WO2011083196A1 - Lipophilic phenolic derivatives as surfactants - Google Patents

Abstract

The present invention reveals a group of compounds derived from phenols such as tyrosol or hydroxytyrosol having a polar part and an apolar part being an alkylic chain of variable length. As a consequence of the physicochemical properties thereof these compounds may be used as surfactants, for example in food, agrochemical, cosmetic or personal hygiene products or in pharmaceutical products.

Description

 LIPOPHYL PHENOLIC DERIVATIVES AS SURFACTANTS

The present invention relates to the use of a group of compounds derived from lipophilic phenols as surfactants, especially in food, cosmetic and pharmaceutical compositions.

STATE OF THE PREVIOUS TECHNIQUE

Surfactants based on renewable sources are experiencing a growing demand, taking into account environmental aspects, health for the consumer and yields similar or better than those based on petrochemical derivatives. (Hill-Rhode, Fett / Lipid 1999, vol. 101, 25). At the same time, new functionalities in molecules with surface activity, such as having antioxidant capacity, are very desirable in new ecological surfactants. In this case, tirasol and hydroxytyrosol, natural phenolic derivatives that are very potent antioxidants, show their ability to be the polar group in a new type of antioxidant surfactants. To obtain ecological surfactants, compounds obtained from renewable sources such as palm oil or coconut oil are usually used as a hydrophobic chain. The choice of polar groups from renewable sources has focused on carbohydrates and amino acids. In this way, n-alkyl polyglycosides, sorbitan esters, fatty acid and sugar esters and amino acid based surfactants can be prepared.

Polyphenols are very abundant in nature, especially in the plant kingdom, and are very polar compounds. They have interesting biological properties, such as caffeic acid, known for its antiviral, anti-inflammatory and anti-arteriosclerotic properties; Resveratrol, with cardioprotective and anticancer effects; and the phenols of olive oil, specifically hydroxytyrosol, which inhibits the oxidation of lipoproteins from Low human density (LDL) (a critical stage in atherosclerosis) and platelet aggregation and also exhibits anti-inflammatory and anti-cancer properties. At the same time, some of these natural phenolic derivatives are being used as antioxidants for food preservation, such as catechins of green tea extracts and rosmarinic acid and its derivatives found in rosemary extracts. In fact, tyrosol and, especially, hydroxytyrosol have shown greater antioxidant capacity in oils than various commonly used food antioxidants, such as α-tocopherol (E-307), or butyl hydroxytoluene (BHT, E-321). (Mateos, Domínguez, Espartero, Cert, J. Agrie. Food Chem. 2003, vol. 51, 7170; Ranalli, Lucera, Contento, J. Agrie. Food Chem. 2003, vol. 51, 7636; Artajo, Romero, Morello , Motilva, J. Agrie. Food Chem. 2006, vol. 54, 6079). In recent years, lipophilic derivatives of some very polar phenolic antioxidants have been prepared to facilitate their incorporation into fats and oils. For example, fatty acid esters of isoflavones, lipophilic derivatives of clovamide or poly (lauroyl - (+) - catechin) have been synthesized. Since hydroxytyrosol is one of the most potent and promising antioxidants described to date, lipophilic hydroxytyrosol derivatives have also been prepared to facilitate their incorporation into fats and oils. The compounds prepared are ester or ether type derivatives with alkyl or alkenyl chains. First, ester derivatives with fatty acids were prepared on the primary hydroxyl or on the phenolic hydroxyls both by classical chemical route and by Enzymatic route with the use of enzymes (Torres de Pinedo, Peñalver, Rondón, & Morales, Tetrahedron 2005 vol. 61, 7654; Trujillo et al., J Agrie Food Chem 2006, vol. 54, 3779; Grasso et al. Bioorg Chem 2007, vol. 35, 137 Torres de Pinedo, Peñalver, Pérez-Victoria, Rondón, & Morales, Food Chem 2007, vol. 105, 657; and patents ES2233208; ES2246603). Ether derivatives with aliphatic alcohols substituted at the primary alcohol position have also been prepared (Pereira-Caro, Madrona, Bravo, Espartero, Alcudia, Cert & Mateos, Food Chem. 2009, vol. 1 15, 86). All these lipophilic hydroxytyrosol compounds are very good antioxidants in different food matrices. Its antioxidant capacity is as high as that of hydroxytyrosol itself and better than other lipophilic antioxidants currently used such as α-tocopherol (E-307), butyl hydroxytoluene (BHT, E-321) or ascorbyl palmitate (E-304) (Trujillo et al., J Agrie Food Chem 2006; Torres de Pinedo, Peñalver, Pérez-Victoria, Rondón, & Morales, Food Chem 2007; Pereira-Caro, Madrona, Bravo, Espartero, Alcudia, Cert & Mateos, Food Chem 2009 ; Medina, Lois, Alcantara, Lucas & Morales, J Agrie Food Chem 2009, vol. 57, 9773).

In the case of the antioxidant tyrosol, lipophilic derivatives have also been prepared. Specifically, tyrosol esters have been synthesized with substituted fatty acids in the position of the primary alcohol. In addition, it has been described that its antioxidant capacity in oils is slightly lower than that of tyrosol. (Mateos, Trujillo, Pereira-Caro, Madrona & Espartero, J Agrie Food Chem 2008, vol. 56, 10960).

These lipophilic tyrosol and hydroxytyrosol derivatives have also been prepared in order to protect tyrosol and hydroxytyrosol from degradation in biological media so that they can exert their antioxidant power for longer in vivo. Thus, the protection of the antioxidant in tyrosol and hydroxytyrosol esters with fatty acids in the primary or / and phenolic positions of phenol has been demonstrated and its use in cardiovascular, hepatic and renal diseases (ES2193874) and in neurodegenerative diseases (ES2256472) has been protected .

To date, very few examples of antioxidants with surface activity have been described, such as alkanoyl-6-O-ascorbic acid esters, alkylammonium ascorbate salts, tocopheryl polyethylene glycol succinate and alkylammonium BHT salts. DESCRIPTION OF THE INVENTION

The present invention provides a group of compounds derived from phenols such as tyrosol or hydroxytyrosol which due to their physicochemical properties can be used as surfactants, either in food, agrochemical, cosmetic, personal hygiene products or in pharmaceutical products.

In a main aspect, the present invention relates to the use of a

compound of formula (I)

Formula (I)

where

 Ri to R5 are independently selected from H, C1-C4 alkyl or an OH group, where at least one of R1 to Rs is an OH group,

R ₆ is a C1-C20 alkyl group;

n is a value between 1 and 6;

as a surfactant The term "alkyl" refers, in the present invention, to aliphatic, linear or branched chains, having 1 to 20 carbon atoms, for example, methyl, ethyl, n-propyl, / -propyl, n-butyl, ferc-butyl, sec-butyl, n-pentyl, n- hexyl, etc. Preferably the alkyl group has between 6 and 12 carbon atoms. More preferably it is n-octyl, n-decyl or n-dodecyl. The alkyl groups may be optionally substituted by one or more substituents such as halogen, hydroxyl, azide, carboxylic acid or a substituted or unsubstituted group selected from amino, amido, carboxylic ester, ether, thiol, acylamino or carboxamido. When the alkyl group is substituted, it is preferably substituted by one or more amine, amide or ether groups, which in turn may or may not be substituted by alkyl, amide, cycloalkyl or ethers groups and these, in turn, may also be substituted or no.

In the present invention, the term "surfactant" refers to substances that reduce the surface tension on the contact surface between two phases (for example, two insoluble liquids in one another) by adsorption of these molecules at the interface. The term surfactant is equivalent to surfactant. These properties are due to their structure: the surfactants are composed of a hydrophobic part and a hydrophilic moiety, which makes them amphiphilic molecules. Upon contact with water the individual molecules are oriented in such a way that the hydrophobic part protrudes from the aqueous phase or interacts with the hydrophobic chains of other molecules forming aggregates in which the hydrophobic parts remain in the center and the water soluble remains orient towards the periphery interacting with the water. These structures are called micelles. Depending on the dissociation properties of the surfactant in the presence of water, they are classified as ionic or non-ionic; and within the ionic ones according to the load that the part that presents the surface activity possesses, they will be anionic, cationic or amphoteric.

In a preferred embodiment, n is a value between 2 and 4, more preferably 2.

In a preferred embodiment, at least one of Ri to R5 is an OH group. In another more preferred embodiment, R3 is an OH group. In another more preferred embodiment, R2 and R3 are an OH group. In another preferred embodiment, R 6 is a C ₁ -C ₁₈ alkyl group. In a more preferred embodiment, R6 is a C6-C12 alkyl.

In a preferred embodiment, the present invention relates to the use as a surfactant of a compound selected from the list comprising hydroxytyrosol hexanoate, hydroxytyrosol octanoate hydroxytyrosol decanoate and hydroxytyrosol dodecanoate

In another preferred embodiment, the present invention relates to the use as a surfactant of a compound selected from the list comprising tyrosol hexanoate, tyrosol octanoate and tyrosol decanoate.

In another preferred embodiment, the present invention relates to the use of the compounds of formula (I) as described above as surfactants in food, agrochemical, cosmetic-dermatological, personal hygiene or pharmaceutical products.

Due to the amphiphilic character of these phenolic fatty acid esters, the compounds of formula (I) described in the present invention possess surfactant properties, in addition to antioxidants, which makes them very useful additives for use in products of the agrochemical industries, food, cosmetic-dermatological and pharmaceutical.

The compounds of the present invention are suitable, due to their low or no toxicity, for use as surfactants in food preparations such as, but not limited to, foods in general, food supplements, functional or nutraceutical foods. They can also be used in cosmetic or dermatological products such as, but not limited to, personal hygiene products (soap, gel shampoo, deodorant, creams, lotions etc.) or tanning and sun protection products that can be presented in the form of oil, lotion, gel, spray or cream. The compounds of the present invention are also suitable as surfactants in agrochemicals such as, but not limited to, herbicides, pesticides or insecticides. Throughout the description and the claims the word "comprises" and its variants are not intended to exclude other technical characteristics, additives, components or steps. For those skilled in the art, other objects, advantages and features of the invention will be derived partly from the description and partly from the practice of the invention. The following examples and graphs are provided by way of illustration, and are not intended to be limiting of the present invention.

DESCRIPTION OF THE FIGURES

Fig. 1. Diagram of surface tension versus concentration for the series of fatty acid esters and tyrosol. Fig. 2. Relationship between CMC and acyl alkyl chain length in the series of tyrosol and hydroxytyrosol esters.

Fig. 3. Diagram of surface tension versus concentration for the series of fatty acid esters and hydroxytyrosol.

EXAMPLE

The compounds of the present invention on which the experimental part has focused are the following: I tie

 just

to

 to

 oato

 Oito

 u iü to

 aio

 iafc

ito

ito

The fatty acid and tyrosol and hydroxytyrosol esters have been prepared by enzymatic acylation of tyrosol and hydroxytyrosol using immobilized lipase B from Antarctic Candida (Novozym 435®). The reactions were carried out in terf-butyl methyl ether and the acylating agents were the corresponding vinyl esters of the different alkyl chains. The yields were very high in all cases after the filtration of the enzymes and short column chromatography of the reaction mixture.

Next, the surface tension for the series of fatty acid esters and tyrosol was determined. The surface tension / log graphs of the compound concentration for this series are shown in Figure 1. It can be seen that for tyrosol (1), tyrosol acetate (3) and tyrosol butyrate (4) there is no stabilization of surface tension (at higher concentrations the samples are not soluble). Although these compounds show an activity that decreases surface tension, they do not behave as surfactants, since the self-aggregation characteristic of a micellar system does not occur. On the contrary, when the alkyl chain length of the acyl group is increased, a suitable hydrophilic / lipophilic balance is achieved and, consequently, the typical curve shape of a surfactant for hexanoate (5), octanoate ( 6) and tyrosol decanoate (7). Tyrosol laurate (8) showed very little water solubility, the corresponding surface tension measurements not being possible.

The physicochemical parameters obtained for these compounds are shown in Table 1. In addition to the CMC values, the following data were also calculated: the surface tension for the CMC (YCMC) related to the effectiveness of the surfactant, PC20 (corresponding to -log C20, where C20 is the concentration necessary to decrease the tension by 20 units surface of pure water, that is, 52 mN / m) related to the performance of the surfactant, the maximum adsorption of surfactant r _max and the area occupied per molecule at the saturated interface (A). When the CMC log is plotted against the number of carbons in the acyl alkyl chain (Figure 2), a linear decrease in CMC is observed, as is the case in conventional surfactants. The formation of micelles must take place at lower concentrations with the longer lipophilic chains to avoid the greater hydrophobic repulsion of these chains with the water molecules. In addition, it can be observed that the efficacy of these compounds (in terms of the minimum surface tension available for the surfactant) is very similar, with tyrosol octanoate and tyrosol decanoate being the best (41, 1 and 41.5 mN / m, respectively). Regarding performance (in terms of parameter PC20), the longer the alkyl chain, the higher the PC20 values, indicating that a lower concentration of tyrosol decanoate is needed to decrease the surface tension of the aqueous phase by 20 units ( 52 mN / m). PM HLB compound

3,240 x 10 ^"

Tir hexanoate. (5) 236.3 10.2 0.9 44.0 0.32 3.49 5 1, 3

 10

4,712 x 10 ^"

Tir octanoate. (6) 264.4 9.2 0.073 41, 1 0.029 4.54 35.3

 10

5, 175 x 10 ^"

Decanoate of Tir. (7) 292.4 8.3 0.013 41.5 0.0055 5.26 32.0

 10

196.2 14.0 2, 187 x 10 ^"

HT acetate (9) 3.0 57.7 - - 76.0

 10

HT Butyrate (10) 224.3 12.2 1.5 45.8 0.75 3, 12 3.50 x 10 ^"10 47.5

HT Hexanoate (11) 252.3 10.9 1, 2 39.6 0.34 3.47 3.91 x 10 ^"10 42.5

HT Octanoate (12) 280.4 9.8 0.38 30.5 0.03 4.52 3.43 x 10 ^"10 48.4

HT Decanoate (13) 308.4 8.9 0.09 28.0 0.007 5, 15 4.21 x 10 ^"10 39.4

HT Laurate (14) 336.5 8, 1 0.0055 39.0 0.0015 5.58 3.97 x 10 ^"10 41, 9

4,034 x 10 ^"

HT myristate (15) 364.5 7.5 0.0035 59.5 - - 41, 2

 10

4,286 x 10 ^"

HT palmitate (16) 392.6 7.0 0.002 62.0 - - 38.8

 10

 Brij 30 ®

362.5 9.4 0.0035 30.0 0.0024 5.62 3.80 x 10 ^"10 44.0

(alkylethoxylated ester)

 Tween 20 ®

3,560 x 10 ^" (1227.5 monolaurate 16.6 0.0169 35.0 0.0025 5.61 46.6

 10 sorbitan-polyoxyethylene)

n-octyl glycoside 292.4 1 1, 1 25 -30.0 - - 4.0 x 10 ^"10 41.0

Table 1: Parameters of molecular weight, HLB, CMC, surface tension, area per molecule, C20, PC20, Γ and A of the esters of fatty acids and tyrosol (tyros) and hydroxytyrosol (HT) prepared and of various non-ionic surfactants conventional.

The surface tension / log representation of the product concentration for the series of fatty acid and hydroxytyrosol esters can be seen in Figure 3. For this series, even hydroxytyrosol esters with chains Short alkyl (C2 and C4) show a relatively good surface activity although the decrease in surface tension is only moderate. The most outstanding surfactant properties are shown by hydroxytyrosol derivatives with an acyl chain length between C6 and C12 (hydroxytyrosol hexanoate 11 and hydroxytyrosol laurate 14). In fact, the best efficacy values (YCMC), observed for hydroxytyrosol octanoate 12 and hydroxytyrosol decanoate 13 (30.5 and 28.0 mN / m, respectively, Table 1) are in the same range as those observed for commonly used non-ionic surfactants, such as Brij 30®, Tween 20® or n-octyl glycoside. When longer chain fatty acids, such as myristic acid (C14) and palmitic acid (C16), are bound to hydroxytyrosol, a drastic decrease in surfactant efficacy (59.5 and 62.0 mN / m) is observed. respectively, Table 1). Finally, hydroxytyrosol stearate, which contains the longest alkyl chain in this series, exhibited very little water solubility and did not decrease surface tension at any concentration. It seems that the optimal HLB values to obtain suitable surfactant properties are between 8 and 1 1, for both the tyrosol and hydroxytyrosol series. When analyzing the entire series of fatty acid and hydroxytyrosol esters, it can be seen that, as with other surfactants, the longer the alkyl chain length, the lower the CMC values observed (Figure 2). Regarding theoretical efficiency, the logical trend is as follows: higher value of PC20 when the alkyl chain length increases. This is correct to a point where the hydrophilic-lipophilic balance is not optimal, in this case, the hydroxytyrosol myristate with an HLB of 7.5. It is important to comment that hydroxytyrosol octanoate, with the best surface activity properties of the HT series, proved to be the best antioxidant in a fish oil in water emulsion system compared to hydroxytyrosol, hydroxytyrosol acetate, hydroxytyrosol butyrate, Hydroxytyrosol laurate and the commonly used octyl gallate. One possible explanation could be that hydroxytyrosol octanoate is preferably located on the surface of the micelles to avoid oxidation due to its excellent surfactant properties. When the CMC values of fatty acid esters and thiol and hydroxytyrosol are compared with the same alkyl chain length (Figure 2), the derivatives of the sunflower show lower values than those of hydroxytyrosol. This fact may be due to the lower hydrophilic nature of the tirasol compounds, since they only have one hydroxyl group in the aromatic cycle compared to the two hydroxytyrosol derivatives. When the acyl chain length increases, the difference between equivalent derivatives becomes even greater. Referring to other parameters of surface activity, such as efficacy, hydroxytyrosol derivatives show values of y _C mc lower than those of thiol esters and similar to those of surfactants commonly used in industry (see Table 1). Therefore, fatty acid and hydroxytyrosol esters, which are better antioxidants than their counterparts with thiol, also show better surfactant properties.

In conclusion, these data reveal that powerful antioxidants, such as esters of fatty acids and sunflower and hydroxytyrosol, are excellent surfactants when adequate hydrophilic-lipophilic balance (HLB) is achieved. These results open the door to potential new applications of these surfactant antioxidants, for example, in the food, agrochemical, pharmaceutical, detergent or personal hygiene industries.

Description of the experimental procedures: 1. Synthesis of compound 12 (hydroxytyrosol octanoate):

Antarctic Candida lipase B (Novozym 435®, 180 mg) and the acyl donor, vinyl octanoate (4.41 g, 25.97 mmol, 5 ml_, 20 eq), were added to a hydroxytyrosol solution (200 mg , 1,298 mmol) in t-butyl methyl ether (45 ml_). The reaction mixture was stirred (400 rpm) at 40 ° C for 1 h. The reaction was cooled, the enzyme was filtered and the filtrate was evaporated to dryness. The crude was purified by flash column chromatography (hexane: ethyl acetate, 4: 1) to obtain hydroxytyrosol octanoate (12) as a yellowish oil (360 mg, 98% yield).

2. Measurement of surface tension and aggregation properties

Surface tension measurements were made at 23 ° C according to the Wilhelmy plate method on a Krüss K12 tensiometer. Samples were prepared by successive dilutions of a concentrated initial solution. Before each measurement of surface tension, the samples were kept at rest for 30 minutes to reach equilibrium.

The possible aggregation properties of the tyrosol and hydroxytyrosol derivatives are demonstrated from the adsorption isotherms obtained when the surface tension is plotted against the logarithm of the concentration. The typical profile of a surfactant consists of a linear decrease in surface tension when the concentration of compound increases, followed by a stabilization of surface tension when the concentration corresponding to the interface saturation is reached. The intersection of the two linear portions of the graph determines the critical micellar concentration (CMC).

The area occupied per molecule adsorbed at the water / air interface (in A ² ) can be obtained from the equation: A = 10 ¹⁶ / N _A - Γ, where N _A is Avogadro's number and Γ is adsorption in the saturated interface expressed in mol / cm ² , calculated according to the Gibbs equation: Γ = - (dy / log C) /2,303 n RT, where n is the number of molecular species in solution (n = 1 for non-ionic compounds, as in our case) and (dy / log C) is the slope of the linear portion of the graph before the CMC is reached.

Claims

one . Use of a compound of formula (I)

Formula (I)  where  Ri to R5 are independently selected from H, C1-C4 alkyl or an OH group, where at least one of R1 to R5 is an OH group; R ₆ is a C1-C20 alkyl group;  n is a value between 1 and 6;  as a surfactant 2. Use of a compound according to claim 1 wherein n is a value between 2 and 4. 3. Use of a compound according to claim 2 wherein n is 2. 4. Use of a compound according to any one of claims 1 to 3 wherein R ₃ is an OH group. 5. Use of a compound according to any one of claims 1 to 3 wherein R2 and R3 are an OH group. 6. Use of a compound according to any one of claims 1 to 5 wherein R6 is a C1-C18 alkyl group. 7. Use of a compound according to claim 6 wherein R6 is an alkyl 8. Use of the compound according to claim 1, selected from the list comprising hydroxytyrosol hexanoate, hydroxytyrosol decanoate hydroxytyrosol octanoate and hydroxytyrosol dodecanoate. 9. Use of the compound according to claim 1, selected from the list comprising tyrosol hexanoate, tyrosol octanoate and tyrosol decanoate. 10. Use of a compound according to any of claims 1 to 9 as a surfactant for the preparation of a food composition. eleven . Use of a compound according to any one of claims 1 to 9 as a surfactant in cosmetic and personal hygiene products. 12. Use of a compound according to any of claims 1 to 9 as a surfactant in sunscreen products. 13. Use of a compound according to any one of claims 1 to 9 as a surfactant in agrochemicals. 14. Use of a compound according to any of claims 1 to 9 as a surfactant in a pharmaceutical composition.