Ferulic acid and nicotinamide eutectic crystal and preparation method and application thereof

Abstract

The invention relates to the technical field of cosmetics, in particular to a ferulic acid and nicotinamide eutectic crystal and a preparation method and application thereof.The ferulic acid and nicotinamide eutectic crystal is a monoclinic system, the space group is C2 / c, and the cell parameters are as follows: # imgabs0 # imgabs1 # alpha = 90 degrees, beta = 102.627 (3) degrees and gamma = 90 degrees, the co-crystal is obtained by putting an aqueous solution of ferulic acid and nicotinamide into a reaction kettle and carrying out high-temperature and high-pressure reaction, and can be applied to cosmetics, health care products, foods and medicines. The eutectic crystal disclosed by the invention has the advantages of no irritation, good transdermal absorbability and good stability.

Description

Technical Field

[0001] The present invention relates to the technical field of cosmetics, and in particular to a co-crystal of ferulic acid and niacinamide, and a preparation method and application thereof. Background Art

[0002] Ferulic acid, chemically known as 4-hydroxy-3-methoxycinnamic acid, is a derivative of cinnamic acid (also known as cinnamic acid). It has good antioxidant, sunscreen, whitening and anti-inflammatory effects. Ferulic acid also has health functions such as anti-thrombotic, anti-bacterial and anti-inflammatory, tumor inhibition, prevention and treatment of hypertension, heart disease, and enhancement of sperm motility. It has low toxicity and is easily metabolized by the human body.

[0003] Nicotinamide is the amide form of vitamin B3 (niacin), also known as vitamin B3 amide or niacinamide acid. It is a member of the vitamin B family and can directly participate in the redox process in the body as an enzyme coenzyme and play an important role. Nicotinamide has a variety of physiological functions, such as protecting the nervous system, promoting digestion and metabolic health, etc. It can also be used for nutritional supplements, improving sleep quality, and preventing or alleviating diseases such as fatty liver. In addition, niacinamide also has the effects of whitening, lightening spots, anti-aging, and repairing the skin barrier.

[0004] However, ferulic acid is an organic weak acid. The higher the temperature, the higher the pH value of the solution, and its stability will deteriorate. Therefore, the addition of ferulic acid to the formulation system may deteriorate the stability of the formulation system. Over time, ferulic acid will also degrade, affecting the quality of the product. Both niacinamide and ferulic acid are irritating to the skin and may cause discomfort symptoms such as redness, swelling, and itching. Therefore, its application in the field of cosmetics and health products is subject to certain restrictions. Summary of the invention

[0005] The present invention solves the problems in the related art, and proposes a co-crystal of ferulic acid and nicotinamide, a preparation method and application thereof, so as to obtain a co-crystal which is non-irritating, has good transdermal absorbability and good stability, and can be applied to cosmetics, foods, health products and medicines.

[0006] In order to solve the above technical problems, the present invention is achieved by the following technical scheme: a co-crystal of ferulic acid and nicotinamide, wherein the co-crystal of ferulic acid and nicotinamide is a monoclinic system, the space group is C2 / c, and the unit cell parameters are: α=90°,β=102.627(3)°,γ=90°,the unit cell volume is

[0008] As a preferred embodiment, the eutectic formula of ferulic acid and nicotinamide is C 16 H 22N2O8, the mass ratio of ferulic acid to niacinamide is 1:1.

[0009] As a preferred embodiment, the XRD spectrum of the cocrystal of ferulic acid and nicotinamide has characteristic diffraction peaks at least at 2θ angles of 4.286°, 8.580°, 14.572°, 17.459°, 20.184°, 26.055°, and 26.862°.

[0010] As a preferred embodiment, the XRD spectrum of the cocrystal of ferulic acid and nicotinamide has characteristic diffraction peaks at least at 2θ angles of 15.489°, 16.391°, 24.845°, 25.229°, 29.093°, 29.297°, and 29.398°.

[0011] As a preferred embodiment, the infrared spectrum of the co-crystal of ferulic acid and nicotinamide is at least 3309 cm -1 、2921cm -1 、2847cm -1 、2356cm -1 、2160cm -1 、1629cm -1 、1516cm -1 、1416cm -1 、1397cm -1 、1277cm -1 、1206cm -1 、1127cm -1 、1073cm -1 、1031cm -1 、524cm -1 、511cm -1 、495cm -1 、484cm -1 、471cm -1 、454cm -1 、446cm -1 、422cm -1 There are characteristic peaks.

[0012] A method for preparing a cocrystal of ferulic acid and nicotinamide, comprising the following steps:

[0013] S1. Weigh niacinamide and ferulic acid according to the ratio, add them into pure water and stir until they are completely dissolved;

[0014] S2, adding the solution obtained in S1 into the reactor, maintaining the high temperature and high pressure reaction for 50 to 70 minutes;

[0015] S3, leaving the cooled solution to stand at room temperature to form crystals;

[0016] S4. Filter and grind into fine powder to obtain crystalline powder of ferulic acid and niacinamide.

[0017] As a preferred embodiment, in step S1, the mass ratio of ferulic acid, niacinamide and anhydrous ethanol is 3:3:34.

[0018] As a preferred solution, in step S2, the stirring speed is 200-300 r / min, the temperature is 80-90° C., and the pressure is 15-20 MPa.

[0019] As a preferred solution, in step S3, the standing time is 2 to 8 hours.

[0020] As a preferred solution, in step S4, the grinding time is 60 minutes.

[0021] In another aspect of the present invention, the co-crystal of ferulic acid and niacinamide can be used in cosmetics, foods, health products, and medicines.

[0022] Compared with the prior art, the present invention has the following beneficial effects:

[0023] (1) The co-crystal of ferulic acid and niacinamide obtained by the present invention is non-irritating and mild in nature compared with individual ferulic acid and niacinamide, and can be used in cosmetics without causing irritation to the skin;

[0024] (2) The co-crystal of ferulic acid and nicotinamide obtained by the present invention has better transdermal absorption than ferulic acid, and therefore, it is applied to cosmetics and is easily absorbed after being applied to the skin;

[0025] (3) Compared with ferulic acid, the co-crystal of ferulic acid and nicotinamide of the present invention has improved stability, and when it is used in medicines, cosmetics, foods, and health products, the shelf life can be extended. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 It is a schematic diagram of the molecular structure of the ferulic acid and nicotinamide cocrystal of the present invention;

[0027] Figure 2 is a single crystal image of the ferulic acid and nicotinamide cocrystal of the present invention;

[0028] Figure 3 is the XRD pattern of the ferulic acid and nicotinamide cocrystal of the present invention;

[0029] Figure 4 is a DSC graph of the ferulic acid and nicotinamide cocrystal of the present invention;

[0030] Figure 5 is the infrared spectrum of the ferulic acid and nicotinamide cocrystal of the present invention;

[0031] Figure 6This is a test diagram of the irritation of the ferulic acid and nicotinamide co-crystal of the present invention;

[0032] Figure 7 This is a test chart of the irritation of ferulic acid of the present invention;

[0033] Figure 8 This is a data graph of the skin surface percentage of the ferulic acid and niacinamide cocrystal and ferulic acid after transdermal absorption of the present invention;

[0034] Fig. 9 This is a data graph of the percentage of ferulic acid and niacinamide cocrystal and ferulic acid in the skin after transdermal absorption of the present invention;

[0035] Fig.10 This is a data graph of the percentage of receptor fluid after transdermal absorption of ferulic acid and nicotinamide cocrystal and ferulic acid of the present invention;

[0036] Fig.11 This is a stability test diagram of the ferulic acid and nicotinamide cocrystal and the ferulic acid aqueous solution of the present invention. DETAILED DESCRIPTION

[0037] 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, rather than all the embodiments. The following description of at least one exemplary embodiment is actually only illustrative and is by no means intended to limit the present invention and its application or use. 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.

[0038] It should be noted that the terms used herein are only for describing specific embodiments and are not intended to limit the exemplary embodiments according to the present application. As used herein, unless the context clearly indicates otherwise, the singular form is also intended to include the plural form. In addition, it should be understood that when the terms "comprise" and / or "include" are used in this specification, it indicates the presence of features, steps, operations, devices, components and / or combinations thereof.

[0039] Unless otherwise specifically stated, the relative arrangement of the parts and steps described in these embodiments, numerical expressions and numerical values ​​do not limit the scope of the present invention. At the same time, it should be understood that, for ease of description, the sizes of the various parts shown in the accompanying drawings are not drawn according to the actual proportional relationship. The technology, method and equipment known to ordinary technicians in the relevant field may not be discussed in detail, but in appropriate cases, the technology, method and equipment should be regarded as a part of the authorization specification. In all examples shown and discussed here, any specific value should be interpreted as being merely exemplary, rather than as a limitation. Therefore, other examples of exemplary embodiments may have different values. It should be noted that similar reference numerals and letters represent similar items in the following drawings, so once a certain item is defined in an accompanying drawing, it does not need to be further discussed in subsequent drawings.

[0040] In the description of the present invention, it is necessary to understand that the directions or positional relationships indicated by directional words such as "front, back, up, down, left, right", "lateral, vertical, perpendicular, horizontal" and "top, bottom" are usually based on the directions or positional relationships shown in the drawings. They are only for the convenience of describing the present invention and simplifying the description. Unless otherwise specified, these directional words do not indicate or imply that the devices or elements referred to must have a specific direction or be constructed and operated in a specific direction. Therefore, they cannot be understood as limiting the scope of protection of the present invention. The directional words "inside and outside" refer to the inside and outside relative to the contours of each component itself.

[0041] For ease of description, spatially relative terms such as "above", "above", "on the upper surface of", "above", etc. may be used here to describe the spatial positional relationship between a device or feature and other devices or features as shown in the figure. It should be understood that spatially relative terms are intended to include different orientations of the device in use or operation in addition to the orientation described in the figure. For example, if the device in the accompanying drawings is inverted, the device described as "above other devices or structures" or "above other devices or structures" will be positioned as "below other devices or structures" or "below other devices or structures". Thus, the exemplary term "above" can include both "above" and "below". The device can also be positioned in other different ways (rotated 90 degrees or in other orientations), and the spatially relative descriptions used here are interpreted accordingly.

[0042] In addition, it should be noted that the use of terms such as "first" and "second" to limit components is only for the convenience of distinguishing the corresponding components. If not otherwise stated, the above terms have no special meaning and therefore cannot be understood as limiting the scope of protection of the present invention.

[0043] Example 1

[0044] A method for preparing a cocrystal of ferulic acid and nicotinamide, comprising the following steps:

[0045] S1. Weigh niacinamide and ferulic acid according to the ratio, add them into pure water and stir until they are completely dissolved;

[0046] S2, add the solution obtained in S1 into the reactor, stir at a speed of 250r / min, a temperature of 85°C, a pressure of 17.5MPa, and a reaction time of 60min;

[0047] S3, leaving the cooled solution at room temperature for 6 hours to form crystals;

[0048] S4. Filter and grind into fine powder for 60 minutes to obtain crystalline powder of ferulic acid and niacinamide.

[0049] The proportions are as follows (mass percentage):

[0050] Material Name Ratio Ferulic acid 7.5％ Niacinamide 7.5％ Pure water 85％

[0051] Example 2

[0052] A method for preparing a cocrystal of ferulic acid and nicotinamide, comprising the following steps:

[0053] S1. Weigh niacinamide and ferulic acid according to the ratio, add them into pure water and stir until they are completely dissolved;

[0054] S2, add the solution obtained in S1 into the reactor, stir at a speed of 200r / min, a temperature of 95°C, a pressure of 20MPa, and a reaction time of 50min;

[0055] S3, leaving the cooled solution at room temperature for 6 hours to form crystals;

[0056] S4. Filter and grind into fine powder for 60 minutes to obtain crystalline powder of ferulic acid and niacinamide.

[0057] The proportions are as follows (mass percentage):

[0058] Material Name Ratio Ferulic acid 7.5％ Niacinamide 7.5％ Pure water 85％

[0059] Example 3

[0060] A method for preparing a cocrystal of ferulic acid and nicotinamide, comprising the following steps:

[0061] S1. Weigh niacinamide and ferulic acid according to the ratio, add them into pure water and stir until they are completely dissolved;

[0062] S2, add the solution obtained in S1 into the reactor, stir at a speed of 300r / min, a temperature of 80°C, a pressure of 15MPa, and a reaction time of 70min;

[0063] S3, leaving the cooled solution at room temperature for 6 hours to form crystals;

[0064] S4. Filter and grind into fine powder for 60 minutes to obtain crystalline powder of ferulic acid and niacinamide.

[0065] The proportions are as follows (mass percentage):

[0066] Material Name Ratio Ferulic acid 7.5％ Niacinamide 7.5％ Pure water 85％

[0067] The molecular structure of the co-crystal of ferulic acid and nicotinamide obtained in the above example is as follows Figure 1 As shown, the molecular formula is C 16 H 22 N2O8.

[0068] The co-crystal of ferulic acid and nicotinamide obtained in Example 1 was subjected to X-ray diffraction analysis. The instrument used was: X-ray diffractometer (model D8 Endeavor); the specific test parameters were:

[0069] Voltage, current: 40kV, 15mA

[0070] Target: Cu ka1 / 2 = 0.15418nm

[0071] Test range: 3-60°

[0072] Step size: 0.02°

[0073] Scan time: 0.5s / 1s

[0074] Divergence slit: 1mm

[0075] Get as Figure 3 As shown in the XRD pattern, the XRD pattern of the co-crystal of ferulic acid and nicotinamide has characteristic diffraction peaks at least at 2θ angles of 4.286°, 8.580°, 14.572°, 17.459°, 20.184°, 26.055°, and 26.862°, and the XRD pattern of the co-crystal of ferulic acid and nicotinamide also has characteristic diffraction peaks at at least 2θ angles of 15.489°, 16.391°, 24.845°, 25.229°, 29.093°, 29.297°, 29.398°, etc.

[0076] The co-crystal of ferulic acid and nicotinamide obtained in Example 1 was subjected to X-ray single crystal diffraction test using a single crystal X-ray diffractometer (model Bruker D8 Venture); specific parameters: ceramic X-ray tube, 2.2kW Cu target; operating voltage and current: 40kV40mA; LynxEye SSD 160-2 energy dispersive detector.

[0077] The obtained X-ray single crystal diffraction test results are shown in Table 1:

[0078] Table 1: Single crystal data of ferulic acid and nicotinamide co-crystal

[0079]

[0080]

[0081] Table 2 shows the atomic coordinates of the ferulic acid and nicotinamide cocrystal prepared in the present invention (×10 4 ) and isotropic atomic displacement parameters are used to analyze the data, with U(eq) defined as one-third of the trace of the orthogonal Uij tensor.

[0082] Table 2 Atomic coordinates and isotropic atomic displacement parameters of ferulic acid and nicotinamide cocrystals

[0083]

[0084]

[0085] Table 3 is the anisotropic atomic displacement parameter analysis data of the ferulic acid and nicotinamide cocrystal prepared in the present invention, wherein the anisotropic displacement factor index is in the following form: -2π 2 [h 2 (a*) 2 U 11 +k 2 (b*) 2 U 22 +…+2hka*b*U 12 ].

[0086] Table 3 Anisotropic atomic displacement parameters of ferulic acid and nicotinamide cocrystals

[0087]

[0088]

[0089] Table 4 is the analytical data of the bond lengths and bond angles of the ferulic acid and nicotinamide co-crystals prepared in the present invention.

[0090] Table 4 Bond lengths and bond angles of ferulic acid and nicotinamide cocrystals

[0091]

[0092]

[0093] Table 5 Torsion angle of ferulic acid and nicotinamide cocrystal

[0094]

[0095]

[0096] Table 6 Hydrogen bonding of niacinamide ferulic acid cocrystal

[0097]

[0098] Symmetry transformations used to generate equivalent atoms: #1: +X, 1-Y, -0.5+Z; #2: 1.5-X, 0.5-Y, -Z; #3: +X, -1+Y, +Z; #4: 2-X, 1-Y, 2-Z; #5: 0.5+X, 0.5+Y, 1+Z; #6: 2-X, +Y, 1.5-Z;

[0099] The co-crystal of ferulic acid and nicotinamide obtained in Example 1 was subjected to DSC test, and the test parameters were as follows: temperature 25-150°C, heating rate 1.00K / min, Ar 20.0ml / min, and the following was obtained: Figure 4 As shown, from Figure 4 It can be seen that there is only a characteristic endothermic peak around 132°C, indicating that ferulic acid and niacinamide form a eutectic rather than a simple physical blend (a physical blend will have characteristic endothermic peaks of both ferulic acid and niacinamide).

[0100] The ferulic acid and nicotinamide cocrystal obtained in Example 1 was subjected to infrared testing to obtain the following Figure 5 The infrared spectrum shown is from Figure 5 It can be seen that the cocrystal of ferulic acid and nicotinamide is at least 3309 cm -1 、2921cm -1 、2847cm -1 、2356cm -1 、2160cm -1 、1629cm -1 、1516cm -1 、1416cm -1 、1397cm -1 、1277cm -1 、1206cm -1 、1127cm -1 、1073cm -1 、1031cm -1 、524cm-1 、511cm -1 、495cm -1 、484cm -1 、471cm -1 、454cm -1 、446cm -1 、422cm -1 There are characteristic peaks.

[0101] Performance Test:

[0102] 1. Irritation test:

[0103] Test method: Chicken embryo chorioallantoic membrane test for cosmetic eye irritation / corrosion (SN / T2329)

[0104] Test equipment: fully automatic incubator

[0105] Sample Information:

[0106]

[0107] The results of the chicken embryo test are as follows:

[0108] serial number Sample name Test concentration Test results 1# Cocrystal of Ferulic Acid and Nicotinamide 1.0％ Non-irritating 2# Ferulic acid 0.5％ Mild irritation

[0109] According to the above table data and Figure 6 and Figure 7 It is shown in the data that 1.0% ferulic acid and niacinamide cocrystal is non-irritating and 0.5% ferulic acid is slightly irritating.

[0110] 2. Transdermal absorption test

[0111] Sample Information:

[0112]

[0113] Detection method:

[0114] Weibo Haitai R&D Center's miniature pig skin surface release test method and ferulic acid UPLC-MS detection method.

[0115] Test equipment:

[0116] Waters Xevo G3 QTof mass spectrometer, electronic balance (OHRUS), TB-8 transdermal absorption diffusion instrument.

[0117] Test results:

[0118]

[0119] From the above test results and Figure 8-10It can be seen that using ferulic acid as the target and miniature pig skin as the model, it was found that the transdermal absorption of ferulic acid and niacinamide cocrystal was significantly better than that of ferulic acid.

[0120] 3. Stability test

[0121] Sample Information:

[0122]

[0123] Detection method:

[0124] Weibo Haitai R&D Center Ferulic Acid Content Testing Method.

[0125] Test equipment:

[0126] Waters E2695 liquid chromatograph, electronic balance (OHRUS), electric constant temperature drying oven.

[0127] Test results:

[0128]

[0129] from Fig.11 As can be seen from the data in the above table, taking ferulic acid content as an indicator, the high temperature stability for 48 hours was examined and it was found that the stability of ferulic acid and niacinamide cocrystal was better than that of ferulic acid.

[0130] The above are preferred implementation modes of the present invention. Those skilled in the art to which the present invention belongs can also change and modify the above implementation modes. Therefore, the present invention is not limited to the above specific implementation modes. Any obvious improvements, substitutions or modifications made by those skilled in the art on the basis of the present invention belong to the protection scope of the present invention.

Claims

1. A co-crystal of ferulic acid and nicotinamide and a preparation method and application thereof, characterized in that: The co-crystal of ferulic acid and nicotinamide is a monoclinic system, the space group is C2 / c, and the unit cell parameters are: α=90°,β=102.627(3)°,γ=90°,the unit cell volume is 2. The co-crystal of ferulic acid and nicotinamide according to claim 1, characterized in that: The co-crystal formula of ferulic acid and nicotinamide is C 16 H 22 N2O8, the mass ratio of ferulic acid to niacinamide is 1:

1.

3. The co-crystal of ferulic acid and nicotinamide according to claim 1, characterized in that: The XRD spectrum of the cocrystal of ferulic acid and nicotinamide has characteristic diffraction peaks at least at 2θ angles of 4.286°, 8.580°, 14.572°, 17.459°, 20.184°, 26.055°, and 26.862°.

4. The co-crystal of ferulic acid and nicotinamide according to claim 3, characterized in that: The XRD spectrum of the cocrystal of ferulic acid and nicotinamide has characteristic diffraction peaks at least at 2θ angles of 15.489°, 16.391°, 24.845°, 25.229°, 29.093°, 29.297°, and 29.398°.

5. The co-crystal of ferulic acid and nicotinamide according to claim 1, characterized in that: The infrared spectrum of the co-crystal of ferulic acid and nicotinamide is at least 3309 cm -1 、2921cm -1 、2847cm -1 、2356cm -1 、2160cm -1 、1629cm -1 、1516cm -1 、1416cm -1 、1397cm -1 、1277cm -1 、1206cm -1 、1127cm -1 、1073cm -1 、1031cm -1 、524cm -1 、511cm -1 、495cm -1 、484cm -1 、471cm -1 、454cm -1 、446cm -1 、422cm -1 There are characteristic peaks.

6. A method for preparing a co-crystal of ferulic acid and nicotinamide as claimed in any one of claims 1 to 5, characterized in that: Here are the steps: S1. Weigh niacinamide and ferulic acid according to the ratio, add them into pure water and stir until they are completely dissolved; S2, adding the solution obtained in S1 into the reactor, maintaining the high temperature and high pressure reaction for 50 to 70 minutes; S3, leaving the cooled solution to stand at room temperature to form crystals; S4. Filter and grind into fine powder to obtain crystalline powder of ferulic acid and niacinamide.

7. The co-crystal of ferulic acid and nicotinamide and the preparation method thereof according to claim 6, characterized in that: In step S1, the mass ratio of ferulic acid, niacinamide and anhydrous ethanol is 3:3:

34.

8. The co-crystal of ferulic acid and nicotinamide and the preparation method thereof according to claim 6, characterized in that: In step S2, the stirring speed is 200-300 r / min, the temperature is 80-90° C., the pressure is 15-20 MPa, and the reaction time is 60 min.

9. The method for preparing the co-crystal of ferulic acid and nicotinamide according to claim 6, characterized in that: In step S3, the standing time is 2 to 8 hours, and in step S4, the grinding time is 60 minutes.

10. Use of the co-crystal of ferulic acid and nicotinamide as claimed in any one of claims 1 to 5 in cosmetics, foods, health products and medicines.

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