EP3426631A1

EP3426631A1 - Aqueous n-acyl amino acid solutions

Info

Publication number: EP3426631A1
Application number: EP17707498.6A
Authority: EP
Inventors: Markus Nahrwold; Nadia KONATÉ
Original assignee: Minasolve Germany GmbH
Current assignee: Minasolve SAS
Priority date: 2016-03-08
Filing date: 2017-02-21
Publication date: 2019-01-16
Also published as: DE102016104205A1; US20190091124A1; MA43685A; CN108779065A; WO2017153161A1

Abstract

The invention relates to a method for synthesizing aqueous N-acyl amino acid solutions. Said method does not require any solid to be isolated and yields solutions that have a low impurity content. The invention further relates to the corresponding aqueous N-acyl amino acid solutions and the use thereof in cosmetic and pharmaceutical preparations.

Description

Aqueous solutions of / V-acyl amino acids

The invention relates to a process for the preparation of aqueous solutions of / V-acyl-amino acids. The process does not require isolation of a solid and gives solutions with a low content of impurities. Furthermore, the invention comprises the corresponding aqueous solutions of / V-acyl-amino acids, and their use in cosmetic and pharmaceutical preparations.

/ V-acyl amino acids ("lipoamino acids") are used in cosmetic and pharmaceutical products, examples of which are capryloylglycine (I) and undecylenoylglycine (II), which are the / V-acylamides of Amino acid glycine and the fatty acids caprylic acid (= octanoic acid) or undecenoic acid.

Capryloylglycine (I) is commercially available under the trade name "Caprocine" from MINASOLVE.Capryloylglycine has a broad antimicrobial activity against bacteria, fungi and yeasts.The substance can be used as a preservative and as a deodorant.In addition, capryloylglycine effectively inhibits the growth of The substance also inhibits the growth of the yeast Malassezia Furfur (Pityrosporum ovale), which contributes to the formation of dandruff on the scalp, and inhibits the enzyme 5-alpha reductase, Propionibacterium acnes, which is responsible for the development of acne. which positively regulates the production of sebum in the skin, so capryloylglycine can reduce sebum production in the skin, reducing the tendency to develop dandruff and acne / V acyl amino acids are generally low in toxicity and well tolerated by the skin is her application interesting in cosmetic and pharmaceutical products.

/ V-acyl amino acids are usually solids that are only moderately soluble in water. For incorporation into cosmetic or pharmaceutical formulations / V-acyl amino acids are therefore neutralized with the aid of bases and thus converted into their water-soluble carboxylic acid salts. In this case, strongly corrosive basic substances are often used. applies, for example, sodium hydroxide or potassium hydroxide. The strong bases are not compatible with all raw materials used in cosmetic or pharmaceutical preparations. In this case, the neutralization of the / V-acyl amino acids may need to be carried out in a separate stirred vessel. Alternatively, / V-acyl amino acids are dissolved in hot water or in another lipophilic solvent. In this type of application, the free / V-acyl amino acid causes a lowering of the pH in the formulation. This may also affect the stability of a formulation. In general, the handling of solids is associated with disadvantages. In general, it must be ensured by means of long stirring times that the solid has completely dissolved in the chosen solvent. Furthermore, it may lead to dust, the z. B. leads to irritation of the skin, eyes and / or respiratory tract. If necessary, it also leads to a contamination of the working environment. Overall, the use of solid / V-acyl amino acids is associated with an increased time, energy, material, and thus costs.

On an industrial scale, / V-acyl amino acids are prepared by condensation of amino acids with carboxylic acid chlorides or anhydrides in alkaline aqueous solution (Schotten-Baumann reaction). Examples of such syntheses are described in the literature, inter alia in FR 2771632 A1 (SEPPIC, priority: 01.12.1997) and WO2006 / 010590 A1 (Sinerga, priority: 30.07.2004). As a result of the chemical reaction results in a basic crude product solution, in addition to the / V-acyl-amino acid salt at least one inorganic salt such. As sodium chloride (NaCl) in equimolar amount. In principle, this non-purified aqueous / V-acyl amino acid solution can already be used as a raw material for cosmetic or pharmaceutical products. The disadvantage, however, is that the inorganic salts contained in the solution can interact with other components of a formulation. For example, such salts can affect the rheology of an emulsion or gel. Another disadvantage is the presence of free alkyl carboxylic acids in the crude product solution. Alkylcarboxylic acids are a by-product of the Schotten-Baumann synthesis which arise as a result of hydrolysis of the activated carboxylic acid. Depending on the length of their carbon chain alkylcarboxylic acids can irritate the skin and have a characteristic, inappropriate odor. Another drawback with the direct application of the non-purified / V-acyl-amino acid solutions in cosmetics is the occasional staining.

As a rule, the reaction mixtures obtained as described above are therefore further worked up. In the mixture contained / V-acyl amino acids are precipitated by acidification and the precipitated solid optionally with the aid of a suitable organic see (co) solvent crystallized. At the same time, this cleaning step also removes organic impurities, for example unreacted free amino acids. The isolation and drying of the purified solid, however, means an additional expenditure of labor time and material, which leads to higher production costs.

The object of the invention is the preparation of concentrated aqueous solutions of / V-acyl amino acids, which are obtained directly and without solids isolation from a reaction mixture. The aqueous concentrate should contain the / V-acyl-amino acid in high purity, while the by-products and waste products should be contained in the lowest possible concentration. The aqueous solution should also be chemically and physically stable over a wide temperature range, as odorless as possible and little colored.

The object has surprisingly been achieved by the production method described below:

• The basic crude product solution from a Schotten-Baumann reaction is acidified in the presence of an organic solvent. The solvent is selected from substances that are only slightly miscible with water, but at the same time form an azeotropic mixture with water. In the course of acidification, the N-acyl-amino acid passes into the organic solvent phase.

• Inorganic salts and free amino acids are removed by washing the organic product solution with water.

The organic product solution is extracted with an aqueous solution of a base.

The / V-acyl-amino acid passes as a water-soluble salt back into the aqueous solution.

After renewed phase separation, the solvent residues contained in the aqueous product solution are removed by azeotropic distillation. By further distillation of water further by-steam volatile by-products can be removed. This applies, for example, to the free alkylcarboxylic acids which are formed as hydrolysis products in the course of the Schotten-Baumann reaction. For this purpose, the pH during the distillation in a neutral range of about 6 - 7 set. In general, / V-acyl-amino acids are stronger acids than the alkyl-only fatty acids. Therefore, the fatty acids are in equilibrium at neutral pH in equilibrium partly as steam-volatile free carboxylic acids, while the / V-acyl amino acids are preferably present as non-volatile salts.

• A final pH adjustment to> 6.5 stabilizes the / V acyl amino acid as the carboxylic acid salt in the aqueous solution. The solutions obtained according to the invention are advantageous in many respects over the solids or salt-containing solutions known as prior art: they can easily be metered in as liquids and incorporated into liquid mixtures. They do not produce any or only slight pH changes. The solutions are practically free of inorganic salts, and thus show no negative interaction with salt-sensitive substances such as polymeric thickeners or salt-thickened surfactant gels. Furthermore, the solutions contain only a small amount of free alkylcarboxylic acids, which has a positive effect on their odor and their skin tolerance. In addition, the preparation of the solutions obtained according to the invention is inexpensive, since no solid / liquid T rennung is required.

Any aminocarboxylic acid (amino acid) can be used as starting material for the synthesis of the / V-acyl-amino acid. Chiral amino acids can be used both as enantiomerically pure or diastereomerically pure compounds, as well as mixtures of different stereoisomers. Any additional functional groups present within the amino acids are optionally protected by suitable protecting groups. Furthermore, short peptides with up to 6 amino acids can be used. Preferably, the amino acid component is selected from alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, glycylglycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, dihydroxyphenylalanine (DOPA), proline, serine, threonine, tryptophan , Tyrosine, valine, 3-aminopropionic acid (beta-alanine) and 4-aminobutyric acid (gamma-aminobutyric acid, GABA). Most preferably, the amino acid component is selected from glycine and glycylglycine.

The fatty acid component is selected from any aliphatic fatty acid having a chain length of 6 to 22 carbons, preferably 6 to 12 carbons. The fatty acid can be saturated, monounsaturated or polyunsaturated. It can contain either one or two carboxylic acid functions. Preferably, the / V -acyl amino acid contains at least one of the following radicals: hexanoyl (caproyl), heptanoyl (enanthoyl), octanoyl (capryloyl), nonanoyl (perlagonyl), decanoyl (caprinoyl), undecylenoyl, dodecanoyl (lauryl), tetradecanoyl (myristyl ), Hexadecanoyl (palmitoyl), heptadecanoyl (margarinoyl), octadecanoyl (stearyl), eicosanoyl (arachinoyl), docosanoyl (behenoyl), hexadecenoyl (palmitoleinoyl), octadecenoyl (oleyl), eicosenoyl (Gadoloyle), docosenoyl (erucyl), octadecadienoyl (linoloyl ), Octadecatrienoyl (linolenoyl), eicosatetraenoyl (arachidoyl). Particularly preferably, the / V-acyl-amino acid contains one of the radicals octanoyl (capryloyl) and undecylenoyl. For the synthesis of the / V-acyl-amino acid, the carboxylic acid can be activated as an acid halide, as a mixed anhydride or as a symmetrical anhydride. Preferably, the carboxylic acid is activated as the acid chloride.

To lower the pH of the crude product solution, any acid can be used whose acidity is higher than that of the synthesized / V-acyl-amino acid. Preference is given to using inorganic acids and / or their acid salts, e.g. Hydrochloric acid, sulfuric acid, sodium hydrogen sulfate, potassium hydrogen sulfate, phosphoric acid, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium dihydrogen phosphate and / or dipotassium hydrogen phosphate. The adjusted pH is <7. Preferably, the pH is between 0 and 5, more preferably between 0.5 and 3.0.

As organic solvents for the aqueous work-up of the / V-acyl-amino acid solution, it is possible to use any organic solvents which are immiscible or not completely miscible with water. Either individual solvents or solvent mixtures can be used. Preference is given to using esters (for example ethyl acetate, butyl acetate, isopropyl acetate, isobutyl acetate), ethers (for example ie / f-butylmethyl ether, diisopropyl ether, 2-methyltetrahydrofuran), aromatic hydrocarbons (for example toluene, xylene), aliphatic hydrocarbons (for example heptane, cyclohexane, Methylcyclohexane), ketones (eg ethyl methyl ketone, / so-butyl methyl ketone), halogenated hydrocarbons (eg dichloromethane, dichloroethane, chloroform) and / or alcohols (eg n-butanol, isobutanol, amyl alcohol). Particularly preferably used are ethyl acetate, toluene, 2-methyltetrahydrofuran and / or ie f-butyl methyl ether.

The phase separations in the course of the aqueous workup can be carried out at any temperature at which both phases are present as a liquid. Typically, this is the case at temperatures from -20 ° C to +100 ° C. Preferably, the phase separation is carried out at +10 ° C to +80 ° C, more preferably at +30 ° C to +60 ° C. The phase separation can also take place under overpressure.

The azeotropic distillation to remove excess organic solvent may be at any pressure. The distillation can be carried out at atmospheric pressure (1013 mbar ± 50 mbar) and / or in vacuo and / or under overpressure.

As the base during the Schotten-Baumann reaction and for the conversion of the / V-acyl-amino acid into the aqueous product solution, any alkali or alkaline earth bases can be used. be set. Preference is given to using sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate and / or potassium hydrogencarbonate. The bases used can be used either as solids or as aqueous solutions.

The pH of the / V-acyl amino acid solution prepared according to the invention can be between pH 5 and pH 14. Preferably, the final product solution is adjusted to a pH between pH 6.5 and pH 8.5 inclusive.

The concentration of the / V-acyl-amino acid in the prepared solutions according to the invention can be between 1% and 90%, preferably 10-50%, particularly preferably 20-40%. The values given are in terms of percent by weight based on the free N-acyl amino acid. In this case, the / V-acyl-amino acid is present mainly as a salt with the base used for the neutralization. However, depending on the pH, some of the N-acyl amino acid may be present as the free carboxylic acid.

Also according to the invention are prepared by the described method aqueous solutions of / V-acyl amino acids. The solutions according to the invention are clear, stable and homogeneous over a wide temperature range. Crystallization of the solid components at low temperature occurs as little as a chemical decomposition of the components at higher temperature. Preferably, the solutions according to the invention in a temperature range from -20 ° C to +80 ° C are physically and chemically stable. Typically, the aqueous solutions according to the invention are themselves conservative and thus stable to colonization or decomposition by microorganisms. Therefore, it is usually not necessary to protect the solutions of the invention with the help of additional preservatives.

If necessary, the solutions according to the invention may contain further auxiliaries. These may be, for example, preservatives, cosmetic solvents, surface-active substances (surfactants / emulsifiers) and / or water-soluble polyhydric alcohols.

The solutions according to the invention can be used as raw materials in cosmetics and / or personal care products and / or pharmaceutical preparations. They can fulfill functions that generally contribute to a positive influence on age-related and / or environmental skin or hair changes. They can be used, for example, as preservatives, deodorants, anti-acne agents, anti-dandruff agents, skin light, enzyme inhibitor and / or pH regulator can be used. Other possible applications without excluding character include the use as a conditioner, foam intensifier, (co) emulsifier and / or (co) surfactant, enzyme inhibitor, light and UV protection, and for the regulation of sebum production and / or influencing the rheology or Viscosity.

Using the solution according to the invention, it is also possible to produce a product, in particular a cosmetic and / or pharmaceutical and / or dermatological and / or hygienic product, containing a solution as explained above. In other words, the solution according to the invention is used in cosmetic and / or pharmaceutical and / or dermatological and / or hygienic products. As "hygienic preparation" or "hygienic product" in particular household or cleaning products, and fragrance preparations are understood.

The addition of the solutions according to the invention to the cosmetic and / or pharmaceutical and / or dermatological and / or hygienic product may take place at any time during production, e.g. during the production of an aqueous phase or at the end of the production process.

The solutions according to the invention are also used in a product, in particular a cosmetic or dermatological product, containing the solutions according to the invention, the product containing 0.05-10.0% by weight of at least one / V-acyl amino acid. The respective product can be present in any form, in particular as:

a. Solution,

b. Suspension,

c. Emulsion,

d. Gel,

e. Ointment,

f. Paste,

G. Powder,

H. in pieces or as a block of solid,

i. Foam,

j. formulation system based on microencapsulation, liposomes or similar microscopic structures,

k. Combinations of forms a - j Examples / experimental part

Example 1 - Preparation of an aqueous solution of capryloylgliccin:

Glycine (50 g) and sodium hydroxide (51 g) are dissolved in water (250 mL). Octanoyl chloride (87 g) is added. To the basic solution is added MTBE (500 mL), followed by 36% hydrochloric acid (50 g). The phases are separated and the organic phase is washed with water. Then the organic phase is treated with water (600 ml) and the pH of the mixture is adjusted to pH> 6.5 with sodium hydroxide. The organic phase is separated off. From the aqueous phase excess organic solvent and water are distilled off at atmospheric pressure until a concentration of 30 wt .-% of capryloylglycine based on the free acid is reached. The pH of the aqueous solution is finally adjusted to pH 7.5-8.5 with sodium bicarbonate. The solution contains <0.1% sodium chloride and <0.5% octanoic acid.

The 30% aqueous capryloylglycine solution meets the A criteria of a preservative loading test according to ISO 1 1930. Thus, this solution is protected against microbiological contamination. An additional preservative is not required.

Example 2 - Anti-Dandruff Shampoo:

Raw material suppliers: 1) Evonik, 2) BASF, 3) Minasolve, 4) Lubrizole, 5) SFA, 6) Orco

The raw materials of phase A are taken up with stirring in water. The solution according to the invention is added (phase B). The thickener (phase C) is added with vigorous stirring. The ingredients of phase D are added sequentially, followed by common salt (phase E). The mixture is stirred until the solid is completely dissolved. Finally, the pH is adjusted (phase F). The shampoo meets the A criteria of a preservative loading test according to ISO 1 1930. Example 3 - Facial Cleanser:

Raw Material Suppliers: 1) Dow; 2) Minasolve; 3) Jungbunzlauer; 4) BASF; 5) Evonik; 6) bell; 7) Orco

Methylcellulose is added with stirring at RT in water. The pH should not exceed 7.5 (phase A). Pentiol Green + and xanthan gum are mixed (Phase B) and the mixture is added to Phase A. The mixture is stirred until homogeneous. The solution according to Example 1 is added, followed by a little sodium hydroxide solution (phase C). The mixture is stirred for 15-20 minutes until fully thickened. Phase D surfactants are added with stirring in the order listed. Subsequently, the raw materials of phase E are added successively with stirring in the order given. Finally, the pH is adjusted. The product meets the A criteria of a preservative loading test according to ISO 1 1930.

Example 4 - Roll-On Deodorant:

Raw Material Suppliers: 1) Lubrizol, 2) Jungbunzlauer, 3) Minasolve, 4) SFA Carbopol is dispersed in water and stirred until fully hydrated. Xanthan gum is added and the mixture is stirred until the solid is completely dispersed (Phase A). The inventive solution according to Example 1 is added, followed by a little sodium hydroxide solution (Phase B). The raw materials of phase C are added with stirring. Finally, perfume is added, the pH adjusted and buffer solution added. The product meets the A criteria of a preservative loading test according to ISO 1 1930.

Example 5 - Skin Moisturizing O / W Lotion:

Raw Material Suppliers: 1) Minasolve, 2) Jungbunzlauer, 3) BASF, 4) AAK, 5) Caesar & Loretz

Xanthan gum is mixed with Pentiol Green + and then added with stirring in water. The mixture is stirred until homogeneous (phase A). The solution according to the invention (phase B) is added and the mixture is heated to 75-80 ° C. In a separate vessel, phase C is mixed and heated to 75-80 ° C. Phase C is added to Phase A + B while mixing with an Ultra-Turrax. The emulsion is stirred for 3 minutes at a high shear rate and then for a further 30 minutes with a propeller stirrer. During cooling, the stirrer speed is lowered. At T <40 ° C tocopherol is added (phase D). At room temperature, the pH is adjusted (phase E). The product meets the A criteria of a preservative loading test according to ISO 1 1930.

Comparative Example 6 Skin Moisturizing O / W Lotion Prepared with Solid Capryloyl Gliccin:

Phase raw material INCI name%

Water Aqua 60.6

A Pentiol Green + ⁽¹⁾ Pentylene Glycol 2.0

Xanthan Gum PC ⁽⁾ Xanthan gum 0.5

Water Aqua 20.0

B Sodium Hydroxide (50%) Aqua (and) Sodium Hydroxide 0.8

Caprocine ⁽¹⁾ Capryloyl Glycine 2.0 Emulgade PL 68/50 ⁽³⁾ Cetearyl Glucoside (and) Cetearyl Alcohol 5.0 c Lipex Sheasoft ⁽⁴⁾ Butyrospermum Parkii (Shea) Butter 3.0

Jojoba Oil ⁽⁵⁾ Simmondsia Chinensis (Jojoba) Seed 0/7 3.0

Hazelnut Seed Oil ⁽⁵⁾ Corylus Avellana (Hazel) Seed 0/7 3.0

D DL-a-tocopherol (> 97%) tocopherol 0.1

E Citric Acid (25%) Aqua (and) Citric Acid pH 5.5

Xanthan gum is mixed with Pentiol Green + and then added with stirring in water. The mixture is stirred until homogeneous (phase A). In a separate boiler, demineralized water is initially charged and mixed with aqueous sodium hydroxide solution. Then solid capryloyl glycine is added with stirring. The mixture is stirred until a clear solution has formed (phase B). Phase B is metered to Phase A and the mixture is then heated to 75-80 ° C. In a third separate vessel, phase C is mixed and heated to 75-80 ° C. Phase C is added to Phase A + B while mixing with an Ultra-Turrax. The emulsion is stirred for 3 minutes at a high shear rate and then for a further 30 minutes with a propeller stirrer. During cooling, the stirrer speed is lowered. At T <40 ° C tocopherol is added (phase D). At room temperature, the pH is adjusted (phase E). The product meets the A criteria of a preservative loading test according to ISO 1 1930.

Claims

claims

1 . A process for preparing an aqueous solution of an alkali or alkaline earth salt of capryloylglycic acid and / or undecenoylglycic acid, comprising the following steps:

(1) Condensation of an activated carboxylic acid from the group of 1-octanoic acid

(Caprylic acid) and undecenoic acid in the form of an acid halide, a mixed

Anhydride or a symmetrical anhydride with glycine in aqueous solution, to give a free N-acyl-glycine,

(2) acidifying the resulting solution and extracting the free / V-acyl-glycine into a water-immiscible organic solvent;

(3) conversion of the / V-acyl-glycine into an aqueous solution with the addition of base, and

(4) Removal of water vapor volatile impurities from the aqueous solution by azeotropic distillation of water.

2. The method according to claim 1, characterized in that the organic solvent used forms an azeotrope with water.

3. The method according to at least one of claims 1 and 2, characterized

characterized in that the capryloylglycine or undecenoylglycine as alkali or

Alkaline earth salt is transferred into an aqueous solution.

4. The method according to at least one of claims 1 to 3, characterized in that the capryloylglycine or undecenoylglycine is converted as sodium and / or potassium salt in an aqueous solution.

5. The method according to at least one of claims 1 to 4, characterized in that the free caprylic acid or undecenoic acid is removed by steam distillation at pH <8 from the aqueous capryloylglycine or undecenoylglycine solution.

6. The method according to at least one of claims 1 to 5, characterized in that the resulting aqueous solution 10-50 wt .-% of the respective salt of

Capryloylglycine or undecenoylglycine contains.

7. The method according to at least one of claims 1 to 6, characterized in that the resulting aqueous solution contains not more than 2 wt .-% of free caprylic acid or undecenoic acid.

8. The method according to any one of claims 1-7, characterized in that the obtained aqueous solution contains not more than 1 wt .-% of inorganic salts.

9. Use of a solution obtained according to claim 6 to 8 solution by incorporation into a cosmetic or dermatological product.

10. Use of a solution obtained according to claim 6 to 8 for

Growth inhibition or killing of microorganisms.

1 1. Use of a solution obtained according to claims 6 to 8 for the preservation of cosmetic or dermatological products.