CN114349809A

CN114349809A - Beta-nicotinamide mononucleotide crystal form A and preparation method thereof

Info

Publication number: CN114349809A
Application number: CN202011092298.5A
Authority: CN
Inventors: 洪鸣凰; 齐明辉; 任国宾; 季伟杰; 郭春阳
Original assignee: East China University of Science and Technology
Current assignee: East China University of Science and Technology
Priority date: 2020-10-13
Filing date: 2020-10-13
Publication date: 2022-04-15

Abstract

The invention provides a crystal form A of beta-nicotinamide mononucleotide and a preparation method thereof. Specifically, the crystal form A has 3 or more than 3X-ray powder diffraction characteristic peaks selected from the following group: 19.9 +/-0.2 degrees, 20.9 +/-0.2 degrees, 21.7 +/-0.2 degrees, 23.0 +/-0.2 degrees and 23.3 +/-0.2 degrees. Compared with amorphous substances, the crystal form A of the invention has small solvent residue and high stability, and is very suitable for patent medicine.

Description

Beta-nicotinamide mononucleotide crystal form A and preparation method thereof

Technical Field

The invention relates to the field of medicines, and particularly relates to a crystal form A of beta-nicotinamide mononucleotide and a preparation method thereof.

Background

The invention provides a novel chemical crystal form of beta-nicotinamide mononucleotide, which has a structural formula shown in formula I, wherein the beta-nicotinamide mononucleotide is one of substances inherent to a human body, plays an important role in the generation of human body cell energy, participates in the synthesis of intracellular NAD + (nicotinamide adenine dinucleotide, also called coenzyme I and important coenzyme for cell energy conversion), plays a key role in the energy metabolism of cells, and is used for anti-aging research.

Recently, attention has been directed to their use in the treatment, amelioration, palliation, slowing, control, prevention and/or reversal of age-related degenerative disorders (e.g., age-related obesity, increased age-related blood lipid levels, decreased age-related insulin sensitivity, decreased age-related memory function and age-related changes in eye function (e.g., macular degeneration).

The bioavailability of the same drug may vary with different crystal forms, and the stability, fluidity and compressibility of the same drug may also vary, so that the physicochemical properties have certain influence on the application of the drug.

Therefore, the need in the art is to provide a crystalline form of β -nicotinamide mononucleotide that has low solvent residue, high stability, and is suitable for pharmaceutical use.

Disclosure of Invention

The invention aims to provide a crystal form of beta-nicotinamide mononucleotide, which has the advantages of small solvent residue, high stability and suitability for drug preparation.

In a first aspect of the present invention, there is provided crystalline form a of β -nicotinamide mononucleotide, said crystalline form a having 3 or more X-ray powder diffraction characteristic peaks (2 Θ) selected from the group consisting of: 19.9 +/-0.2 degrees, 20.9 +/-0.2 degrees, 21.7 +/-0.2 degrees, 23.0 +/-0.2 degrees and 23.3 +/-0.2 degrees.

In another preferred embodiment, the form a has the following characteristic peaks of X-ray powder diffraction: 19.9 +/-0.2 degrees, 20.9 +/-0.2 degrees, 21.7 +/-0.2 degrees, 23 +/-0.2 degrees and 23.3 +/-0.2 degrees.

In another preferred embodiment, the form a has 1 or more X-ray powder diffraction characteristic peaks selected from the group consisting of: 12.6 +/-0.2 degrees, 18.9 +/-0.2 degrees, 25.5 +/-0.2 degrees, 26.5 +/-0.2 degrees and 29.7 +/-0.2 degrees.

In another preferred embodiment, the form a has the following characteristic peaks of X-ray powder diffraction: 12.6 +/-0.2 degrees, 18.9 +/-0.2 degrees, 19.9 +/-0.2 degrees, 20.9 +/-0.2 degrees, 21.7 +/-0.2 degrees, 23.0 +/-0.2 degrees, 23.3 +/-0.2 degrees, 25.5 +/-0.2 degrees, 26.5 +/-0.2 degrees and 29.7 +/-0.2 degrees.

In another preferred embodiment, the form a has 1 or more X-ray powder diffraction characteristic peaks selected from the group consisting of: 7.6 +/-0.2 degrees, 11.5 +/-0.2 degrees, 18.1 +/-0.2 degrees, 30.3 +/-0.2 degrees and 31.0 +/-0.2 degrees.

In another preferred embodiment, the form a has the following characteristic peaks of X-ray powder diffraction: 7.6 +/-0.2 degrees, 11.5 +/-0.2 degrees, 12.6 +/-0.2 degrees, 18.1 +/-0.2 degrees, 18.9 +/-0.2 degrees, 19.9 +/-0.2 degrees, 20.9 +/-0.2 degrees, 21.7 +/-0.2 degrees, 23.0 +/-0.2 degrees, 23.3 +/-0.2 degrees, 25.5 +/-0.2 degrees, 26.5 +/-0.2 degrees, 29.7 +/-0.2 degrees, 30.3 +/-0.2 degrees and 31.0 +/-0.2 degrees.

In another preferred embodiment, the form A has X-ray powder diffraction characteristic peaks shown in Table 1.

In another preferred embodiment, the form a has one or more characteristics selected from the group consisting of:

(a) an X-ray powder diffraction pattern (XRPD) of form A substantially as shown in figure 1;

(b) a Differential Scanning Calorimetry (DSC) pattern of form a substantially as shown in figure 2; and/or

(c) The thermogravimetric analysis (TGA) of form a is substantially as shown in figure 3.

In a second aspect of the present invention, there is provided a process for the preparation of form a according to the first aspect of the present invention, comprising the steps of:

providing a mixture (usually a solution) of beta-nicotinamide mononucleotide in an inert solvent, and crystallizing at low temperature to obtain the crystal form A.

In another preferred embodiment, the inert solvent is selected from the group consisting of: C1-C6 alkyl alcohol, acetonitrile, acetone, N-methylpyrrolidone, tetrahydrofuran, 1, 4-dioxane, DMF, DMSO, water, or a combination thereof.

In another preferred example, the inert solvent is a mixed solvent of water and a solvent selected from the group consisting of: C1-C6 alkyl alcohol, acetonitrile, acetone, N-methyl pyrrolidone, tetrahydrofuran, 1, 4-dioxane, DMF and DMSO.

In another preferred embodiment, the water in the mixed solvent accounts for 10-50%, preferably 20-40%, and more preferably 1/3% of the volume of the mixed solvent.

In another preferred embodiment, the low temperature is-10 to 10 ℃, more preferably 4 ± 2 ℃.

In another preferred embodiment, after the precipitation at low temperature, a separation (e.g. filtration) and/or drying step is further included.

In another preferred embodiment, said β -nicotinamide mononucleotide is present in said inert solvent at a concentration of 30mg/ml to 200mg/ml, preferably, such as 50mg/ml, 100mg/ml or 150 mg/ml.

In a third aspect of the present invention, there is provided a further process for the preparation of form a according to the first aspect of the present invention, comprising the steps of:

providing a solution of beta-nicotinamide mononucleotide in water, standing (such as normal temperature) and volatilizing to obtain the crystal form A.

In another preferred embodiment, the concentration of said β -nicotinamide mononucleotide in water is from 50 to 300mg/ml, such as 100mg/ml, 150mg/ml or 200 mg/ml.

In a fourth aspect of the present invention, there is provided a pharmaceutical composition comprising: beta-nicotinamide mononucleotide crystal form A and a pharmaceutically acceptable carrier.

In a fifth aspect of the present invention, there is provided a use of the crystalline form a according to the first aspect of the present invention or the pharmaceutical composition according to the fourth aspect of the present invention for the preparation of a medicament for the treatment and/or prevention of age-related degenerative disorders.

In another preferred embodiment, the age-related degenerative disorder is selected from the group consisting of: age-related obesity, an increase in age-related blood lipid levels, a decrease in age-related insulin sensitivity, a decrease in age-related memory function, and an age-related change in eye function (e.g., macular degeneration), or a combination thereof.

In a sixth aspect of the present invention, there is provided a method for treating and/or preventing age-related degenerative disease, comprising the steps of: administering to a subject in need thereof a therapeutically or prophylactically effective amount of form a according to the first aspect of the invention or a pharmaceutical composition according to the fourth aspect of the invention.

In another preferred embodiment, the subject is a mammal.

In another preferred embodiment, the mammal is selected from the group consisting of: human, rat, mouse.

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 β -nicotinamide mononucleotide form a;

figure 2 is a DSC profile of form a;

figure 3 is a TGA profile of form a;

figure 4 is an XRPD pattern of amorphous form of β -nicotinamide mononucleotide;

FIG. 5 is a TGA profile of β -nicotinamide mononucleotide in amorphous form;

figure 6 is a graph comparing the light stability XRPD of form a;

figure 7 is a comparison of the high temperature stability XRPD of form a;

FIG. 8 is a comparison of the high humidity (40 ℃, 75% RH) stability XRPD of form A;

figure 9 is an XRPD comparison of high humidity (25 ℃, 92.5% RH) stability of form a.

Detailed Description

The inventor provides a beta-nicotinamide mononucleotide crystal form A through extensive and intensive research and a large number of screens and tests. Surprisingly, the crystal form A has small solvent residue (weight loss at 100 ℃ is less than 0.2%), high stability and is very suitable for patent medicine. The present invention has been completed based on this finding.

Term(s) for

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.

As used herein, the term "about" when used in reference to a specifically recited value means that the value may vary by no more than 1% from the recited value. For example, as used herein, the expression "about 100" includes 99 and 101 and all values in between (e.g., 99.1, 99.2, 99.3, 99.4, etc.).

As used herein, the term "comprising" or "includes" can be open, semi-closed, and closed. In other words, the term also includes "consisting essentially of …," or "consisting of ….

As used herein, the terms "room temperature" and "ambient temperature" refer to a temperature of 4-30 ℃, preferably, 20 ± 5 ℃.

As used herein, the terms "crystalline form" or "polymorph" are used interchangeably.

As used herein, the term "n or more than n" refers to a number that includes n as well as any positive integer greater than n (e.g., n +1, …), where the upper bound Nup is the number of all values in the group. For example, "1 or more" includes not only 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 …, but also ranges such as "2 or more", "3 or more", "4 or more", "5 or more", "6 or more", "7 or more", "8 or more", "9 or more", "10 or more" as well as positive integers of the upper limit Nup.

Active ingredient

As used herein, the term "active ingredient" or "active compound" refers to β -nicotinamide mononucleotide crystalline form a of the invention.

Preparation method

Form a of the present invention can be prepared using crystallization methods commonly used in the art.

In general, production scale crystallization can be accomplished by manipulating the solution such that the solubility limit of the compound of interest is exceeded. This can be accomplished by a variety of methods, for example, dissolving the compound at relatively high temperatures and then cooling the solution below the saturation limit. Or by boiling, atmospheric evaporation, vacuum drying, or by some other method to reduce the liquid volume. The solubility of the compound of interest may be reduced by adding an anti-solvent or a solvent in which the compound has low solubility or a mixture of such solvents. Another alternative is to adjust the pH to reduce solubility. For a detailed description of the Crystallization see crystallation, third edition, J W Mullins, Butterworth-Heineman Ltd., 1993, ISBN 0750611294.

Optimization of crystallization may include seeding the crystallization medium with crystals of the desired form. In addition, many crystallization methods use a combination of the above strategies. One example is to dissolve the compound of interest in a solvent at elevated temperature, followed by the addition of an appropriate volume of anti-solvent in a controlled manner so that the system is just below the saturation level. At this point, seeds of the desired form may be added (and the integrity of the seeds maintained) and the system cooled to complete crystallization.

Pharmaceutical compositions and methods of administration

The crystal form A has excellent activity of treating age-related degenerative diseases, so the crystal form A and the pharmaceutical composition containing the crystal form A as a main active ingredient can be used for treating, improving, relieving, slowing, controlling, preventing and/or reversing age-related degenerative diseases.

The crystal form A can be used for treating the following diseases (but is not limited to): age-related obesity, an increase in age-related blood lipid levels, a decrease in age-related insulin sensitivity, a decrease in age-related memory function, and an age-related change in eye function (e.g., macular degeneration), or a combination thereof.

The pharmaceutical compositions of the present invention comprise a polymorph of the present invention in a safe and effective amount range, together with pharmaceutically acceptable excipients or carriers.

Wherein "safe and effective amount" means: the amount of the compound (or polymorph) is sufficient to significantly ameliorate the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000mg of the polymorph/dose of the invention, more preferably, 10-200mg of the polymorph/dose of the invention. Preferably, said "dose" is a capsule or tablet.

"pharmaceutically acceptable carrier" refers to: one or more compatible solid or liquid fillers or gel substances which are suitable for human use and must be of sufficient purity and sufficiently low toxicity. By "compatible" is meant herein that the components of the composition are capable of being combined with the active ingredients of the present invention and with each other without significantly diminishing the efficacy of the active ingredient. Examples of pharmaceutically acceptable carrier moieties are cellulose and its derivatives (e.g., sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (e.g., stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (e.g., propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (e.g., propylene glycol, glycerin, mannitol, sorbitol, etc.), and the like

) Wetting agents (e.g., sodium lauryl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, and the like.

The mode of administration of the polymorph or pharmaceutical composition of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.

Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active ingredient is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following: (a) fillers or extenders, for example, microcrystalline cellulose, starch, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, for example, glycerol; (d) disintegrating agents, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, sodium carbonate, crospovidone, croscarmellose sodium; (e) slow solvents, such as paraffin; (f) absorption accelerators, e.g., quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glycerol monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage forms may also comprise buffering agents.

Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared using coatings and shells such as enteric coatings and other materials well known in the art. They may contain opacifying agents and the release of the active ingredient in such compositions may be delayed in a certain portion of the digestive tract. Examples of embedding components which can be used are polymeric substances and wax-like substances. If desired, the active ingredient may also be in microencapsulated form with one or more of the above excipients.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly employed in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-butylene glycol, dimethylformamide and oils, especially cottonseed, groundnut, corn germ, olive, castor and sesame oils or mixtures of such materials and the like.

In addition to these inert diluents, the compositions can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

Suspensions, in addition to the active ingredients, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these materials, and the like.

Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols and suitable mixtures thereof.

Dosage forms of the polymorphic forms of the invention for topical administration include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants which may be required if necessary.

The polymorphs of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds.

When the pharmaceutical composition is used, a safe and effective amount of the polymorphic substance of the present invention is suitable for mammals (such as human beings) to be treated, wherein the administration dose is a pharmaceutically-considered effective administration dose, and for a human body with a weight of 60kg, the daily administration dose is usually 1-2000mg, preferably 10-500 mg. Of course, the particular dosage will depend upon such factors as the route of administration, the health of the patient, and the like, and is within the skill of the skilled practitioner.

The main advantages of the invention include:

1. the beta-nicotinamide mononucleotide crystal form A has high thermal stability, high humidity stability, no solvent residue, high purity and high solubility (more than 450mg/ml of water), and is very suitable for patent medicine.

2. The crystal form A is not easy to raise, collect and waste in the manufacturing process of split charging and other medicines, and is beneficial to protecting the health of operators.

3. The preparation method of the crystal form A is simple, low in production cost and capable of being prepared in a large scale.

The invention is further illustrated with reference to specific embodiments. It should be understood that these examples are for illustrative purposes only and are not intended to limit 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.

General procedure

X-ray powder diffraction (XRPD)

The X-ray powder diffraction, operation and analysis steps of the invention are as follows:

a Rigaku Ultima IV powder diffractometer was used, which was irradiated with Cu-K (40kV, 40mA) at room temperature using a D/tex Ultra detector. The scan range was from 3 ° to 45 ° in the 2 interval, and the scan speed was 20 °/min.

The differences in measurements associated with such X-ray powder diffraction analysis results arise from a number of factors including: (a) errors in sample preparation (e.g., sample height), (b) instrument errors, (c) calibration differences, (d) operator errors (including errors in determining peak position), and (e) properties of the substance (e.g., preferred orientation errors). Calibration errors and sample height errors often result in a shift of all peaks in the same direction. When a flat holder is used, small differences in sample height will result in large shifts in XRPD peak positions. Systematic studies show that sample height differences of 1mm can result in peak shifts of 2 θ up to 1 °. These shifts can be identified from the X-ray diffraction patterns and can be eliminated by compensating for them (using the system calibration factor for all peak position values) or recalibrating the instrument. As described above, measurement errors from different instruments can be corrected by applying a system calibration factor to make the peak positions consistent.

Differential Scanning Calorimetry (DSC) analysis

In the present invention, the Differential Scanning Calorimetry (DSC) analysis, the operation and analysis steps are as follows:

using a TA Q2000 differential scanning calorimeter with N₂The temperature rise rate is 10 ℃/min under the atmosphere.

Thermogravimetric (TGA) analysis

In the present invention, Thermogravimetric (TGA) analysis, the operating and analytical steps are as follows:

using TA Q500 thermogravimetric analyzer and N₂The temperature rise rate is 10 ℃/min under the atmosphere.

Example 1

Preparation of crystal form A of beta-nicotinamide mononucleotide

1.1 weighing 100mg of beta-nicotinamide mononucleotide raw material into a container, adding 1ml of water soluble clear solution, standing for volatilization, and drying the solid in vacuum to obtain the beta-nicotinamide mononucleotide crystal form A.

1.2 weighing 100mg of beta-nicotinamide mononucleotide raw material into a container, adding 1ml of water soluble clear solution, adding 5-10 times of methanol, separating out solid, filtering to obtain solid, and drying in vacuum to obtain the beta-nicotinamide mononucleotide crystal form A.

1.3 weighing 100mg of beta-nicotinamide mononucleotide raw material into a container, adding 1ml of water-soluble clear solution, adding 5-10 times of ethanol, separating out solid, filtering to obtain solid, and drying in vacuum to obtain the beta-nicotinamide mononucleotide crystal form A.

1.4 weighing 100mg of beta-nicotinamide mononucleotide raw material into a container, adding 1ml of water soluble clear solution, adding 5-10 times of n-propanol, separating out solid, filtering to obtain solid, and drying in vacuum to obtain the beta-nicotinamide mononucleotide crystal form A.

1.5 weighing 100mg of beta-nicotinamide mononucleotide raw material into a container, adding 1ml of water soluble clear solution, adding 5-10 times of isopropanol, separating out solid, filtering to obtain solid, and drying in vacuum to obtain the beta-nicotinamide mononucleotide crystal form A.

1.6 weighing 100mg of beta-nicotinamide mononucleotide raw material into a container, adding 1ml of water soluble clear solution, adding 5-10 times of acetonitrile, separating out solid, filtering to obtain solid, and drying in vacuum to obtain the beta-nicotinamide mononucleotide crystal form A.

1.7 weighing 100mg of beta-nicotinamide mononucleotide raw material into a container, adding 1ml of water soluble clear solution, adding 5-10 times of acetone, separating out solid, filtering to obtain solid, and drying in vacuum to obtain the beta-nicotinamide mononucleotide crystal form A.

1.8 weighing 100mg of beta-nicotinamide mononucleotide raw material into a container, adding 1ml of water soluble clear solution, adding 5-10 times of N-methylpyrrolidone, separating out solid, filtering to obtain solid, and drying in vacuum to obtain the beta-nicotinamide mononucleotide crystal form A.

1.9 weighing 100mg of beta-nicotinamide mononucleotide raw material into a container, adding 1ml of water soluble clear solution, adding 5-10 times of tetrahydrofuran, separating out solid, filtering to obtain solid, and drying in vacuum to obtain the beta-nicotinamide mononucleotide crystal form A.

1.10 weighing 100mg of beta-nicotinamide mononucleotide raw material into a container, adding 1ml of water-soluble clear solution, adding 5-10 times of 1, 4-dioxane, separating out solid, filtering to obtain solid, and drying in vacuum to obtain the beta-nicotinamide mononucleotide crystal form A.

1.11 weighing 100mg of beta-nicotinamide mononucleotide raw material into a container, adding 1ml of water soluble clear solution, adding 5-10 times of DMF, separating out solid, filtering to obtain solid, and drying in vacuum to obtain the beta-nicotinamide mononucleotide crystal form A.

1.12 weighing 100mg of beta-nicotinamide mononucleotide raw material into a container, adding 1ml of water-soluble clear solution, adding 5-10 times of DMSO, separating out solid, filtering to obtain solid, and drying in vacuum to obtain the beta-nicotinamide mononucleotide crystal form A.

1.13 weighing 100mg of beta-nicotinamide mononucleotide raw material into a container, adding water and methanol with the volume ratio of 1: 2 to dissolve and clear at 50 ℃, slowly cooling to 4 ℃, separating out solid, filtering to obtain solid, and drying in vacuum to obtain the beta-nicotinamide mononucleotide crystal form A.

1.14 weighing 100mg of beta-nicotinamide mononucleotide raw material into a container, adding water and ethanol with the volume ratio of 1: 2, dissolving and clearing at 50 ℃, slowly cooling to 4 ℃, separating out solid, filtering to obtain solid, and drying in vacuum to obtain the beta-nicotinamide mononucleotide crystal form A.

1.15 weighing 100mg of beta-nicotinamide mononucleotide raw material into a container, adding water and acetone with the volume ratio of 1: 2 to dissolve and clear at 50 ℃, slowly cooling to 4 ℃, separating out solid, filtering to obtain solid, and drying in vacuum to obtain the beta-nicotinamide mononucleotide crystal form A.

1.16 weighing 100mg of beta-nicotinamide mononucleotide raw material into a container, adding water and N-methyl pyrrolidone with the volume ratio of 1: 2, dissolving and clearing at 50 ℃, slowly cooling to 4 ℃, separating out solid, filtering to obtain solid, and drying in vacuum to obtain the beta-nicotinamide mononucleotide crystal form A.

1.17 weighing 100mg of beta-nicotinamide mononucleotide raw material into a container, adding water and tetrahydrofuran with the volume ratio of 1: 2 to dissolve and clear at 50 ℃, slowly cooling to 4 ℃, separating out solid, filtering to obtain solid, and drying in vacuum to obtain the beta-nicotinamide mononucleotide crystal form A.

1.18 weighing 100mg of beta-nicotinamide mononucleotide raw material into a container, adding water and DMF (dimethyl formamide) at 50 ℃ in a volume ratio of 1: 2 for dissolving, slowly cooling to 4 ℃, separating out solid, filtering to obtain solid, and drying in vacuum to obtain the beta-nicotinamide mononucleotide crystal form A.

1.18 weighing 100mg of beta-nicotinamide mononucleotide raw material into a container, adding water and DMSO with the volume ratio of 1: 2, dissolving at 50 ℃, slowly cooling to 4 ℃, precipitating solid, filtering to obtain solid, and drying in vacuum to obtain the beta-nicotinamide mononucleotide crystal form A.

The crystal form A of the beta-nicotinamide mononucleotide prepared by the invention. The diffraction pattern is shown in fig. 1, and the diffraction peaks of the XRPD pattern of form a are listed in table 1 below:

table 1 XRPD pattern of form a

DSC analysis is carried out on the crystal form A in the example 1, and the DSC chart of the crystal form A is shown in figure 2, wherein an endothermic peak corresponds to a melting decomposition process.

Thermogravimetric (TGA) analysis was performed on form a of example 1, and the TGA profile is shown in fig. 3, which shows essentially no weight loss before decomposition (< 0.2% weight loss before 100 ℃).

The amorphous beta-nicotinamide mononucleotide XRPD pattern is shown in figure 4, and the TGA pattern is shown in figure 5.

As can be seen in FIG. 5, the weight loss of amorphous form of β -nicotinamide mononucleotide was 1.655% before 100 ℃, suggesting that there was significant solvent residue.

In addition, amorphous β -nicotinamide mononucleotide is unstable and is easily converted to form a after standing in air for 48 h.

The crystal form A of the invention has almost no solvent residue, high purity and high stability.

Example 2 light stability

The experimental conditions are as follows: temperature: at 25 ℃ under 4500Lux light conditions.

As shown in fig. 6, the results show that the crystal form a is stable under the condition of 4500Lux illumination at 25 ℃ for 5 days and 10 days, and has good illumination stability.

Example 3 high temperature stability

As shown in fig. 7, the results show that form a is stable at 60 ℃ for 5 days and 10 days, and has good high temperature stability.

Example 4 high humidity stability 1

As shown in fig. 8, the results show that form a is stable under conditions of 40 ℃, 75% RH for 5 days and 10 days.

Example 5 high humidity stability 2

As shown in fig. 9, the results show that form a is stable under conditions of 25 ℃, 92.5% RH for 5 days and 10 days.

EXAMPLE 6 pharmaceutical composition

Beta-nicotinamide mononucleotide crystal form A20 g

140g of starch

Microcrystalline cellulose 60g

The materials are evenly mixed according to a conventional method and then are filled into common gelatin capsules to obtain 1000 capsules.

In conclusion, the crystal form A has high thermal stability, high humidity stability, no solvent residue, high purity and high solubility (more than 450mg/ml water), and is very suitable for being used for patent medicine. In addition, the crystal form A is not easy to raise, collect and waste in the manufacturing process of split charging and other medicines, and is beneficial to protecting the health of operators.

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

1. Form A of beta-nicotinamide mononucleotide, characterized in that said form A has 3 or more X-ray powder diffraction characteristic peaks selected from the group consisting of: 19.9 +/-0.2 degrees, 20.9 +/-0.2 degrees, 21.7 +/-0.2 degrees, 23.0 +/-0.2 degrees and 23.3 +/-0.2 degrees.

2. Form a according to claim 1, having the following X-ray powder diffraction characteristic peaks: 19.9 +/-0.2 degrees, 20.9 +/-0.2 degrees, 21.7 +/-0.2 degrees, 23 +/-0.2 degrees and 23.3 +/-0.2 degrees.

3. Form a according to claim 1, having 1 or more X-ray powder diffraction characteristic peaks selected from the group consisting of: 12.6 +/-0.2 degrees, 18.9 +/-0.2 degrees, 25.5 +/-0.2 degrees, 26.5 +/-0.2 degrees and 29.7 +/-0.2 degrees.

4. Form a according to claim 3, having the following X-ray powder diffraction characteristic peaks: 12.6 +/-0.2 degrees, 18.9 +/-0.2 degrees, 19.9 +/-0.2 degrees, 20.9 +/-0.2 degrees, 21.7 +/-0.2 degrees, 23.0 +/-0.2 degrees, 23.3 +/-0.2 degrees, 25.5 +/-0.2 degrees, 26.5 +/-0.2 degrees and 29.7 +/-0.2 degrees.

5. Form a according to claim 1, having 1 or more X-ray powder diffraction characteristic peaks selected from the group consisting of: 7.6 +/-0.2 degrees, 11.5 +/-0.2 degrees, 18.1 +/-0.2 degrees, 30.3 +/-0.2 degrees and 31.0 +/-0.2 degrees.

6. Form a according to claim 1, wherein the form a has one or more characteristics selected from the group consisting of:

7. A process for the preparation of form a according to claim 1, comprising the steps of:

providing a mixture of beta-nicotinamide mononucleotide in an inert solvent, and crystallizing at a low temperature to obtain the crystal form A.

8. A process for the preparation of form a according to claim 1, comprising the steps of:

9. A pharmaceutical composition, comprising: beta-nicotinamide mononucleotide crystal form A and a pharmaceutically acceptable carrier.

10. Use of the crystalline form a according to claim 1 and the pharmaceutical composition according to claim 9 for the preparation of a medicament for the treatment and/or prevention of age-related degenerative disorders.