Co-crystal of VC and nicotinamide as well as preparation method and application of co-crystal

Abstract

The invention relates to the technical field of eutectic crystals, in particular to a eutectic crystal of VC and nicotinamide as well as a preparation method and application thereof, the eutectic crystal of VC and nicotinamide is a triclinic system, the space group is P1, the cell parameters are as follows: # imgabs 0 # alpha = 93.197 (6) degrees, beta = 94.030 (6) degrees, gamma = 97.352 (5) degrees, and the cell volume is # imgabs 1 #. The eutectic crystal is obtained by dissolving VC and nicotinamide in pure water, standing and crystallizing; the obtained eutectic crystal can be applied to cosmetics, health care products, food and medicines. The eutectic crystal provided by the invention has the advantages of no irritation, easy absorption and good stability.

Description

Technical Field

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

[0002] Vitamin C is a monoclinic crystal that is usually in the form of flakes or sometimes needles. It is odorless, sour, easily soluble in water, and has strong reducing properties. It participates in the complex metabolic processes of the body, can promote growth and enhance resistance to disease, and can be used as a nutritional supplement, antioxidant, and wheat flour improver. Vitamin C is used as an analytical reagent in the laboratory, such as a reducing agent, masking agent, etc. Although vitamin C has significant whitening and anti-oxidation effects in cosmetic applications, it also has defects such as instability, difficulty in absorption, easy oxidation and inactivation, usage restrictions, and possible allergic reactions.

[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, anti-aging, and repairing the skin barrier. However, niacinamide is irritating to the skin to a certain extent, which may cause discomfort symptoms such as redness, swelling, and itching on the skin; moreover, niacinamide is easily affected by oxidation and photodegradation, which affects its effectiveness. Therefore, its application in the fields of cosmetics and health products is subject to certain restrictions. Summary of the invention

[0004] The present invention solves the problems in the related art and provides a co-crystal of VC and nicotinamide and a preparation method and application thereof. The obtained co-crystal has the advantages of being non-irritating, having good transdermal absorbability and good stability.

[0005] In order to solve the above technical problems, the present invention is achieved by the following technical solutions: a co-crystal of VC and nicotinamide, wherein the co-crystal of VC and nicotinamide is a triclinic system, the space group is P1, and the unit cell parameters are: α=93.197(6)°,β=94.030(6)°,γ=97.352(5)°,the unit cell volume is

[0006] As a preferred embodiment, the co-crystal formula of VC and nicotinamide is C 12 H 14 N 2 O 7 .

[0007] As a preferred embodiment, the XRD spectrum of the co-crystal of VC and nicotinamide has characteristic diffraction peaks at least at 2θ angles of 10.346°, 12.987°, 16.576°, 17.981°, 24.647°, 28.443°, and 28.973°.

[0008] As a preferred embodiment, the XRD spectrum of the co-crystal of VC and nicotinamide also has characteristic diffraction peaks at 2θ angles of 5.167°, 12.253°, 20.935°, 22.938°, 23.916°, 24.859°, 30.425°, 37.031°, and 38.073°.

[0009] As a preferred embodiment, the infrared spectrum of the co-crystal of VC and nicotinamide is at least 3424 cm -1 、3197cm -1 、2905cm -1 、1735cm -1 、1659cm -1 、1475cm -1 、1447cm -1 、1411cm -1 、1308cm -1 、1227cm -1 、1201cm -1 、1146cm -1 、1136cm -1 、1120cm -1 、1087cm -1 、1052cm -1 、1042cm -1 、1027cm -1 、973cm -1 、872cm -1 、833cm -1 、796cm -1 、723cm -1 、702cm -1 、652cm -1 、632cm -1 、575cm -1 、518cm -1 There are characteristic peaks.

[0010] Another aspect of the present invention further provides a method for preparing a co-crystal of VC and nicotinamide, characterized in that the steps are as follows:

[0011] S1. Weigh VC and pure water according to the ratio, and dissolve VC in the pure water by continuous stirring to form a VC solution;

[0012] S2, weigh nicotinamide and add it to the VC solution in S1, and continue stirring until the nicotinamide is completely dissolved;

[0013] S3, leaving the solution in step S2 at room temperature for 4-12 hours to crystallize;

[0014] S4. Filter the crystals in S3 and grind them into fine powder.

[0015] As a preferred embodiment, the mass ratio of VC, niacinamide and pure water is 1:1:3.

[0016] As a preferred solution, in step S2, stirring is performed in a heat-collecting constant temperature heating magnetic stirrer, the temperature is set at 60° C., the speed is set at 200 r / min, and stirring is continued for 10-20 min until nicotinamide is completely dissolved.

[0017] As a preferred solution, in step S3, the grinding time is 60 minutes.

[0018] In another aspect of the present invention, the co-crystal of VC and niacinamide can be used in cosmetics, food, health products, and medicines.

[0019] Compared with the prior art, the present invention has the following beneficial effects:

[0020] (1) The co-crystal of VC and niacinamide obtained by the present invention is non-irritating, which significantly improves the irritation problem of niacinamide, thereby reducing the occurrence of allergies and avoiding the occurrence of redness, swelling, itching and other discomfort symptoms on the skin of consumers when applied in cosmetics;

[0021] (2) The co-crystal of VC and niacinamide obtained by the present invention has good transdermal absorption, which solves the problem of poor absorption of VC and niacinamide, and can be better absorbed by human skin;

[0022] (3) The co-crystal stability of VC and niacinamide obtained by the present invention is better than that of niacinamide, thereby improving the stability in cosmetics, medicines, health products, etc. and better exerting its efficacy. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1 It is a schematic diagram of the molecular structure of VC and nicotinamide co-crystal of the present invention;

[0024] Figure 2 is a single crystal image of the VC and nicotinamide co-crystal of the present invention;

[0025] Figure 3 is the XRD diagram of the VC and nicotinamide co-crystal of the present invention;

[0026] Figure 4 is a DSC graph of VC and nicotinamide co-crystal of the present invention;

[0027] Figure 5 is the infrared spectrum of the VC and nicotinamide co-crystal of the present invention;

[0028] Figure 6 This is a test diagram of the irritation of the VC and nicotinamide co-crystal of the present invention;

[0029] Figure 7 This is a test chart of the irritation of nicotinamide of the present invention;

[0030] Figure 8 This is a data graph of the skin surface percentage after VC niacinamide cocrystal and niacinamide transdermal absorption of the present invention;

[0031] Fig. 9 This is a data graph of the percentage of VC niacinamide cocrystal and niacinamide inside the skin after transdermal absorption of the present invention;

[0032] Fig.10 This is a data graph of the percentage of receptor fluid after VC nicotinamide cocrystal and nicotinamide transdermal absorption of the present invention;

[0033] Fig.11 This is a stability test chart of VC niacinamide cocrystal and niacinamide aqueous solution of the present invention. 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, 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.

[0035] 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.

[0036] 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.

[0037] 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.

[0038] 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.

[0039] 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.

[0040] Instruments used:

[0041] Example 1

[0042] A method for preparing a co-crystal of VC and nicotinamide, comprising the following steps:

[0043] S1. Weigh VC and pure water according to the ratio, and dissolve VC in the pure water by continuous stirring to form a VC solution;

[0044] S2, weigh nicotinamide and add it to the VC solution in S1, stir in a heat-collecting constant temperature heating magnetic stirrer, set the temperature to 60°C and the speed to 200 r / min, and continue stirring for 15 minutes until the nicotinamide is completely dissolved;

[0045] S3, leaving the solution in step S2 at room temperature for 8 hours to crystallize;

[0046] S4. Filter the crystals in S3 through quantitative filter paper and grind into fine powder. The grinding time is 60 minutes.

[0047] The quality ratio is shown in the following table:

[0048] Mutually Material Name Ratio A Niacinamide 20％ B VC 20％ C Pure water 60％

[0049] Example 2

[0050] A method for preparing a co-crystal of VC and nicotinamide, comprising the following steps:

[0051] S1. Weigh VC and pure water according to the ratio, and dissolve VC in the pure water by continuous stirring to form a VC solution;

[0052] S2, weigh nicotinamide and add it to the VC solution in S1, stir in a heat-collecting constant temperature heating magnetic stirrer, set the temperature to 60°C and the speed to 200 r / min, and continue stirring for 10 minutes until the nicotinamide is completely dissolved;

[0053] S3, leaving the solution in step S2 at room temperature for 4 hours to crystallize;

[0054] S4. Filter the crystals in S3 through quantitative filter paper and grind into fine powder. The grinding time is 60 minutes.

[0055] The quality ratio is shown in the following table:

[0056] Mutually Material Name Ratio A Niacinamide 20％ B VC 20％ C Pure water 60％

[0057] Example 3

[0058] A method for preparing a co-crystal of VC and nicotinamide, comprising the following steps:

[0059] S1. Weigh VC and pure water according to the ratio, and dissolve VC in the pure water by continuous stirring to form a VC solution;

[0060] S2, weigh nicotinamide and add it to the VC solution in S1, stir in a heat-collecting constant temperature heating magnetic stirrer, set the temperature to 60°C and the speed to 200 r / min, and continue stirring for 20 minutes until the nicotinamide is completely dissolved;

[0061] S3, leaving the solution in step S2 at room temperature for 12 hours to crystallize;

[0062] S4. Filter the crystals in S3 through quantitative filter paper and grind into fine powder. The grinding time is 60 minutes.

[0063] The quality ratio is shown in the following table:

[0064] Mutually Material Name Ratio A Niacinamide 20％ B VC 20％ C Pure water 60％

[0065] The molecular structure of the co-crystal of VC and nicotinamide obtained in the above example is as follows Figure 1 As shown, the molecular formula is C 12 H 14 N 2 O 7 .

[0066] The co-crystal of VC 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:

[0067] Voltage, current: 40kV, 15mA

[0068] Target: Cu ka1 / 2 = 0.15418nm

[0069] Test range: 3-60°

[0070] Step size: 0.02°

[0071] Scan time: 0.5s / 1s

[0072] Divergence slit: 1mm

[0073] Get as Figure 3 As shown in the XRD pattern, the XRD spectrum of the co-crystal of VC and nicotinamide has characteristic diffraction peaks at 2θ angles of 10.346°, 12.987°, 16.576°, 17.981°, 24.647°, 28.443°, and 28.973°; the XRD spectrum of the co-crystal of VC and nicotinamide also has characteristic diffraction peaks at 2θ angles of 5.167°, 12.253°, 20.935°, 22.938°, 23.916°, 24.859°, 30.425°, 37.031°, 38.073°, etc.

[0074] The co-crystal of VC and nicotinamide obtained in Example 1 was subjected to X-ray single crystal diffraction test using a single crystal X-ray diffractometer (model D8 Venture); specific parameters: ceramic X-ray tube, 2.2kW Cu target; operating voltage and current: 40kV40mA; LynxEye SSD 160-2 energy dispersive detector.

[0075] The obtained X-ray single crystal diffraction test results are shown in Table 1:

[0076] Table 1: Co-crystal data of VC and nicotinamide

[0077]

[0078]

[0079] Table 2 shows the atomic coordinates of the VC 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.

[0080] Table 2 Atomic coordinates and isotropic atomic displacement parameters of VC and nicotinamide cocrystals

[0081]

[0082]

[0083]

[0084] Table 3 is the anisotropic atomic displacement parameter analysis data of the VC and nicotinamide co-crystal 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 ].

[0085] Table 3 Anisotropic atomic displacement parameters of VC and nicotinamide cocrystals

[0086]

[0087]

[0088] Table 4 is the analytical data of the bond lengths and bond angles of the chemical bonds of the VC and nicotinamide co-crystal prepared in the present invention.

[0089] Table 4 Bond lengths and bond angles of VC and nicotinamide cocrystals

[0090]

[0091]

[0092] The co-crystal of VC 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 135°C, indicating that VC and niacinamide form a eutectic rather than a simple physical blend (a physical blend will have characteristic endothermic peaks of both VC and niacinamide).

[0093] The VC and nicotinamide co-crystal 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 eutectic of VC and niacinamide is at least 3424 cm -1 、3197cm -1 、2905cm -1 、1735cm -1 、1659cm -1 、1475cm -1 、1447cm -1 、1411cm -1 、1308cm -1 、1227cm -1 、1201cm -1 、1146cm -1 、1136cm -1 、1120cm -1 、1087cm -1 、1052cm -1 、1042cm -1 、1027cm -1 、973cm -1 、872cm -1 、833cm -1 、796cm -1 、723cm -1 、702cm -1 、652cm -1 、632cm -1 、575cm -1 、518cm -1 There are characteristic peaks.

[0094] Efficacy test:

[0095] 1. Irritation test:

[0096] Test method: Chicken embryo chorioallantoic membrane test for cosmetic eye irritation / corrosion (SN / T2329)

[0097] Test equipment: fully automatic incubator

[0098] Sample Information:

[0099] serial number Sample name concentration Supplier / Source 1# Co-crystal of VC and niacinamide 1％ self made 2# Niacinamide 0.5％ DSM

[0100] The results of the chicken embryo test are as follows:

[0101] serial number Sample name Test concentration Test results 1# VC and niacinamide cocrystal 1.0％ Non-irritating 2# Niacinamide 0.5％ Mild irritation

[0102] According to the above table data and Figure 6 and Figure 7 It is shown that 1.0% VC niacinamide cocrystal is non-irritating and 0.5% niacinamide is slightly irritating.

[0103] 2. Transdermal absorption test

[0104] Sample Information:

[0105] serial number Sample name concentration Supplier / Source 1# Co-crystal of VC and niacinamide 1％ self made 2# Niacinamide 0.5％ DSM

[0106] Detection method:

[0107] Weibo Haitai R&D Center's miniature pig skin surface release test method and niacinamide UPLC-MS detection method.

[0108] Test equipment:

[0109] Waters Xevo G3 QTof mass spectrometer, electronic balance (OHRUS), TB-8 transdermal absorption diffusion instrument.

[0110] Test results:

[0111]

[0112] From the above test results and Figure 8-10 It can be seen that using niacinamide as the target and miniature pig skin as the model, it was found that the transdermal absorption of VC niacinamide cocrystal was significantly better than that of niacinamide.

[0113] 3. Stability test

[0114] Sample Information:

[0115] serial number Sample name concentration Supplier / Source 1# Co-crystal of VC and niacinamide 1％ self made 2# Niacinamide 0.5％ DSM

[0116] Detection method:

[0117] Nicotinamide content testing method of Weibo Haitai R&D Center.

[0118] Test equipment:

[0119] Waters E2695 liquid chromatograph, electronic balance (OHRUS), electric constant temperature drying oven.

[0120] Test results:

[0121] serial number Sample name 0H percentage content % 48H content% 48H content change ratio 1# Co-crystal of VC and niacinamide 0.114 0.113 -0.63％ 2# Niacinamide 0.127 0.125 -1.26％

[0122] from Fig.11 As can be seen from the data in the above table, taking niacinamide content as an indicator, the 48-hour high temperature stability test found that VC niacinamide cocrystal is more stable than niacinamide.

[0123] 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 VC and nicotinamide and a preparation method and application thereof, characterized in that: The co-crystal of VC and nicotinamide is a triclinic system, the space group is P1, and the unit cell parameters are: α=93.197(6)°,β=94.030(6)°,γ=97.352(5)°,the unit cell volume is 2. The co-crystal of VC and nicotinamide according to claim 1, characterized in that: The co-crystal formula of VC and nicotinamide is C 12 H 14 N2O7.

3. The co-crystal of VC and nicotinamide according to claim 1, characterized in that: The XRD spectrum of the co-crystal of VC and nicotinamide has characteristic diffraction peaks at least at 2θ angles of 10.346°, 12.987°, 16.576°, 17.981°, 24.647°, 28.443°, and 28.973°.

4. The co-crystal of VC and nicotinamide according to claim 3, characterized in that: The XRD spectrum of the co-crystal of VC and nicotinamide also has characteristic diffraction peaks at 2θ angles of 5.167°, 12.253°, 20.935°, 22.938°, 23.916°, 24.859°, 30.425°, 37.031°, and 38.073°.

5. The co-crystal of VC and nicotinamide according to claim 1, characterized in that: The infrared spectrum of the co-crystal of VC and nicotinamide is at least 3424 cm -1 、3197cm -1 、2905cm -1 、1735cm -1 、1659cm -1 、1475cm -1 、1447cm -1 、1411cm -1 、1308cm -1 、1227cm -1 、1201cm -1 、1146cm -1 、1136cm -1 、1120cm -1 、1087cm -1 、1052cm -1 、1042cm -1 、1027cm -1 、973cm -1 、872cm -1 、833cm -1 、796cm -1 、723cm -1 、702cm -1 、652cm -1 、632cm -1 、575cm -1 、518cm -1 There are characteristic peaks.

6. A method for preparing a co-crystal of VC and nicotinamide as claimed in any one of claims 1 to 5, characterized in that: Here are the steps: S1. Weigh VC and pure water according to the ratio, and dissolve VC in the pure water by continuous stirring to form a VC solution; S2, weigh nicotinamide and add it to the VC solution in S1, and continue stirring until the nicotinamide is completely dissolved; S3, leaving the solution in step S2 at room temperature for 4-12 hours to crystallize; S4. Filter the crystals in S3 and grind them into fine powder.

7. The co-crystal of VC and nicotinamide and the preparation method thereof according to claim 6, characterized in that: The mass ratio of VC, niacinamide and pure water is 1:1:

3.

8. The method for preparing the co-crystal of VC and nicotinamide according to claim 6, characterized in that: In step S2, stirring is performed in a heat-collecting constant temperature heating magnetic stirrer, the temperature is set at 60° C., the rotation speed is set at 200 r / min, and stirring is continued for 10-20 min until nicotinamide is completely dissolved.

9. The method for preparing the co-crystal of VC and nicotinamide according to claim 6, characterized in that: In step S3, the grinding time is 60 min.

10. Use of the co-crystal of VC and niacinamide as claimed in any one of claims 1 to 5 in cosmetics, food, health products and medicines.

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