Glabridin-nicotinamide eutectic crystal as well as preparation method and application thereof

Abstract

The invention discloses a glabridin-nicotinamide eutectic crystal and a preparation method and application thereof, and belongs to the technical field of eutectic crystals, the eutectic crystal comprises nicotinamide and glabridin molecules, the molecular formula of nicotinamide-glabridin is C26H26N2O5, and the molar ratio of nicotinamide to glabridin is 1: 1. According to the invention, the cocrystal is used as a raw material, complete characterization is carried out on the cocrystal to prove that the cocrystal has certain physical and chemical stability, the stability of nicotinamide is improved after the cocrystal is prepared, and no irritant substance nicotinic acid is generated in cosmetics in a cocrystal stability experiment. And the eutectic crystal is generally neutral, mild, non-irritant, natural and suitable for cosmetics or health care products.

Description

Technical Field

[0001] The present invention relates to the technical field of co-crystals, and in particular to a glabridin-nicotinamide co-crystal and a preparation method and application thereof. Background Art

[0002] The definition of eutectic is that two or more different molecules interact with each other through hydrogen bonds, π-π interactions, van der Waals forces, etc., to form a crystalline material with regular arrangement in the same lattice. Compared with two-phase monomers, eutectic is a new compound. Eutectic is an effective way to change the physical and chemical properties of some components, such as solubility, melting point, hygroscopicity, compressibility, density, etc. Eutectic products are currently widely used in cosmetics, health care products and other industries.

[0003] Nicotinamide is a cosmetic ingredient with whitening, freckle removal, moisturizing, oil control and other effects, but its chemical stability has certain problems: it is easily decomposed into nicotinic acid; glabridin, as a cosmetic "star drug" with antioxidant, anti-aging, anti-inflammatory and skin whitening effects, has poor solubility and certain stability problems. Both nicotinamide and glabridin can be used in cosmetics, and there are literature reports that the combination of glabridin and nicotinamide can enhance the whitening effect. However, there is no combination of nicotinamide-glabridin cocrystal supramolecular compounds on the market. Therefore, a glabridin-nicotinamide cocrystal and its preparation method and use are proposed. Summary of the invention

[0004] The present invention aims to solve at least one of the technical problems existing in the prior art. To this end, one object of the present invention is to provide a glabridin-nicotinamide cocrystal and a preparation method and use thereof.

[0005] To achieve the above object, the present invention provides the following technical solutions:

[0006] A glabridin-nicotinamide cocrystal, the cocrystal comprises nicotinamide and glabridin molecules, the nicotinamide-glabridin molecular formula is C 26 H 26 N2O5, the molar ratio of nicotinamide to glabridin is 1:1, and the characteristic peaks of the X-ray powder diffraction pattern of the nicotinamide-glabridin cocrystal are at 3.5°±0.2°, 7.0°±0.2°, 10.5°±0.2, 13.6°±0.2°, 14.0°±0.2°, 15.5°±0.2°, 17.2°±0.2°, 17.9°±0.2°, 18.5°±0.2°, 19.3°±0.2°, 20.4°±0.2°, 23.9°±0.2°, 26.1°±0.2°, and 27.7°±0.2° at a 2θ angle.

[0007] As a further optimization scheme of the present invention, the eutectic is a monoclinic system, a C2 space group, and a unit cell parameter of α=90°, β=110.50(3)°, γ=90°,

[0008] As a further optimization scheme of the present invention, the infrared analysis spectrum of the co-crystal is at 3436cm -1 ±2cm -1 、2972cm -1 ±2cm -1 、1677cm -1 ±2cm -1 、1613cm -1 ±2cm -1 、1477cm -1 ±2cm -1 、1521cm -1 ±2cm -1 、1390cm -1 ±2cm -1 、1086cm -1 ±2cm -1 、1174cm -1 ±2cm -1 、1115cm -1 ±2cm -1 、1212cm -1 ±2cm -1 、1294cm -1 ±2cm -1 、1053cm -1 ±2cm -1 、977cm -1 ±2cm -1 、721cm -1 ±2cm -1 、641cm -1 ±2cm -1 There are characteristic peaks at

[0009] In particular, the infrared analysis spectrum of the co-crystal is also at 1375cm -1 ±2cm -1 、1360cm -1 ±2cm -1 、1154cm -1 ±2cm -1 、1436cm -1 ±2cm -1 、1337cm -1 ±2cm -1 、847cm -1 ±2cm -1 、892cm -1 ±2cm -1 、791cm-1 ±2cm -1 、773cm -1 ±2cm -1 、534cm -1 ±2cm -1 There are characteristic peaks.

[0010] As a further optimization scheme of the present invention, the differential scanning calorimetry analysis spectrum of the co-crystal has a characteristic endothermic peak near 138.9±2°C.

[0011] A method for preparing glabridin-nicotinamide cocrystal, wherein the method is selected from one of the following two methods:

[0013] Method 1: Solid-state synthesis method:

[0014] Weigh nicotinamide into a sample bottle, add the corresponding solvent to make them all in a suspended state, then add 1.0 eq.-2 eq. of glabridin, stir overnight at room temperature, collect the solid by suction filtration, and obtain glabridin cocrystals after vacuum drying;

[0015] Method 2: Wet grinding method:

[0016] Weigh glabridin and nicotinamide in a ratio of 1:1, add 200 μL of the corresponding solvent, grind with 1 eq of solid in a mortar, and then collect the powder for PXRD test.

[0017] As a further optimization scheme of the present invention, in method 1, the stirring time is 5-18h.

[0018] As a further optimization scheme of the present invention, in method 1, the solvent is one or more of methanol, ethanol, acetonitrile, ethyl acetate, and acetone / water;

[0019] In method 2, the solvent is one or more of methanol, ethanol, acetonitrile, ethyl acetate, and an acetone / water mixed solvent.

[0020] Use of glabridin-nicotinamide cocrystal in the preparation of cosmetics, health products, food, medicine, pharmaceutical excipients and feed.

[0021] Compared with the prior art, the present invention has the following beneficial effects:

[0022] The glabridin-nicotinamide cocrystal proposed in the present invention is a brand-new cocrystal supramolecular compound, in which nicotinamide and glabridin molecules are interconnected by hydrogen bonds. The cocrystal is generally neutral, mild and non-irritating, and is suitable for cosmetics or health products. Nicotinamide and glabridin can both be used in cosmetics. After being made into a cocrystal, the melting point is relatively high, so that the stability of nicotinamide is improved, and no nicotinic acid, an irritant substance in cosmetics, is found in the cocrystal stability experiment. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1 This is one of the characterization result diagrams of nicotinamide-glabridin cocrystal I of the present invention;

[0024] Figure 2 This is the second figure of the characterization results of the nicotinamide-glabridin cocrystal I of the present invention;

[0025] Figure 3 This is the third figure of the characterization results of nicotinamide-glabridin cocrystal I of the present invention;

[0026] Figure 4 This is the fourth figure of the characterization results of nicotinamide-glabridin cocrystal I of the present invention;

[0027] Figure 5 It is a PXRD overlay of nicotinamide, glabridin and glabridin co-crystal of the present invention;

[0028] Figure 6 is a single crystal structure diagram of the present invention;

[0029] Figure 7 This is a small view of the nicotinamide-glabridin co-crystal of Examples 1 to 5 of the present invention;

[0030] Figure 8 This is a small attempt to form a nicotinamide-glabridin co-crystal according to Examples 6 to 10 of the present invention;

[0031] Fig. 9 This is a small view of the nicotinamide-glabridin co-crystal of Examples 11 to 14 of the present invention;

[0032] Fig.10 This is a comparison diagram of the enlarged and small-scale test of the nicotinamide-glabridin co-crystal of Example 15 of the present invention;

[0033] Fig.11 This is a DSC comparison chart of nicotinamide-glabridin co-crystal and nicotinamide monomer. DETAILED DESCRIPTION

[0034] The following will be combined with the drawings in the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0035] Sample test conditions:

[0036] (1) XRPD

[0037] Testing equipment: Rigaku SmartLab SE

[0038] Detection conditions: X-ray tube voltage 400, X-ray tube current 40 mA, scanning range 3-40° (2θ), step size 0.02°, scanning speed 5° / min.

[0039] Testing basis: Appendix IXF X-ray powder diffraction method of the People's Republic of China (2010 edition, Part II)

[0040] (2)TGA

[0041] Testing instrument: NETZSCH STA 449F3

[0042] Detection conditions: Nitrogen, 50mL / min

[0043] Scanning program: 30-400℃, heating rate: 10℃ / min

[0044] Test sample mass: 5mg (alumina sample pan)

[0045] Testing basis: JY / T 014-1996 General rules for thermal analysis methods

[0046] (3)DSC

[0047] Testing instrument: NETZSCH STA 449F3

[0048] Detection conditions: Nitrogen, 50mL / min

[0049] Scanning program: 30~400℃, heating rate: 10℃ / min

[0050] Test sample mass: 5mg (alumina sample pan)

[0051] Testing basis: JY / T 014-1996 General rules for thermal analysis methods

[0052] (4) Micro ED

[0053] Testing instrument: JEOL 2100PLUS

[0054] Detection conditions: ambient temperature 100K, acceleration voltage 200kV, wavelength

[0055] (5) Infrared spectroscopy

[0056] Detection instrument: PE Fourier transform infrared microscope system (Spotlight 200i)

[0057] Detection conditions: Potassium bromide tablet method

[0058] Testing basis: GB / T 6040-2002 General rules for infrared spectroscopy analysis

[0059] Embodiment 1

[0060] Weigh 50 mg of nicotinamide into a sample bottle, add 0.3 mL of methanol to make them all suspended, then add 1 eq. of glabridin, stir overnight at room temperature, collect the solid by suction filtration, and obtain glabridin cocrystals after vacuum drying.

[0061] The characterization results of X-ray powder diffraction, thermogravimetric analysis, differential scanning calorimetry, infrared spectroscopy, and nuclear magnetic resonance of the cocrystal are as follows: Figure 1-Figure 4 As shown, DSC comparison of nicotinamide-glabridin cocrystal and nicotinamide monomer Fig.11 shown.

[0062] The eutectic powder in Example 1 was subjected to MicroED testing, and the structure analysis was performed using Olex2 and ShelXL. The crystal structure data are shown in Tables 1 to 7.

[0063]

[0064]

[0065] Table 1 Crystallographic parameters and structure refinement parameters

[0066]

[0067]

[0068]

[0069]

[0070] Table 2 Atomic coordinates and isotropic parameters

[0071]

[0072]

[0073] Table 3 Bond length

[0074]

[0075]

[0076]

[0077]

[0078] Table 4 Bond angles

[0079]

[0080] Table 5 Hydrogen bonds

[0081]

[0082]

[0083]

[0084]

[0085] Table 6 Torsion angle

[0086]

[0087]

[0088]

[0089] Table 7 Hydrogen atom coordinates

[0090] Embodiment 2

[0091] Weigh 50 mg of nicotinamide into a sample bottle, add 0.4 mL of ethanol to make them all suspended, then add 1 eq. of glabridin, stir overnight at room temperature, collect the solid by suction filtration, and obtain glabridin cocrystals after vacuum drying.

[0092] Embodiment 3

[0093] Weigh 50 mg of nicotinamide into a sample bottle, add 1 mL of acetonitrile to make them all suspended, then add 1 eq. of glabridin, stir overnight at room temperature, collect the solid by suction filtration, and obtain glabridin cocrystals after vacuum drying.

[0094] Embodiment 4

[0095] Weigh 50 mg of nicotinamide into a sample bottle, add 0.2 mL of acetone / water to make them suspended, then add 1 eq. of glabridin, stir overnight at room temperature, collect the solid by suction filtration, and obtain glabridin cocrystals after vacuum drying.

[0096] Embodiment 5

[0097] Weigh 50 mg of nicotinamide into a sample bottle, add 0.2 mL of tetrahydrofuran to make them all suspended, then add 1.0 eq. of glabridin, stir overnight at room temperature, collect the solid by suction filtration, and the sample is amorphous after vacuum drying.

[0098] The molar ratio of nicotinamide to glabridin in Examples 1 to 5 is 1:1. The nicotinamide-glabridin cocrystal is prepared as follows: Figure 7 shown.

[0099] Embodiment 6

[0100] Weigh glabridin and nicotinamide in a ratio of 1:1, add 200 μL of methanol, grind with 1 eq of solid in a mortar, and collect the powder for PXRD test, the result is glabridin cocrystal.

[0101] Embodiment 7

[0102] Weigh glabridin and nicotinamide in a ratio of 1:1, add 200 μL of ethanol, grind with 1 eq of solid in a mortar, and collect the powder for PXRD test, the result is glabridin cocrystal.

[0103] Embodiment 8

[0104] Weigh glabridin and nicotinamide in a ratio of 1:1, add 200 μL of acetonitrile, grind with 1 eq of solid in a mortar, and collect the powder for PXRD test, the result is glabridin cocrystal (containing a small amount of nicotinamide monomer).

[0105] Embodiment 9

[0106] Weigh glabridin and nicotinamide in a ratio of 1:1, add 200 μL of ethyl acetate, grind with 1 eq of solid in a mortar, and collect the powder for PXRD test, the result is glabridin cocrystal (containing a small amount of nicotinamide monomer).

[0107] Embodiment 10

[0108] Weigh glabridin and nicotinamide in a ratio of 1:1, add 200 μL of acetone / water, grind with 1 eq of solid in a mortar, and collect the powder for PXRD analysis (containing a small amount of nicotinamide monomer).

[0109] Wherein, the molar ratio of nicotinamide to glabridin in Examples 6 to 10 is 1:1, and the nicotinamide-glabridin cocrystal is prepared as follows: Figure 8 shown.

[0110] Embodiment 11

[0111] About 50 mg of nicotinamide was weighed into a sample bottle, and 1 mL of ethyl acetate was added to make them all suspended. Then 1.2 eq. of glabridin was added, stirred at room temperature overnight, and the solid was collected by suction filtration. After vacuum drying, the glabridin cocrystal (containing a small amount of nicotinamide monomer) was obtained.

[0112] Embodiment 12

[0113] About 50 mg of nicotinamide was weighed into a sample bottle, and 1 mL of ethyl acetate was added to make them all suspended. Then 1.5 eq. of glabridin was added, and stirred overnight at room temperature. The solid was collected by suction filtration, and the glabridin cocrystal was obtained after vacuum drying.

[0114] Embodiment 13

[0115] About 50 mg of nicotinamide was weighed into a sample bottle, and 1 mL of ethyl acetate was added to make them all suspended. Then 1.8 eq. of glabridin was added, stirred at room temperature overnight, and the solid was collected by suction filtration, and the glabridin cocrystal was obtained after vacuum drying.

[0116] Embodiment 14

[0117] About 50 mg of nicotinamide was weighed into a sample bottle, and 1 mL of ethyl acetate was added to make them all suspended. Then 2 eq. of glabridin was added, and stirred at room temperature overnight. The solid was collected by suction filtration, and the glabridin cocrystal was obtained after vacuum drying.

[0118] In Examples 11 to 14, the molar ratio of nicotinamide to glabridin is 1:1.2 to 1:2. The nicotinamide-glabridin cocrystal is prepared as follows: Fig. 9 shown.

[0119] Embodiment 15

[0120] To prepare the nicotinamide-glabridin cocrystal, weigh about 1g of nicotinamide into a sample bottle and add 20mL of ethyl acetate to make it all suspended. Then add 1.5eq. glabridin and stir overnight at room temperature. Collect the solid by suction filtration and vacuum dry to obtain the glabridin cocrystal. Comparison between the scaled-up preparation of nicotinamide-glabridin cocrystal and the pilot test Fig.10 shown.

[0121] Embodiment 16

[0122] Stability test of niacinamide: About 30 mg of niacinamide monomer and the cocrystal sample of Example 15 were placed in an environment of 60°C (closed), 25°C & 90% RH (open), light (5000 Lux ± 500 Lux; closed) and 40°C & 75% RH (open) under accelerated conditions for 5 days, 10 days, 20 days, and 30 days, and then sent for testing to determine the niacin content.

[0123] The nicotinic acid content was determined by high performance liquid chromatography. The chromatographic conditions were: C18, 4.6x250mm (5μm), mobile phase potassium dihydrogen phosphate-acetonitrile-methanol (0-2min, 90:5:5; 6min, 35:10:55; 10min, 35:20:45; 12min, 35:55:10; 20min, 35:55:10; 25min, 95:5:5), detection wavelength was 262nm, flow rate was 1.0mL·min-1, column temperature was 35℃, and injection volume was 5μL.

[0124] The test results are shown in Table 8:

[0125]

[0126] Table 8

[0127] As can be seen from Table 8, compared with niacinamide alone, no niacin was detected in the glabridin-niacinamide cocrystal sample under high temperature, high humidity, light and accelerated aging conditions. This result shows that the formation of the cocrystal effectively inhibits the conversion process of niacinamide to niacin, thereby significantly reducing the potential irritation of niacinamide to the skin.

[0128] Embodiment 17

[0129] Stability test of glabridin cocrystal: ~30 mg of glabridin monomer and the cocrystal sample of Example 15 were placed in an environment of 60°C (closed), 25°C & 90% RH (open), illumination (5000Lux±500Lux; closed) and 40°C & 75% RH (open) under accelerated conditions for 5 days, 10 days, 20 days and 30 days, and XRPD and HPLC tests were performed respectively.

[0130] The purity of the cocrystal was determined by high performance liquid chromatography. The chromatographic conditions were: C18, 4.6x250mm (5μm), mobile phase potassium dihydrogen phosphate-acetonitrile-methanol (0-2min, 90:5:5; 6min, 35:10:55; 10min, 35:20:45; 12min, 35:55:10; 20min, 35:55:10; 25min, 95:5:5), detection wavelength of 230nm, flow rate of 1.0mL·min-1, column temperature of 35℃, injection volume of 5μL. The test results are shown in Tables 9 and 10:

[0131]

[0132] Table 9

[0133]

[0134] Table 10

[0135] As can be seen from Tables 9 and 10, the crystal form and purity of the glabridin-nicotinamide cocrystal did not change significantly, and the physical and chemical properties remained stable, indicating that the cocrystal system has good physical and chemical stability and can maintain its original properties under various environmental conditions.

[0136] Embodiment 18

[0137] The glabridin monomer and the co-crystal sample of Example 15 were subjected to a transdermal permeation test, and the steps were as follows:

[0138] Step 1: Add water to the receiving pool and preheat it (the sample solubility must meet the sink conditions during the experiment, the temperature is 37±1℃);

[0139] Step 2: Fix the pig skin of appropriate size between the supply tank and the receiving tank;

[0140] Step 3: Add the receiving cell liquid, remove the bubbles, and stir in the diffusion cell;

[0141] Step 4: Add the sample to be tested into the supply pool;

[0142] Step 5: Take points and take / replenish fluid at regular intervals (1 to 6 hours), and then perform HPLC test on the filtrate.

[0143] The test results are shown in Table 11:

[0144]

[0145] Table 11

[0146] Embodiment 19

[0147] Biomedia solubility test: Weigh a certain amount of glabridin monomer and the cocrystal sample of Example 15 in a sample bottle, and then add 1-2 mL of water to form a suspension. All suspensions were shaken at 200 rpm at 37°C, and samples were taken at 0.5 h, 2 h, 6 h and 24 h. The filtrate was then subjected to HPLC test. The test results are shown in Table 12:

[0148]

[0149] Table 12

[0150] As can be seen from Table 12, compared with glabridin monomer, the solubility of glabridin-nicotinamide cocrystal in aqueous solvents has been improved, although the increase is not large. This helps the cocrystal raw materials to be more evenly dispersed in aqueous solvents during application, thereby improving its bioavailability on human skin and enhancing its efficacy.

[0151] Parts not involved in the present invention are the same as the prior art or can be implemented by the prior art. Although the embodiments of the present invention have been shown and described, it is understood by those skilled in the art that various changes, modifications, substitutions and variations can be made to these embodiments without departing from the principles and spirit of the present invention, and the scope of the present invention is defined by the appended claims and their equivalents.

Claims

1. A glabridin-nicotinamide cocrystal, characterized in that: The co-crystal comprises nicotinamide and glabridin molecules, wherein the nicotinamide-glabridin molecular formula is C 26 H 26 N2O5, the molar ratio of nicotinamide to glabridin is 1:1, and the characteristic peaks of the X-ray powder diffraction pattern of the nicotinamide-glabridin cocrystal are at 3.5°±0.2°, 7.0°±0.2°, 10.5°±0.2°, 13.6°±0.2°, 14.0°±0.2°, 15.5°±0.2°, 17.2°±0.2°, 17.9°±0.2°, 18.5°±0.2°, 19.3°±0.2°, 20.4°±0.2°, 23.9°±0.2°, 26.1°±0.2°, and 27.7°±0.2° at a 2θ angle.

2. The glabridin-nicotinamide cocrystal according to claim 1, characterized in that: The eutectic is monoclinic, with a C2 space group and unit cell parameters of α=90°, β=110.50(3)°, γ=90°, 3. The glabridin-nicotinamide cocrystal according to claim 1, characterized in that: The infrared analysis spectrum of the co-crystal is at 3436 cm -1 ±2cm -1 、2972cm -1 ±2cm -1 、1677cm -1 ±2cm -1 、1613cm -1 ±2cm -1 、1477cm -1 ±2cm -1 、1521cm -1 ±2cm -1 、1390cm -1 ±2cm -1 、1086cm -1 ±2cm -1 、1174cm -1 ±2cm -1 、1115cm -1 ±2cm -1 、1212cm -1 ±2cm -1 、1294cm -1 ±2cm -1 、1053cm -1 ±2cm -1 、977cm -1 ±2cm -1 、721cm -1 ±2cm -1 、641cm -1 ±2cm -1 There are characteristic peaks at In particular, the infrared analysis spectrum of the co-crystal is also at 1375cm -1 ±2cm -1 、1360cm -1 ±2cm -1 、1154cm -1 ±2cm -1 、1436cm -1 ±2cm -1 、1337cm -1 ±2cm -1 、847cm -1 ±2cm -1 、892cm -1 ±2cm -1 、791cm -1 ±2cm -1 、773cm -1 ±2cm -1 、534cm -1 ±2cm -1 There are characteristic peaks.

4. The glabridin-nicotinamide cocrystal according to claim 1, characterized in that: The differential scanning calorimetry analysis spectrum of the co-crystal has a characteristic endothermic peak near 138.9±2°C.

5. A method for preparing a glabridin-nicotinamide cocrystal according to any one of claims 1 to 4, characterized in that: The method is selected from one of the following two methods: Method 1: Solid-state synthesis method: Weigh 1 g of nicotinamide into a sample bottle, add the corresponding solvent to make them all in a suspended state, then add 1.0 eq.-2 eq. of glabridin, stir at room temperature, collect the solid by suction filtration, and vacuum dry to obtain glabridin cocrystal; Method 2: Wet grinding method: Weigh glabridin and nicotinamide in a ratio of 1:1, add 200 μL of the corresponding solvent and grind in a mortar, and then collect the powder for PXRD test.

6. The method for preparing a glabridin-nicotinamide cocrystal according to claim 5, characterized in that: In method 1, the stirring time is 5-18h.

7. The method for preparing a glabridin-nicotinamide cocrystal according to claim 5, characterized in that: In method one, the solvent is one or more of methanol, ethanol, acetonitrile, ethyl acetate, and acetone / water mixed solvent; In method 2, the solvent is one or more of methanol, ethanol, acetonitrile, ethyl acetate, and an acetone / water mixed solvent.

8. Use of the glabridin-nicotinamide co-crystal according to any one of claims 1 to 5 in the preparation of cosmetics, health products, foods, medicines, pharmaceutical excipients and feeds.

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