CN112521292B - Eutectic crystal of betaine and organic acid and preparation method and application thereof - Google Patents
Eutectic crystal of betaine and organic acid and preparation method and application thereof Download PDFInfo
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- CN112521292B CN112521292B CN202011506793.6A CN202011506793A CN112521292B CN 112521292 B CN112521292 B CN 112521292B CN 202011506793 A CN202011506793 A CN 202011506793A CN 112521292 B CN112521292 B CN 112521292B
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- Prior art keywords
- betaine
- eutectic
- organic acid
- azelaic acid
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- C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C229/06—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton
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Abstract
The invention discloses a eutectic crystal of betaine and organic acid, a preparation method and application thereof, wherein the method comprises the following steps: providing betaine and organic acid, and uniformly mixing the betaine and the organic acid to obtain a mixture; wherein the melting point of the organic acid is less than the melting point of the betaine; and stirring and heating the mixture to melt under an inert atmosphere, cooling to normal temperature after the mixture reacts, and purifying to obtain the eutectic of betaine and organic acid. The organic acid and the betaine are adopted to form the eutectic, the comprehensive effect of the obtained eutectic of the betaine and the organic acid is good, the eutectic of the organic acid and the betaine is formed by adopting a heating and melting method, the stability of the obtained eutectic of the betaine and the organic acid is high, and the organic acid with a lower melting point is adopted, so that the heating and melting temperature is reduced, and the preparation difficulty is reduced.
Description
Technical Field
The invention relates to the technical field of eutectics, in particular to a betaine and organic acid eutectic and a preparation method and application thereof.
Background
Betaine is a quaternary ammonia type water-soluble alkaloid derived from beet and widely exists in nature. Since betaine has a very important role in biological metabolism, it has been added to animal feed primarily as a dietary supplement in the past 50 years. Betaine is used as an organic penetrant, can be used for balancing cell volume and cell moisture content, plays a unique role in moisturizing and protecting cell performance, and in the prior art, the comprehensive effect of betaine is improved by organic acid, but the betaine and the organic acid are only simply mixed, so that the effect is not obviously improved.
Accordingly, the prior art is yet to be improved and developed.
Disclosure of Invention
The invention aims to solve the technical problems that betaine and organic acid are only simply mixed and the effect is not obviously improved in the prior art, and provides a preparation method and application of a eutectic of betaine and organic acid.
The technical scheme adopted by the invention for solving the technical problem is as follows:
a preparation method of a eutectic crystal of betaine and organic acid comprises the following steps:
providing betaine and organic acid, and uniformly mixing the betaine and the organic acid to obtain a mixture; wherein the melting point of the organic acid is less than the melting point of the betaine;
and stirring and heating the mixture to melt under an inert atmosphere, cooling to normal temperature after the mixture reacts, and purifying to obtain the eutectic of betaine and organic acid.
The preparation method of the eutectic crystal of betaine and organic acid is characterized in that the organic acid comprises: one or more of azelaic acid, succinic acid, adipic acid, sebacic acid, acetic acid, oleic acid, linoleic acid and lactic acid.
The preparation method of the eutectic of betaine and organic acid comprises the steps of heating at the temperature of 60-120 ℃ and reacting for 1-24 hours.
The preparation method of the eutectic crystal of the betaine and the organic acid is characterized in that the molar ratio of the betaine to the organic acid is 1: 1-2.
The preparation method of the co-crystal of the betaine and the organic acid is characterized in that the melting point of the organic acid is less than 200 ℃.
The preparation method of the eutectic of betaine and organic acid comprises the following steps of:
dissolving a crude product obtained by reacting the mixture in a solvent, and filtering to obtain an eutectic solution;
and concentrating the eutectic solution in a vacuum state to obtain a supersaturated solution, recrystallizing, filtering, washing and drying to obtain the eutectic of betaine and organic acid.
The preparation method of the co-crystal of betaine and organic acid comprises the following steps: one or more of methanol, ethanol, isopropanol, N-methylpyrrolidone, tetrahydrofuran, benzene, toluene, petroleum ether, N-hexane, acetone, dioxane, N-dimethyldiamide, ethyl acetate or acetonitrile.
The preparation method of the eutectic crystal of betaine and organic acid is characterized in that the recrystallization temperature is less than 5 ℃.
A co-crystal of betaine and an organic acid, which is prepared by the steps of the method for preparing a co-crystal of betaine and an organic acid according to any one of the above.
An application of the eutectic crystal of betaine and organic acid in preparation of medicines or cosmetics is provided.
Has the advantages that: the organic acid and the betaine are adopted to form the eutectic, the comprehensive effect of the obtained eutectic of the betaine and the organic acid is good, the eutectic of the organic acid and the betaine is formed by adopting a heating and melting method, the stability of the obtained eutectic of the betaine and the organic acid is high, and the organic acid with a lower melting point is adopted, so that the heating and melting temperature is reduced, and the preparation difficulty is reduced.
Drawings
FIG. 1 is a structural diagram of a betaine 1, 9-azelaic acid eutectic compound according to the present invention.
FIG. 2 is the nuclear magnetic hydrogen spectrum of the betaine 1, 9-azelaic acid eutectic in the present invention.
FIG. 3 is a thermogravimetric analysis curve of the betaine 1, 9-azelaic acid co-crystal of the present invention.
FIG. 4 is a flow chart of the process for the preparation of the co-crystals of betaine and organic acid according to the invention.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention clearer and clearer, the present invention is further described in detail below with reference to the accompanying drawings and examples. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
Referring to fig. 1-4, the present invention provides some embodiments of a method for preparing a co-crystal of betaine and an organic acid.
Betaine is a quaternary ammonia type water-soluble alkaloid derived from beet and widely exists in nature. Since betaine has a very important role in biological metabolism, it has been added to animal feed primarily as a dietary supplement in the past 50 years. Later, betaine was found to be an organic osmolyte that can be used to balance cell volume and cell moisture content, to play a unique moisturizing and cell protective role, and is increasingly used in the cosmetic industry as a new fine chemical.
As shown in fig. 4, the preparation method of the eutectic crystal of betaine and organic acid of the present invention comprises the following steps:
step S100, providing betaine and organic acid, and uniformly mixing the betaine and the organic acid to obtain a mixture; wherein the melting point of the organic acid is less than the melting point of the betaine.
Specifically, the betaine is specifically glycine betaine or glycine trimethylamine inner salt, and the organic acid refers to an organic compound containing a carboxyl group in a molecule.
The structural formula of betaine is as follows:
the organic acids include: one or more of azelaic acid, succinic acid, adipic acid, sebacic acid, acetic acid, oleic acid, linoleic acid and lactic acid, the structural formula of 1, 9-azelaic acid is as follows:
the structural formula of succinic acid is as follows:
the structural formula of adipic acid is as follows:
the structural formula of sebacic acid is as follows:
the structural formula of acetic acid is as follows:
the structural formula of lactic acid is as follows:
the structural formula of oleic acid is as follows:
the structural formula of linoleic acid is as follows:
1, 9-azelaic acid is a natural 9-carbon saturated branched dicarboxylic acid from rhododendron, also known as azelaic acid. The 1, 9-azelaic acid has good bacteriostatic and bactericidal effects, can selectively act on melanocytes with abnormal physiological functions to inhibit the cytotoxic action and excessive activity of the melanocytes, has little or almost no harm to normal cells, and generally plays roles of controlling oil, removing acnes, whitening and removing freckles in cosmetics. 1, 9-azelaic acid has concentration dependence for inhibiting the activity of human epidermal melanocyte, and the higher the concentration is, the stronger the inhibiting effect is.
According to the invention, the organic acid with a lower melting point and the betaine are adopted to form the eutectic crystal, and when the mixture of the organic acid and the betaine is heated and melted, the organic acid with a lower melting point can reduce the heating and melting temperature. The betaine is usually in a powder form, and the organic acid is usually in a powder form, and when the betaine and the organic acid are mixed, stirring may be performed to sufficiently mix them, thereby obtaining a mixture. Of course, grinding and mixing of the powdered reactants may also be performed.
In the mixture, the ratio of betaine and organic acid can be determined according to the needs, and the ratio of reactants can be determined according to the structure of reactants, wherein the betaine has a nitrogen atom and an oxygen atom, the organic acid has at least one carboxyl, and the hydrogen atom on the carboxyl in the organic acid can form hydrogen bonds with the nitrogen atom and the oxygen atom on the betaine respectively, so that eutectic crystal is formed. In the invention, the molar ratio of the betaine to the organic acid is 1: 1-2, and the amount of the organic acid is larger than that of the betaine.
Preferably, the organic acid is long-chain organic acid, which is beneficial to the formation of weak interactions such as hydrogen bonds among molecules and spontaneously presents a stable three-dimensional structure which is regularly arranged in parallel. Under the condition of no external force action, molecules can spontaneously polymerize, recognize and form a more functional eutectic polymer with stable structure through internal hydrogen bonds, electrostatic action and the like.
In order to reduce the preparation difficulty of the eutectic of betaine and organic acid, the melting point of the organic acid is less than that of the betaine, and the organic acid with lower melting point is adopted to form the eutectic with the betaine. And the eutectic is formed by adopting a melting mode, so that the preparation steps of obtaining the eutectic of the betaine and the organic acid are simple, and the thermal stability of the eutectic obtained by adopting the melting method is better.
The betaine and the organic acid can be uniformly stirred in the reactor, or can be uniformly mixed and then put into the reactor for reaction in the subsequent steps.
And S200, stirring and heating to melt the mixture under an inert atmosphere, cooling to normal temperature after the mixture reacts, and purifying to obtain the eutectic of betaine and organic acid.
Specifically, the inert atmosphere includes: helium, neon, argon, nitrogen, and the like. Since the mixture subsequently needs to be heated to a higher temperature, it is necessary to heat the molten mixture under an inert atmosphere. Specifically, the mixture is heated while stirring. The heating temperature is 60-120 ℃, the heating rate is 0.1-5 ℃/min, and the reaction time is 1-24 h.
In the heating process, the mixture forms a melt, the betaine and the organic acid react to form eutectic molecules, in the cooling process, the eutectic molecules are solidified and crystallized to obtain a crude product, and the crude product is purified to obtain the eutectic of the betaine and the organic acid. The cooling rate is 0.1-5 ℃/min. The ordinary temperature here means 25 ℃.
The eutectic crystal is a crystal formed by combining two or more precursors under the action of hydrogen bonds, other non-covalent bonds, electrostatic action, hydrophobic action and other forces under a certain condition, is a brand new solid raw material with biological activity, and can well improve the water solubility, metabolic stability, dispersion rate, bioavailability and other physicochemical properties of the eutectic precursor. The most important application value of the eutectic technology in the field of cosmetics is to improve the physicochemical properties of the eutectic structures while maintaining two or more functional groups of the eutectic structures. The eutectic compound can improve the properties of the raw materials to a greater extent, has great application value in the field of cosmetics, and has positive influence on the research and design of cosmetic formulas.
The step S200 includes:
and step S210, dissolving a crude product obtained by reacting the mixture in a solvent, and filtering to obtain a eutectic solution.
And S220, concentrating the eutectic solution in a vacuum state to a supersaturated solution for recrystallization, and filtering, washing and drying to obtain the eutectic of betaine and organic acid.
Specifically, since the amount of the organic acid is excessive, that is, the crude product may contain an excessive amount of the organic acid (of course, betaine and organic acid which do not form a eutectic molecule may be contained), the eutectic molecule is more soluble and the organic acid is less soluble in dissolving the crude product, and thus impurities such as the organic acid can be removed by filtration. The method comprises the steps of dissolving and filtering a crude product to obtain an eutectic solution, concentrating the eutectic solution in a vacuum state to obtain a supersaturated solution (approximately evaporating a solvent with the volume of 4/5 eutectic solution), precipitating eutectic due to supersaturation of eutectic molecules in the supersaturated solution, filtering the precipitated eutectic continuously, washing, and naturally recrystallizing for several times (for example, 2-3 times), and finally drying the eutectic, wherein a vacuum drying oven is specifically adopted for drying, and the drying temperature is 50-70 ℃.
The solvent may include: one or more of methanol, ethanol, isopropanol, N-methylpyrrolidone, tetrahydrofuran, benzene, toluene, petroleum ether, N-hexane, acetone, dioxane, N-dimethyldiamide, ethyl acetate or acetonitrile. Of course, other polar solvents may also be employed. The invention adopts a low-temperature recrystallization mode to precipitate crystals, and concretely, the supersaturated solution is recrystallized at the temperature of less than 5 ℃. Of course, the temperature of recrystallization may be less than 0 ℃.
Taking 1, 9-azelaic acid as an example of organic acid, betaine 1, 9-azelaic acid forms a crystalline solid with uniform and stable spatial distribution and ordered triclinic system through intermolecular hydrogen bond and intermolecular electrostatic interaction. The maximum solubility of the eutectic in water reaches 13.92g/L, which is 5.8 times of the maximum water solubility of 1, 9-azelaic acid monomer; in addition, in a rabbit standard Derez eye-staining experiment, the eutectic concentration reaches 37mg, and slight stimulation is generated on the rabbit eyes, so that compared with the stimulation on the rabbit eyes caused by 10mg of betaine and 3mg of 1, 9-azelaic acid, the mildness of the eutectic is greatly improved. In addition, the eutectic crystal also shows better stability and compatibility, the characteristics are very beneficial to the efficacy exertion of the raw materials and the shelf life of the product, and the application of the active ingredients of the insoluble raw materials in the formula of the pharmaceutical cosmetic can be further promoted, so that the eutectic crystal has wider application prospect and medical value.
The molecular formula of the betaine 1, 9-azelaic acid is C14H27NO6The bonding mode is mainly intermolecular hydrogen bonding. Two ends of 1, 9-azelaic acid are respectively provided with a carboxyl group which can form hydrogen bonds with N and O on betaine, wherein N on betaine is used as a receptor of the hydrogen bonds, and-OH in the carboxyl group at one end of 1, 9-azelaic acid is used as a donor of the hydrogen bonds to form a O-H.N hydrogen bond; the O on the betaine is used as an acceptor of another hydrogen bond, and the-OH in the carboxyl group at the other end of the 1, 9-azelaic acid is used as a donor of the hydrogen bond to form a second O-H.O hydrogen bond. The molecules spontaneously assume a stable three-dimensional structure with a regular arrangement in parallel. Under the condition of no external force action, molecules can spontaneously polymerize, recognize and form a more functional eutectic polymer with stable structure through internal hydrogen bonds, electrostatic action and the like.
The invention provides a betaine 1, 9-azelaic acid eutectic, which is a triclinic crystal system, a p-1 space group and has the crystal cell parameters of
α＝107.893(11)β is 95.272(10) °, γ is 101.453(9) °, Z is 2, and the unit cell volume is
Molecular formula C14H27NO6. The betaine 1, 9-azelaic acid eutectic compound of the present invention is shown in figure 1.
The invention prepares the eutectic molecules with organic acid, and the generated eutectic molecules have the advantages of good water solubility, high permeability, small irritation, small using amount, low effective concentration, good whitening effect, strong moisturizing effect and the like, and are particularly suitable for moisturizing, cleansing and children product formulas. The betaine and the organic acid are arranged into regular triclinic system eutectic crystals according to a certain sequence through a hydrogen bond network formed by the betaine and the organic acid and other intermolecular forces. The brand new eutectic raw material improves the solubility, the bioavailability, the irritation and the like of the precursor without influencing the functional group and the efficacy performance of the precursor, greatly improves the performance of the raw material, and provides great technical support for the research, development and utilization of insoluble raw materials in the pharmaceutical and cosmetic industry.
The invention has the following advantages:
1. the raw materials of the eutectic crystal do not contain any toxic and harmful substances, and have no potential harm harmful to human bodies. 2. The eutectic crystal is prepared from betaine and an organic acid, retains original functional groups of two precursors, and improves the physicochemical properties of the precursors. Compared with organic acid, the whitening and moisturizing liquid has the advantages of easy water solubility, small using amount, low effective concentration, strong whitening effect, good moisturizing effect and the like. 3. The eutectic crystal has rich and complete effects: promoting cell to absorb water, maintaining skin water balance, improving skin moisture retention ability, and regulating skin oil secretion; the conversion and formation of melanin and the conversion and proliferation of melanocytes are inhibited, and the whitening and freckle removing effects are exerted; then the product is anti-allergic and non-irritant; promoting cell regeneration, improving skin elasticity, and maximizing product efficacy. 4. The solubility of the betaine 1, 9-azelaic acid eutectic reaches 13.92g/L, and is only 2.4g/L relative to 1, 9-azelaic acid monomer, which is improved by 5.8 times, the improvement of the solubility is beneficial to the uniform dispersion of the eutectic raw material when applied in a water-based solvent, the effective concentration can be reached under a lower dosage, and the absorption and utilization of the eutectic raw material by human skin can be improved. 5. The eutectic is prepared by an innovative solvent-free mixed crystallization method, the product yield is more than 96 percent, and the traditional process yield for producing similar eutectic products is lower than 90 percent. The breakthrough progress not only saves the production cost but also improves the production efficiency for the industrial production of products. 6. The eutectic crystal is prepared at a higher temperature in the preparation process, so that the obtained product has good thermal stability, and the addition of the eutectic crystal at any stage of cosmetic preparation does not influence the activity.
Detailed description of the preferred embodiment
A preferable method for preparing the betaine 1, 9-azelaic acid eutectic comprises the following steps: the first step is as follows: weighing 0.01mol of betaine and 1, 9-azelaic acid, placing the mixture in a reactor, and introducing inert gas into the reactor to protect the reaction. And (3) sealing the reactor, slowly heating to 95 ℃, reacting for 2 hours, naturally cooling the reactor, and cooling to room temperature to obtain the betaine 1, 9-azelaic acid eutectic crude product. The second step is that: and recrystallizing the eutectic crude product. Methanol is used as a solution (the proportion of 10ml to 1 g) to dissolve the betaine 1, 9-azelaic acid eutectic, and after complete dissolution, impurities in the crude product are removed by a filter membrane. The purified eutectic solution was concentrated to supersaturation (based on the volume of solution approximately evaporated 4/5). And (3) placing the supersaturated solution at the low temperature of 2-5 ℃ for crystallization. And filtering the eutectic product, fully washing the product, repeatedly recrystallizing for 2-3 times, and drying the final product at 60 ℃ for more than 24 hours. Obtaining the betaine 1, 9-azelaic acid eutectic with the purity of more than 99 percent.
The betaine 1, 9-azelaic acid eutectic is characterized by a nuclear magnetic resonance instrument and a thermogravimetric analyzer, and the obtained nuclear magnetic resonance hydrogen spectrogram (shown in figure 2) and thermogravimetric analysis curve chart (shown in figure 3) successfully prepare the betaine 1, 9-azelaic acid eutectic with correct structural formula and good crystal structure. In this example, the betaine 1, 9-azelaic acid co-crystal prepared at 95 ℃ had a melting point of 80-82 ℃, a decomposition temperature of 245 ℃ and a solubility of 13.92 g/L.
The betaine 1, 9-azelaic acid eutectic prepared in this example is composed of a molecule of betaine and a molecule of 1, 9-azelaic acid to form a basic structural unit of the eutectic, wherein O, N on betaine and two-OH groups on 1, 9-azelaic acid form intermolecular hydrogen bonds, i.e., O-H.N and O-H.O, and the crystallographic parameters are triclinic system, P-1 space group, and the unit cell parameters are
A is 107.893(11) °, β is 95.272(10) °, γ is 101.453(9) °, Z is 2, and unit cell volume is
Molecular formula C14H27NO6. The crystallization parameters of the betaine 1, 9-azelaic acid co-crystal obtained in this example are shown in Table 1:
TABLE 1 crystallization parameters of the cocrystals
Atomic coordinates of betaine 1, 9-azelaic acid cocrystal obtained in this example (. times.10)4) And equivalent isotropic atomic displacement parameter
Analytical data are shown in Table 2, U (eq) is defined as orthogonal UijOne third of the trace amount of tensor.
TABLE 2 atomic coordinates and equivalent Isotropic atomic Displacement parameters of the eutectic
Betaine 1, 9-nonane prepared in this exampleAnisotropy atom displacement parameter of diacid eutectic
The analytical data are shown in table 3, where the anisotropic atomic displacement factor powers are in the form: -2 pi2[h2a*2U11+2hka*b*U12+…]。
TABLE 3 Anisotropic atomic Shift parameters of the cocrystals
The betaine 1, 9-azelaic acid eutectic obtained in this example has a long bond length
The analytical data are shown in Table 4.
TABLE 4 bond length of each chemical bond of the cocrystals
The analytical data of each bond angle (°) of the betaine 1, 9-azelaic acid cocrystal obtained in this example are shown in table 5.
TABLE 5 eutectic bond angles of each chemical bond
The data of the twist angle (°) analysis of each chemical bond of the betaine 1, 9-azelaic acid co-crystal obtained in this example are shown in table 6.
TABLE 6 twist angle of each chemical bond of the eutectic
The hydrogen atom coordinates of the betaine 1, 9-azelaic acid cocrystal obtained in this example
And isotropic atomic displacement parameter
Analytical data are shown in Table 7.
TABLE 7 hydrogen atom coordinates and Isotropic atom Displacement parameters of the eutectic
As shown in fig. 2, the nuclear magnetic hydrogen spectrum data of the betaine 1, 9-azelaic acid eutectic prepared in this example is:1H NMR(400MHz，MeOD)δ3.85(s，2H)，3.28(s，9H)，2.28(t，J＝7.4Hz，4H)，1.65-1.55(m，4H)，1.35(s，6H)。
the optimum temperature for the reaction set-up was obtained by the following experiment: the first step is as follows: 0.01mol of each of betaine and 1, 9-azelaic acid is weighed by 10 parts, each of betaine and 1, 9-azelaic acid is placed in a reactor, and inert gas is introduced into the reactor to protect the reaction. Sealing the reactor, heating to 65 deg.C, 70 deg.C, 75 deg.C, 80 deg.C, 85 deg.C, 90 deg.C, 95 deg.C, 100 deg.C, 105 deg.C and 110 deg.C, reacting for 1-24h, sampling, testing, determining whether the reaction is complete, and recording the time required for reaction at different temperatures. And after the reaction is finished, taking out the reactor, naturally cooling, and cooling to room temperature to obtain the betaine 1, 9-azelaic acid eutectic crude product. The time required for the reaction at the various temperatures is shown in table 7A below:
TABLE 7A time required for the reaction at different temperatures
| Reaction temperature/. degree.C | 65 | 70 | 75 | 80 | 85 |
| Reaction time length/min | 934 | 755 | 737 | 621 | 108 |
| Reaction temperature/. degree.C | 90 | 95 | 100 | 105 | 110 |
| Reaction time length/min | 105 | 105 | 98 | 95 | 96 |
The second step is that: according to the reaction time recorded in the table above, 6 temperatures such as 85 ℃, 90 ℃, 95 ℃, 100 ℃, 105 ℃ and 110 ℃ are preferably selected for incremental reaction. Weighing 0.05mol of betaine and azelaic acid, operating according to the experimental flow in the step one, obtaining a reaction crude product, and then recrystallizing the reaction crude product: methanol is used as a solution (the proportion of 10ml to 1 g) to dissolve the betaine 1, 9-azelaic acid eutectic, and after complete dissolution, impurities in the crude product are removed by a filter membrane. The purified eutectic solution was concentrated to supersaturation (based on the volume of solution approximately evaporated 4/5). And (3) placing the supersaturated solution at the low temperature of 2-5 ℃ for crystallization. And filtering the eutectic product, fully washing the product, repeatedly recrystallizing for 2-3 times, and drying the final product at 60 ℃ for more than 24 hours. Obtaining the betaine 1, 9-azelaic acid eutectic with the purity of more than 99 percent. The product data obtained for the reactions at different temperatures are shown in table 7B below:
TABLE 7B data of the products obtained by the reaction at different temperatures
And (4) conclusion: according to the experimental conditions and the experimental results, the optimum reaction temperature range of the betaine 1, 9-azelaic acid can be screened to be 90-95 ℃, the time required for complete reaction in the temperature range is short, the yield is high, the product crystal system is a stable triclinic crystal system, the shape is a flaky crystal with uniform size, and the yield exceeds 98%. Therefore, the purposes of high reaction rate, high yield, high product quality and the like can be achieved by selecting 90-95 ℃ as the reaction temperature.
Detailed description of the invention
A method for preparing a betaine 1, 9-azelaic acid eutectic comprises the following steps: the first step is as follows: 0.01mol of betaine and 1, 9-azelaic acid are weighed out and placed in a reactor. Introducing argon to ensure that the whole reaction process is carried out under the inert gas atmosphere, heating the sealed reactor to 80 ℃, reacting for 6 hours, naturally cooling the reactor, and cooling to room temperature to obtain the betaine 1, 9-azelaic acid eutectic solution. The second step is that: and recrystallizing the eutectic crude product. Dissolving betaine 1, 9-azelaic acid eutectic in ethyl acetate solution (10ml to 1 g), and filtering to remove impurities in the crude product after complete dissolution. The purified eutectic solution was concentrated to supersaturation (based on the volume of solution approximately evaporated 4/5). And (3) placing the supersaturated solution at the low temperature of 2-5 ℃ for crystallization. And filtering the eutectic product, fully washing the product, repeatedly recrystallizing for 2-3 times, and drying the final product in a vacuum drying oven at 60 ℃ for 24 hours. The obtained eutectic crystal 2.8824g of betaine 1.9-azelaic acid with purity more than 98% is obtained, and the yield is 94.39%.
Detailed description of the preferred embodiment
A method for preparing a betaine 1, 9-azelaic acid eutectic comprises the following steps: the first step is as follows: 0.01mol of betaine hydrochloride and 1, 9-azelaic acid are weighed, the betaine hydrochloride is added into a reactor, and argon is introduced to create an anaerobic reaction atmosphere. Slowly heating the reactor to 80 ℃, and reacting for 6h to obtain the betaine 1, 9-azelaic acid eutectic solution. The second step is that: and recrystallizing the eutectic crude product. Methanol is used as a solution (the proportion of 10ml to 1 g) to dissolve the betaine 1, 9-azelaic acid eutectic, and after complete dissolution, impurities in the crude product are removed by a filter membrane. The purified eutectic solution was concentrated to supersaturation (based on the volume of solution approximately evaporated 4/5). And (3) placing the supersaturated solution at the low temperature of 2-5 ℃ for crystallization. And then filtering the eutectic product, filtering and fully washing the eutectic product, repeatedly recrystallizing for 2-3 times, and drying the final product in a vacuum drying oven at 60 ℃ for 24 hours. The obtained eutectic crystal 2.8972g of betaine 1.9-azelaic acid with purity more than 98% is obtained, and the yield is 94.88%.
The invention also carries out efficacy evaluation detection on the betaine 1, 9-azelaic acid eutectic:
experimental example 1
Anti-inflammatory efficacy study of betaine 1, 9-azelaic acid eutectic
According to the invention, an anti-inflammatory efficacy test based on 'outdoor Ultraviolet (UVB) -keratinocyte' is carried out on betaine monomers, 1, 9-azelaic acid monomers and betaine 1, 9-azelaic acid eutectic.
1. The test cells were: keratinocytes are formed. 2. Irradiation conditions: 300mJ/cm2. 3. Method of material preparation and testing: keratinocytes were seeded in 6-well plates and placed in incubators with appropriate temperature, relative humidity and carbon dioxide concentration for a stringent incubation culture for 24 h. Dividing the cells into 6-well plates after the cell plating rate in the 6-well plates reaches the standardAnd (3) group administration, wherein the administration is uniformly carried out on each hole according to the same dose, the cultivation is continued for 24 hours in an incubator with the same temperature, humidity and carbon dioxide concentration, and three groups of the administration are arranged in parallel in each group. After the culture is finished, irradiating the corresponding groups under the same condition, then performing liquid replacement operation on all pore plates needing to be subjected to superoxide dismutase (SOD) activity detection in the later period, replacing fresh culture solution, and placing in an incubator under the same condition for culturing for 24h again. Finally, the cultured keratinocytes were tested for inflammatory factors (IL-1. alpha., TNF. alpha., IL-8) and inflammatory mediators (PGE2) using enzyme-linked immunosorbent assay (ELISA). 4. Preparing liquid: test article working solutions were prepared according to table 8.
Table 8 experimental design
Note: the BC group is a blank control group, the NC group is a negative control group, and the PC group is a positive control group.
5. The test results are shown in tables 9 to 12.
TABLE 9 summary of IL-1. alpha. assay results
Note: the BC group is a blank control group, the NC group is a negative control group, and the PC group is a positive control group.
As can be seen from Table 9, the content of IL-1. alpha. in the negative control group was significantly increased as compared with the blank group; compared with a negative control group, the content of IL-1 alpha in the positive control group is obviously reduced; the experiment is effective. Compared with a negative control group, the 1, 9-azelaic acid group has no obvious inhibition effect on the IL-1 alpha content of keratinocytes; the content of the IL-1 alpha of the eutectic group and the betaine group is reduced, and particularly the content of the IL-1 alpha of the eutectic group is reduced remarkably. Compared with the betaine group, the eutectic of the invention only has the dosage of 0.25mg/ml, and has the lower dosage of administration than the betaine group with the dosage of 5mg/ml, so that the IL-1 alpha content in the keratinocytes is reduced more remarkably, namely: the cocrystal group of the present invention was administered at a concentration of only 5% of that of the betaine group, but it had a 1.50-fold effect of reducing IL-1. alpha. content in keratinocytes as compared with the betaine group.
TABLE 10 summary of TNF-alpha assay results
Note: the BC group is a blank control group, the NC group is a negative control group, and the PC group is a positive control group.
As can be seen from Table 10, the content of TNF-alpha in the negative control group was significantly increased compared to that in the blank group; compared with a negative control group, the content of TNF-alpha in the positive control group is obviously reduced; the experiment is effective. Compared with a negative control group, the 1, 9-azelaic acid group has no obvious inhibition effect on the content of TNF-alpha; the TNF-alpha content of the eutectic group and the betaine group is obviously reduced. Compared with the betaine group, the co-crystal of the invention only has a more significant reduction of the content of TNF-alpha in keratinocytes at a dosage of 0.25mg/ml, lower than the dosage of 5mg/ml in the betaine group, namely: the co-crystal group of the present invention was administered at a concentration of only 5% of that of the betaine group, but it showed a 3.36-fold effect in reducing the TNF-. alpha.content of keratinocytes as compared to the betaine group.
TABLE 11 summary of IL-8 assay results
Note: the BC group is a blank control group, the NC group is a negative control group, and the PC group is a positive control group.
As can be seen from Table 11, the content of IL-8 in the negative control group was significantly increased compared to the blank group; compared with a negative control group, the content of IL-8 in the positive control group is obviously reduced; the experiment is effective. Compared with a negative control group, the 1, 9-azelaic acid group has no obvious inhibition effect on the content of IL-8; the IL-8 content of the eutectic group and the betaine group is obviously reduced. Compared with the betaine group, the eutectic group of the invention only has the dosage of 0.25mg/ml and lower than the betaine group with 5mg/ml, and the IL-8 content in the keratinocytes is reduced more remarkably, namely: the co-crystal of the present invention was administered at a dose of only 5% of that administered in the betaine group, but the effect of reducing IL-8 content in keratinocytes was more pronounced than in the betaine group.
TABLE 12 summary of PGE2 test results
Note: the BC group is a blank control group, the NC group is a negative control group, and the PC group is a positive control group.
As can be seen from table 12, the content of PGE2 in the negative control group was significantly increased compared to the blank group; the content of PGE2 in the positive control group is obviously reduced compared with that in the negative control group; the experiment is effective. The 1, 9-azelaic acid, betaine and cocrystal groups of the invention all had a reduced content of PGE2 compared to the negative control group. The cocrystal group of the present invention reduced the keratinocyte PGE2 content by more than the effect of 1, 9-azelaic acid on cells at a concentration that did not exert a toxic effect on cells, compared to the 1, 9-azelaic acid group. Compared with the betaine group, the cocrystal group of the invention only has the dosage of 0.25mg/ml and lower than the 5mg/ml dosage of the betaine group, so that the content of PGE2 in the keratinocytes is reduced more obviously, namely: the co-crystal group of the present invention was administered at a dose of only 5% of that of the betaine group, but its effect of lowering keratinocyte PGE2 was 1.62 times that of the betaine group.
Based on the results of the assays for inflammatory factors (IL-1 α, TNF- α, IL-8) and inflammatory mediators (PGE2), the results were as follows, in comparison to the groups: (1)1, 9-azelaic acid has inhibiting effect on PGE2 generated under UVB stimulation under the exposure dose of 0.008mg/ml, and has no obvious inhibiting effect on IL-1 alpha, TNF-alpha and IL-8; (2) the betaine has obvious inhibition effect on IL-1 alpha, TNF-alpha, PGE2 and IL-8 generated by UVB stimulation under the exposure dose of 5 mg/mL; (3) the co-crystal of the invention has obvious inhibition effect on IL-1 alpha, TNF-alpha, IL-8 and PGE2 generated by UVB stimulation only by an exposure dose of 0.25mg/mL, and the inhibition intensity is basically greater than that of betaine under an exposure dose of 5mg/mL, which is enough to prove that the co-crystal of the invention has excellent anti-inflammatory effect. In this experimental example, according to the experimental results, the anti-inflammatory ability of the cells of the experimental raw materials is ranked as: the betaine 1, 9-azelaic acid eutectic is more than betaine and more than 1, 9-azelaic acid; the eutectic crystal of the invention has strong anti-inflammatory effect.
Experimental example 2
And (3) researching the whitening effect of the betaine 1, 9-azelaic acid eutectic. The invention carries out whitening efficacy test based on melanocytes on betaine monomers, 1, 9-azelaic acid monomers and betaine 1, 9-azelaic acid eutectic.
1. The test cells were: melanocytes. 2. Method of material preparation and testing: the melanocytes are inoculated into a 6-well plate, and then the 6-well plate is placed in an incubator with proper temperature, relative humidity and carbon dioxide concentration for incubation and culture for 24 h. After the cell plating rate reaches the standard, uniformly administering the drug to each hole according to the same dose, continuously culturing for 72h in an incubator with the same condition, and setting three parallel groups. After the culture is completed, the culture solution is discarded, melanocytes are digested by adding pancreatin with proper concentration, the melanocytes are digested for a short time in a thermostat with the temperature of 37 ℃, then the cells are collected into a centrifuge tube, a cell mixed solution is centrifuged by using a high-speed centrifuge, and supernatant is discarded. Adding distilled water, absolute ethyl alcohol and diethyl ether into each tube according to a certain proportion, uniformly mixing, standing at room temperature for about half an hour, centrifuging by using a high-speed centrifuge, and discarding the supernatant. A1 mol/L aqueous solution of NaOH containing 10% DMSO was added. And heating the samples and the standard solutions with different concentrations in a high-temperature water bath for about half an hour. 200 mu L of suspension is taken from each tube of sample and put into a 96-well plate, 2 multiple wells are arranged, and the absorbance value is measured on an enzyme linked immunosorbent assay instrument at the wavelength of 405 nm. 3. Preparing liquid: test article working solutions were prepared as follows in table 13.
Table 13 test design
Note: the BC group was a blank control group and the PC group was a positive control group.
4. The test results are shown in Table 14.
TABLE 14 summary of melanin content measurements
Note: the BC group was a blank control group and the PC group was a positive control group.
As can be seen from table 14, the melanin content of the positive control group was significantly decreased compared to the blank group, indicating that this test is effective. Compared with the blank group, the 1, 9-azelaic acid has no obvious inhibition effect on the melanin content; the melanin content of the betaine group and the inventive cocrystal group was significantly reduced. Compared with the betaine group, the co-crystal group of the invention only has 0.15mg/ml, and has lower dosage than the betaine group of 10mg/ml, so that the reduction of the melanin content of the melanocyte is more remarkable, namely: the cocrystal group of the present invention was administered at a dose of only 1.5% of that of the betaine group, but it had a 1.17-fold effect of decreasing the melanin content of melanocytes as compared with the betaine group.
And (4) conclusion: according to the result of the melanin content detection, compared with a blank control, the betaine and the eutectic are obviously reduced under the exposure dose of 10mg/mL and 0.15mg/mL, so that the melanin content is obviously reduced, and the whitening effect is prompted. However, the cell melanin is reduced by the eutectic under an extremely low dosage with the concentration of 1.5% of that of the betaine group, so that the whitening effect of the eutectic is far greater than that of the betaine group.
Experimental example 3
Research on antioxidant effect of betaine 1, 9-azelaic acid eutectic
The invention carries out the oxidation resistance efficacy test based on UVB-keratinocyte on betaine monomer, 1, 9-azelaic acid monomer and betaine 1, 9-azelaic acid eutectic.
1. The test cells were: UVB-keratinocytes. 2. Method of material preparation and testing: inoculating keratinocyte into 6-well plate, placing in incubator with appropriate temperature, relative humidity and carbon dioxide concentration, and performing strict and reasonable incubation culture for 24 h. And after the cell plating rate reaches the standard, the cells are subjected to grouped administration, the administration is uniformly performed on each hole according to the same dose, the cells are continuously cultured for 24 hours in an incubator with unchanged temperature, relative humidity and carbon dioxide concentration, and three groups are arranged in parallel in each group. After the culture is finished, irradiating corresponding groups under the same conditions, then performing liquid replacement operation on all pore plates which need to be subjected to superoxide dismutase (SOD) activity detection and Reactive Oxygen Species (ROS) detection in the later period, replacing fresh culture solution, and placing the culture solution in an incubator under the same conditions for continuous culture for 24 hours. And finally, detecting the antioxidant factors of the cultured keratinocytes. 3. Preparing liquid: test article working solutions were prepared as in table 15 below.
Table 15 test design
Note: the BC group is a blank control group, the NC group is a negative control group, and the PC group is a positive control group.
5. The test results are shown in tables 16 and 17.
TABLE 16 summary of ROS results
Note: the BC group is a blank control group, the NC group is a negative control group, and the PC group is a positive control group.
As can be seen from table 16, the negative control group had a significant increase in ROS content compared to the blank group; compared with a negative control group, the ROS content of the positive control group is obviously reduced; the experiment is effective. Compared with a negative control group, the ROS content of the cocrystal group, the betaine group and the 1, 9-azelaic acid group of the invention are all obviously reduced. The co-crystallized group of the present invention was administered at a dose of only 0.25mg/ml, compared to the betaine group and the 1, 9-azelaic acid group, and the decrease of ROS content in keratinocytes was most significant.
TABLE 17 summary of SOD results
Note: the BC group is a blank control group, the NC group is a negative control group, and the PC group is a positive control group.
As can be seen from table 17, the negative control group had significantly reduced SOD activity compared to the blank group; compared with a negative control group, the activity of the SOD in the positive control group is obviously improved; the experiment is effective. Compared with a negative group, the 1, 9-azelaic acid group has no obvious influence on the SOD activity, and the SOD activities of the eutectic group and the betaine group are obviously improved. Compared with the betaine group, the administration dosage of the cocrystal group is only 0.25mg/ml, and the administration dosage is lower than that of the betaine group by 5mg/ml, so that the activity of SOD in keratinocytes is increased more remarkably, namely: the administration dose of the cocrystal group of the present invention was only 5% of that of the betaine group, but the effect of increasing SOD activity in keratinocytes was 1.16 times.
To summarize: according to the detection result of antioxidant factors (ROS, SOD), compared with a negative control: (1)1, 9-azelaic acid has no obvious influence on SOD activity of cells under UVB stimulation under the exposure dose of 0.008mg/ml, has obvious inhibition effect on ROS generated by the cells under the UVB stimulation, but the action effect is the worst in three groups of experimental groups; (2) under the exposure dose of 5mg/mL, the betaine has positive influence on the SOD activity of cells under the stimulation of UVB, the SOD activity is obviously improved, and the cell generation ROS under the stimulation of UVB also has obvious inhibition effect, but the expression effect of the betaine is not the same as that of the eutectic at the concentration of 0.25 mg/mL; (3) the co-crystal only has an exposure dose of 0.25mg/mL, and has a positive effect on the SOD activity of cells under UVB stimulation, and the SOD activity is increased most obviously in three test substances; the cell ROS generation under the stimulation of UVB is also obviously inhibited; and the inhibition intensity is larger than that of betaine at 5mg/ml and 1, 9-azelaic acid.
In this experimental example, according to the experimental results, the cell antioxidant capacity of the experimental raw materials is ranked as: the betaine 1, 9-azelaic acid eutectic is more than betaine and more than 1, 9-azelaic acid; the eutectic crystal of the invention has strong antioxidant effect.
Experimental example 4
Acute eye irritation test of betaine 1, 9-azelaic acid cocrystal
According to the invention, an acute eye irritation test based on 'rabbit eyeballs' is carried out on betaine, 1, 9-azelaic acid monomer and betaine 1, 9-azelaic acid eutectic.
1. The test animals were: experimental grade big ear rabbit. 2. Evaluation indexes are as follows: eye irritation response score table, see table 18.
TABLE 18 eye irritation response points Table
3. Evaluation indexes are as follows: criteria for evaluation of eye irritation are shown in Table 19.
TABLE 19 evaluation criteria for eye irritation
| Strength of | Score value |
| Non/micro-irritancy | 0-3 |
| Mild irritation | 4-8 |
| Moderate irritation | 9-12 |
| Stimulation of intensity | 13-16 |
4. Method of material preparation and testing:
(1) check before dosing. Both eyes of each animal were examined with 1% fluorescein sodium 24h before the test, and animals with eye irritation symptoms, corneal defects, and conjunctival lesions were not used for the test.
(2) Methods of administration. The experimental rabbit was dropped with 2 drops of a sample of a certain concentration in the left eye and 2 drops of 0.9% sodium chloride injection in the right eye as a control. The administration is carried out 3 times daily, each time is 4h apart, and the administration is carried out for 7 days continuously. Note: the sample concentration was gradually increased until the experiment produced a mild irritation. Namely: the concentration at this time is the lowest stimulation concentration in the rabbit eye stimulation experiment.
(3) And (4) observing. 1h after each day of dosing, eye examinations were performed with 1% sodium fluorescein in both eyes and with a slit lamp, and conjunctival, cornea, iris and other lesions were observed and scored according to Table 1. The ocular cornea, iris, and conjunctival irritation response scores for each animal were added to give a total score at each observation time. The degree of irritation was judged according to the criterion of evaluation of eye irritation.
5. As a result: the sodium chloride injection with the concentration of 0.9 percent has no stimulation to conjunctiva, cornea, iris and the like of the experimental rabbit eye; when the concentration of the betaine reaches 9mg, slight irritation is generated to rabbit eyes; when the concentration of the 1, 9-azelaic acid reaches 3mg, the composition causes slight irritation to rabbit eyes; the eutectic concentration of betaine 1, 9-azelaic acid reaches 28mg, which causes slight irritation to rabbit eyes.
6. And (4) conclusion: after the betaine and the 1, 9-azelaic acid are prepared into the eutectic, the irritation is greatly reduced, the technical progress is brought to the improvement of the production process and the use safety of the raw materials for food, medicine and cosmetic raw material production enterprises, and the subsequent development and utilization of the raw materials in products are facilitated.
Experimental example 5
This example describes the use of betaine 1, 9-azelaic acid co-crystal in a child moisturizing cream, stability evaluation, and human efficacy evaluation.
1. The formula of the children moisturizing cream taking the eutectic crystal as the raw material comprises the following components:
the formula of the face cream (calculated by mass percent) is as follows: 15-80% of deionized water, 1-5% of emulsifier, 5-20% of humectant, 0.1-2.0% of thickener, 3-24% of humectant, 0.5-3% of stabilizer, 3-8% of emollient and 0.1-15% of other components. As shown in table 20, a formula of the moisturizing cream for children using the eutectic crystal of the present invention as a raw material is exemplified.
Table 20 composition of cream raw materials table
| Component name | Content (wt%) |
| Deionized water | 75 |
| Mineral oil | 8 |
| Glycerol | 5 |
| Steareth-2 | 3.5 |
| Cetyl alcohol | 2.5 |
| Hyaluronic acid sodium salt | 1.5 |
| Arachidic acid | 1.5 |
| Carbomer | 1 |
| Betaine 1, 9-azelaic acid eutectic | 0.5 |
| Propylene glycol | 0.5 |
| Tocopherol acetate | 0.5 |
| Phenoxyethanol | 0.5 |
2. The preparation process is carried out according to the following steps: step 1: an oil phase mixture was prepared. Mixing the oil phase raw materials, heating to 80 + -3 deg.C, stirring and mixing uniformly, and keeping the temperature for 20 min. Step 2: an aqueous phase mixture was prepared. All aqueous phase materials were mixed and heated to 75 ℃ until completely dissolved. And step 3: and (4) mixing. Pouring the obtained oil phase mixture into the water phase mixture under the condition of continuous stirring, continuously stirring for 2-5min at the stirring speed of 10-30r/min, and then homogenizing for 5-10min at the homogenizing speed of 2500-5000r/min and the temperature of 60-70 ℃ by using a homogenizer to obtain a mixture. And 4, step 4: and (5) adding materials. And (3) reducing the temperature of the mixture to room temperature, adding a pH regulator, continuously stirring and uniformly mixing, adding the rest components, supplementing 100 parts by weight of deionized water, continuously homogenizing for 5-10min by using a homogenizer at the speed of 3000-6000r/min, and then reducing the temperature to room temperature, thus obtaining the child facial cream with the water replenishing and moisturizing effects. And 5: and (7) sealing and storing. And (4) filling the face cream into a storage barrel, strictly sealing the storage barrel, and moving the storage barrel to a product sterile storage room for storage. Step 6: and (6) quality inspection. And (4) performing quality inspection on the cream, and quantitatively packaging in an aseptic packaging room after the cream is qualified. And 7: and (5) finishing. And packaging the product, spraying the code to obtain a finished product, and warehousing.
3. The safety evaluation of the children moisturizing cream containing the betaine 1, 9-azelaic acid eutectic disclosed by the invention comprises the following steps:
testing a sample: a moisturizing cream for children containing the betaine 1, 9-azelaic acid eutectic is provided. And (3) testing items: the skin of the human body has an irritant reaction to the moisturizing cream for children containing the eutectic crystal. The test method comprises the following steps: human skin patch test. The method comprises the following specific operations: selecting a proper spot tester, selecting 80 qualified volunteers to test by a closed spot test method, and adding 80 parts of each of a cream sample and a blank control (without any substance) sample into the spot tester one by one. And sticking the spot patch and the blank patch on the inner sides of the left and right forearms of the subject, and pressing with palm to uniformly stick the patches on the skin for 48 h. Removing patch for about 20min at 6h, 24h and 48h respectively, observing skin reaction according to the following table standard, and recording the observation result.
The test results are shown in tables 21 to 22:
skin reaction grading standard of table 21 patch experiment
TABLE 22 summary of Patch test results
And (3) analysis: the patch test selects the forearm trunk skin with more dendritic cells, has simple operation, safer inspection, less adverse reaction and accurate experimental result. As can be seen from the above table, neither the test group nor the blank group exhibited adverse reactions. The safety of the children cream containing the eutectic is good, and the eutectic can be used as a cosmetic raw material in the production process of a formula of a children skin care product.
4. Evaluation of moisture retention of a child moisturizing cream containing the betaine 1, 9-azelaic acid eutectic of the invention:
experimental groups: children's face cream prepared by using eutectic crystal containing betaine 1, 9-azelaic acid as raw material
Control group: children's cream prepared by using distilled water to replace betaine 1, 9-azelaic acid eutectic
Testing a sample: a children moisturizing cream containing the betaine 1, 9-azelaic acid eutectic and a children moisturizing cream without the betaine 1, 9-azelaic acid eutectic are prepared (the children moisturizing cream containing the betaine 1, 9-azelaic acid eutectic is prepared according to the formula, the eutectic part is replaced by distilled water, and the children moisturizing cream without the betaine 1, 9-azelaic acid eutectic is prepared). And (3) testing items: skin moisture content (TEWL) rate of change for both child moisturizing creams. The test method comprises the following steps: the skin moisture content of the subject was measured using a skin moisture tester and the TEWL rate of change was calculated according to the formula. The method comprises the following specific operations: 200 test subjects who meet the standard were selected, and 3 × 3cm2 areas on the inner side of the upper arm of the test subject were used as test areas. The test subject washes the area to be tested with clear water before testing, sits still for 30min in a constant temperature and humidity environment, then wears latex gloves to uniformly smear the sample on the test area according to the usage amount of 1.5mg/cm2, and adopts a CorneometerCM825 skin moisture content tester to respectively test the skin TEWL value of the test subject when the test subject uses the cream and 4h after the test subject uses the cream. TEWL rate of change ═ T4-T0)/T 0100% of the total weight; wherein, T0: after the subject applied the cream, the skin moisture content was tested for initial values. T is4: the skin moisture content was measured 4 hours after the subjects used the cream. The results are shown in Table 23:
TABLE 23 Experimental groups Change in percutaneous moisture loss (TEWL)
TABLE 24 Change in percutaneous moisture loss (TEWL) for control group
| Numbering | Control group | Numbering | Control group | Numbering | Control group | Numbering | Control group |
| 1 | -22.0 | 26 | -33.2 | 51 | -39.5 | 76 | -36.5 |
| 2 | -23.5 | 27 | -29.6 | 52 | -32.5 | 77 | -32.5 |
| 3 | -25.5 | 28 | -23.5 | 53 | -33.6 | 78 | -36.9 |
| 4 | -26.5 | 29 | -28.6 | 54 | -34.5 | 79 | -31.5 |
| 5 | -28.5 | 30 | -29.6 | 55 | -30.9 | 80 | -29.5 |
| 6 | -29.6 | 31 | -32.0 | 56 | -31.5 | 81 | -36.5 |
| 7 | -35.5 | 32 | -36.0 | 57 | -23.6 | 82 | -31.5 |
| 8 | -32.5 | 33 | -32.8 | 58 | -39.5 | 83 | -30.5 |
| 9 | -32.6 | 34 | -29.4 | 59 | -35.5 | 84 | -38.5 |
| 10 | -33.5 | 35 | -25.1 | 60 | -29.5 | 85 | -32.5 |
| 11 | -34.5 | 36 | -26.5 | 61 | -26.6 | 86 | -29.5 |
| 12 | -39.5 | 37 | -27.5 | 62 | -23.5 | 87 | -35.5 |
| 13 | -31.2 | 38 | -29.8 | 63 | -25.5 | 88 | -39.5 |
| 14 | -32.1 | 39 | -21.5 | 64 | -35.6 | 89 | -32.5 |
| 15 | -31.5 | 40 | -26.5 | 65 | -32.5 | 90 | -34.5 |
| 16 | -34.5 | 41 | -21.0 | 66 | -35.6 | 91 | -29.5 |
| 17 | -36.5 | 42 | -31.9 | 67 | -39.5 | 92 | -21.5 |
| 18 | -35.2 | 43 | -35.5 | 68 | -21.5 | 93 | -25.5 |
| 19 | -29.5 | 44 | -36.9 | 69 | -28.5 | 94 | -23.5 |
| 20 | -32.0 | 45 | -29.6 | 70 | -23.5 | 95 | -23.5 |
| 21 | -28.1 | 46 | -23.9 | 71 | -35.6 | 96 | -21.5 |
| 22 | -24.5 | 47 | -34.5 | 72 | -36.9 | 97 | -39.5 |
| 23 | -26.5 | 48 | -32.5 | 73 | -32.4 | 98 | -35.5 |
| 24 | -28.6 | 49 | -26.5 | 74 | -32.5 | 99 | -32.5 |
| 25 | -26.5 | 50 | -26.9 | 75 | -25.5 | 100 | -38.5 |
As can be seen from the data in table 23 and table 24 above, the absolute value of the change rate of TEWL value in the experimental group is significantly lower than that in the control group, i.e., the skin water loss rate of the subjects in the experimental group is significantly lower than that of the subjects in the control group, which indicates that the moisturizing effect of the moisturizing cream for children containing the betaine 1, 9-azelaic acid eutectic of the present invention is better than that of the moisturizing cream for children containing no betaine 1, 9-azelaic acid eutectic of the present invention.
Example 6
This example describes the application, stability evaluation and human efficacy evaluation of a betaine 1, 9-azelaic acid co-crystal in whitening anti-aging cream.
1. The formula of the whitening anti-aging cream taking the betaine 1, 9-azelaic acid eutectic as the raw material comprises the following components in percentage by weight:
the formula of the face cream (calculated by mass percent) is as follows: 15-80% of deionized water, 1-5% of emulsifier, 5-20% of humectant, 0.1-2.0% of thickener, 3-24% of humectant, 0.5-3% of stabilizer, 3-8% of emollient and 0.1-15% of other components. As shown in table 25, a whitening anti-aging cream formulation containing the betaine 1, 9-azelaic acid eutectic of the present invention as a raw material is exemplified.
Table 25 composition of cream raw materials table
| Component name | Content (wt%) |
| |
80 |
| Glycerol | 6 |
| Ethyl hexyl palmitate | 3.5 |
| Propylene glycol | 2.5 |
| Carbomer | 2 |
| Glycyrrhizic acid dipotassium salt | 1 |
| Lactic acid | 0.75 |
| Betaine 1, 9-azelaic acid eutectic | 2.75 |
| Panthenol | 0.5 |
| PEG-3 polydimethylsiloxane | 0.25 |
| Triethanolamine | 0.35 |
| Phenylpropanolethanol | 0.2 |
| EDTA disodium salt | 0.1 |
| Hyaluronic acid sodium salt | 0.05 |
| Phenoxyethanol | 0.05 |
2. The preparation process is carried out according to the following steps:
step 1: an oil phase mixture was prepared. Mixing the oil phase raw materials, heating to 80 + -3 deg.C, stirring and mixing uniformly, and keeping the temperature for 20 min. Step 2: an aqueous phase mixture was prepared. All aqueous phase materials were mixed and heated to 75 ℃ until completely dissolved. And step 3: and (4) mixing. Pouring the obtained oil phase mixture into the water phase mixture under the condition of continuous stirring, continuously stirring for 2-5min at the stirring speed of 10-30r/min, and then homogenizing for 5-10min at the homogenizing speed of 2500-5000r/min and the temperature of 60-70 ℃ by using a homogenizer to obtain a mixture. And 4, step 4: and (5) adding materials. And (3) reducing the temperature of the mixture to room temperature, adding a pH regulator, continuously stirring and uniformly mixing, adding the rest components, supplementing 100 parts by weight of deionized water, continuously homogenizing for 5-10min by using a homogenizer at the speed of 3000-6000r/min, and then reducing the temperature to room temperature, thus obtaining the cream with the whitening and anti-aging effects. And 5: and (7) sealing and storing. And (4) filling the face cream into a storage barrel, strictly sealing the storage barrel, and moving the storage barrel to a product sterile storage room for storage. Step 6: and (6) quality inspection. And (4) performing quality inspection on the cream, and quantitatively packaging in an aseptic packaging room after the cream is qualified. And 7: and (5) finishing. And packaging the product, spraying the code to obtain a finished product, and warehousing.
3. The whitening and anti-aging facial cream containing the betaine 1, 9-azelaic acid eutectic disclosed by the invention is evaluated in whitening effect:
(1) and (3) testing conditions are as follows: the ambient temperature is 20-22 deg.C, and relative humidity is 55%. (2) Sample use requirements: the sample size provided was 50 ml/person, and the subjects were used 2 times each morning and evening for 4 weeks, during which time a uniform delivery of sunscreen product was used. (3) The subject claims: the skin health men and women aged 18-40 years are 30 each, and are divided into experimental group and control group at random. Experimental groups: the whitening anti-aging face cream prepared by the eutectic is used as required. Control group: the skin whitening and anti-aging face cream prepared by the eutectic crystal is not used, but the same sun cream (the skin to be tested cannot have pigmentation such as birthmarks, color spots and the like, and cannot be subjected to laser spot removal and face-lifting) is used by a test group, so that the test subject must be a group who can theoretically and conditionally complete the whole test. (4) Requirements during the test: the tested part can not use any preparation which influences whitening and freckle removing; the whitening health care product can not be taken; other whitening products cannot be used; attention is paid to sun protection by means of a sun-shading device or the like. (5) And (3) testing time: the day before the start of the product, and every seventh day of four weeks. (6) Face test area: cheek skin 3cm from the right side of nose tip, and forehead skin 2.5cm above the eyebrow. The test results are shown in table 26:
TABLE 26 comparison of MI values for melanin content of skin of volunteers
And (4) conclusion: the results in the table show that after the test data are processed, the test cream can be obviously seen to effectively reduce the skin melanin content; statistical analysis showed significant differences in the change between the experimental and control groups (p <0.05) from day 7. The results show that the whitening and anti-aging cream containing the betaine 1, 9-azelaic acid eutectic can obviously reduce the content of melanin in the skin, and the cream has the effects of fading and whitening.
4. The whitening and anti-aging facial cream containing the betaine 1, 9-azelaic acid eutectic disclosed by the invention is evaluated in whitening effect:
testing a sample: a whitening anti-aging face cream containing the betaine 1, 9-azelaic acid eutectic is disclosed.
The test method comprises the following steps: 100 tested women are selected, the ages of the women are 25-45 years old, the living habits are that the women face computers and stay up night in overtime for a long time, and the skin has the conditions of dryness, fine wrinkles, darkness and the like with different degrees, and a double-blind test is carried out on 25 people in each group by adopting a random grouping principle. The test site was facial skin and the test time was one day before the cream was applied and every 7 days after the cream was applied (28 days total experiment). The subject skin data was collected, collated and analyzed, and the results are shown in table 27 below:
whitening and antiaging effects of surface 27 cream
The data in the table 27 show that the whitening and anti-aging cream containing the betaine 1, 9-azelaic acid eutectic has definite efficacy, and the whitening and anti-aging effects are obvious. The product is beneficial to improving the skin brightness, restoring the skin vitality, delaying the skin aging and playing a role in tightening the skin after being used for a long time.
It is to be understood that the invention is not limited to the examples described above, but that modifications and variations may be effected thereto by those of ordinary skill in the art in light of the foregoing description, and that all such modifications and variations are intended to be within the scope of the invention as defined by the appended claims.
Claims (8)
1. A preparation method of a eutectic crystal of betaine and organic acid is characterized by comprising the following steps:
providing betaine and azelaic acid, and uniformly mixing the betaine and the azelaic acid to obtain a mixture; wherein the melting point of azelaic acid is less than the melting point of betaine;
stirring and heating the mixture to melt the mixture under an inert atmosphere, cooling the mixture to normal temperature after the mixture reacts, and purifying to obtain a eutectic of betaine and azelaic acid;
the heating temperature is 60-120 ℃, and the reaction time is 1-24 h;
the eutectic of betaine and azelaic acid is a triclinic system, a p-1 space group and the parameters of unit cells are
A is 107.893(11) °, β is 95.272(10) °, γ is 101.453(9) °, Z is 2, and unit cell volume is
2. The method for preparing a co-crystal of betaine and organic acid according to claim 1, wherein the molar ratio of betaine to azelaic acid is 1: 1-2.
3. Process for the preparation of co-crystals of betaine and organic acid according to claim 1, characterized in that the melting point of azelaic acid is less than 200 ℃.
4. A process for the preparation of co-crystals of betaine and organic acid according to any of claims 1 to 3, wherein said purification results in co-crystals of betaine and azelaic acid comprising:
dissolving a crude product obtained by reacting the mixture in a solvent, and filtering to obtain an eutectic solution;
and (3) concentrating the eutectic solution in a vacuum state to obtain a supersaturated solution, recrystallizing, filtering, washing and drying to obtain the eutectic of betaine and azelaic acid.
5. The method for preparing a co-crystal of betaine and organic acid according to claim 4, wherein the solvent comprises: one or more of methanol, ethanol, isopropanol, N-methylpyrrolidone, tetrahydrofuran, benzene, toluene, petroleum ether, N-hexane, acetone, dioxane, N-dimethyldiamide, ethyl acetate or acetonitrile.
6. Process for the preparation of co-crystals of betaine and organic acid according to claim 4, wherein the temperature of recrystallization is less than 5 ℃.
7. A co-crystal of betaine and an organic acid, which is produced by the steps of the method for producing a co-crystal of betaine and an organic acid according to any one of claims 1 to 6;
the eutectic of betaine and azelaic acid is a triclinic system, a p-1 space group and the parameters of unit cells are
A is 107.893(11) °, β is 95.272(10) °, γ is 101.453(9) °, Z is 2, and unit cell volume is
8. Use of a co-crystal of betaine and organic acid as defined in claim 7 in the preparation of a medicament or in the preparation of a cosmetic.
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