DE2112639A1 - Solubilization of water and aqueous solutions in non-aqueous liquids - Google Patents

Description

Patent attorneys
Dr. Ing.Walter Abitz
Dr. Dieter F. Morf
Dr. Hans-A. Brauns March 16, 1971

8München86, Ptetueneuereir. 28 .. -,

Merck & Co., Inc.
Rahway, New Jersey, Y. St. A.

Solubilization of water and aqueous solutions in non-aqueous liquids

The invention relates to the solubilization of water or aqueous solutions in non-aqueous liquids and in particular a single phase system that has both Contains water as well as oil. It is different from an emulsification, which is a two-phase system.

There are many cases of liquid preparations containing both water and oil that are useful as would be an intimate mixture and not separate in two phases. An example of this is an aqueous one Solution of ascorbic acid, which is combined with orange oil, for example, to create a tasty liquid preparation to manufacture. Another example is one

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aqueous solution of a water-soluble vitamin such as B ₁ and the solubilization of this aqueous solution in, for example, peanut oil. It is obviously desirable and expedient that such mixtures of aqueous solutions and an oil remain as an intimate mixture on standing and that they do not separate into two phases.

Heretofore this has been achieved by using a suspending agent or an emulsifying agent so that a two-phase system was obtained, but objections have been raised about such masses because the Agents have a bad taste or have an adverse physiological effect. Another The disadvantage of these previously known mixtures is that the emulsion or suspension due to inadequate Stability can break. -i-

The invention uses the known but not developed Technology of micellization or micelle formation in non-aqueous systems. A feature of the invention is that a surfactant associates in solution and forms micelles above a certain concentration. The critical micelle concentration (CMC) is characteristic of a given surfactant / solvent system. The micelles obtained vary depending on the size, shape and complexity. The feature of the invention is therefore that aqueous solutions in non-aqueous liquids using surface-active Means above their critical micelle

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concentrations are solubilized.

Solubilization occurs in the system of the invention because a micelle solutions in non-aqueous solution water-soluble substance to form a single-phase system. Since the solubilized in this system Substance is not dispersed in the non-aqueous material as a separate phase, none occurs Emulsification. When carrying out the invention, water or aqueous solutions are taken up by suitable micelles, formed by the selected surfactant. These surfactants can be any of the known molecules having a hydrophobic chemical group and a hydrophilic group ^ and if it concerns substances to be ingested, the molecules are physiologically compatible.

The surfactant should be 0.5 to 20 wt .- ^ the non-aqueous liquid to which it is added. Examples of surface active agents are the following:

Dioctyl Sodium Sulphosuecinate

Triglycerol monooleate

Decaglycerine dioleate

ethoxylated stearic acid

Caprylic acid

Lecithin

n-dodecylamine caproate

n-octadecylamine caproate

Hexanolamine oleate

Hexanolamine caproate

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cC -. Monocaprine

cC - monolaurin

oC - monomyristine

oC - monostearin

Zinc caprylate

Zinc laurate or Ni, Mg, Cu,

Zinc myristate

Zinc stearate

Dinonylnaphthalene sulfonate

Iripentyl methylbenzene'-sulfonate

Polyethylene nonylphenol ether

Dodecyl ammonium butyrate

Dodecyl ammonium propionate

The non-aqueous liquid is generally an oil, but it can also be other hydrophobic liquid. Examples of oils to which these surfactants can be added are
common edible oils from corn, olives, coconut, cottonseed, peanut, and similar sources. The hydrophobic liquids to which the surfactants are to be added can even be volatile substances which can be used as a carrier in the application of the preparation and which can be evaporated as the case may be, such as η-hexane and n-heptane. Other explanations for this are given in the examples.

The water to be combined with the system of surfactant and hydrophobic liquid provides 0.5 to 20 wt .- ^ of the system. The dissolved in water Substance can be any water-soluble medicinal product,

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such as aspirin, a food such as ascorbic acid or food additives, such as face masking materials and flavor enhancing materials. The examples provide typical explanations of these water-soluble agents.

The following examples show typical embodiments of the invention:

example 1

0.5 g dioctyl sodium sulfosuccinate (Cyanamid's Complemix IT.F.) were formed in 5 »0 g of USP orange oil solved by a clear single-phase system. This was titrated with water. 0.57 ml of water were slowly added Stirring added. A clear single-phase system resulted and remained over a period of half a year, during which it was stored. Thus 11 »4% water was solubilized.

Example 2

A solution (i) was made by dissolving 2.5 g of ascorbic acid made in 10.0 ml of distilled water. A solution (II) was prepared by dissolving 1.0 g of dioctyl sodium sulfosuccinate made in 10.0 g of orange oil.

1.0 ml of solution I was added dropwise to 11.0 g of solution II with stirring. A clear single phase system resulted (III). Thus, ascorbic acid was about in the orange oil

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18.75 mg of ascorbic acid per ml of the resulting liquid system incorporated. The analysis of III for Ascorbic acid showed the following changes over time:

Time ascorbic acid

mg / ml of the total system

Beginning week • Example 3 18.75 1 Weeks 15.40 2 Weeks 14.15 3 12.70

A solution (i) was made by dissolving 1.0 g of dioctyl sodium sulfosuccinate made in 10.0 g of orange oil. 1.0 ml of water was added to I with stirring, whereby a single-phase system (II) was formed.

0.3333 g of ascorbic acid was added to II. The system (III) was stirred overnight. The next morning it was found that III was present as a phase. III thus contained 28.1 mg ascorbic acid per ml III. The ascorbic acid was lying in water as a $ 25.0 solution.

0.0833 g of ascorbic acid was added to III and the system IT was stirred over fold. The next morning it was found that IV was present as a phase. Thus IV contained 35.0 mg per ml III. The ascorbic acid was in water as a "29.41 % -i.ge solution.

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Example 4-

I. 1.0 ml of water was dissolved in 10.0 g of orange oil using 1.0 g of dioctyl sodium sulfosuccinate solubilized.

II. 1.0 ml of 20 # aqueous ascorbic acid was solubilized in 10.0 g of orange oil using 1.0 g of dioctyl sodium sulfosuccinate. '

Systems I and II were left in a refrigerator overnight kept. The next morning, System II was still present as a phase, while System I was deposition showed. The micelles with incorporated solution appeared to be more stable than the micelles in which only water was present was incorporated.

example 5

Dioctyl sodium sulfosuccinate did not form any water-solubilizing micelles in soybean oil. The addition of benzyl alcohol to soybean oil resulted in a medium in which micelle formation occurred. The solubilizing capacity of the solvent system increased as the amount of benzyl alcohol was increased. This is reflected in the table below. The surface active agent is 10 i> wt./wt. the mix.

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960CH ₉ OH in
(iCHpOH / soybean oil
mixture example 6th $> H ₂ O
s ^ olubilislert (related
on the weight of the
! Solvent) 11.1 1.6 20.0 3.2 33.0 4.0 50.0 5.6 100.0 20.0

This example shows the application of the invention for the addition of heptane to bread dough to make the known cheap To obtain the effect of achieving a more uniform structure - · <-

7.3 ml of n-heptane and 0.5 g of sodium dioctyl sulfosuccinate were stirred into a single phase system (I). 0.55 ml of 20% aqueous ascorbic acid was added dropwise with stirring ren added to I, whereby a single phase system (II) was formed.

In the initial experiment the concentration of ascorbic acid was 14.92 mg / ml II. After one week the trial yielded 13.6 mg / ml II. After two weeks the trial yielded 12.6 mg / ml II.

The preparation can be added to bread dough in an amount to provide the desired amount of heptane. Hexane can be used instead of heptane.

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Example 7

7.6 ml η-hexane and 0.5 g sodium dioctyl sulfosuccinate were stirred into a single phase system (I). 0.55 ml of 20% aqueous ascorbic acid was added dropwise added to I with stirring to form a single phase system (II).

In the initial experiment the concentration of ascorbic acid was 14.62 mg / ml II. After a week the experiment gave 13.5 mg / ml. Subject two weeks resulted in the experiment 12.3 mg / ml II.

Example 8

0.5 g of sodium dioethyl sulfosuccinate was dissolved in 5.0 g of n-heptane to produce a single-phase system (I) solved. 2.0 g of ascorbic acid were dissolved in 8.0 g of aqueous glycerine to form a clear solution (II). 0.55 ml of II was added dropwise to I with stirring to form a single phase system (III).

In the initial experiment the concentration of ascorbic acid was 14.35 mg / ml III. After 10 days the experiment gave 13.2 mg / ml III.

Example 9

0.5 g of sodium dioctyl sulfosuccinate was added in 5.0 g η-hexane dissolved to obtain a single-phase system (i). 2.0 g of ascorbic acid was dissolved in 8.0 g of aqueous glycerin dissolved to form a clear solution II. 0.55 ml II

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were added dropwise with stirring to I to form a single phase system (III).

In the initial experiment, the concentration was on Ascorbic acid 14.38 mg ascorbic acid / ml III. After 10 days the experiment gave 13 »2 mg / ml III. After 24 days the experiment gave 12.36 mg / ml III.

Example 10

0.5 g Hatrium dioctyl sulfosuccinate were dissolved in 5 g of corn oil at 75 ⁰ C to obtain a single phase (I), which remained at room temperature, dissolved. When 0.04 ml of aqueous ascorbic acid was added to I with stirring, a system (II) with permanent turbidity was obtained.

After adding 0.45 g of oleic acid to I, a result was obtained Single phase system (III). 0.16 ml of 20% aqueous ascorbic acid was added dropwise to III with stirring. This resulted in a single phase system (IV).

Example 11

1.0 g of sodium dioctyl sulfosuccinate were in 10.0 ml Benzyl alcohol dissolved to obtain 10.9 ml of system I.

4.0 ml of I was stirred in 10.9 ml of cotton oil, with a Single phase system (II) was obtained. 0.48 ml $ 20 each aqueous ascorbic acid was added dropwise to II to give a single phase system III which was 6.4 mg Ascorbic acid / ml.

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Example 12

1.0 g of sodium dioctyl sulfosuceinate was added in 10.0 ml Benzyl alcohol dissolved to give 10.9 ml of System I.

1.0 ml of 20 # aqueous ascorbic acid was added dropwise added with stirring to 6.5 ml I to achieve a single-phase system II.

II was added dropwise with stirring to 10.9 ml of cotton " seed oil was added to achieve a single-phase system III which contained 12.1 mg ascorbic acid / ml.

Example 13

2.0 g triglycerin monooleate and 6 mg decaglycerin dioleate were in 10.9 ml cottonseed oil to preserve the system.

I solved.

0.26 ml of 20 # aqueous ascorbic acid became slow added to I with stirring, a single-phase system

II containing 4 mg ascorbic acid / ml. (

Example 14

0.3 g of ethoxylated stearic acid and 1.35 ml of caprylic acid were dissolved in 10.9 ml of cottonseed oil to achieve the System I solved.

0.08 ml of 20 # aqueous ascorbic acid were added to I under Stirring was added to obtain a single phase system II containing 1.3 mg ascorbic acid / ml.

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The products of the above examples which contained ascorbic acid can be consumed in this form or added to beverages such as non-alcoholic beverages. Products with other nutrients are illustrated by the following examples.

Example 15

System III is produced according to Example 2. Solution I can be replaced by a solution consisting of 10.0 ml Water in which one or more of the following substances are dissolved is built up:

3.0 S. Ascorbic acid 0.1 ε Thiamine mononitri t 1.0 S. Niacinamide 0.2 G Pyridoxine hydrochloride 0.5 S. Cyanocobalamin 0.5 E. Calcium pantothenate Example 16

System III is prepared according to Example 2 ". Solution I can be replaced by a solution made up of 10.0 ml of water in which 6 g of iron (II) sulfate heptahydrate are dissolved have been put together.

Example 17

The systems can be prepared as in Example 5, but with 20 $ aqueous ascorbic acid in place used by water.

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Example 18

The systems can be prepared as in Example 5, but using a solution instead of water which has been prepared by dissolving one or more of the following ingredients in 10.0 ml of water is:

3.0 g of ascorbic acid

0.1 g thiamine mononitrate

1.0 g of hiacinamide

0.2 g pyridoxine hydrochloride

0 »5 g of cyanocobalamin

0.5 g calcium pantothenate

Example 19

The systems can be prepared as in Example 5, but with 37> 5 $ aqueous iron (II) sulfate heptahydrate is used in place of water.

Example 20

A system according to IY in Example 10 can be prepared, with the addition of that to system III A solution was added to 20% aqueous ascorbic acid which can be prepared by dissolving one or more of the following ingredients in 10 ml of water became:

3fO g of ascorbic acid

0.1 g thiamine mononitrate

1.0 g macinamide

0 »2 g pyridoxine hydrochloride

0 »5 g of cyanocobalamin

0.5 g calcium pantothenate

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Example 21

A system such as the system IY in Example 10 can be made, but instead of the system III added aqueous ascorbic acid a 5 $ solution the anthelmintic agent known as thiabendazole can be added.

Example 22

A system such as system IV according to Example 10 can be produced in which, instead of the aqueous ascorbic acid added to system III, a 50 % aqueous solution of a commercially available mixture of disodium inosinate and disodium guanylate can be added. These 5 * nucleotides are flavor enhancers. The end product of nucleotides in vegetable oil can be incorporated into salad oils to improve the taste of salad dressings.

The nucleotides are usually in the presence of enzymes in raw meat, losing their flavor enhancing properties Dephosphorized in character. The solubilized nucleotides are protected from these enzymes. You can so mixed with raw minced meat on an industrial scale for storage, transport and later use will. The solubilized nucleotides can also be used as a convenient method of adding these nucleotides to stews and also to cooked meat at the table will.

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Example 25

A system such as System III in example 11 can be prepared using a 50 $ solution of 5'-Nucleo tiden is added to the system II. The beneficial effects according to Example 22 also apply here.

Example 24

A system such as that of Example 10 can be made using instead of corn oil Peanut oil is used. The peanut oil containing solubilized ascorbic acid can be incorporated into peanut butter will.

Example 25 A system such as that of Example 10

can be prepared using a 50 # aqueous solution of a commercially available hickory smoke flavor or similar condensed smoke flavor can be used. The product obtained can be used for flavoring food that has been smoked in the usual way Meat and poultry are used. The advantage is better penetration through the meat tissue.

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Example 26

A system such as System IV in Example 10 can be made, using in place of the to. an aqueous solution containing 25% sodium nitrite and sodium nitrate each is added to the aqueous ascorbic acid added to system III.

The product obtained can be used in conventional curing or Pickling treatments of meat can be used. The non-aqueous phase ensures increased penetration of the Eleischgewebes through the curing or pickling agent.

The invention has the following advantages:

1.Water-soluble materials can become liquids, with which they are otherwise incompatible, ... are admitted, e.g. B.

a) water-soluble nutrients in essential oils for inclusion in carbonated beverages and non-foaming beverages,

b) water-soluble nutrients in vegetable oils for inclusion on the surface of crackers the surface of grain, in peanut butter,

c) water-soluble curing agents in oils for injection into meat for improved distribution through the tissue,

d) water-soluble taste improvers solubilized in oils for protection against enzymes and for better Compatibility with meat.

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2. Increased stability of the solubilized material. For example, it is protected from oxidation by entrapment protected in the micelles.

3. Materials with an unpleasant taste converted into pleasant lipophilic liquids are solubilized are masked in terms of taste.

4 · Hexane or heptane added to bread dough ingredients immediately before mixing in about 0.5 _A to 0.6 $> Alkane per 100 g flour has a beneficial "effect. The bread obtained has a softer texture and a more uniform corn structure than comparative breads.

Ascorbic acid added to bread dough in about 10 ppm flour leads to a reduction in the requirements of the Mixing speed of the dough. Ascorbic acid is short-lived in dough; it is enzymatic or otherwise at oxidized during processing.

Using the invention, ascorbic acid can be converted into hexane, heptane or other organic solvents ( tel can be incorporated, whereby

a) the advantage of the reduced mixing speed with the beneficial effects of the organic solvent is combined on the structure,

b) ascorbic acid encased within micelle structures is protected from degradation.

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Any of the surfactants exemplified above can be used for those in the examples specified specific agents are applied if they are between their critical micelle concentration and their maximum addition concentration MAC can be used. You can also use other water-soluble nutrients and titarns, for example the B vitamins ascorbic acid for example in Examples 15 and 16 replace. Other water-soluble drugs, ζ. Β. Aspirin can be used in place of thiabendazole in Example 21.

The micelle formation occurring in these examples requires an arrangement of the surface-active monomers, so that their polar head groups are at the center of the micelle are arranged and the hydrocarbon or hydrophobic groups to the outside, in the non-aqueous solvent extend. This arrangement of the hydrophobic groups of the micelle in the oil or other non-aqueous solvent is essential for the completeness of the Distribution or solution of the miceils through the solution

aient

medium decisive. Also the aggregation of the hydrophilic or polar head groups at the center of the miceils

. as a solution to the aqueous solution (sometimes referred to as a solubilizate) that contains the nutrient, that contains medicinal products or other edible or edible materials. Since this appearance is practically on occurs on a molecular basis throughout the system, the mixture is a solution and not a two-phase system, that results from emulsification.

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Since the essential aspect of the invention is the use of micelle formation of the surface-active agent for solubilizing water-soluble consumables in oils or non-aqueous liquids, the technical basis for this physical phenomenon is not of considerable importance. Therefore, a study of change in energy at the interface between the hydrocarbon chain to the micelle formation in the non-aqueous solvent is not important, nor is an investigation which is composed of "

Dipole-dipole interactions between main groups in the micelle center resulting in energy change for implementation necessary for the invention. The occurrence of micelle formation and in particular the CMC is easily known by Factors such as light scattering, increase in boiling point, freezing point depression, sedimentation equilibrium, Diffusion or viscosity or the rate of sedimentation and many others such as the absence of a two-phase emulsion system that can be broken.

The size and shape of the micelles is important for the implementation ( of the invention taking into account that a small micelle necessarily requires a small amount of the water solution absorbed, not critical. The more polar the monomer, the larger the micelle formed from it. Some Micelles can be formed from just a few or about 10 surfactant monomers, while in contrast for such a small aggregation some large micelles can contain between 500 and 1000 monomers. The micelles only have to be shaped so well that they form a colloidal solution in the non-aqueous liquid and that these colloidal particles take up and incorporate into themselves the material which is otherwise in the oil or

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oil-like solution is insoluble.

The general requirement is that the surfactant Agent is present at and preferably above its CMC in the non-aqueous liquid and that the Solubilizate at and preferably below its ability absorbed in or on the surfactant to become, is present. The upper limits are that the surfactant does not do its so-called MAC or maximum addition concentration should exceed and that the solubilizate its ability in or on the surfactants, agents to be absorbed ^ do not exceed target. Those mentioned in connection with the above listing of typical examples of surfactants Percentage quantities provide information on the possible physical ranges. If the maximum quantities have been exceeded, an increase in the transparency or opacity occurs at the same time. Usually shows up When examined visually, a turbidity and a deviation from a single isotropic solution, but it may be more accurate Determination by opacimeter and other common equipment and test methods for this purpose.

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Claims (10)

Claims 1. Method of solubilizing water-soluble orally absorbable substances in a non-aqueous liquid, characterized in that a non-aqueous liquid, a pharmaceutically acceptable surfactant - in an amount between its CMC and its MAC in the liquid, water in an amount similar to that of the surfactant * is absorbed, and a water-soluble orally ingestible substance in an amount that is dissolved in the water will be combined. 2. The method according to claim 1, characterized in that the substance is mixed separately with the water the surfactant is mixed separately with the liquid and these two mixtures then be combined. 3. The method according to claim 1, characterized in that the surfactant is added to the liquid, then the water is added and finally ( the substance is added. 4. Solubilized single-phase system, characterized by a non-aqueous liquid, a pharmaceutically acceptable one surfactant in an amount between its CMC and its MAC in this liquid, Water in the amount that is absorbed by the surfactant and is water-soluble orally ingestible Substance in the amount that is dissolved in the water. - 21 - 109885/1828 13 602 5. System according to claim 4, characterized in that the liquid is a vegetable oil. 6. System according to claim 4> characterized in that the liquid is a volatile hydrocarbon, 7. System according to claim 4, characterized in that the substance is a nutrient. 8. System according to claim 4, characterized in that the substance is a medicament. 9 · System according to claim 4, characterized in that the substance is a food additive. 10. System according to claim 4, characterized in that the substance is a flavor. \ '· - 22 - 109885/1828