JPH0375210B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a method for uniformly dispersing and solubilizing water-insoluble substances in an aqueous system using a specific higher alcohol monoether of diglycerin or triglycerin. Moreover, in the present invention, "solubilization" means solubilization and microemulsion formation. In general, the solubilization of water-insoluble substances into aqueous systems is a phenomenon that first occurs due to the presence of a surfactant, and the type of surfactant, the compound to be solubilized, and the amount of solubilization are extremely selective. The presence of a significant amount of active agent is necessary for the phenomenon to occur. On the other hand, when we look at solubilization from an industrial perspective, it covers a wide range of applications such as foods, cosmetics, and pharmaceuticals, but the types of surfactants that can be used are limited in terms of solubilizing ability and safety. ing. For example, examples of the application of solubilization to pharmaceuticals include injections and infusions, and in the case of such drugs, the properties of surfactants prevent the drug from clogging in capillaries. Therefore, solubilization with dissolution equilibrium or solubilization ability or microemulsification ability with a narrow particle size distribution and an average particle size of 0.3 μm or less is required, and in addition, there should be no safety problems. has become an essential requirement. Solubilizers or emulsifiers conventionally used for this purpose include lecithin, polyoxyethylene cetyl ether, polyoxyethylene sorbitan monooleate, and hydrogenated castor oil ethylene oxide adduct. Among these, lecithin is a biologically derived substance and is highly safe and widely used as an emulsifier. However, as a surfactant, it has weak hydrophilicity and is insoluble in water, so it can solubilize non-water-soluble substances in aqueous systems. I can't. Furthermore, since it is a biologically derived ingredient,
It had drawbacks such as lack of stability such as preservative and rancidity. On the other hand, polyoxyethylene cetyl ether, polyoxyethylene sorbitan monooleate, and hydrogenated castor oil ethylene oxide adducts all have ethylene oxide chains as hydrophilic groups, so there is a risk of elution of formalin and a decrease in pH due to decomposition of the ethylene oxide chains. It comes with gender.
The decrease in PH is especially due to the PH of solubilized substances and emulsified substances.
This was a fatal flaw when stability was required. Therefore, the present inventor focused on polyglycerin-based emulsifiers that have been used as emulsifiers for food and cosmetics in recent years and has excellent safety, and as a result of various studies, found that among monoethers of polyglycerin and higher alcohols, The present invention was completed based on the discovery that certain substances have excellent solubilization ability and can solubilize not only animal and vegetable oils but also various water-insoluble substances. The present invention uses diglycerin and/or triglycerin and an unsaturated aliphatic alcohol having 18 to 24 carbon atoms or a β-branched monohydric alcohol having 16 to 24 carbon atoms to solubilize a water-insoluble substance in an aqueous system. The present invention relates to a method for solubilizing a water-insoluble substance, which comprises adding a surfactant having a monoether content of 90% by weight or more based on the total weight%. Examples of the higher alcohol component constituting the monoether of diglycerin or triglycerin and higher alcohol contained in the surfactant used in the present invention include unsaturated aliphatic alcohols having 18 to 24 carbon atoms, such as oleyl alcohol, Dyl alcohol, linoleyl alcohol, linolenyl alcohol, jojoba alcohol, etc., and alcohols with 16 or more carbon atoms
24 β-branched monohydric alcohols such as 2-hexyldecanol, 2-heptylundecanol, 2-
Octyldodecanol, Huainoxocol,
Examples include 2-decyltetradecanol.
All of the monoethers obtained here have low melting points, are liquid or paste-like at room temperature, and are water-soluble and have solubilizing ability. Among these, those having a Krafft point of 0° C. or lower are particularly preferred from the viewpoint of practical use. Therefore, even if they are monoethers, saturated aliphatic alcohol monoethers or terminally branched monohydric alcohol monoethers that give a high melting point or precipitate crystals cannot be applied to the present invention. Next, although the amount of the surfactant according to the present invention added to an aqueous system can vary widely depending on the type of water-insoluble substance to be solubilized and the purpose of the obtained solubilized material, it is usually 0.2-10 relative to total weight
A range of 0.4 to 5% by weight is sufficient, and a range of 0.4 to 5% by weight is preferable when considering a balance between more stable solubilization ability and higher safety. However, the specific diglycerin monoether or triglycerin monoether in the surfactant must be contained alone or in a mixed system in an amount of 90% by weight or more based on the total weight of the surfactant. If the content is less than 90% by weight, the solubilizing ability decreases and the object of the present invention cannot be achieved. Here, surfactants containing diglycerin monoether or triglycerin monoether having such solubilizing ability have not been available in the past. This is because conventional polyglycerin ether surfactants are produced by adding glycidol to polyglycerin under an alkali catalyst, or by adding epichlorohydrin to a higher alcohol and then saponifying it with an alkali to form a higher alcohol ether. It was guiding me. These ethers synthesized using glycidol give complex mixtures, and in synthesis using epihalohydrins such as epichlorohydrin, halogen removal may be incomplete or complex products may be produced during the desalting reaction. It was difficult to purify it to a high degree of purity. Therefore, the present inventors did not use the conventional method of adding glycidol or epichlorohydrin to higher alcohols, but instead added glycerin or diglycerin to higher alcohol glycidyl ether. A surfactant having a triglycerin higher alcohol monoether content of 90% by weight or more is obtained. Below, Synthesis Examples 1 to 3 according to the present invention
Comparative synthesis example 1 according to the conventional method is shown below. Synthesis Example 1 Triglycerin monooleyl ether 1.4 g (0.061 mol) of metallic sodium was added to 515 g (3.1 mol) of anhydrous diglycerin to produce an alcoholate at 120°C. Heat this to 180℃,
Oleyl glycidyl ether with vigorous stirring
196 g (0.6 mol) was added dropwise over 5 hours, and after the addition was completed, the reaction was continued for 2 hours under the same conditions. After cooling to room temperature, the upper layer was taken out and subjected to silica gel column chromatography, and the target product was obtained as a colorless to pale yellow liquid by fractionation using chloroform:methanol=95:5. Yield 118g (yield 40%). Synthesis Example 2 Triglycerin monojojoba alcohol ether Glycidyl ether of jojoba alcohol 236 instead of oleyl glycidyl ether in Synthesis Example 1
It was synthesized in the same manner using g (0.6 mol). The target product was a pale yellow to yellow liquid to paste. Yield 118g (yield 35%). Synthesis Example 3 Diglycerin mono-2-hexyldecyl ether 1 g (0.04 mol) of sodium metal was added to 380 g (4.1 mol) of glycerin to produce an alcoholate at 130°C. This was heated to 180°C, and 239 g (0.8 mol) of 2-hexyldecyl glycidyl ether was added dropwise over 4 hours while stirring vigorously, and the reaction was continued under the same conditions for 4 hours even after the dropwise addition was completed.
After cooling to room temperature, the upper layer was taken out and subjected to silica gel column chromatography, and chloroform:
The desired product was obtained as a colorless liquid by fractionation using methanol = 98:2. Yield 125g (yield 40%). Comparative Synthesis Example 1 Tetraglycerin oleyl ether mixture 0.1 g (0.004 mol) of sodium metal was added to 134 g (0.5 mol) of oleyl alcohol to produce an alcoholate. Glycidol 148 at 135℃
g (2.0 mol) was added dropwise over about 8 hours. After the dropwise addition was completed, the reaction was continued for 3 hours under the same conditions. After neutralizing the product with hydrochloric acid, insoluble matter was separated and volatile matter was removed under reduced pressure to obtain a mixture containing tetraglycerol oleyl ether in the form of a yellow paste. Yield 215
g (yield 76%). Next, there are many substances that can be solubilized by the solubilization method of the present invention, such as animal and vegetable oils, interesterified fats and oils, fatty acid esters, aliphatic alcohols, aliphatic hydrocarbons, aromatic hydrocarbons, alicyclic Examples include hydrocarbons, naphthenic hydrocarbons, various mineral oils, fragrances, silicone oils, etc., but all can be solubilized to varying degrees as long as they are substantially water-insoluble. Also, a mixture of the above substances or a substance dissolved in a solvent can be similarly solubilized. Furthermore, when solubilizing a substance to be solubilized in an aqueous system containing the surfactant, the amount of solubilization varies depending on the type of substance to be solubilized;
Usually, the amount can be up to 3 to 6 times the weight of the surfactant. In addition, as a means of solubilization, a method for obtaining the solubilization in a short time is to stir and add an aqueous phase containing a water-soluble substance to an oil phase containing a surfactant. Even if the method of adding the aqueous phase and the oil phase is changed, there is no problem in obtaining a solubilized system. The surfactant of the present invention overturns the conventional wisdom that higher alcohol ethers of diglycerin or triglycerin are water-in-oil emulsifiers or liposomal dispersants. It is surprising that water-insoluble substances can be solubilized. This is because, as mentioned above, conventional polyglycerol higher alcohol ether surfactants were insoluble in water because of the distribution of the glycerin chain addition forms. Therefore, in the case of conventional diglycerin or triglycerin higher alcohol ethers, systems using them as surfactants are only used as stabilizers for water-in-oil emulsions or liposomal dispersants. was the current situation. On the other hand, hexaglycerin nonyl phenyl ether, which is made by increasing the degree of polymerization of glycerin to increase hydrophilicity, has also been synthesized, but it ignores the concept of HLB and is used as a solubilizer to solubilize water-insoluble substances. That was difficult. This is because all of these contain unpolymerized glycerin ether compounds.
This was because HLB became lipophilic due to the distribution of polyglycerol chains. Furthermore, it has been extremely difficult to increase the purity of surfactants produced by such conventional methods through purification. Next, the solubilization method of the present invention can be applied to a wide range of fields, including pharmaceuticals such as the above-mentioned infusions and injections, foods and cosmetics that require safety. It is something. Here, in order to evaluate the solubilizing ability of the surfactant according to the present invention, triglycerol monooleyl ether obtained in Synthesis Example 1 and diglycerin mono-2-hexyldecyl ether obtained in Synthesis Example 3 were used. , using the tetraglycerin oleyl ether mixture obtained in Synthesis Comparative Example 1 as a comparative product,
A test was conducted on the solubilizing power of decane, a type of hydrocarbon. As a method, each of the above surfactants was added to 100 g of an aqueous phase containing 3% by weight at 20°C.
Deccan 1g, 5g, 10g, 15g, 20g respectively
The solubilization state when adding was evaluated. The results are shown in Table 1.

[Table] ○: Transparent solubilization △: Microemulsion ×: Separation As is clear from Table 1 above, the surfactant according to the present invention has much better solubilizing power than the comparative surfactant. This demonstrated the superiority of the solubilization method of the present invention. Furthermore, a formalin elution test was conducted on the triglycerol monooleyl ether obtained in Synthesis Example 1 according to the present invention, cetomacrogol, polysorbate 80, and hydrogenated castor oil ethylene oxide adducts, which have been conventionally used as solubilizers for pharmaceuticals and cosmetics. (1 wt% aqueous surfactant solution) The results are shown in Table 2.

[Table] As shown in Table 2 above, the surfactant according to the present invention is highly safe as formalin is less eluted than conventional surfactants. Examples are shown below. Example 1 0.8 g of a cosmetic fragrance was added to 1 g of diglycerin mono-2-hexyldecyl ether, and 98 g of an aqueous phase containing a water-soluble additive was added thereto under stirring to obtain a transparent solubilized product. Example 2 20 g of liquid paraffin was added to 5 g of triglycerin monooleyl ether, and 75 g of an aqueous phase was added thereto under stirring to obtain a blue translucent solubilized material. Example 3 3 g of vitamin A palmitate was added to 3 g of triglycerin jojoba alcohol monoether, and 94 g of an aqueous phase containing water-soluble additives was added thereto under stirring to obtain a transparent solubilized product. Example 4 Drops 20 g of soybean oil was added to 5 g of triglycerin monooleyl ether, and 75 g of an aqueous phase containing 5 g of glycerin and 5 g of an essential amino acid mixture was added under stirring to obtain a microemulsion-like drop. .

Claims (1)

[Claims] 1. When solubilizing a water-insoluble substance in an aqueous system,
The content concentration of monoether of diglycerin and/or triglycerin and unsaturated aliphatic alcohol having 18 to 24 carbon atoms or β-branched monohydric alcohol having 16 to 24 carbon atoms is 90% by weight or more out of the total weight%. A method for solubilizing a water-insoluble substance, characterized by adding a certain surfactant. 2 The amount of surfactant added is based on the total weight of the aqueous system.
A method for solubilizing a water-insoluble substance according to claim 1, wherein the amount is 0.2 to 10% by weight.