnight at 10-15 ℃, precipitating a large amount of white solid, and performing suction filtration to obtain 9.2kg of nicotinamide ribose chloride crystal form 1A.

Step c, preparing nicotinamide riboside crystal: under the protection of argon, 9.2kg of the obtained nicotinamide riboside solid is dissolved in 2.2L of dichloromethane solution, the mixture is stirred for 2h at the temperature of 10-12 ℃, centrifuged, the solid is pulped for 2h by dichloromethane, centrifuged, and the obtained solid is placed at the temperature of 20 ℃ for vacuum drying to obtain nicotinamide riboside chloride 1B and white powder 9.1 kg. The purity of the nicotinamide riboside chloride prepared by the method is more than 98 percent, and the total yield of the route is 80 percent.

The above reaction/cooling time is based on a production of several tens of kg. When the amount to be prepared is small, the time can be appropriately shortened without causing a significant influence on the morphology and appearance of the crystals.

The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims (10)

1. A crystalline form 1A of β -nicotinamide riboside chloride, characterized in that: in an X-ray powder diffraction pattern, characterized by: the crystal form 1A has diffraction peaks at 2 θ ═ 13.0 ° ± 0.2 °, 14.0 ° ± 0.2 °, 23.8 ° ± 0.2 °, 24.5 ° ± 0.2 °, and 25.4 ° ± 0.2 °.

2. Crystalline form 1A of β -nicotinamide ribochloride according to claim 1, characterized in that: in a DSC pattern, the crystal form 1A has an absorption peak at 80 +/-3 ℃ and 111 +/-3 ℃;

further, the temperature rise rate in the range of 30 to 200 ℃ is 10 ℃ when analyzed by differential scanning calorimetry.

3. A crystalline form 1B of β -nicotinamide ribochloride, characterized in that: in an X-ray powder diffraction pattern, the crystalline form 1B has diffraction peaks at 2 θ ═ 5.0 ° ± 0.2 °, 15.6 ° ± 0.2 °, 21.6 ° ± 0.2 °, and 26.4 ° ± 0.2 °.

4. Crystalline form 1B of β -nicotinamide ribochloride according to claim 3, characterized in that: in a DSC pattern, the crystal form 1B has an absorption peak at 122 +/-3 ℃;

further, the temperature rise rate in the range of 30 to 200 ℃ is 10 ℃ when analyzed by differential scanning calorimetry.

5. A process for the preparation of crystalline form 1A of β -nicotinamide ribochloride according to claim 1 or 2, characterized in that: the method comprises the following steps:

carrying out condensation and deacetylation reactions on beta-tetraacetyl ribose and nicotinamide under the catalytic action of a catalyst, quenching the reaction after the reaction is finished, and treating the reaction product by using organic alkali to obtain a nicotinamide ribose crude product;

and (3) introducing hydrogen chloride gas into the nicotinamide ribose crude product solution to carry out chlorination, wherein the temperature of the chlorination reaction is 0-30 ℃, and the time of the chlorination reaction is 8-16h, so as to prepare the crystal form 1A of the beta-nicotinamide ribose chloride.

6. The process of preparing crystalline form 1A of β -nicotinamide ribochloride according to claim 5, characterized in that: the catalyst is TMSOTf, TESOTf or TMSCl;

in some embodiments, the molar ratio of β -tetraacetyl ribose, nicotinamide, and catalyst is 1:0.2 to 1: 5;

in some embodiments, the condensation and deacetylation reaction temperature is 20-45 ℃; the reaction time is 2-3 h;

in some embodiments, the solvent system for the condensation, deacetylation reaction is dichloromethane, chloroform, dichloroethane, tetrahydrofuran, 1, 4-dioxane, or acetonitrile.

7. The process of preparing crystalline form 1A of β -nicotinamide ribochloride according to claim 5, characterized in that: the quenching reaction is realized by controlling the temperature of a reaction system and adding water into the reaction system;

in some embodiments, the organic base is potassium carbonate, sodium carbonate, potassium bicarbonate, sodium ethoxide, sodium methoxide, or potassium tert-butoxide;

in some embodiments, the temperature of the chlorination reaction is 0-30 ℃ and the time of the chlorination reaction is 8-16 h;

in some embodiments, the solvent for the chlorination reaction is ethyl acetate, dichloromethane, chloroform, methanol, or ethanol.

8. A process for preparing crystalline form 1B of β -nicotinamide ribochloride of claim 3 or 4, characterized in that: the method comprises the following steps:

under the protection of inert gas, dissolving the crystal form 1A of the beta-nicotinamide riboside chloride prepared by the preparation method of any one of claims 5 to 7 by using a solvent, stirring and cooling for 2 to 48 hours at the temperature of between 30 ℃ below zero and 25 ℃, and directly performing suction filtration or performing suction filtration after adding an anti-solvent to obtain the beta-nicotinamide riboside chloride with a crystal structure.

9. The process for preparing crystalline form 1B of β -nicotinamide ribochloride according to claim 8, characterized in that: dissolving the prepared beta-nicotinamide riboside chloride with methanol, ethanol, isopropanol, N-butanol, glycerol, ethylene glycol, tert-butanol, 1-butanol, 2-butanol, ethylene glycol dimethyl ether, acetone, acetonitrile, N-dimethylformamide, 1, 2-dimethoxyethane, dimethyl sulfoxide, hexamethylphosphoramide, hexamethyl-ortho-triamide, N-methyl-2-pyrrolidone, pyridine, water, dichloromethane or chloroform.

10. The process for preparing crystalline form 1B of β -nicotinamide ribochloride according to claim 8, characterized in that: the anti-solvent is methyl tert-butyl ether;

in some embodiments, after adding the anti-solvent to the cooled solution, the method further comprises the step of cooling for a set time;

further, the temperature of the additional cooling is 25 ℃, 20 ℃, 15 ℃, 10 ℃, 0 ℃, 10 ℃, 15 ℃, 20 ℃ or 30 ℃, and the time of the additional cooling is 2h, 4h, 8h, 12h, 20h, 24h, 30h, 36h or 48 h.

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