NICOTINAMIDE MONONUCLEOTIDE-ISONICOTINE COCRYSTAL AND COMPOSITION THEREOF

Abstract

The present disclosure aims to solve the technical problems of larger content/weight difference and inconsistent quality of nicotinamide mononucleotide (NMN) medicines or health care products due to poor fluidity of existing nicotinamide mononucleotide crystals, and provides a nicotinamide mononucleotide-isonicotine cocrystal. Cu-Kαradiation is used for the cocrystal, and X-ray powder diffraction represented by an angle 2θ has diffraction peaks at 9.6±0.2°, 13.3±0.3°, 22.8±0.2° and 36.5±0.2°. The cocrystal has a higher bulk density than existing crystals, thereby significantly improving the fluidity of the nicotinamide mononucleotide. Therefore, the technical problems of larger content/weight difference and inconsistent quality of the NMN medicines or health care products in the production of enterprises may be well solved.

Claims

1. A nicotinamide mononucleotide-isonicotine cocrystal, wherein Cu-Kαradiation is used, and X-ray powder diffraction represented by an angle 2θ has diffraction peaks at 9.6±0.2°, 13.3±0.3°, 22.8±0.2° and 36.5±0.2°.

2. The nicotinamide mononucleotide-isonicotine cocrystal according to claim 1, wherein the Cu-Kαradiation is used, and the X-ray powder diffraction represented by the angle 2θ has diffraction peaks at 9.6±0.2°, 9.8±0.2°, 10.6±0.2°, 13.3±0.3°, 16.3±0.2°, 21.3±0.2°, 22.8±0.2°, 32.1±0.2° and 36.5±0.2°.

3. The nicotinamide mononucleotide-isonicotine cocrystal according to claim 1, wherein the cocrystal has an X-ray powder diffraction spectrum substantially as shown in FIG. 1.

4. The nicotinamide mononucleotide-isonicotine cocrystal according to claim 1, wherein a differential scanning calorimetry analysis diagram of the cocrystal has endothermic peaks at 55.8±3° C. and 151.9±3° C.

5. The nicotinamide mononucleotide-isonicotine cocrystal according to claim 1, wherein the cocrystal has a differential scanning calorimetry analysis diagram substantially as shown in FIG. 2.

6. A nicotinamide mononucleotide composition, wherein the composition contains the nicotinamide mononucleotide-isonicotine cocrystal according to claim 1.

7. A medicine or health care product, wherein an active pharmaceutical ingredient of the medicine or health care product contains the nicotinamide mononucleotide-isonicotine cocrystal according to claim 1.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0016] FIG. 1 is an X-ray powder diffraction spectrum of a nicotinamide mononucleotide-isonicotine cocrystal provided by the present disclosure; and

[0017] FIG. 2 is a differential scanning calorimetry analysis diagram of the nicotinamide mononucleotide-isonicotine cocrystal provided by the present disclosure.

DETAILED DESCRIPTION OF THE EMBODIMENTS

[0018] The present disclosure is further described in detail below with reference to the accompanying drawings and specific examples. The following examples are to explain the present disclosure. The present disclosure is not limited to the following examples.

[0019] Raw materials and reagents used in the following examples were all purchased from the market, unless otherwise specified.

[0020] With reference to a method disclosed by an example 1 in Chinese patent application CN108697722A, a nicotinamide mononucleotide anhydrous crystal (form 1) was prepared.

[0021] With reference to a method disclosed by an example 4 in Chinese patent application CN108697722A, a nicotinamide mononucleotide dimethyl sulfoxide solvate crystal (form 2) was prepared.

Example 1

[0022] Preparation of the nicotinamide mononucleotide-isonicotine cocrystal provided by the present disclosure

[0023] 67 g of β-nicotinamide mononucleotide and 24 g of isonicotine were dissolved in 2 L of water, then 2 L of acetone was slowly dropwise added, and stirring was performed while dropwise adding. During the dropwise adding, the temperature of a solution was kept at 30° C. After dropwise adding, the temperature of the solution was lowered to 8° C., and standing was performed to wait for crystals to be precipitated. After crystal precipitation, the solution was filtered to obtain the nicotinamide mononucleotide-isonicotine cocrystal.

[0024] The nicotinamide mononucleotide-isonicotine cocrystal prepared above was subjected to X-ray powder diffraction:

[0025] A PANalytical X′Pert Empyrean X-ray powder diffractometer (PW3040/60, Dutch PANalytical Analytical Instruments Ltd.) was used, wherein Cu-Kαradiation is adopted, a wavelength is 1.54 Å, a divergence slit is 1°, an X-ray tube voltage is 45 kV, an X-ray tube current is 40 mA, a scanning range is 2-40° (2θ), a step length is 0.0130°, and step time is 78.7950 s. A powder sample was flattened on a microsample plate and then tested. An X-ray powder diffraction spectrum of the nicotinamide mononucleotide-isonicotine cocrystal provided by the present disclosure is as shown in FIG. 1. Peaks and intensities corresponding to a diffraction angle 2θ are as shown in a table 1.

TABLE-US-00001 TABLE 1 Relative 2θ (°) intensity (%) 9.6 15.3 9.8 6.8 10.6 8.9 13.3 100.0 16.3 16.5 17.1 3.1 19.4 4.7 20.1 4.3 21.3 11.9 21.8 5.5 22.8 28.2 25.7 2.5 26.2 3.2 26.8 4.9 31.4 3.7 32.1 15.3 32.6 4.6 32.9 3.5 36.2 6.0 36.5 23.4

[0026] The nicotinamide mononucleotide-isonicotine cocrystal prepared above was subjected to differential scanning calorimetric (DSC) curve measurement:

[0027] DSC measurement was performed with a seal plate device in a TA Instruments Q2000. A sample (about 1-3 mg) was weighed in an aluminum plate, capped with a Tzero, accurately recorded to 1/100 mg, and transferred to an instrument for measurement. The instrument was purged with nitrogen at 50 mL/min. Data was collected between room temperature and 220° C. at a heating rate of 10° C./min. Endothermic peaks were plotted downwards, and the data was analyzed with TA Universal Analysis. A differential scanning calorimetry analysis diagram of the nicotinamide mononucleotide-isonicotine cocrystal provided by the present disclosure is as shown in FIG. 2, wherein an abscissa represents the temperature (Temperature, ° C.), and an ordinate represents the heat flow (Heat Flow, W/g) released by a substance per unit mass.

Example 2

[0028] Bulk Density Measurement

[0029] A proper amount of samples of a crystal in a form 1, a crystal in a form 2 and the nicotinamide mononucleotide-isonicotine cocrystal prepared in the example 1 were taken respectively, screened with a sieve (1.00 mm, No. 18), accurately weighed, and slowly poured into a glass graduated measuring cylinder. The tops were scraped flat. The apparent volumes were recorded. The bulk densities were calculated. Experimental results are as shown in a table 2.

TABLE-US-00002 TABLE 2 Crystal Bulk density g/ml Form 1 0.15 Form 2 0.22 Cocrystal in example 1 0.68

Example 3

[0030] Content Difference Measurement

[0031] A proper amount of a crystal in a form 1, a crystal in a form 2 and the nicotinamide mononucleotide-isonicotine cocrystal prepared in the example 1 were taken respectively and screened with a 200-mesh sieve. A capsule shell was fixed to a capsule board. A body board was filled with powder. The powder was poured on the body board and scraped back and forth with a powder scraping plate. After the capsule shell was filled up with the powder, the excess powder on the body board was scraped off to obtain a capsule. Then the capsule obtained by filling was measured with reference to an inspection method for content difference of capsules in the 0103 capsule general principle of the “Pharmacopoeia of the People's Republic of China” (2020 edition). A content difference value X (%) of the content of each capsule corresponding to each group of the crystal in the form 1, the crystal in the form 2 and the cocrystal in the example 1 and average content after comparison was calculated respectively. Then an absolute value of each content difference value was taken. An average value X of each group was calculated.

[00001]$\stackrel{\_}{X}=\frac{X1+X2+.Math.\mathrm{Xn}}{n}.$

Results are as shown in a table 3.

TABLE-US-00003 TABLE 3 Average content Crystal difference  (%) Form 1 28.8 Form 2 26.0 Cocrystal in example 1 5.5 indicates data missing or illegible when filed