WO2018111044A1 - Three-component cocrystal - Google Patents

Abstract

The present invention relates to a method for preparing a three-component cocrystal comprising kojic acid, tranexamic acid, and nicotinamide. The method of the present invention is characterized in that a two-component cocrystal is first prepared, and then a three-component cocrystal is prepared, wherein when, regardless of the blending ratio of tranexamic acid, nicotinamide, and kojic acid used in the reaction, the molar ratio of three components, tranexamic acid : nicotinamide : kojic acid is 1 : 1 : 1 in the resultant three-component cocrystal, a most stable solid form was shown. The three-component cocrystal prepared by the method of the present invention can maintain physical and chemical stability when used in a solid-phase or liquid-phase cosmetic composition, and thus can be applied to various cosmetic compositions.

Description

3-component cocrystal

This patent application claims priority to Korean Patent Application No. 10-2016-0171314 filed with the Korean Intellectual Property Office on December 15, 2016, the disclosure of which is incorporated herein by reference.

The present invention relates to a three-component cocrystal with excellent physicochemical properties and stability, and having a whitening effect, and a preparation method thereof.

The blackening of the skin is generally affected by the degree of UV exposure, and it is well known that melanin is produced in melanocytes (melanocytes) present in the skin epidermis of the human body. When the skin is exposed to ultraviolet rays, melanocytes produce melanin, which causes the skin to become black or often cause pigmentation such as blemishes. Melanin, the main component of skin discoloration, is produced from a protein called tyrosine by an enzyme called tyrosinase. Therefore, the inhibition of tyrosinase activity in melanocytes is effective in pigmentation and whitening.

In Asia, where white skin is accepted as a standard of beauty, various treatments for whitening and products that are effective in whitening are steadily gaining popularity. Whitening products were originally developed mainly for the treatment of pigmentation, but various cosmetic products are used for cosmetic purposes today.

Hydroquinone has long been known as an active ingredient for representative whitening. Hydroquinone is known as a representative tyrosinase inhibitor. Hydroquinone is known for its side effects, such as causing tissue blackening (ochronosis), but today, at low concentrations, side effects are perceived to be mild or negligible. Nevertheless, some countries prohibit the use of hydroquinone due to carcinogenic issues or require it to be prescribed only by a doctor.If it contains less than 1-2% of hydroquinone, it is irrelevant to cosmetics. It may be commercially available. Hydroquinone, on the other hand, can be decomposed by light and oxygen, which often raises stability issues as a raw material for cosmetics.

Arbutin is a glycosylated hydroquinone and can be viewed as a precursor of hydroquinone. It is found in bilberry and is often used in whitening products as an extract of plants. The mechanism of action of arbutin on whitening is due to the inhibition of tyrosinase, like hydroquinone. In terms of safety, they generally tend to be less sensitive than hydroquinone, which is often perceived as safer for consumers by the fact that it is a component of plant extracts, but the bacteria in the body can break down arbutin and convert it into hydroquinone. It was also published at the conference that some of the safety issues were not different from hydroquinone. In vitro experiments with human melanocytes have shown that arbutin concentrations of 300 μg / mL can inhibit tyrosinase activity and reduce melanin content, and below these concentrations cytotoxicity is not of concern. This was confirmed. On the other hand, there is not much research on the efficacy of arbutin in humans, and controversy about the actual whitening effect is often raised.

Today, the three most widely proven ingredients for whitening are as follows. Kojic acid of [Formula 1] is well known to inhibit the activity of tyrosinase in melanocytes by copper-chelating formation. Tyrosinase is an enzyme containing copper and is involved in the biosynthesis of DOPA (3,4-dihydroxyphenylalanine), a precursor of melanin. Kojic acid inhibits the activity of tyrosanase by copper-chelating.

Kojic acid, on the other hand, is a substance that is problematic in stability for use as a composition of cosmetics. Since kojic acid is decomposed by light and oxygen, the contents may be discolored and the efficacy may be inactivated by the decomposition of kojic acid during long-term preservation of raw materials or the preparation and storage of the composition, thereby reducing the whitening effect. Raw materials of kojic acid require methods such as shading, low temperature conditions, nitrogen filling, etc. for long-term preservation, and it is difficult to manufacture cosmetic compositions due to raw material and formulation stability issues.

[Formula 1] Kojic acid (Kojic acid)

Melanin, which causes blackening of the skin, is produced by melanocytes in the basal layer of the skin and transferred to keratinocytes (Keratinocytes) in the epidermal layer to give a skin color. Tranexamic acid of [Formula 2] inhibits the mechanism by which keratinocytes exposed to ultraviolet light transmit melanin synthesis to melanocytes. On the other hand, it has a mechanism of suppressing inflammation caused by ultraviolet rays and is known as an effective material for whitening.

[Formula 2] Tranexamic acid (Tranexamic acid)

Nicotinamide (Chemical Formula 3), which has been used as an active ingredient for long-term whitening, not only inhibits the migration of melanin formed from melanocytes to keratinocytes, but also has an anti-inflammatory and anti-inflammatory effect. It is also reported to have an improvement effect on acne and skin aging.

[Chemical Formula 3] Nicotinamide

Republic of Korea Patent No. 10-0365072 introduces a synthetic derivative of kojic acid produced a dimer through the ester bond to overcome the instability of kojic acid.

Korean Unexamined Patent Application Publication No. 10-2013-0014519 introduces a whitening cosmetic composition comprising as an active ingredient of tranexamic acid and nicotinic acid amide.

US 2013/0171079 discloses a cosmetic composition for the purpose of improving the stability of kojic acid.

International publication WO2006 / 003965 introduces a whitening cosmetic composition including tranexamic acid.

The present inventors have attempted to secure a novel cocrystal with a stable lattice arrangement using these three materials with whitening active ingredient materials by different mechanisms. As a result, the present inventors attempted to form a novel lattice having a quantitative molar ratio using three components of kojic acid, tranexamic acid and nicotinamide, and confirmed that these lattice arrangements form physicochemically stable cocrystals. The present invention has been completed.

Accordingly, it is an object of the present invention to provide a process for preparing cocrystals comprising kojic acid, tranexamic acid and nicotinamide.

Another object of the present invention is to provide a three-component cocrystal with improved stability, hygroscopicity, physicochemical properties and excellent properties as a raw material and ingredient of a cosmetic composition.

According to one aspect of the present invention, the present invention provides a method for preparing a three-component cocrystal comprising the following steps: with tranexamic acid, nicotinamide and kojic acid. Preparing a two-component cocrystal by reacting two components selected from the group consisting of stirring under an alcohol solvent; And stirring the remaining one component other than the two components and the two component cocrystal under an alcohol solvent to prepare a three component cocrystal.

The present inventors have attempted to secure a novel cocrystal with a stable lattice arrangement using these three materials with whitening active ingredient materials by different mechanisms. As a result, the present inventors used the three components of kojic acid, tranexamic acid and nicotinamide to form a novel lattice having a quantitative molar ratio, and it was confirmed that these lattice arrangements form physicochemically stable cocrystals. .

The whitening active ingredients are kojic acid, tranexamic acid and nicotinamide, and the recommended concentration of these cosmetic products varies depending on the country, but kojic acid and tranexa ginseng are recommended within 2% of the cosmetic composition. Within% is recommended.

The present inventors set forth and experimentally demonstrate the following goals in the present invention:

(1) the three-component cocrystal is stable as a raw material for cosmetics by forming a new lattice of individual substances in a quantitative molar ratio;

(2) the quantitative molar ratio of the three individual substances is determined at a fixed dose used in the cosmetic composition at a ratio meaningful in terms of safety and effectiveness; And

(3) The three-component cocrystal should be stable and formulated not only as a physicochemical property such as stability and hygroscopicity of a crystalline solid but also as a component of various cosmetic compositions.

The most difficult point in the above (1) was to secure a stable crystalline form that can significantly improve the raw material stability of kojic acid among the three components, and kojic acid is vulnerable to light, heat and moisture regardless of crystallinity as a single component. The new crystalline solids containing additional components are the part that must be able to overcome this.

Accordingly, the present inventors expect that when the three components are reacted at a constant molar ratio, a new crystalline solid having a different characteristic from a simple mixture can be obtained, and the reactants are mixed in various ratios under various conditions. Tried. However, despite various attempts, if all three components were reacted at once, the desired new crystalline solid could not be obtained.

When two components were reacted in advance, a novel two-component cocrystal was prepared and isolated, and then, when the other component was reacted with the two-component cocrystal, the desired three-component cocrystal was obtained. Thus, it was confirmed that the three-component cocrystal obtained by the stepwise reaction is a novel crystalline solid different from any one of the three components or the previously prepared two-component cocrystal.

The present inventors have tried various combinations in the preparation of the three-component cocrystal, the most ideal of which is reacted first with tranexamic acid and nicotinamide to obtain the two-component cocrystal, and then the kojic acid is added thereto. Reaction was found to be the most efficient method (see Example 1).

In the above (2), the reaction was attempted to optimize the reaction by taking various molar ratios of the mixing ratio of the respective whitening active ingredients. Keeping in mind the content of the composition of the corresponding component recommended for cosmetics, in consideration of the molecular weight of each of the substances was tried in the direction to complete the three-component cocrystal by the production of two-component cocrystal in various ratio molar ratio (Example 2 Reference).

In addition, the inventors have conducted a study for preparing cocrystal under various reaction conditions (stirring time and temperature, solvent). The reaction was carried out by stirring for a certain period of time under a specific solvent and analyzing the crystalline form obtained by filtering and drying the precipitated solid, and after a lot of trials and trials, the molar ratio of the three components was 1: 1: 1. It can be seen that a new crystalline form is formed, which is completely different from and has new properties.

In the above (3) it was confirmed that the three-component cocrystal can have advantages not only as a solid raw material but also as a liquid component such as a cosmetic composition. That is, the present inventors confirmed that among the components constituting the three-component cocrystal, tranexamic acid and nicotinamide contribute to stabilization of kojic acid in the aqueous solution (see Example 3).

EMBODIMENT OF THE INVENTION Hereinafter, the manufacturing method of the tricomponent cocrystal of this invention is demonstrated in detail.

(a) Preparation of Bicomponent Cocrystals

First, two components selected from the group consisting of tranexamic acid, nicotinamide and kojic acid are reacted by stirring in an alcohol solvent to prepare a two-component cocrystal.

The present inventors could not obtain the desired new crystalline solid when all three components were reacted at the same time. Thus, the two components were reacted in advance to prepare a novel two-component cocrystal, which was isolated and then separated. A method was used in which the component was reacted with a bicomponent cocrystal to obtain a tricomponent cocrystal.

According to one embodiment of the present invention, the two-component cocrystal may be prepared by first reacting trinexamic acid and nicotinamide in the three components. The first reaction of trinexamic acid and nicotinamide among the three components is most efficient for cocrystal formation, but the reaction of two components of different combinations first is not excluded.

According to one embodiment of the present invention, the preparation of the two-component cocrystal comprises the steps of: (i) stirring the two-components for 10-30 minutes in an alcohol solvent, and then concentrating at 40-55 ° C .; And (ii) adding alcohol to the resultant of step (i), stirring for 20-40 minutes, and then concentrating at 40-55 ° C. According to one embodiment of the present invention, the preparation of the two-component cocrystal comprises the steps of: (i) stirring the bicomponent in an alcohol solvent for 15-25 minutes, and then concentrating at 40-55 ° C .; And (ii) adding alcohol to the resultant of step (i), stirring for 25-35 minutes, and then concentrating at 40-55 ° C. According to another embodiment of the present invention, the preparation of the bicomponent cocrystal comprises the steps of: (i) stirring the bicomponent in an alcohol solvent for 15-25 minutes, and then concentrating at 50 ° C; And (ii) adding alcohol to the resultant of step (i), stirring for 25-35 minutes, and then concentrating at 50 ° C. According to a particular embodiment of the present invention, the preparation of the bicomponent cocrystal comprises the steps of: (i) stirring the bicomponent in an alcohol solvent for 20 minutes and then concentrating at 50 ° C; And (ii) adding alcohol to the resultant of step (i), stirring for 30 minutes, and then concentrating at 50 ° C.

According to one embodiment of the invention, the concentration is concentrated under reduced pressure or vacuum, it is carried out about 30 minutes to 1 hour.

The alcohol used in the bicomponent cocrystal production may be selected from the group consisting of C ₁ to C ₄ lower alcohols and mixed solvents thereof, such as methanol, ethanol, propanol, butanol, normal-propanol, iso-propanol, normal Butanol and mixed solvents thereof. According to one embodiment of the invention, the alcohol is methanol.

(b) Preparation of Three-Component Cocrystals

Then, the remaining one component is stirred under the two-component cocrystal and the alcohol solvent to prepare a three-component cocrystal.

According to one embodiment of the present invention, the preparation of the three-component cocrystal (i) after mixing the remaining components other than the two-component cocrystal with the two-component cocrystal for 20-40 minutes in an alcohol solvent, 40-55 ℃ Concentrating in; And (ii) adding alcohol to the resultant of step (i), stirring at room temperature, and then concentrating. According to one embodiment of the present invention, the preparation of the three-component cocrystal (i) after mixing the remaining components other than the two components with the two-component cocrystal and stirred for 25-35 minutes in an alcohol solvent, 40-55 ℃ Concentrating in; And (ii) adding alcohol to the resultant of step (i), stirring at room temperature, and then concentrating. According to another embodiment of the present invention, the preparation of the three-component cocrystal (i) is mixed with the two-component cocrystal other than the two components and stirred for 25-35 minutes in an alcohol solvent, then concentrated at 50 ℃ Doing; And (ii) adding alcohol to the resultant of step (i), stirring at room temperature, and then concentrating. According to a specific embodiment of the present invention, the preparation of the three-component cocrystal is (i) mixing the remaining components other than the two-component with the two-component cocrystal, stirred for 30 minutes in an alcohol solvent, and then concentrated at 50 ℃ ; And (ii) adding alcohol to the resultant of step (i), stirring at room temperature, and then concentrating.

According to one embodiment of the invention, the concentration is concentrated under reduced pressure or vacuum, it is carried out about 30 minutes to 1 hour.

The alcohol used in the three-component cocrystal production may be selected from the group consisting of C ₁ to C ₄ lower alcohols and mixed solvents thereof, such as methanol, ethanol, propanol, butanol, normal-propanol, iso-propanol and normal Butanol and the like. According to one embodiment of the invention, the alcohol is methanol.

According to one embodiment of the present invention, after the steps (i) and (ii), it may further comprise the step of adding a non-polar solvent to the reaction product of step (ii), stirred at room temperature and then filtered. For example, the nonpolar solvent may be cyclohexane, acetone, acetonitrile, ethyl acetate, methyl acetate, fluoroalkane, pentane, hexane, 2,2,4-trimethylpentane, decane, cyclopentane, diisobutylene, 1- Pentene, 1-chlorobutane, 1-chloropentane, o-xylene, diisopropyl ether, 2-chloropropane, toluene, 1-chloropropane, chlorobenzene, benzene, diethyl ether, diethyl sulfide, chloroform, dichloro Methane, 1,2-dichloroethane, anneal, diethylamine, ether, carbon tetrachloride, THF (Tetrahydrofuran) and mixed solvents thereof. According to one embodiment of the invention, the nonpolar solvent is cyclohexane.

According to one embodiment of the invention, after the filtration step with the non-polar solvent, the resultant may be hot air dried at about 45-55 ℃ to obtain the target compound.

According to one embodiment of the present invention, trinexamic acid and nicotinamide are first reacted to produce a bicomponent cocrystal, and then the bicomponent cocrystal and the kojic acid are reacted to prepare a tricomponent cocrystal.

On the other hand, the inventors have found that after many trials and trials and errors, the three-component crystalline form of the present invention is completely different from the mixture when the molar ratio is about 1: 1: 1, and a new crystalline form having new properties is formed. For example, in the reaction of tranexamic acid, nicotinamide and kojic acid, the mixing ratio is 1: 2: 1 or 1: 1: 2. Even in the case of the stepwise reaction of 2: 1: 1 or 1: 2: 2, 2: 1: 2, 2: 2: 1, the fixed solids obtained by filtering and washing the precipitated solid It was confirmed that the stable solid form to be maintained was 1: 1: 1. According to one embodiment of the invention, the molar ratio of tricomponent in the tricomponent crystal of the present invention is tranexamic acid: nicotinamide: kojic acid = 1: 1: 1.

In addition, the three-component crystalline form having the molar ratio showed physical and chemical stability not only in the solid but also in the liquid state.

According to another aspect of the present invention, the present invention is a three-component cocrystal prepared by the method of the present invention, wherein the molar ratio of the three components in the cocrystal is tranexamic acid: nicotinamide: kojic acid = 1: 1: 1 A three component cocrystal is provided. In this case, the trinexamic acid and nicotinamide component constituting the three-component cocrystal contribute to stabilization of the kojic acid, thereby suppressing discoloration due to decomposition of the kojic acid.

According to another aspect of the present invention, the present invention provides a 2θ diffraction angle of 8.44 ± 0.2 °, 10.60 ± 0.2 °, 14.18 ± 0.2 °, 18.01 ± 0.2 °, 19.25 ± 0.2 ° in powder X-ray diffraction (PXRD) analysis. Tranexamic acid is characterized by a specific peak at 21.30 ± 0.2 ° and 25.45 ± 0.2 °, respectively, and an endothermic peak at an endothermic onset temperature of 96 ± 2 ° C and an endothermic temperature of 99 ± 3 ° C in differential scanning calorimetry (DSC) analysis. A mole ratio of nicotinamide to kojic acid is provided.

The features and advantages of the present invention are summarized as follows:

(a) The present invention relates to a method for producing a three-component cocrystal comprising whitening active ingredients kojic acid, tranexamic acid and nicotinamide.

(b) The method of the present invention is characterized by preparing a two-component cocrystal first, followed by a three-component cocrystal, and irrespective of the blending ratio of konexic acid of tranexamic acid and nicotinamide used in the reaction, The molar ratio of the three components in the resulting three-component cocrystal was found to be the most stable solid form when tranexamic acid: nicotinamide: kojic acid = 1: 1: 1.

(c) The three-component cocrystal prepared by the method of the present invention has an advantage that it can be applied to various cosmetic compositions because it can maintain physicochemical stability when used in a solid or liquid cosmetic composition.

Figure 1 shows the 1H-NMR results of the three-component cocrystal with the molar ratio of Tranexamic acid: nicotinamide: kojic acid = 1: 1: 1.

FIG. 2 shows an XRD overlay graph after formation of XRD and co-crystal of each of the three components. Comparing the XRD 2-theta diffraction angles of the crystalline XRD of each individual component with the XRD 2-theta diffraction angle of the three-component cocrystal of the present invention, it can be seen that in the three-component cocrystal, a new peak that does not exist in the individual crystalline form is observed. You can also see the difference. SW27: three-component cocrystal

3A shows XRD data of kojic acid. 3b shows XRD data of nicotinamide. 3C shows the XRD data of tranexamic acid. FIG. 3D shows the XRD data of the three component cocrystal with the ratio of tranexamic acid: nicotinamide: kojic acid = 1: 1: 1.

4A-4B show FT-IR data of kojic acid. 4C-4D show FT-IR data of nicotinamide. 4E-4F show FT-IR data of tranexamic acid. 4G-4H show FT-IR data of three-component co-crystals with tranexamic acid: nicotinamide: kojic acid = 1: 1: 1 molar ratio. Fig. 4i shows the FT-IR overlay graph after formation of the FT-IR and the co-crystal of each of the three components. The FT-IR overlap of FIG. 4I shows the difference between the crystalline form of each individual component and the pattern of infrared wavelengths of the three-component cocrystal of the present invention. SW27: three-component cocrystal

Fig. 5 shows the results of differential scanning dose meter (DSC) measurement of three-component cocrystals having a ratio of tranexamic acid: nicotinamide: kojic acid = 1: 1: 1.

Hereinafter, the present invention will be described in more detail with reference to Examples. These examples are intended to illustrate the present invention in more detail, and it is apparent to those skilled in the art that the scope of the present invention is not limited by these examples according to the gist of the present invention.

Example

Example 1 Cocrystal Formation of Tranexamic Acid, Nicotinamide and Kojic Acid

15.7 g of tranexamic acid and 12.2 g of nicotinamide were added to 70 ml of methanol, and stirred for 20 minutes, and then concentrated under reduced pressure at 45-50 ° C. for 30 minutes. Then, 50 ml of methanol was added thereto, stirred for 30 minutes, and concentrated under reduced pressure at 45-50 ° C. for 1 hour. 14.2 g of kojic acid was added thereto, 100 ml of methanol was added thereto, and after stirring for 30 minutes at room temperature, the methanol was concentrated under reduced pressure at 45-50 ° C. 150 ml of methanol was further added thereto, and vigorously stirred at room temperature for 30 minutes, followed by concentration under reduced pressure. 120 ml of cyclohexane was added to the concentrated product, the mixture was stirred at room temperature for 1 hour, filtered, and hot-air dried at 50 ° C. to obtain the desired tricomponent crystalline compound in a yield of 90%.

The obtained compound has a 2θ diffraction angle of 8.44 ± 0.2 °, 10.60 ± 0.2 °, 14.18 ± 0.2 °, 18.01 ± 0.2 °, 19.25 ± 0.2 °, 21.30 ± 0.2 ° and 25.45 ± 0.2 ° in powder X-ray diffraction (PXRD) analysis. Each of the specific peaks in the, characterized in that the endothermic peak at the endothermic onset temperature 96 ± 2 ℃, endothermic temperature 99 ± 3 ℃ in the differential scanning calorimetry (DSC) analysis.

Example 2: Preparation of Cocrystal with Various Molar Ratios of Three Components

The inventors have attempted to optimize the reaction by varying the molar ratio of the blending ratio of the respective whitening active ingredients. With the content of the composition of the corresponding component recommended for cosmetics in mind, in consideration of the molecular weight of each of the substances in various ratios of molar ratios through the production of two-component cocrystal to try to complete the three-component cocrystal.

Table 1 below shows the sequence and the molar ratio of each attempted to prepare the three-component cocrystal.

Reaction Sequence and Equivalence of Three-Component Cocrystal

Method 1: Reaction of konexic acid with nicotinamide followed by tranexamic acid
-	Kojic acid	Nicotinamide	Tranexamsan
Equivalent (molar ratio)	One	One	One
	One	One	2
	One	2	One
	2	One	One
	One	2	2
	2	One	2
	2	2	One
Method 2: Nicotinamide Reaction After Kojic Acid + Tranexamic Acid Reaction
-	Kojic acid	Nicotinamide	Tranexamsan
Equivalent (molar ratio)	One	One	One
	One	One	2
	One	2	One
	2	One	One
	One	2	2
	2	One	2
	2	2	One
Method 3: Sequence of Kojic Acid after Tranexamic Acid + Nicotinamide Reaction
-	Kojic acid	Nicotinamide	Tranexamsan
Equivalent (molar ratio)	One	One	One
	One	One	2
	One	2	One
	2	One	One
	One	2	2
	2	One	2
	2	2	One

In addition, the present inventors conducted a study to prepare a cocrystal by the ratio of Table 1 under various reaction conditions (stirring time and temperature, solvent). The reaction was carried out by stirring for a certain period of time under a specific solvent, and the crystalline form obtained through filtration and drying of the precipitated solid was analyzed. After many trials and trials, the crystalline form of the three components has a molar ratio of about 1: 1: It was found that when 1, a new crystalline form was formed which was completely different from the mixture and had new properties. For example, in the reaction of tranexamic acid with nicotinamide and kojic acid, the mixing ratio is 1: 2: 1 or 1: 1: 2. Even in the case of the stepwise reaction of 2: 1: 1 or 1: 2: 2, 2: 1: 2, 2: 2: 1, the fixed solids obtained by filtering and washing the precipitated solid It was confirmed that the stable solid form to be maintained was 1: 1: 1.

When the solvent is treated under the condition that the extra single active ingredient which does not form coctalite is washed away, coctaltal is obtained in a ratio of 1: 1: 1 as a stable crystalline solid, which is exactly also tranexamic acid and nicotine. The amide was first reacted to obtain a bicomponent cocrystal of 1: 1, and it was confirmed that a stable new crystalline form could be obtained only when the kojic acid was reacted with the equivalent thereto.

On the other hand, under solvent conditions where no extra single active ingredient is washed off, solids in the form of a mixture of cocrystal and a surplus of a single component may be obtained or in the form of a mixture of individual crystalline forms instead of forming a specific crystalline form. It was confirmed.

In the present invention, the 1: 1: 1 crystalline solid could be obtained by inducing a step reaction and precipitation under organic solvent conditions, but the reaction yield was low and required improvement. This is due to the loss of reactants that are washed off through filtration and washing, and because of the low overall yield, new methods have to be devised for industrial use. Therefore, the present inventors found that 1: 1: 1 crystalline form was the most thermodynamically stable crystalline form, and attempted to optimize the method of efficiently obtaining such crystalline form by minimizing the loss of reaction and industrially using a number of trials and errors. A production method was established which yields three component crystalline forms with possible excellent yields.

Example 3: Stability Test of Cocrystal

It was confirmed that the three-component cocrystal of the present invention may have advantages not only as a solid raw material but also as a liquid component such as a cosmetic composition. Among the three components, kojic acid is weak to light and heat, and in aqueous solution, it becomes colored by oxidation reaction over time. The color change due to the decomposition of kojic acid in aqueous solution ranges from pale yellow to dark yellow to brown.

Table 2 shows the degree of discoloration over time after adding kojic acid and tricomponent cocrystal in an aqueous solution. A 1% aqueous solution was made and stored on the basis of kojic acid, and photographed under the same conditions on Day 1, Day 7, and Day 28, and compared with the values of the yellow color chart of 20 steps. Sample A was prepared by dissolving 1 g of kojic acid in distilled water to obtain a total weight of 100 g.Sample B was dissolved in distilled water by dissolving 2.966 g of kojic acid, tranexamic acid, and nicotinamide three-component cocrystals having a 1: 1: 1 ratio. The weight is 100 g, and the kojic acid contained in the two aqueous solutions corresponds to 1% concentration.

The change of yellow color according to the change of the kojic acid 1% solution (Sample A) and the 3-component cocrystal solution (Sample B) containing 1% kojic acid

Sample

Day 1	Day 7	Day 28
A	One	8	20
B	One	2	3

By the end of Day 28, Sample A turned dark yellow, while Sample B retained the pale yellow color (level 3) color, so that the three-component cocrystal solution suppressed the discoloration caused by the decomposition of kojic acid in the liquid phase. You can see that. This result means that the remaining two components of the three-component cocrystal contribute to the stabilization of kojic acid in the aqueous phase.

Claims (9)

1. Process for preparing a three component cocrystal comprising the following steps:

   Preparing a two-component cocrystal by stirring two components selected from the group consisting of tranexamic acid, nicotinamide and kojic acid by stirring in an alcohol solvent; And

   Preparing a three-component cocrystal by stirring the remaining one-component other than the two-component and the two-component cocrystal under an alcohol solvent.
2. The method of claim 1, wherein the bicomponent cocrystal is prepared by (i) stirring the bicomponent in an alcohol solvent for 10-30 minutes, and then concentrating at 40-55 ° C; And (ii) adding alcohol to the resultant of step (i), stirring for 20-40 minutes, and then concentrating at 40-55 ° C.
3. The method of claim 1, wherein the three-component cocrystal is prepared by (i) mixing the remaining components other than the two-component cocrystal with the two-component cocrystal, stirring for 20-40 minutes in an alcohol solvent, and then concentrating at 40-55 ° C. step; And (ii) adding alcohol to the resultant of step (i) and stirring at room temperature, followed by concentration.
4. The method of claim 3, wherein the method further comprises the steps of (i) and (ii), and then adding a nonpolar solvent to the reaction product of step (ii), stirring at room temperature, and then filtering. Manufacturing method.
5. The method of claim 1, wherein the alcohol is selected from the group consisting of C ₁ to C ₄ lower alcohols and mixed solvents thereof.
6. The method according to claim 1, wherein the production method is a two-component cocrystal with trinecsamic acid and nicotinamide first, followed by reacting the two-component cocrystal with kojic acid to prepare a three-component cocrystal. Manufacturing method.
7. 7. The method according to claim 6, wherein the molar ratio of the three components in the three-component crystal is tranexamic acid: nicotinamide: kojic acid = 1: 1: 1.
8. A tricomponent cocrystal prepared by the method of claim 1, wherein the molar ratio of tricomponent in the cocrystal is trinexamic acid: nicotinamide: kojic acid = 1: 1: 1.
9. In powder X-ray diffraction (PXRD) analysis, the 2θ diffraction angles are specific at 8.44 ± 0.2 °, 10.60 ± 0.2 °, 14.18 ± 0.2 °, 18.01 ± 0.2 °, 19.25 ± 0.2 °, 21.30 ± 0.2 ° and 25.45 ± 0.2 °, respectively. The molar ratio of tranexamic acid: nicotinamide: kojic acid is characterized by a peak and an endothermic peak at an endothermic onset temperature of 96 ± 2 ° C. and an endothermic temperature of 99 ± 3 ° C. in a differential scanning calorimetry (DSC) analysis. 1 person Samsung Crystal.

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