Dihydroavenanthramide d powder

Abstract

The present invention relates to a method for producing a powder comprising Dihydroavenanthramide D and to a powder comprising Dihydroavenanthramide D.

Description

[0001] Dihydroavenanthramide D powder

[0002] The present invention relates to a method for producing a powder comprising Dihydroav- enanthramide D and to a powder comprising Dihydroavenanthramide D.

[0003] Dihydroavenanthramide D is a compound with particular importance in the cosmetic industry. Dihydroavenanthramide D belongs to the family of Avenanthramides, i.e. anthranilic acid amides, and is also described as hydroxyphenyl propamidobenzoic acid. Dihydroavenanthramide D is described by the CAS number 697235-49-7 (as listed by the European Chemicals Agency) and corresponds to the following chemical structure:

[0004] Dihydroavenanthramide D

[0005] Dihydroavenanthramide D has been described for several cosmetic applications. For example, WO 2006 / 134013 A1 describes an application of Dihydroavenanthramide D for alleviating itching and / or for reducing skin reddening. US 2006 / 089413 A1 describes that Dihydroavenanthramide D can be used forthe inhibition of the substance P-induced release of histamine from mast cells. In this way, pruritus, skin reddening, weal development or allergic skin reactions may be prevented.

[0006] Typically, Dihydroavenanthramide D is formulated in a cosmetic or pharmaceutical composition including further substances. Dihydroavenanthramide D is a rather lipophilic compound and has a poor solubility in aqueous solvents. Thus, Dihydroavenanthramide D is usually first dissolved in a suitable solvent and subsequently the obtained mixture is further processed to a cosmetic or pharmaceutical composition.

[0007] For further processing the mixture comprising Dihydroavenanthramide D to a cosmetic or pharmaceutical composition, it is important that Dihydroavenanthramide D is completely dissolved. Dissolving Dihydroavenanthramide D requires time, which is a rather critical factor in the production of cosmetic or pharmaceutical compositions, particularly in industrial scale. Time-consuming production steps increase the costs of the produced product and limit the maximum production quantities per time. Thus, it is particularly advantageous to reduce the required time of certain steps in production processes.

[0008] Thus, reducing the time required for dissolving, preferably completely dissolving, Dihydroavenanthramide D is highly advantageous. There is thus a need for improving the solubility properties of Dihydroavenanthramide D.

[0009] For the dissolution of Dihydroavenanthramide D, the substance is provided in powder form and dissolved in a solvent. However, one challenge of Dihydroavenanthramide D powder is that the powder often contains Dihydroavenanthramide D in agglomerates. Typically, Dihydroavenanthramide D forms crystals, which then agglomerate. These agglomerates are a challenge for completely dissolving Dihydroavenanthramide D, since the agglomerates tend to form larger and hardly dissolvable clots when added to a solvent. For dissolving these clots, much time and energy are required, which is generally to be reduced in larger- scale production processes.

[0010] The primary object of the present invention was thus to provide Dihydroavenanthramide D with improved solubility properties.

[0011] The primary object of the present invention is solved by a method for producing a powder comprising Dihydroavenanthramide D, wherein Dihydroavenanthramide D is present in the powder in crystalline form, wherein the Dihydroavenanthramide D crystals have a particle size d(0.5) of at least 30 pm the method comprising the steps i) providing Methyl 3-(4-hydroxyphenyl)propionate, ii) providing Methyl 2-aminobenzoate, iii) mixing the Methyl 3-(4-hydroxyphenyl)propionate provided in step i) with the Methyl 2-aminobenzoate provided in step ii), under conditions allowing a peptide coupling reaction, iv) drying the mixture obtained in step iii) to obtain a powder comprising crystallized Dihydroavenanthramide D v) optionally: recrystallizing the crystallized Dihydroavenanthramide D obtained after step iv), preferably in ethyl acetate, acetone, Methyl-tert-butylether, methanol, ethanol, propanol, preferably isopropanol, or a mixture thereof, and vi) optionally: drying the mixture obtained in step v) to obtain a powder comprising crystallized Dihydroavenanthramide D.

[0012] The term Methyl 3-(4-hydroxyphenyl)propionate preferably refers to the compound described by the Cas-No. 5597-50-2, further preferably by the following chemical structure:

[0013] The term Methyl 2-aminobenzoate preferably refers to the compound described by the Cas- No. 134-20-3, further preferably by the following chemical structure:

[0014] Methyl 2-aminobenzoate

[0015] It was surprisingly found that producing a powder comprising Dihydroavenanthramide D with the method according to the invention led to Dihydroavenanthramide D, which was present in larger crystals than when produced with other methods in the art. Furthermore, the Dihydroavenanthramide D crystals obtained with the method according to the invention did not show agglomeration or the agglomeration was strongly reduced.

[0016] Interestingly, the Dihydroavenanthramide D powder obtained with the method according to the invention was described as white, fine powder, whereas the Dihydroavenanthramide D powder obtained with other methods in the art was rather described as slightly yellowish and clumping powder.

[0017] It was surprisingly found that the powder obtained by the method according to the invention showed improved solubility properties compared to the powder obtained by another method in the art. It was found that the time for obtaining complete dissolution, for example in butylene glycol, was strongly reduced for the powder obtained by the method according to the invention.

[0018] The measurement of the geometrical dimensions (e.g. the diameter) of the particles and the size distribution profile as well as the mean particle size can be performed by any suitable method, such as e.g. photon correlation spectroscopy and laser diffraction. Preferably, in the context of the present invention the mean particle size is determined by using a particle size analyser (e.g. Mastersizer 2000, Malvern Panalytical GmbH, Kassel, Germany).

[0019] In the mixing step iii) of the method according to the invention it is preferred that Dihydroavenanthramide D is completely dissolved or essentially completely dissolved in the obtained mixture. Preferably, the term “essentially completely dissolved” describes that at least 80 wt.-%, preferably at least 85 wt.-%, further preferably at least 87.5 wt.-%, more preferably at least 90 wt.-%, particularly preferably at least 92.5 wt.-%, especially preferably at least 95 wt.- %, even further preferably at least 97.5 wt.-% of Dihydroavenanthramide D, based on the weight of Dihydroavenanthramide D provided in step i), is dissolved.

[0020] The term “coupling reaction”, as used herein, is known in the field of peptide synthesis. Typically, a carboxy group of a compound reacts with an amino group of another compound to form a peptide bond. An alternative to coupling reactions are condensation reactions to form a peptide bond. In case of a coupling reaction between Methyl 3-(4-hydroxy- phenyl)propionate and Methyl 2-aminobenzoate, the carboxymethyl group of Methyl 3-(4- hydroxyphenyl)propionate reacts with the amino group of Methyl 2-aminobenzoate to form a peptide bond and thus forming Dihydroavenanthramide D.

[0021] Preferably, in step iii) of the method according to the invention, the conditions allowing a peptide coupling reaction include a temperature in the range of from 0 to 120 °C, preferably of from 15 to 100 °C, further preferably of from 50 to 90 °C, particularly preferably of from 60 to 85 °C.

[0022] Preferably, in step iii) of the method according to the invention, the conditions allowing a peptide coupling reaction include a time in the range of from 5 min to 24h, preferably of from 10 min to 21 h, further preferably of from 0.5 to 18 h, particularly preferably of from 0.75 to 15 h, especially preferably of from 1 to 10 h.

[0023] Preferably, in step iii) of the method according to the invention, the conditions allowing a peptide coupling reaction include a solvent, preferably water.

[0024] Preferably, in step iii) of the method according to the invention, the conditions allowing a peptide coupling reaction include a solvent-free reaction.

[0025] Preferably in step iii) of the method according to the invention, the Methyl 3-(4-hydroxy- phenyl)propionate provided in step i) and the Methyl 2-aminobenzoate provided in step ii) are mixed with one, two or all solvents) selected from the group consisting of Dimethylformamide, preferably N,N-Dimethylformamide, water and 2-Butoxyethanol. Thus, the method according to the invention preferably further includes the step providing one, two or all solvents) selected from the group consisting of Dimethylformamide, preferably N,N-Dimethylformamide, water, and 2-Butoxyethanol.

[0026] It was surprisingly found that the presence of Dimethylformamide, preferably N,N-Dime- thylformamide, water, and / or 2-Butoxyethanol facilitates the coupling reaction and thus increases the yield of the formed Dihydroavenanthramide D.

[0027] Preferably, mixing Methyl 3-(4-hydroxyphenyl)propionate and Methyl 2-aminobenzoate with one or both solvent(s) as described above may be performed in any order of the compounds to be mixed (e.g. Methyl 3-(4-hydroxyphenyl)propionate and Methyl 2-aminoben- zoate may be mixed first and afterwards one or both solvents are admixed, or Methyl 3-(4- hydroxyphenyl)propionate or Methyl 2-aminobenzoate is mixed with one or both solvents first and then the other compound is admixed, wherein the other compound may be mixed with one or both solvents as well before admixing).

[0028] Dimethylformamide is an organic compound with the formula (CH3)2NC(O)H. Preferably, the term Dimethylformamide refers to / V, / V-Dimethylformamide, which is described by the Cas-No. 68-12-2, preferably by the following chemical structure:

[0029] / V, / V-Dimethylformamide

[0030] 2-Butoxyethanol is an organic compound of the family of glycol ethers with the chemical formula BUOC2H4OH (Bu = CH3CH2CH2CH2). Typically, 2-Butoxyethanol is also named as ethylene glycol monobutyl ether. Preferably, 2-Butoxyethanol is described by the Cas-No. 111-76-2, preferably by the following chemical structure:

[0031] 2-Butoxyethanol Preferably, Dimethylformamide and 2-Butoxyethanol are admixed in step iii) of the method according to the invention, wherein the weight ratio of the Dimethylformamide to the 2- Butoxyethanol admixed in step iii) is in a range of from 1 :5 to 15:1 , preferably in a range of from 1 :2 to 10:1 , further preferably in a range of from 1 :1 to 5:1 , especially preferably in a range of from 1.5:1 to 2:1.

[0032] Preferably, in step iv) of the method according to the invention, the drying is performed by drum drying.

[0033] Preferably, the drying in step iv) of the method according to the invention is performed to achieve a water content of at most 5 wt.-% water, preferably at most 4 wt.-% water, preferably at most 3 wt.-% water, preferably at most 2 wt.-% water, preferably at most 1 wt.-% water, preferably of at most 0.75 wt.-%, particularly preferably of at most 0.5 wt.-%, further preferably of at most 0.25 wt.-%, even further preferably of at most 0.1 wt.-%, based on the total weight of the dried mixture.

[0034] Preferably, in step vi) of the method according to the invention, the drying is performed by drum drying.

[0035] Preferably, the drying in step vi) of the method according to the invention is performed to achieve a water content of at most 5 wt.-% water, preferably at most 4 wt.-% water, preferably at most 3 wt.-% water, preferably at most 2 wt.-% water, preferably at most 1 wt.-% water, preferably of at most 0.75 wt.-%, particularly preferably of at most 0.5 wt.-%, further preferably of at most 0.25 wt.-%, even further preferably of at most 0.1 wt.-%, based on the total weight of the dried mixture.

[0036] Preferably in step v) of the method according to the invention, the solid components are dissolved in the recrystallization medium, preferably ethyl acetate, acetone, Methyl-tert- butylether, methanol, ethanol, propanol, preferably isopropanol, or a mixture thereof, in a weight ratio of 1 : 5 (solid components : recrystallization medium), preferably in boiling heat. It is preferred that the obtained solution is subsequently cooled down and treated with ultrasound or a seed crystal to promote the recrystallization.

[0037] Preferably, the weight ratio of the Methyl 3-(4-hydroxyphenyl)propionate to the Methyl 2- aminobenzoate admixed in step iii) is in a range of from 1 :5 to 25:1 , preferably in a range of from 1 :3 to 20:1 , further preferably in a range of from 1 :1 to 15:1 , especially preferably in a range of from 3:1 to 10:1 , more preferably in a range of from 4:1 to 7.5:1 , even further preferably in a range of from 5.5:1 to 6:1 .

[0038] The present invention further relates to a powder, comprising a) Dihydroavenanthramide D, and b1) Methyl 3-(4-hydroxyphenyl)propionate, and / or b2) Methyl 2-aminobenzoate, wherein Dihydroavenanthramide D is present in crystalline form, wherein the Dihydroavenanthramide D crystals have a particle size d(0.5) of at least 30 pm.

[0039] What was said herein with regard to the method according to the invention applies accordingly to the powder according to the invention.

[0040] As described above, the powder obtained by the method according to the invention provides several advantages. The method according to the invention includes a reaction of Methyl 3-(4-hydroxyphenyl)propionate with Methyl 2-aminobenzoate. Typically, these educts are not consumed to 100 % and a part of the educt(s) remains. Thus, the presence of one or both of these compounds may indicate that the method according to the invention was used for producing the powder. Thus, the powder typically provides the advantages described herein.

[0041] Preferably, the powder according to the invention comprises b1) Methyl 3-(4-hydroxy- phenyl)propionate, and b2) Methyl 2-aminobenzoate.

[0042] As described above, it was surprisingly found that the Dihydroavenanthramide D crystals in the powder obtained with the method according to the invention were larger than the Dihydroavenanthramide D crystals obtained with other methods in the art. It was found that the Dihydroavenanthramide D crystals of the powder obtained with the method according to the invention have a particle size d(0.5) of at least 30 pm, wherein the particle size d(0.5) of the Dihydroavenanthramide D crystals obtained with other methods in the art have a smaller particle size d(0.5). It is preferred for the powder according to the invention that the Dihydroavenanthramide D crystals have a particle size d(0.5) of at least 35 pm, preferably at least 40 pm, particularly preferably at least 45 pm, preferably wherein the Dihydroavenanthramide D crystals have a particle size d(0.5) in the range of from 35 to 100 pm, preferably in the range of from 40 to 80 pm, particularly preferably in the range of from 42.5 to 60 pm., especially preferably in the range of from 45 to 50 pm.

[0043] Further preferably in the powder according to the invention, the Dihydroavenanthramide D crystals have a particle size d(0.9) of at least 140 pm, preferably at least 150 pm, particularly preferably at least 160 pm, preferably wherein the Dihydroavenanthramide D crystals have a particle size d(0.9) in the range of from 140 to 200 pm, preferably in the range of from 150 to 190 pm, particularly preferably in the range of from 160 to 170 pm.

[0044] It was found that larger particle sizes contribute to the improved solubility properties as described herein. However, it was found that the described particle size d(0.5) was only obtained with the method according to the invention. The same applies accordingly for the particle size d(0.9).

[0045] It is preferred for the powder according to the invention that the powder further comprises c) one or more solvent(s) selected from the group consisting of Dimethylformamide, preferably / V, / V-Dimethylformamide, and 2-Butoxyethanol.

[0046] Preferably, the powder according to the invention further comprises c) Dimethylformamide.

[0047] Preferably, the powder according to the invention further comprises c) 2-Butoxyethanol.

[0048] Preferably, the powder according to the invention further comprises c) Dimethylformamide and 2-Butoxyethanol.

[0049] Preferably, the powder according to the invention further comprises c) / V, / V-Dimethylformamide and 2-Butoxyethanol.

[0050] Preferably, the powder according to the invention comprises Dihydroavenanthramide D, Methyl 3-(4-hydroxyphenyl)propionate, Methyl 2-aminobenzoate, Dimethylformamide, preferably / V, / V-Dimethylformamide, and 2-Butoxyethanol.

[0051] It is preferred that the amount of Dihydroavenanthramide D in the powder according to the invention is at least 50 wt.-%, preferably at least 60 wt.-%, preferably at least 70 wt.-%, preferably at least 75 wt.-%, preferably at least 80 wt.-%, preferably at least 85 wt.-%, preferably at least 90 wt.-%, preferably at least 92.5 wt.-%, preferably at least 95 wt.-%, preferably at least 97.5 wt.-%, preferably at least 99 wt.-%, based on the total weight of the powder.

[0052] It is preferred that the amount of Methyl 3-(4-hydroxyphenyl)propionate in the powder according to the invention is in a range of from 0.01 to 30 wt.-%, preferably of from 0.1 to 25 wt.-%, preferably of from 0.5 to 20 wt.-%, preferably of from 1 to 15 wt.-%, preferably of from 2.5 to 10 wt.-%, preferably of from 3 to 8 wt.-%, based on the total weight of the powder.

[0053] It is preferred that the amount of Methyl 2-aminobenzoate in the powder according to the invention is in a range of from 0.01 to 30 wt.-%, preferably of from 0.1 to 25 wt.-%, preferably of from 0.5 to 20 wt.-%, preferably of from 1 to 15 wt.-%, preferably of from 2.5 to 10 wt.-%, preferably of from 3 to 8 wt.-%, based on the total weight of the powder.

[0054] It is preferred that the amount of Dimethylformamide, preferably / V, / V-Dimethylformamide, in the powder according to the invention is in a range of from 0.01 to 30 wt.-%, preferably of from 0.1 to 25 wt.-%, preferably of from 0.5 to 20 wt.-%, preferably of from 1 to 15 wt.- %, preferably of from 2.5 to 10 wt.-%, preferably of from 3 to 8 wt.-%, based on the total weight of the powder.

[0055] It is preferred that the amount of Dimethylformamide, preferably / V, / V-Dimethylformamide, in the powder according to the invention is in a range of from 0.01 to 30 wt.-%, preferably of from 0.1 to 25 wt.-%, preferably of from 0.5 to 20 wt.-%, preferably of from 1 to 15 wt.- %, preferably of from 2.5 to 10 wt.-%, preferably of from 3 to 8 wt.-%, based on the total weight of the powder the amount of Dimethylformamide, preferably / V, / V-Dimethylforma- mide, in the powder according to the invention is in a range of from 0.01 to 30 wt.-%, preferably of from 0.1 to 25 wt.-%, preferably of from 0.5 to 20 wt.-%, preferably of from 1 to 15 wt.-%, preferably of from 2.5 to 10 wt.-%, preferably of from 3 to 8 wt.-%, based on the total weight of the powder.

[0056] It is preferred that the powder according to the invention has a water content of at most 5 wt.-% water, preferably at most 4 wt.-% water, preferably at most 3 wt.-% water, preferably at most 2 wt.-% water, preferably at most 1 wt.-% water, preferably of at most 0.75 wt.-%, particularly preferably of at most 0.5 wt.-%, further preferably of at most 0.25 wt.-%, even further preferably of at most 0.1 wt.-%, based on the total weight of the powder.

[0057] Preferably, the water content as described herein is determined by Karl-Fisher Titration, loss-on-drying method or by a halogen moisture analyser.

[0058] Further preferably, the powder according to the invention is obtainable or obtained by a method according to the invention. The method according to the invention leads to Dihy- droavenanthramide D with the properties described herein, particularly the size and characteristics of the Dihydroavenanthramide D crystals and the improved solubility properties. Thus, the powder obtainable or obtained by a method according to the invention also shares the properties as described herein.

[0059] Fig. 1 shows the results of the visual assessment of Example 3.

[0060] Fig. 2 shows the results of the microscopical assessment of Example 4.

[0061] Further aspects and advantages of the invention result from the subsequent description of preferred examples. Examples

[0062] Example 1 : Producing Dihydroavenanthramide D

[0063] Methyl 3-(4-hydroxyphenyl)propionate and Methyl 2-aminobenzoate were provided in a weight ratio of 5.8 (Methyl 3-(4-hydroxyphenyl)propionate to Methyl 2-aminobenzoate).

[0064] Further, N,N-Dimethylformamide and 2-Butoxyethanol were provided in a weight ratio of 1 .75 (N,N-Dimethylformamide to 2-Butoxyethanol).

[0065] All compounds were mixed and a peptide coupling reaction was performed at a temperature of 75 °C for 10 min. The obtained mixture was then dried to a water content < 0.1 wt.- %.

[0066] The obtained powder was analysed by GC-MS and a high yield of Dihydroavenanthramide D was confirmed.

[0067] Example 2: Producing Dihydroavenanthramide D (comparative example)

[0068] Anthranilic acid is refluxed with Meldrum’s acid in toluene for 3h.

[0069] The obtained product is mixed with 4-hydroxy-benzaldehyde in a 1 :1 ratio and refluxed with 1 eguivalent piperidine in toluene (10:1) for 2h. Reaction water is removed and the mixture is cooled, precipitated and filtered. The obtained product is crystallized with acetone / etha- nol.

[0070] The crystallized product is filtered and washed with water until all chloride is removed. The obtained product is dried and recrystallized with acetone / ethanol.

[0071] A corresponding process is published as Mierina, Inese; et al, The role of carboxylic group position on the antiradical activity of synthetic analogues of oat antioxidants, Journal of Chemical and Pharmaceutical Research 7(6), 2015, 416-427.

[0072] The obtained product is hydrated at a pressure of < 20 bar and over Pd / C in methanol for 8 h at room temperature. A corresponding process is published as Liang, Weizhou; et al, Preparation of 2(3-phe- nylpropanoylamino)benzoic acid derivatives, and CN1 15626879 A.

[0073] The obtained powder was analysed by GC-MS and a high yield of Dihydroavenanthramide D was confirmed.

[0074] Example 3: Visual assessment

[0075] The powders of Example 1 and 2 were produced and visually assessed after the production and after 4 weeks of storage.

[0076] It was found that the powder of Example 1 was a white, fine powder. The powder of Example 2 was slightly yellowish and clumping. The results are shown in Fig. 1 .

[0077] Example 4: Microscopical assessment

[0078] The powders of Example 1 and 2 were produced and assessed by microscopy with a 10x magnitude.

[0079] It was found that the powder of Example 1 showed larger crystals than the powder of Example 2. Furthermore, the powder of Example 1 did not show agglomeration, whereas agglomerates were present in the powder of Example 2. The results are shown in Fig. 2.

[0080] Example 5: Chromametry

[0081] The powders of Example 1 and 2 were produced and completely dissolved in a mixture of butylene glycol and pentylene glycol (weight ratio: 1 :1) and measured with a chromameter.

[0082] The following results were obtained: It was found that the solution containing the powder of Example 2 was slightly more yellowish than the solution containing the powder of Example 1 .

[0083] Example 6: Particle size distribution

[0084] The powders of Example 1 and 2 were produced and analysed with the Mastersizer 2000 (Malvern Panalytical GmbH, Kassel, Germany).

[0085] A particle size d(0.5) of 46.579 and a particle size d(0.9) of 163.476 was measured for the powder of Example 1 .

[0086] The particle size of the powder of Example 2 was also measured, however due to the formation of agglomerates, no unambiguous measurement result could be obtained, since the agglomerates were considered by the Mastersizer 2000 as (very large) particles. Nevertheless, it could be observed that - except for the very large particles - the particle sizes of the powder of Example 2 was in total lower than for the powder of Example 1 .

[0087] Example 7: Solubility assessment

[0088] The powders of Example 1 and 2 were produced.

[0089] Butylene glycol was heated to 70 °C. Pentylene glycol was added while stirring to obtain a mixture M1 .

[0090] Due to the addition of the pentylene glycol, the mixture M1 was cooled to 60 °C and the powder of Example 1 or, respectively, Example 2 was added. Directly after adding the powder, the obtained mixture was stirred and the solubility was visually assessed by eye.

[0091] It was found that the powder of Example 1 was distributed over the whole volume of the mixture M1 when added. In contrast, the powder of Example 2 was mainly sinking to the bottom of the flask when added.

[0092] Both powders distributed over the volume of the mixture when the mixture was stirred.

[0093] However, after 5 minutes of stirring, the mixture including Example 1 was more translucent than the mixture including Example 2, which showed a rather white, milky appearance. After 10 minutes of stirring, this effect was even more pronounced. Thus, the powder of Example 1 was dissolved faster than the powder of Example 2, even though the same conditions were applied for dissolution.

Claims

Claims1 . Method for producing a powder comprising Dihydroavenanthramide D, wherein Dihydroavenanthramide D is present in the powder in crystalline form, wherein the Dihydroavenanthramide D crystals have a particle size d(0.5) of at least 30 pm, the method comprising the steps i) providing Methyl 3-(4-hydroxyphenyl)propionate, ii) providing Methyl 2-aminobenzoate, iii) mixing the Methyl 3-(4-hydroxyphenyl)propionate provided in step i) with the Methyl 2-aminobenzoate provided in step ii), under conditions allowing a peptide coupling reaction, iv) drying the mixture obtained in step iii) to obtain a powder comprising crystallized Dihydroavenanthramide D v) optionally: recrystallizing the crystallized Dihydroavenanthramide D obtained after step iv), preferably in ethyl acetate, acetone, Methyl-tert- butylether, methanol, ethanol, propanol, preferably isopropanol, or a mixture thereof, and vi) optionally: drying the mixture obtained in step v) to obtain a powder comprising crystallized Dihydroavenanthramide D.

2. Method according to claim 1 , wherein in step iii), the Methyl 3-(4-hydroxy- phenyl)propionate provided in step i) and the Methyl 2-aminobenzoate provided in step ii) are mixed with one, two or all solvents) selected from the group consisting of Dimethylformamide, preferably N,N-Dimethylformamide, water and 2-Butoxyethanol.

3. Method according to claim 1 or 2, wherein the weight ratio of the Methyl 3-(4- hydroxyphenyl)propionate to the Methyl 2-aminobenzoate admixed in step iii)is in a range of from 1 :5 to 25:1 , preferably in a range of from 1 :3 to 20:1 , further preferably in a range of from 1 :1 to 15:1 , especially preferably in a range of from 3:1 to 10:1 , more preferably in a range of from 4:1 to 7.5:1 , even further preferably in a range of from 5.5:1 to 6:1 .

4. Method according to any of the preceding claims, wherein in step iv) and / or in step vi) the powder is dried to a water content of at most 5 wt.-% water, preferably at most 4 wt.-% water, preferably at most 3 wt.-% water, preferably at most 2 wt.-% water, preferably at most 1 wt.-% water, preferably of at most 0.75 wt.-%, particularly preferably of at most 0.5 wt.-%, further preferably of at most 0.25 wt.-%, even further preferably of at most 0.1 wt.-%, based on the total weight of the powder.

5. Powder, comprising a) Dihydroavenanthramide D, and b1) Methyl 3-(4-hydroxyphenyl)propionate, and / or b2) Methyl 2-aminobenzoate, wherein Dihydroavenanthramide D is present in crystalline form, wherein the Dihydroavenanthramide D crystals have a particle size d(0.5) of at least 30 pm.

6. Powder according to claim 5, wherein the Dihydroavenanthramide D crystals have a particle size d(0.5) of at least 35 pm, preferably at least 40 pm, particularly preferably at least 45 pm, preferably wherein the Dihydroavenanthramide D crystals have a particle size d(0.5) in the range of from 35 to 100 pm, preferably in the range of from 40 to 80 pm, particularly preferably in the range of from 42.5 to 60 pm., especially preferably in the range of from 45 to 50 pm.

7. Powder according to any of claims 5 to 6, wherein the Dihydroavenanthramide D crystals have a particle size d(0.9) of at least 140 pm, preferably at least 150 pm, particularly preferably at least 160 pm, preferably wherein the Dihydroavenanthramide D crystals have a particle size d(0.9) in the range of from 140 to 200 pm, preferably in the range of from 150 to 190 pm, particularly preferably in the range of from 160 to 170 pm.

8. Powder according to any of claims 5 to 7, further comprising c) one or more solvent(s) selected from the group consisting of Dimethylformamide, preferably / V, / V-Dimethylformamide, and 2-Butoxyethanol.

9. Powder according to any of claims 5 to 8, wherein the amount of Dihydroavenanthramide D in the powder according to the invention is at least 50 wt.-%, preferably at least 60 wt.-%, preferably at least 70 wt.-%, preferably at least 75 wt.-%, preferably at least 80 wt.-%, preferably at least 85 wt.-%, preferably at least 90 wt.-%, preferably at least 92.5 wt.-%, preferably at least 95 wt.-%, preferably at least 97.5 wt.-%, preferably at least 99 wt.-%, based on the total weight of the powder.

10. Powder according to any of claims 5 to 9, wherein the amount of Methyl 3-(4- hydroxyphenyl)propionate in the powder according to the invention is in a range of from 0.01 to 30 wt.-%, preferably of from 0.1 to 25 wt.-%, preferably of from 0.5 to 20 wt.-%, preferably of from 1 to 15 wt.-%, preferably of from 2.5 to 10 wt.-%, preferably of from 3 to 8 wt.-%, based on the total weight of the powder, and / or wherein the amount of Methyl 2-aminobenzoate in the powder according to the invention is in a range of from 0.01 to 30 wt.-%, preferably of from 0.1 to 25 wt.-%, preferably of from 0.5 to 20 wt.-%, preferably of from 1 to 15 wt.-%, preferably of from 2.5 to 10 wt.-%, preferably of from 3 to 8 wt.-%, based on the total weight of the powder.11 . Powder according to any of claims 5 to 10, wherein the amount of Dimethylformamide, preferably / V, / V-Dimethylformamide, in the powder according to the invention is in a range of from 0.01 to 30 wt.-%, preferably of from 0.1 to25 wt.-%, preferably of from 0.5 to 20 wt.-%, preferably of from 1 to 15 wt.-%, preferably of from 2.5 to 10 wt.-%, preferably of from 3 to 8 wt.-%, based on the total weight of the powder, and / or wherein the amount of Dimethylformamide, preferably / V, / V-Dimethylforma- mide, in the powder according to the invention is in a range of from 0.01 to 30 wt.-%, preferably of from 0.1 to 25 wt.-%, preferably of from 0.5 to 20 wt.-%, preferably of from 1 to 15 wt.-%, preferably of from 2.5 to 10 wt.-%, preferably of from 3 to 8 wt.-%, based on the total weight of the powder.

12. Powder according to any of claims 5 to 11 , obtainable or obtained by a method according to any of claims 1 to 4.

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