A glabratine-nicotinamide co-crystal, and a preparation method and use thereof

Abstract

The application discloses a glabridin-nicotinamide co-crystal as well as a preparation method and application thereof, belongs to the technical field of co-crystals, and comprises nicotinamide and glabridin molecules. 26 H 26 N2O5, and the molar ratio of the nicotinamide and the glabridin is 1:1.The application prepares a glabridin-nicotinamide co-crystal, and the co-crystal is completely characterized, and it is proved that the co-crystal has certain physical and chemical stability, the stability of the nicotinamide is improved after being made into the co-crystal, and no stimulating substance nicotinic acid is found in the co-crystal stability experiment. The co-crystal is generally neutral, mild and non-irritating, and is naturally suitable for cosmetics or health products.

Description

Technical Field

[0001] This invention relates to the field of eutectic technology, specifically to a glycyrrhizin-nicotinamide eutectic, its preparation method, and its uses. Background Technology

[0002] Eutectic is defined as a crystalline material formed by two or more different molecules arranged regularly in the same crystal lattice through intermolecular interactions such as hydrogen bonds, π-π interactions, and van der Waals forces. Compared to two-phase monomers, eutectic is a new type of compound. Eutectic is an effective way to modify the physicochemical properties of some components, such as solubility, melting point, hygroscopicity, compressibility, and density. Eutectic products are currently widely used in the cosmetics and health product industries.

[0003] Niacinamide, a cosmetic ingredient with whitening, spot-removing, moisturizing, and oil-controlling effects, has certain chemical stability issues: it easily decomposes into nicotinic acid. Glycyrrhizin, a "star drug" in cosmetics with antioxidant, anti-aging, anti-inflammatory, and skin-whitening properties, has poor solubility and its stability is also questionable. Both niacinamide and glycyrrhizin can be used in cosmetics, and some literature reports that the combination of glycyrrhizin and niacinamide can enhance whitening effects. However, there are currently no known combinations of niacinamide-glycyrrhizin cocrystal supramolecular compounds on the market. Therefore, a glycyrrhizin-niacinamide cocrystal, its preparation method, and its applications are proposed. Summary of the Invention

[0004] The present invention aims to at least solve one of the technical problems existing in the prior art. Therefore, one object of the present invention is to provide a glycyrrhizin-nicotinamide cocrystal, its preparation method, and its uses.

[0005] To achieve the above objectives, the present invention provides the following technical solution:

[0006] A glycyrrhizin-nicotinamide cocrystal, comprising nicotinamide and glycyrrhizin molecules, wherein the nicotinamide-glycyrrhizin molecular formula is C1. 26 H 26 N2O5, wherein the molar ratio of nicotinamide and glycyrrhizin is 1:1, and the characteristic peaks of the nicotinamide-glycyrrhizin eutectic X-ray powder diffraction pattern are located at 2θ angles of 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°.

[0007] As a further optimization of the present invention, the eutectic is a monoclinic crystal system, space group C2, with cell parameters of... α=90°, β=110.50(3)°, γ=90°,

[0008] As a further optimization of the present invention, the infrared spectrum of the eutectic is at 3436 cm⁻¹. -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 It has a characteristic peak;

[0009] In particular, the infrared spectrum of the eutectic is also at 1375 cm⁻¹. -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 It has a characteristic peak.

[0010] As a further optimization of the present invention, the differential scanning calorimetry spectrum of the eutectic has a characteristic endothermic peak near 138.9±2℃.

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

[0012] Method 1: Solid-state synthesis method

[0013] Weigh nicotinamide into a sample vial, add the corresponding solvent to suspend it, then add 1.0 eq.-2 eq. glycyrrhizin, stir overnight at room temperature, collect the solid by filtration, and obtain glycyrrhizin eutectic after vacuum drying;

[0014] Method 2: Wet grinding method

[0015] Glycyrrhizin and nicotinamide were weighed and mixed at a 1:1 ratio, then 200 μL of the corresponding solvent was added, and the mixture was ground with 1 eq of solid in a mortar. The powder was then collected for PXRD testing.

[0016] As a further optimization of the present invention, in method one, the stirring time is 5-18 hours.

[0017] As a further optimization of the present invention, in one method, the solvent is one or more of methanol, ethanol, acetonitrile, ethyl acetate, and acetone / water;

[0018] In Method 2, the solvent is one or more of methanol, ethanol, acetonitrile, ethyl acetate, and acetone / water mixed solvent.

[0019] Uses of glycyrrhizin-nicotinamide eutectic in the preparation of cosmetics, health products, food, pharmaceuticals, pharmaceutical excipients and feed.

[0020] Compared with the prior art, the beneficial effects of the present invention are:

[0021] The glycyrrhizin-nicotinamide cocrystal proposed in this invention is a novel cocrystal supramolecular compound in which nicotinamide and glycyrrhizin molecules are connected to each other by hydrogen bonds. The cocrystal is generally neutral, mild and non-irritating, and suitable for cosmetics or health products. Both nicotinamide and glycyrrhizin can be used in cosmetics. After being made into a cocrystal, the melting point is relatively high, which improves the stability of nicotinamide. Moreover, no nicotinic acid, an irritant in cosmetics, was found to be produced in the cocrystal stability experiment. Attached Figure Description

[0022] Figure 1 This is one of the characterization results of the nicotinamide-glycyrrhizin eutectic I of the present invention;

[0023] Figure 2 This is the second figure showing the characterization results of the nicotinamide-glycyrrhizin eutectic I of the present invention;

[0024] Figure 3 This is the third figure showing the characterization results of the nicotinamide-glycyrrhizin eutectic I of the present invention;

[0025] Figure 4 Figure 4 shows the characterization results of the nicotinamide-glycyrrhizin eutectic I of this invention;

[0026] Figure 5 This is a PXRD overlay image of the eutectic nicotinamide, glycyrrhizin, and glycyrrhizin of the present invention;

[0027] Figure 6 This is a diagram of the single-crystal structure of the present invention;

[0028] Figure 7 These are small-scale attempts at the formation of nicotinamide-licorice eutectic according to Examples 1 to 5 of the present invention;

[0029] Figure 8 These are small-scale attempts at forming a eutectic of nicotinamide-licorice in Examples 6 to 10 of the present invention;

[0030] Figure 9 These are small-scale attempts at forming a eutectic of nicotinamide-licorice in Examples 11 to 14 of the present invention;

[0031] Figure 10 This is a comparison diagram of the amplified and small-scale tests of the nicotinamide-licorice eutectic formation in Example 15 of the present invention;

[0032] Figure 11 This is a DSC comparison chart of nicotinamide-glycyrrhizin eutectic and nicotinamide monomer. Detailed Implementation

[0033] The technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0034] Sample testing conditions:

[0035] (1)XRPD

[0036] Testing instrument: Rigaku SmartLab SE

[0037] Detection conditions: X-ray tube voltage 40 Ω, X-ray tube current 40 mA, scanning range 3-40° (2θ), step size 0.02°, scan speed 5° / min.

[0038] Testing basis: Appendix IX, X-ray powder diffraction method, People's Republic of China (2010 Edition, Part II).

[0039] (2) TGA

[0040] Testing instrument: Netzsch STA 449F3

[0041] Detection conditions: Nitrogen gas, 50 mL / min

[0042] Scanning program: 30-400℃, heating rate: 10℃ / min

[0043] Sample weight: 5 mg (alumina sample dish)

[0044] Testing standard: JY / T 014-1996 General Rules for Thermal Analysis

[0045] (3) DSC

[0046] Testing instrument: Netzsch STA 449F3

[0047] Detection conditions: Nitrogen gas, 50 mL / min

[0048] Scanning program: 30–400℃, heating rate: 10℃ / min

[0049] Sample weight: 5 mg (alumina sample dish)

[0050] Testing standard: JY / T 014-1996 General Rules for Thermal Analysis

[0051] (4) Micro ED

[0052] Testing instrument: JEOL 2100PLUS

[0053] Detection conditions: Ambient temperature 100K, accelerating voltage 200kV, wavelength

[0054] (5) Infrared spectroscopy

[0055] Testing instrument: PE Fourier transform infrared microscope system (Spotlight 200i)

[0056] Detection conditions: Potassium bromide tablet method

[0057] Testing standard: GB / T 6040-2002 General Rules for Infrared Spectroscopic Analysis

[0058] Example 1

[0059] Weigh 50 mg of nicotinamide into a sample vial, add 0.3 mL of methanol to suspend it, then add 1 eq. of glycyrrhizin, stir overnight at room temperature, collect the solid by suction filtration, and obtain glycyrrhizin eutectic after vacuum drying.

[0060] The characterization results of the eutectic by X-ray powder diffraction, thermogravimetric analysis, differential scanning calorimetry, infrared spectroscopy, and nuclear magnetic resonance are as follows: Figures 1-4 As shown, the comparison of nicotinamide-glycyrrhizin eutectic and nicotinamide monomer DSC is as follows: Figure 11 As shown.

[0061] MicroED tests were performed on the eutectic powder of Example 1. The structural analysis was performed using Olex2 and ShelXL, and the crystal structure data are shown in Tables 1-7.

[0062]

[0063]

[0064] Table 1 Crystallographic parameters and structural refinement parameters

[0065]

[0066]

[0067]

[0068]

[0069] Table 2 Atomic coordinates and isotropic parameters

[0070]

[0071]

[0072] Table 3 Bond Lengths

[0073]

[0074]

[0075]

[0076]

[0077] Table 4 Bond Angles

[0078]

[0079] Table 5 Hydrogen Bonds

[0080]

[0081]

[0082]

[0083]

[0084] Table 6 Angle of Torsion

[0085]

[0086]

[0087]

[0088] Table 7 Hydrogen Atom Coordinates

[0089] Example 2

[0090] Weigh 50 mg of nicotinamide into a sample vial, add 0.4 mL of ethanol to suspend it, then add 1 eq. of glycyrrhizin, stir overnight at room temperature, collect the solid by suction filtration, and obtain glycyrrhizin eutectic after vacuum drying.

[0091] Example 3

[0092] Weigh 50 mg of nicotinamide into a sample vial, add 1 mL of acetonitrile to suspend it, then add 1 eq. of glycyrrhizin, stir overnight at room temperature, collect the solid by filtration, and obtain glycyrrhizin eutectic after vacuum drying.

[0093] Example 4

[0094] Weigh 50 mg of nicotinamide into a sample vial, add 0.2 mL of acetone / water to suspend it, then add 1 eq. of glycyrrhizin, stir overnight at room temperature, collect the solid by suction filtration, and obtain glycyrrhizin eutectic after vacuum drying.

[0095] Example 5

[0096] Weigh 50 mg of nicotinamide into a sample vial, add 0.2 mL of tetrahydrofuran to suspend it, then add 1.0 eq. glycyrrhizin, stir overnight at room temperature, collect the solid by filtration, and the sample is amorphous after vacuum drying.

[0097] In Examples 1 to 5, the molar ratio of nicotinamide and glycyrrhizin was 1:1. Small-scale tests were conducted to form a eutectic of nicotinamide and glycyrrhizin. Figure 7 As shown.

[0098] Example 6

[0099] Glycyrrhizin and nicotinamide were weighed and mixed at a 1:1 ratio, then 200 μL of methanol was added, and the mixture was ground with 1 eq of solid in a mortar. The powder was then collected and subjected to PXRD testing, which showed that the mixture was a eutectic of glycyrrhizin.

[0100] Example 7

[0101] Glycyrrhizin and nicotinamide were weighed and mixed at a ratio of 1:1. Then 200 μL of ethanol was added, and the mixture was ground with 1 eq of solid in a mortar. The powder was then collected and subjected to PXRD testing. The result showed that the mixture was a eutectic of glycyrrhizin.

[0102] Example 8

[0103] Glycyrrhizin and nicotinamide were weighed and mixed at a 1:1 ratio. Then, 200 μL of acetonitrile was added, and the mixture was ground with 1 eq of solid in a mortar. The powder was then collected and subjected to PXRD testing. The result showed that the mixture was a eutectic of glycyrrhizin (containing a small amount of nicotinamide monomer).

[0104] Example 9

[0105] Glycyrrhizin and nicotinamide were weighed and mixed at a ratio of 1:1. Then 200 μL of ethyl acetate was added, and the mixture was ground with 1 eq of solid in a mortar. The powder was then collected and subjected to PXRD testing. The result showed that the mixture was a eutectic of glycyrrhizin (containing a small amount of nicotinamide monomer).

[0106] Example 10

[0107] Glycyrrhizin and nicotinamide were weighed and mixed at a 1:1 ratio. Then, 200 μL of acetone / water was added, and 1 eq of solid was ground in a mortar. The powder was then collected for PXRD testing (containing a small amount of nicotinamide monomer).

[0108] In Examples 6 to 10, the molar ratio of nicotinamide to glycyrrhizin was 1:1, and the nicotinamide-glycyrrhizin eutectic was tested on a small scale. Figure 8 As shown.

[0109] Example 11

[0110] Weigh approximately 50 mg of nicotinamide into a sample vial, add 1 mL of ethyl acetate, and suspend the mixture. Then add 1.2 eq. of glycyrrhizin, stir overnight at room temperature, collect the solid by suction filtration, and dry under vacuum to obtain glycyrrhizin eutectic (containing a small amount of nicotinamide monomer).

[0111] Example 12

[0112] Weigh approximately 50 mg of nicotinamide into a sample vial, add 1 mL of ethyl acetate, and suspend the mixture. Then add 1.5 eq. of glycyrrhizin, stir overnight at room temperature, collect the solid by suction filtration, and vacuum dry to obtain glycyrrhizin eutectic.

[0113] Example 13

[0114] Weigh approximately 50 mg of nicotinamide into a sample vial, add 1 mL of ethyl acetate, and suspend the mixture. Then add 1.8 eq. of glycyrrhizin, stir overnight at room temperature, collect the solid by suction filtration, and vacuum dry to obtain glycyrrhizin eutectic.

[0115] Example 14

[0116] Weigh approximately 50 mg of nicotinamide into a sample vial, add 1 mL of ethyl acetate, and suspend the mixture. Then add 2 eq. of glycyrrhizin, stir overnight at room temperature, collect the solid by suction filtration, and vacuum dry to obtain glycyrrhizin eutectic.

[0117] Examples 11 to 14 show that the molar ratio of nicotinamide and glycyrrhizin is 1:1.2 to 1:2, and small-scale tests were conducted to form a eutectic of nicotinamide and glycyrrhizin. Figure 9 As shown.

[0118] Example 15

[0119] To prepare a large-scale nicotinamide-glycyrrhizin eutectic, approximately 1 g of nicotinamide was weighed into a sample vial and 20 mL of ethyl acetate was added to suspend the mixture. Then, 1.5 eq. of glycyrrhizin was added, and the mixture was stirred overnight at room temperature. The solid was collected by filtration and vacuum dried to obtain the glycyrrhizin eutectic. A comparison between the large-scale preparation and small-scale test of the nicotinamide-glycyrrhizin eutectic was provided. Figure 10 As shown.

[0120] Example 16

[0121] Stability test of nicotinamide: Approximately 30 mg of nicotinamide monomer and the eutectic sample of Example 15 were placed in environments of 60°C (closed), 25°C & 90% RH (open), light irradiation (5000 Lux ± 500 Lux; closed), and accelerated conditions of 40°C & 75% RH (open) for 5 days, 10 days, 20 days, and 30 days respectively, and the nicotinic acid content was determined.

[0122] The nicotinic acid content was determined by high performance liquid chromatography (HPLC). Chromatographic conditions: column: C18, 4.6 x 250 mm (5 μm), mobile phase: potassium dihydrogen phosphate-acetonitrile-methanol (0-2 min, 90:5:5; 6 min, 35:10:55; 10 min, 35:20:45; 12 min, 35:55:10; 20 min, 35:55:10; 25 min, 95:5:5), detection wavelength: 262 nm, flow rate: 1.0 mL·min⁻¹, column temperature: 35 °C, injection volume: 5 μL.

[0123] The test results are shown in Table 8:

[0124]

[0125] Table 8

[0126] As shown in Table 8, compared to nicotinamide alone, nicotinic acid was not detected in the glycyrrhizin-nicotinamide cocrystal samples under conditions of high temperature, high humidity, light exposure, and accelerated aging. This result indicates that the formation of the cocrystal effectively inhibited the conversion of nicotinamide to nicotinic acid, thereby significantly reducing the potential skin irritation caused by nicotinamide.

[0127] Example 17

[0128] Stability test of glycyrrhizin eutectic: ~30 mg of glycyrrhizin monomer and the eutectic sample of Example 15 were placed in environments of 60℃ (closed), 25℃ & 90%RH (open), light irradiation (5000Lux±500Lux; closed) and accelerated conditions of 40℃ & 75%RH (open) for 5 days, 10 days, 20 days and 30 days respectively, and XRPD and HPLC were performed respectively.

[0129] The purity of the eutectic was determined by high performance liquid chromatography (HPLC). Chromatographic conditions: column: C18, 4.6 x 250 mm (5 μm), mobile phase: potassium dihydrogen phosphate-acetonitrile-methanol (0-2 min, 90:5:5; 6 min, 35:10:55; 10 min, 35:20:45; 12 min, 35:55:10; 20 min, 35:55:10; 25 min, 95:5:5), detection wavelength: 230 nm, flow rate: 1.0 mL·min⁻¹, column temperature: 35 °C, injection volume: 5 μL. The test results are shown in Tables 9 and 10.

[0130]

[0131] Table 9

[0132]

[0133] Table 10

[0134] As shown in Tables 9 and 10, the crystal form and purity of the glycyrrhizin-nicotinamide eutectic did not change significantly, maintaining stable physical and chemical properties. This indicates that the eutectic system possesses good physical and chemical stability and can retain its original characteristics under various environmental conditions.

[0135] Example 18

[0136] The transdermal permeation test was performed on the eutectic sample of glycyrrhizin monomer and Example 15, as follows:

[0137] Step 1: Add water to the receiving cell and preheat it (the sample solubility needs to meet the leakage conditions during the experiment, and the temperature should be 37±1℃).

[0138] Step 2: Secure the appropriately sized pigskin between the supply pool and the receiving pool;

[0139] Step 3: Replenish the receiving tank liquid, remove air bubbles, and place it in the diffusion tank for stirring;

[0140] Step 4: Add the sample to be tested to the supply tank;

[0141] Step 5: Take samples at regular intervals, collect / replenish the solution (1-6 hours), and then perform HPLC testing on the filtrate.

[0142] The test results are shown in Table 11:

[0143]

[0144] Table 11

[0145] Example 19

[0146] Biological solubility test: A certain mass of glycyrrhizin monomer and the cocrystal sample of Example 15 were weighed into sample bottles, and then 1-2 mL of water was added to form suspensions. 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 filtrates were then analyzed by HPLC. The test results are shown in Table 12:

[0147]

[0148] Table 12

[0149] As shown in Table 12, the solubility of the glycyrrhizin-nicotinamide cocrystal in aqueous solvents is improved compared to that of the glycyrrhizin monomer, although the improvement is not significant. This helps the cocrystal raw material to be more uniformly dispersed in aqueous solvents during application, thereby improving its bioavailability on human skin and enhancing its efficacy.

[0150] All parts not described in this invention are the same as or can be implemented using existing technology. Although embodiments of the invention have been shown and described, it will be 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 invention, the scope of which is defined by the appended claims and their equivalents.

Claims

1. A glycyrrhizin-nicotinamide cocrystal, characterized in that, The eutectic comprises nicotinamide and glycyrrhizin molecules, wherein the nicotinamide-glycyrrhizin molecular formula is C0. 26 H 26 N2O5, wherein the molar ratio of nicotinamide and glycyrrhizin is 1:1, and the characteristic peaks of the X-ray powder diffraction pattern of the nicotinamide-glycyrrhizin eutectic are at 2θ angles of 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°. The eutectic is a monoclinic crystal system, space group C2, with unit cell parameters of... α=90°, β=110.50(3)°, γ=90°, The infrared spectrum of the eutectic is at 3436 cm⁻¹. -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 It has a characteristic peak; The differential scanning calorimetry spectrum of the eutectic showed a characteristic endothermic peak near 138.9±2℃.

2. The glycyrrhizin-nicotinamide eutectic according to claim 1, characterized in that, The infrared spectrum of the eutectic was still at 1375 cm⁻¹. -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 It has a characteristic peak.

3. A method for preparing a glycyrrhizin-nicotinamide cocrystal as described in claim 1, characterized in that, The method is selected from one of the following two methods: Method 1: Solid-state synthesis method Weigh 1g of nicotinamide into a sample vial, add the corresponding solvent to make it in a suspended state, then add 1.0eq.-2eq. of glycyrrhizin, stir at room temperature, collect the solid by suction filtration, and vacuum dry the glycyrrhizin eutectic. The stirring time is 5-18 hours; the solvent is one or more of methanol, ethanol, acetonitrile, ethyl acetate, and acetone / water mixed solvent. Method 2: Wet grinding method Glycyrrhizin and nicotinamide were weighed and mixed in a 1:1 ratio. 200 μL of the corresponding solvent was added and the mixture was ground in a mortar. The powder was then collected for PXRD testing. The solvent is one or more of methanol, ethanol, acetonitrile, ethyl acetate, and acetone / water mixed solvent.

4. The use of the glycyrrhizin-nicotinamide eutectic as described in claim 1 in the preparation of cosmetics.

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