US2524247A - Aqueous solutions of lipoid-soluble vitamins - Google Patents

Aqueous solutions of lipoid-soluble vitamins Download PDF

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US2524247A
US2524247A US38178A US3817848A US2524247A US 2524247 A US2524247 A US 2524247A US 38178 A US38178 A US 38178A US 3817848 A US3817848 A US 3817848A US 2524247 A US2524247 A US 2524247A
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vitamin
solution
polyoxyethylene glycol
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water
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Zentner Margaret Rose
Haas Gerhard Julius
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F Hoffmann La Roche AG
Hoffmann La Roche Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C43/00—Ethers; Compounds having groups, groups or groups
    • C07C43/02—Ethers
    • C07C43/03—Ethers having all ether-oxygen atoms bound to acyclic carbon atoms
    • C07C43/04—Saturated ethers
    • C07C43/10—Saturated ethers of polyhydroxy compounds
    • C07C43/11—Polyethers containing —O—(C—C—O—)n units with ≤ 2 n≤ 10

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  • Patented-Oct. a 1950 AQUEOUS SOLUTIONS OF mom-SOLUBLE VITAMINS Margaret Rose Zentner, Newark, N. 1., and Gerhard Julius Haas, New York, N. Y., assignors to Hoflmann-La Roche Inc., Nutley, N. J., a corporation of New Jersey No Drawing. Application July 10, 1948, Serial No. 38,178
  • the present invention relates to the solubilization of lipoidor fat-soluble, water-insoluble vitamins such as vitamins A, D and E and the like, and more particularly to aqueous solutions of such vitamins in which said vitamins are dissolved in an amount greater than their normal water solubility.
  • the invention also relates to new compounds which are employed as solubllizers in producing such solutions.
  • lipoidor fat-soluble vitamins can be dissolved by 4-higher aliphatic oxybuty] ethers of polyoxyethylene glycol LOUIS-4,000.
  • the numerals 1,000- 4,000 refer to the approximate molecular weight of the polyoxyethylene glycol combined with the higher aliphatic oxybutyl portion of the molecule.
  • the solubilizing compounds which we employ can be represented by the following formula:
  • R represents a long carbon-link chain having at least twelve carbon atoms and :r represents a number of oxyethylene groups so that the polyoayethylene group has a molecular weight of from about LOW-i000.
  • the i-oleyloxybutyl ether of polyoxyethylene glycol 1,000 has been found to be particularly effective for the solubilization of the lipoid-soluble, water-insoluble vitamins, which are substantially free of fats (glycerides of the higher fatty acids), as for example, high potency vitamins A, D or E, or mixed A and D concentrates which are free of fats; as well as concentrates of such vitamins which may contain fats which naturally occur therewith, or other fats.
  • compositions of the fat-soluble vitamins and the i-oleyloxybutyl others of polyoxyethylene glycol 1,000 readily dissolve in water or other aqueous media, as for example, aqueous solutions of the water-soluble vitamins, such as vitamin B1, riboflavin, vitamin Be or pyridoxine, nicotinic acid or its amide, pantothenic acid and the salts thereof, and vitamin C or ascorbic acid.
  • aqueous solutions of the water-soluble vitamins such as vitamin B1, riboflavin, vitamin Be or pyridoxine, nicotinic acid or its amide, pantothenic acid and the salts thereof, and vitamin C or ascorbic acid.
  • solubilizing agent based on the total volume of the vitamin aqueous solution can be varied but the preferred amount ranges from about 10 to 20 per cent. It will be understood that only those amounts need be employed which will yield clear solutions of the vitamin active substances.
  • the vitamin concentrates may be separately mixed with the solubilizing agent in the presence of water; or mixed concentrates, such as concentrates of vitamins A and D, may be employed to form the solutions comprising the present invention.
  • mixed concentrates such as concentrates of vitamins A and D
  • concentrates substantially tree of fats as for example, those obtained from fish liver oils by saponification, solvent ex-- traction, and further purification in the known manner.
  • vitamin D obtained from fish liver oils by saponification and solvent extraction and further purification
  • crystalline vitamin D such as calciferol or crystalline vitamin D2 such as is obtained from activated ergosterol by purification
  • synthetic forms of vitamin D such as activated dehydrocholesterol
  • Synthetic forms of vitamin A such as vitamin A alcohol and esters can also be readily solubilized by the aforesaid solubilizers.
  • vitamin A may also be a fatcontaining concentrate obtained, for example, in the known manner by the molecular distillation. of fish liver oils whereby a part of the naturally accompanying fats are removed. In these concentrates the vitamin A is primarily in the form of its ester. Thus distilled vitamin A concentrates containing from 400,000 to 700,000 USP units of vitamin A per gram, and vitamin D concentrates containing, for example, about 100,000 to 1,000,000 USP units of vitamin D per gram can be readily solubilized according to our invention. Although accompanied by varying amounts oi fats which are normally associated with these concentrates, the vitamin concentrates readily go into solution with the aforementioned solubilizers forming compositions which readily dissolve in aqueous media to yield clear, stable solutions.
  • the method for preparing the so lutions involves dissolving the vitamin concentrates by mixing" said substances with the liqueiicd solubilizing agent in any desired proportions.
  • Water or aqueous solutions as for example, aqueous solutions oi a water-soluble vitamin may be added and the mixing continued until the resulting solution appears clear.
  • a suitable solution containing water-soluble vitamins which may be incorporated with the fat-soluble, water insoluble vitamins is one made up of the following:
  • Solution I 0.26 gram oi? vitamin B2, 2.6 grams of gallic acid as a solubilizer therefor, 0.332 gram of niacinamide, 9.6 grams of vitamin C, 0.33 gram of vitamin B1 and approximately 60 cc. of water. This is designated hereafter as Solution I.
  • the new solubilizers are particularly effective in solubilizing synthetic vitamin A alcohol and its esters, and natural vitamin A accompanied by fats such as vitamin A concentrate obtained by molecular distillation in the known manner.
  • Example 1 Ten grams of mono(4-oleyloxybutyl)ether of polyoxyethylene glycol 1,000 are melted by heating and 2.02 grams of a mixed vitamin A and D concentrate and 0.0138 gram of irradiated ergosterol having a potency of 1,000,000 units oi. vitamin D per gram are added thereto.
  • the mixed concentrate is obtained in the known manner by molecular distillation of fish liver oils and contains 558,566 units of vitamin A in the natural ester form, and 79,791 units of vitamin D as irradiated ergosterol per gram.
  • a clear, viscous solution is obtained. 1.5 cc. of diethanolamine and 7.0 cc. of water are added to the solution, which is stirred while warming. A clear solution results which remains so upon further dilution with 60 cc. of the aqueous solution containing the water-soluble vitamins, designated as I above.
  • the pH of this solution is 4.45. It can be adjusted to 5.5 by the addition of a suitable alkali, such as diethanolamine without change in appearance of the solution.
  • the solution after being made up to 100 cc. contains per cc., 11,280 units of vitamin A and 1,750 units of vitamin D.
  • the solution is characterized by its unusual stability, remaining clear on prolonged standing at 45 (3., room temperature, and also at 4 C.
  • Example 2 Ten grams of mono(4-oleyloxybutyl)ether of polyoxyethylene glycol 1,000 are melted by heating and 2.02 grams of the same mixed vitamin A and D concentrate as described in Example 1 and 0.0138 gram of irradiated ergosterol containing 1,000,000 units of vitamin D per gram are added thereto. After mixing, 7.0 cc. of water are added and the mixture warmed while stirring. A clear solution is obtained which remains so upon further dilution with water.
  • Example 3 Ten grams of mono(4-oleyloxybutyl) ether of polyoxyethylene glycol 1.000 are melted by heating and 0.74 gram of svnthetic vitamin A acetate having a potency of 1,520,000 units of vitamin A per gram and 0.174 gram of irradiated ergosterol having a potency of 1,000,000 units of vitamin D per gram are added. After mixing, a clear, viscous solution results. To this solution 1.5 cc. of diethanolamine and 7.0 cc. of water are added, and the mixture warmed while stirring. A clear solution results which remains so after the addition of 60.0 cc. of solution I. After being made up to 100 cc. with water, this solution contains 11,248 units of vitamin A and 1,740 units of vitamin D per cc. The pH of this solution is 4.2. It can be adjusted to pH 5.5 without change in appearance.
  • Example 4 Six grams of mono(4-oleyloxybutyl) ether of polyoxyethylene glycol 1,000 are melted by heating and 0.74 gram of synthetic vitamin A acetate having a potency of 1,520,000 units of vitamin A per gram and 0.174 gram of irradiated ergosterol having a potency of 1,000,000 units of vitamin D per gram are mixed. Water is slowly added while stirring. The resulting solution is clear and contains, after being made up to cc., 11,248 units of vitamin A and 1,740 units of vitamin D per cc.
  • Example 5 Thirty grams of mono(4-oleyloxybutyl) ether of polyoxyethylene glycol 1,000 are melted by heating, and 0.96 gram of mixed vitamin A and D concentrate, 1.5 cc. of diethanolamine and 7.0 cc. of water are added and the mixture stirred while warming. A clear solution results which remains so after the addition of 60 cc. of Solution I. This solution contains, after being made up to 100 cc. with distilled water, 12,000 units of vitamin A and 1,700 units of vitamin D per cc.
  • the mixed vitamin A and D concentrate employed in this example contains 1,250,000 units of vitamin A and 178,000 units of vitamin D per gram.
  • the concentrate is substantially free of fat and is obtained from fish liver oils by saponification, solvent extraction-and further purification in the known manner.
  • Example 6 7 Fifteen grains of mono(4-oleyloxybutyl) ether oi. polyoxyethylene glycol 1,000 are melted by heating, and 0.96 gram of a mixed vitamin A and D concentrate described in Example 5 are added thereto. Seven cc. of water are added while mixing and warming the resulting solution. A clear solution results which remains 50 upon further dilution with water. This solution when made up to 100 cc. contains 12,000 units of vitamin A and 1,700 units of vitamin D in 1 cc.
  • Example 7 20.0 grams of mono(4-oleyloxybutyl)ether of polyoxyethylene glycol 1,000, 0.764 gram of synthetic vitamin A palmitate having a potency of 1,475,000 units per gram, 0.180 gram of irradiated ergosterol having a potency of 1,000,000 units per gram, 2.0 cc. of diethanolamine and 14.0 cc. of H20 are warmed in a water bath while mixing until a clear solution is obtained. 60.0 cc. of Solution I are added. A clear solution results which, after being made up to 100 00., contains 11,269
  • Example 8 7.0 grams of mono(4-oleyloxybutyl) ether of polyoxyethylene glycol 1,000, 0.3772 gram of synthetic vitamin A alcohol having a potency of 2,981,000 units per gram, 0.180 gram of irradiated ergosterol (1,000,000 units per gram), 2.0 cc. of diethanolamine and 14.0 cc. of H20 are warmed in a water bath until clear solution is obtained. 60.0 cc. of Solution I are added. A clear solution results. This solution contains, after being made up to 100 cc., 11,240 units of vitamin A per cc. and 1800 units of D per cc.
  • Example 9 15.0 grams of mono(4-oleyloxybutyl)ether of polyoxyethylene glycol 1,000 and 1.0 gram of a-tocopherol are warmed; H2O is slowly added to make up 100 cc. while warming. A clear solution results. 1 cc. of this solution contains 10 mg. a-tocopherol.
  • mono(4-oleyloxybutyl) ether as a solubilizing agent in the above examples, there can be employed, in general, mono(4-higher aliphaticoxybutyl) ethers of polyoxyethylene glycol 1,000-4,000 as, for example, the mono(4-lauryloxybuty1) ethers of polyoxyethylene glycol 1,000-4,000, oxybutyllethers of polyoxyethylene glycol 1,000- 4,000 and the monoG-stearyloxybutyl)ethers of polyoxyethylene glycol 1,000-4,000.
  • solubilizing agents are new compounds. They can be prepared in general by reacting 4-higher aliphatic oxy'butyl halides as, for example, 4-oleyl-, 4-1auryl-, 4-cetyl-, and 4- stearyl-, oxybutyl bromides with an alkali metal derivative of a polyoxyethylene glycol having a molecular weight of from 1,000-4,000.
  • a clear, stable fat-containing aqueous solution comprising vitamins A and D and as a solubilizer therefor the mono(4-oleyloxybutyl)ether of polyoxyethylene glycol 1,000.
  • R is a hydrocarbon radical having at least twelve carbon atoms, and :1: is a number so that the polyoxyethylene group has a molecular weight of from about 1,000-4,000.
  • R is a hydrocarbon radical having at least twelve carbon atoms
  • a: is a number so that the polyoxyethylene group has a molecular weight of from about 1,000-4,000, which comprises reacting the alkali metal alcoholate of a higher fatty alcohol containing at least twelve carbon atoms with dibromobutane and reacting the resulting reaction product with an alkali metal derivative of a polyoxyethylene glycol having a molecular weight of 1,000-4,000.
  • a method of preparing 4-oleyloxybutyl ether of polyoxyethylene glycol 1,000 which comprises reacting 4-bromobutyl oleyl ether with a mono-sodium derivative of polyoxyethylene glycol 1,000.

Description

Patented-Oct. a, 1950 AQUEOUS SOLUTIONS OF mom-SOLUBLE VITAMINS Margaret Rose Zentner, Newark, N. 1., and Gerhard Julius Haas, New York, N. Y., assignors to Hoflmann-La Roche Inc., Nutley, N. J., a corporation of New Jersey No Drawing. Application July 10, 1948, Serial No. 38,178
The present invention relates to the solubilization of lipoidor fat-soluble, water-insoluble vitamins such as vitamins A, D and E and the like, and more particularly to aqueous solutions of such vitamins in which said vitamins are dissolved in an amount greater than their normal water solubility. The invention also relates to new compounds which are employed as solubllizers in producing such solutions.
According to our invention we have found that lipoidor fat-soluble vitamins can be dissolved by 4-higher aliphatic oxybuty] ethers of polyoxyethylene glycol LOUIS-4,000. The numerals 1,000- 4,000 refer to the approximate molecular weight of the polyoxyethylene glycol combined with the higher aliphatic oxybutyl portion of the molecule. The solubilizing compounds which we employ can be represented by the following formula:
wherein R represents a long carbon-link chain having at least twelve carbon atoms and :r represents a number of oxyethylene groups so that the polyoayethylene group has a molecular weight of from about LOW-i000.
The i-oleyloxybutyl ether of polyoxyethylene glycol 1,000 has been found to be particularly effective for the solubilization of the lipoid-soluble, water-insoluble vitamins, which are substantially free of fats (glycerides of the higher fatty acids), as for example, high potency vitamins A, D or E, or mixed A and D concentrates which are free of fats; as well as concentrates of such vitamins which may contain fats which naturally occur therewith, or other fats. The resulting compositions of the fat-soluble vitamins and the i-oleyloxybutyl others of polyoxyethylene glycol 1,000 readily dissolve in water or other aqueous media, as for example, aqueous solutions of the water-soluble vitamins, such as vitamin B1, riboflavin, vitamin Be or pyridoxine, nicotinic acid or its amide, pantothenic acid and the salts thereof, and vitamin C or ascorbic acid.
To obtain clear, stable, aqueous solutions of the water-insoluble vitamins, it is only required to mix the aforementioned solubilizers with water and with the vitamin concentrates. The amount of the solubilizing agent based on the total volume of the vitamin aqueous solution can be varied but the preferred amount ranges from about 10 to 20 per cent. It will be understood that only those amounts need be employed which will yield clear solutions of the vitamin active substances.
In practicing the invention to prepare aqueous 12 Claims. (CL 167-81) solutions, the vitamin concentrates may be separately mixed with the solubilizing agent in the presence of water; or mixed concentrates, such as concentrates of vitamins A and D, may be employed to form the solutions comprising the present invention. As a source of vitamins A and D there may be employed concentrates substantially tree of fats, as for example, those obtained from fish liver oils by saponification, solvent ex-- traction, and further purification in the known manner. In addition to vitamin D obtained from fish liver oils by saponification and solvent extraction and further purification, crystalline vitamin D such as calciferol or crystalline vitamin D2 such as is obtained from activated ergosterol by purification, and synthetic forms of vitamin D, such as activated dehydrocholesterol, can be employed. Synthetic forms of vitamin A such as vitamin A alcohol and esters can also be readily solubilized by the aforesaid solubilizers.
Another source of vitamin A may also be a fatcontaining concentrate obtained, for example, in the known manner by the molecular distillation. of fish liver oils whereby a part of the naturally accompanying fats are removed. In these concentrates the vitamin A is primarily in the form of its ester. Thus distilled vitamin A concentrates containing from 400,000 to 700,000 USP units of vitamin A per gram, and vitamin D concentrates containing, for example, about 100,000 to 1,000,000 USP units of vitamin D per gram can be readily solubilized according to our invention. Although accompanied by varying amounts oi fats which are normally associated with these concentrates, the vitamin concentrates readily go into solution with the aforementioned solubilizers forming compositions which readily dissolve in aqueous media to yield clear, stable solutions.
In general, the method for preparing the so lutions involves dissolving the vitamin concentrates by mixing" said substances with the liqueiicd solubilizing agent in any desired proportions. Water or aqueous solutions, as for example, aqueous solutions oi a water-soluble vitamin may be added and the mixing continued until the resulting solution appears clear. An example of a suitable solution containing water-soluble vitamins which may be incorporated with the fat-soluble, water insoluble vitamins is one made up of the following:
0.26 gram oi? vitamin B2, 2.6 grams of gallic acid as a solubilizer therefor, 0.332 gram of niacinamide, 9.6 grams of vitamin C, 0.33 gram of vitamin B1 and approximately 60 cc. of water. This is designated hereafter as Solution I.
The new solubilizers are particularly effective in solubilizing synthetic vitamin A alcohol and its esters, and natural vitamin A accompanied by fats such as vitamin A concentrate obtained by molecular distillation in the known manner.
The following examples will serve to illustrate our invention:
Example 1 Ten grams of mono(4-oleyloxybutyl)ether of polyoxyethylene glycol 1,000 are melted by heating and 2.02 grams of a mixed vitamin A and D concentrate and 0.0138 gram of irradiated ergosterol having a potency of 1,000,000 units oi. vitamin D per gram are added thereto. The mixed concentrate is obtained in the known manner by molecular distillation of fish liver oils and contains 558,566 units of vitamin A in the natural ester form, and 79,791 units of vitamin D as irradiated ergosterol per gram. After mixing, a clear, viscous solution is obtained. 1.5 cc. of diethanolamine and 7.0 cc. of water are added to the solution, which is stirred while warming. A clear solution results which remains so upon further dilution with 60 cc. of the aqueous solution containing the water-soluble vitamins, designated as I above.
The pH of this solution is 4.45. It can be adjusted to 5.5 by the addition of a suitable alkali, such as diethanolamine without change in appearance of the solution. The solution, after being made up to 100 cc. contains per cc., 11,280 units of vitamin A and 1,750 units of vitamin D.
The solution is characterized by its unusual stability, remaining clear on prolonged standing at 45 (3., room temperature, and also at 4 C.
Example 2 Ten grams of mono(4-oleyloxybutyl)ether of polyoxyethylene glycol 1,000 are melted by heating and 2.02 grams of the same mixed vitamin A and D concentrate as described in Example 1 and 0.0138 gram of irradiated ergosterol containing 1,000,000 units of vitamin D per gram are added thereto. After mixing, 7.0 cc. of water are added and the mixture warmed while stirring. A clear solution is obtained which remains so upon further dilution with water.
Example 3 Ten grams of mono(4-oleyloxybutyl) ether of polyoxyethylene glycol 1.000 are melted by heating and 0.74 gram of svnthetic vitamin A acetate having a potency of 1,520,000 units of vitamin A per gram and 0.174 gram of irradiated ergosterol having a potency of 1,000,000 units of vitamin D per gram are added. After mixing, a clear, viscous solution results. To this solution 1.5 cc. of diethanolamine and 7.0 cc. of water are added, and the mixture warmed while stirring. A clear solution results which remains so after the addition of 60.0 cc. of solution I. After being made up to 100 cc. with water, this solution contains 11,248 units of vitamin A and 1,740 units of vitamin D per cc. The pH of this solution is 4.2. It can be adjusted to pH 5.5 without change in appearance.
Example 4 Six grams of mono(4-oleyloxybutyl) ether of polyoxyethylene glycol 1,000 are melted by heating and 0.74 gram of synthetic vitamin A acetate having a potency of 1,520,000 units of vitamin A per gram and 0.174 gram of irradiated ergosterol having a potency of 1,000,000 units of vitamin D per gram are mixed. Water is slowly added while stirring. The resulting solution is clear and contains, after being made up to cc., 11,248 units of vitamin A and 1,740 units of vitamin D per cc.
Example 5 Thirty grams of mono(4-oleyloxybutyl) ether of polyoxyethylene glycol 1,000 are melted by heating, and 0.96 gram of mixed vitamin A and D concentrate, 1.5 cc. of diethanolamine and 7.0 cc. of water are added and the mixture stirred while warming. A clear solution results which remains so after the addition of 60 cc. of Solution I. This solution contains, after being made up to 100 cc. with distilled water, 12,000 units of vitamin A and 1,700 units of vitamin D per cc.
The mixed vitamin A and D concentrate employed in this example contains 1,250,000 units of vitamin A and 178,000 units of vitamin D per gram. The concentrate is substantially free of fat and is obtained from fish liver oils by saponification, solvent extraction-and further purification in the known manner.
Example 6 7 Fifteen grains of mono(4-oleyloxybutyl) ether oi. polyoxyethylene glycol 1,000 are melted by heating, and 0.96 gram of a mixed vitamin A and D concentrate described in Example 5 are added thereto. Seven cc. of water are added while mixing and warming the resulting solution. A clear solution results which remains 50 upon further dilution with water. This solution when made up to 100 cc. contains 12,000 units of vitamin A and 1,700 units of vitamin D in 1 cc.
Example 7 20.0 grams of mono(4-oleyloxybutyl)ether of polyoxyethylene glycol 1,000, 0.764 gram of synthetic vitamin A palmitate having a potency of 1,475,000 units per gram, 0.180 gram of irradiated ergosterol having a potency of 1,000,000 units per gram, 2.0 cc. of diethanolamine and 14.0 cc. of H20 are warmed in a water bath while mixing until a clear solution is obtained. 60.0 cc. of Solution I are added. A clear solution results which, after being made up to 100 00., contains 11,269
' units of vitamin A per cc. and 1800 units of vitamin D per cc.
Example 8 7.0 grams of mono(4-oleyloxybutyl) ether of polyoxyethylene glycol 1,000, 0.3772 gram of synthetic vitamin A alcohol having a potency of 2,981,000 units per gram, 0.180 gram of irradiated ergosterol (1,000,000 units per gram), 2.0 cc. of diethanolamine and 14.0 cc. of H20 are warmed in a water bath until clear solution is obtained. 60.0 cc. of Solution I are added. A clear solution results. This solution contains, after being made up to 100 cc., 11,240 units of vitamin A per cc. and 1800 units of D per cc.
Example 9 15.0 grams of mono(4-oleyloxybutyl)ether of polyoxyethylene glycol 1,000 and 1.0 gram of a-tocopherol are warmed; H2O is slowly added to make up 100 cc. while warming. A clear solution results. 1 cc. of this solution contains 10 mg. a-tocopherol.
Instead of employing the mono(4-oleyloxybutyl) ether as a solubilizing agent in the above examples, there can be employed, in general, mono(4-higher aliphaticoxybutyl) ethers of polyoxyethylene glycol 1,000-4,000 as, for example, the mono(4-lauryloxybuty1) ethers of polyoxyethylene glycol 1,000-4,000, oxybutyllethers of polyoxyethylene glycol 1,000- 4,000 and the monoG-stearyloxybutyl)ethers of polyoxyethylene glycol 1,000-4,000.
The aforementioned solubilizing agents are new compounds. They can be prepared in general by reacting 4-higher aliphatic oxy'butyl halides as, for example, 4-oleyl-, 4-1auryl-, 4-cetyl-, and 4- stearyl-, oxybutyl bromides with an alkali metal derivative of a polyoxyethylene glycol having a molecular weight of from 1,000-4,000.
The following example will illustrate in detail the method of producing the mono(4-oleyloxybutyDether of polyoxyethylene glycol 1,000. It will be understood that the lauryl, cetyl, stearyl and other higher aliphatic oxybutyl compounds of this type can be produced in the same manner:
134 grams moi) of oleyl alcohol and 11.5 grams of sodium A; moll-were reacted by stirring and refluxing in 200 cc. of dry dioxane. The reaction proceeded slowly and the solution be came milky, but after thirteen hours, there was still some unreacted sodium left. Hence more grams of oleyl alcohol were added and, after sixteen hours total refluxing time, all the sodium had disappeared. To the resulting solution of the sodium alcoholate of oleyl alcohol, 130 grams of 1,4-dibromobutane (B. P.-194/764 mm.) were added, and the mixture refluxed for four hours. Then 200 cc. of water were added to dissolve the sodium bromide which had precipitated. Most of the dioxane was removed by distilling oil 200 cc. in vacuo. Then an additional 100 cc. of water were added, and 100 cc. of benzene. The aqueous layer was separated off and discarded, thesolvents removed from the organic layer by distillation in vacuo. The residue was fractionated in vacuo. The fraction boiling between 1'70-190 C. at 0.3 mm. was taken. For further purification, the 4-bromobutyl oleyl ether thus formed was shaken with two portions of 40 cc. of methanol in which it is insoluble, and dried under vacuum.
50 grams (0.050 mol) of "Carbowax 1,000 (a commercial polyoxyethylene glycol having a molecular weight of 1,000) were reacted with 1.25 grams of sodium (0.054 mol) by refluxing in 150 cc. of dioxane for six hours. Then grams (0.416 mol) of the oley1-4-bromobuty1 ether were added. The sodium bromide, which precipitated, was then filtered off and the filtrate evaporated in vacuo. 65 grams of a waxy water-soluble solid resulted, which was the 4-oleyloxybutyl ether of polyoxyethylene glycol 1,000.
It can be represented by the following formula:
a: standing for a number of oxyethylene groups so that the polyoxyethylene group has a molecular weight of about 1,000.
When in the above examplethe oleyl alcohol is replaced by a lauryl alcohol, cetyl alcohol, stearyl alcohol, the corresponding 4-lauryl-, 4-cetyl-, and 4-stearyl-oxybutyl ethers of polyoxyethylene glycols 1,000 are obtained in the identical manner.
When polyoxyethylene glycols having a molecular weight of 3,000 and 4,000 are employed, the corresponding derivatives of polyoxyethylene glycols having a molecular weight of 3,000 and 4,000 are obtained.
the mono(4-cetyl- We claim:
1. An aqueous solution of water-insoluble. lipoid-soluble vitamin and as a-solubilizer therefor a mono(4-oley1oxybutyl)ether of polyoxyethylene glycol 1,000.
2. A clear, stable aqueous solution containing vitamins A and D and as a solubilizer therefor the mono(4-oleyloxybutyl) ether of polyoxyethylene glycol 1,000.
3. A clear, stable fat-containing aqueous solution comprising vitamins A and D and as a solubilizer therefor the mono(4-oleyloxybutyl)ether of polyoxyethylene glycol 1,000.
4. A clear, stable aqueous solution of vitamin A acetate, and as a solubilizer therefor, the mono(4-oleyloxybuty1)ether 0f polyoxyethylene glycol 1,000.
5. A clear, stable aqueous solution of vitamin A palmitate, and as a solubilizer therefor, the mono(4-oleyloxybutyl)ether of polyoxyethylene glycol 1,000.
6. A clear, stable aqueous solution of a-tocopherol and as a solubilizer therefor, the mono(4- oleyloxybutyDether of polyoxyethylene glycol 1,000
7. A composition of matter of the formula:
in which R is a hydrocarbon radical having at least twelve carbon atoms, and :1: is a number so that the polyoxyethylene group has a molecular weight of from about 1,000-4,000.
8. 4-oleyloxybutyl ether of polyoxyethylene glycol 1,000.
9. 4-lauryloxybutyl ether of polyoxyethylene glycol 1,000.
10. 4-stearyloxybutyl ether of polyoxyethylene glycol 1,000. r
11. A process for producing a compound which can be represented by the following formula:
in which R is a hydrocarbon radical having at least twelve carbon atoms, and a: is a number so that the polyoxyethylene group has a molecular weight of from about 1,000-4,000, which comprises reacting the alkali metal alcoholate of a higher fatty alcohol containing at least twelve carbon atoms with dibromobutane and reacting the resulting reaction product with an alkali metal derivative of a polyoxyethylene glycol having a molecular weight of 1,000-4,000.
12. A method of preparing 4-oleyloxybutyl ether of polyoxyethylene glycol 1,000 which comprises reacting 4-bromobutyl oleyl ether with a mono-sodium derivative of polyoxyethylene glycol 1,000.
MARGARET ROSE ZENTNER. GERHARD JULIUS HAAS.
REFERENCES CITED The following references are of record in the file of this patent:
UNITED STATES PATENTS Number Name Date 2,185,969 Schultze Jan. 2, 1940 2,425,755 Roberts Aug. 19, 1947

Claims (1)

  1. 7. A COMPOSITION OF MATTER OF THE FORMULA:
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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2721161A (en) * 1951-10-23 1955-10-18 American Home Prod Ascorbic acid preparation
US2771394A (en) * 1953-07-10 1956-11-20 Colgate Palmolive Co Hair grooming preparation
DE970772C (en) * 1951-06-05 1958-10-30 Wander Ag Dr A Process for the production of aqueous, in particular concentrated aqueous solutions of vitamins D and / or D.
DE1079281B (en) * 1956-03-22 1960-04-07 Uhu Werk H Process for the manufacture of a bath additive
EP0055817A2 (en) * 1980-12-19 1982-07-14 BASF Aktiengesellschaft Stable and injectable soluble forms of beta-carotene, and methods of preparing them

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2185969A (en) * 1935-05-24 1940-01-02 Winthrop Chem Co Inc Clear aqueous solutions of lipins and process of preparing the same
US2425755A (en) * 1944-06-01 1947-08-19 Carbide & Carbon Chem Corp Mixtures of polyoxyalkylene monohydroxy compounds and methods of making such mixtures

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2185969A (en) * 1935-05-24 1940-01-02 Winthrop Chem Co Inc Clear aqueous solutions of lipins and process of preparing the same
US2425755A (en) * 1944-06-01 1947-08-19 Carbide & Carbon Chem Corp Mixtures of polyoxyalkylene monohydroxy compounds and methods of making such mixtures

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE970772C (en) * 1951-06-05 1958-10-30 Wander Ag Dr A Process for the production of aqueous, in particular concentrated aqueous solutions of vitamins D and / or D.
US2721161A (en) * 1951-10-23 1955-10-18 American Home Prod Ascorbic acid preparation
US2771394A (en) * 1953-07-10 1956-11-20 Colgate Palmolive Co Hair grooming preparation
DE1079281B (en) * 1956-03-22 1960-04-07 Uhu Werk H Process for the manufacture of a bath additive
EP0055817A2 (en) * 1980-12-19 1982-07-14 BASF Aktiengesellschaft Stable and injectable soluble forms of beta-carotene, and methods of preparing them
EP0055817B1 (en) * 1980-12-19 1986-08-13 BASF Aktiengesellschaft Stable and injectable soluble forms of beta-carotene, and methods of preparing them

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