US2463461A

US2463461A - Aqueous solutions of riboflavin

Info

Publication number: US2463461A
Application number: US5681A
Authority: US
Inventors: Hoffer Max
Original assignee: F Hoffmann La Roche AG
Current assignee: F Hoffmann La Roche AG; Hoffmann La Roche Inc
Priority date: 1948-01-31
Filing date: 1948-01-31
Publication date: 1949-03-01
Anticipated expiration: 1966-03-01

Description

Patented Mar. 1, 1949 AQUEOUS SOLUTIONS or am'omvm Max Hofler, Nutley, N. 1., assignor to 1108mm:-

La Roche Inc., Nntley, N. 1., a corporatlon of New Jersey No Drawing. Application January 31, 1948, Serial No. 5,681

The present invention relates to aqueous solutions of riboflavin commonly known as vitamin 3:. More particularly, the invention relates to the solubilizing of riboflavin alone and riboflavin in multi-vitamin compositions.

As is well known, riboflavin is highly insoluble in water and other solvents suitable for pharmaceutical preparations. Its solubility is only about 0.013 per cent in water. Howeventherapeutic preparations in the form of solutions require concentrations of riboflavin which are from 200 to 500 times higher than the amount of riboflavin normally soluble in water.

Numerous proposals to solubilize riboflavin have been made and many compounds for this purpose are described in patent literature. Compounds such as nicotinamide, water soluble salts of nicotinic acid, salts of 2,4-dihydroxy-benzoic acid, salts of monoalkyl ethers of 2,4-dihydroxybenzoic acid, acetamidine hydrochloride, alkali metal salts of gallic acid, urea and n-alkyl'ated amides of lower fatty acids have been proposed as solubilizers for riboflavin. While these compounds exhibit to some extent in each case a solubilizing action, many of them are accompanied by either rather high toxicity or undesirable sideeflects after oral or parenteral administration,

usually because of the large quantities of thesolubilizer that must be employed in relation to the amount of riboflavin solubilized. In other instances the solutions obtained are unstable and the solubilizer itself may decompose.

According to my invention I have found that amides or gentisic acid with lower aliphatic hydroxy amines can be employed to solubilize riboflavin. These compounds exert a rather strong solubilizing action on riboflavin permitting use of a relatively small amount of the compounds to maintain therapeutic amounts 'of riboflavin in solution. The new solubilizers also show very low toxicity and less side-efiects upon parenteral or oral administration than the compounds heretofore described.

The amides of gentisic acid with lower aliphatic hydroxy amines which I have found eflective for solubilizing riboflavin can be represented by the following formula:

wherein X is a lower divalent aliphatic radical having at least two carbon'atoms and at most,

4 Claims. (Cl. 167-81) 2 three carbon atoms. Among the compounds coming under this formula which we have found particularly eflective for their solubilizing action are N-(p-hydroxyethyl) gentisamide and N- (p-hydroxypropyl) -gentisamide.

In addition to their greater solubilizing power, the solubilizers are also characterized by their stability towards acids and alkalies within relatively wide limits. They accordingly allow preparation of riboflavin solutions over a wide range of pH. This feature is particularly important since vitamin deficiencies are of a complex nature and may be due to the lack of several vitamins at the same time. Accordingly, in the case of the so-called vitamin B complex, it is highly advisable to use a combination of vitamins B1 and 32- However, it is known that vitamin B1 is stable in the form of its hydrochloride in strongly acid solution. 0n the other hand, in weakly acid solution it decomposes, breaking down and losing its activity at a pH of 5-6. In neutral and alkaline solutions it is unstable, Thus, if riboflavin is to be administered at the same time with vitamin B1 hydrochloride, a pH of below 5 is necessary to maintain stability of the vitamin B1. Accordingly" a solubilizer for riboflavin which is to be employed in combination with vitamin B1 must be one which will not only solubilize the riboflavin, but one which will itself be stable at below a pH of 5. The new solubilizers not only meet these requirements on the acid side, but also may be employed to solubilize riboflavin at higher pHs where the presence of vitamin B1 is not indicated.

The manufacture of the new aqueous solutions of riboflavin generally involves preparing a water solution of the lower aliphatic hydroxy amide oi gentisic acid followed by the addition of riboflavin, usually while warming. Additional vitamins suchas vitamin B1, niacinamide, pantothenic acid, vitamin C and the like may be added, if desired. The final product may be diluted with water to the desired volume and the pH adjusted to the desired value. I

If desired, preparation of the composition may be carried out in an inert atmosphere as a precautionary measure to avoid decomposition of any of the ingredients. A suitable inert gas such as carbon dioxide, or nitrogen may be employed for this purpose.

The compounds which I employ as solubilizers are new substances and their preparation is described indetail in application of Johr. L. Huck, Jr., Serial No. 5,683, flled January 31, 1948. In general as described in this application, the

5 amides of gentisic acid with lower aliphatic hy- Example 1 N- (B-hydroxyethyl) -gentisamid CONE-CHr-OHzOH 168 grams, (1 mol) of methylgentisate are stirred into 200 cc. of benzene, 244 grams (4 mols) of monoethanolamine are added and heated under stirring to '75-80 C. in a nitrogen atmosphere. The benzol and the methanol formed are distilled ofi at the same time. The residue is now heated in a vacuum in order to distill oil the excess of ethanolamine at a bath temperature not substantially exceeding 180 C. (preferably at 150 0.). The residue is acidified with hydrochloric acid and allowed to cool for crystallization. The crystals are sucked off and washed with a small amount of ice cold water. They can, if necessary, be recrystallized from water. The N-(B-hydroxyethyl)-gentisamide forms white prisms. The compound melts at 145-148 C.

Example, 2

N- (B-hydroxypropyl) -gentisamide 4] O-NH-OHa-CHOH-CH:

168 grams (1 mol) of methylgentisate, 300 grams (4 mols) of 1-amino-propanol-2 are reacted} as described in Example 1. The product can be recrystallized from water and forms white prisms of M. P. 141142.

The following examples will serve to illustrate the novel compositions containing solubilized riboflavin:

Example 3 20 grams of N-(p-hydroxyethyl)-gentisamide are dissolved in 600 cc. of water while slightly warming at about 50-60 C. To this is added 3.3 grams of riboflavin, and the mixture heated by refluxing until solution of the riboflavin is efiected. The solution is then diluted to 1,000 cc. with distilled water.

Example 4 38 grams of N-(fl-hydroxypropyl) -gentisamide are dissolved in 1,000 cc. of water. To this is added 6.6 grams of riboflavin and the mixture refluxed until the riboflavin goes into solution. The solution is then diluted to 2,000 cc. with distilled water.

Example 5 19 grams of N-(fi-hydroxyethyl)-gentisamide are dissolved in 600 cc. of water while slightly warming at about 50-60" C. To this is added a mixture of 3.8 grams of riboflavin and 21 grams of niacinamide, and the mixture refluxed until the riboflavin goes into solution. The solution is cooled to about 25 C. Thereafter 31.46 grams of sodium ascorbate and 27.5 grams of vitamin C are slowlyadded to the cooled solution with constant stirring. There are then incorporated with stirring 12 grams of vitamin B1, 3.3 grams of vitamin B6 and 106.4 cc. of an aqueous sodium pantothenate solution containing 47 mgm. of sodium pantothenate per cc. and the solution is adjusted to the desired volume, that is, 1,000 cc. by addition of distilled water. All the operations are preferably carried out under an atmosphere of carbon dioxide. The pH of the solution is 4.3.

Example 6 32 grams of N-(fl-hydroxypropygl) -gentisamide are dissolved in 1,000 cc. of water. To this is addedi6.6 grams of riboflavin and 42 grams of niacinamide and the mixture refluxed until the riboflavin goes into solution. The solution is cooled to about 25 C. Thereafter grams of vitamin C and 62.86 grams of sodium ascorbate are slowly added to the cooled'solution with constant stirring. There are then added 24 grams of vitamin B1, 6.6 grams of vitamin B6, 5 grams of sodium pantothenate in cc. of water, and sufilcient water to give a total volume of solution of about 2,000 cc. All the operations are carried out under an atmosphere of carbon dioxide. The

pH of the solution is 4.3.

If desired, a dry composition of riboflavin and the lower hydroxy aliphatic amide of gentisic acid can be prepared for use in making up aqueous solutions of riboflavin as they are desired, the amide being present in an amount sufficient to substantially increasethe solubility of riboflavin in the aqueous media. In this connection similar proportions as disclosed above, of the ingredients may be mixed together to prepare the dry compositions, and these subsequentlydissolved in water alone, or together with other vitamins when it is desired to prepare multi-vitamin compositions.

I claim:

1. An aqueous solution containing riboflavin in a concentration higher than 0.013 per cent and a lower alkylolamide of gentisic acid as a solubilizer for the riboflavin.

2. An aqueous solution containing riboflavin in a concentration higher than 0.013 per cent and N- (fi-hydroxyethyl) -gentisamide.

3. An aqueous solution containing riboflavin in a concentration higher than 0.013 per cent and N B-hydroxypropyl) -gentisamide.

4. The composition of claim 1 in which the pH is below 5.

MAX HOFFER.

REFERENCES CITED The following references are of record in the file of this patent:

UNITED STATES PATENTS Number Name Date 1,675,500 Kropp July 3, 1928 1,990,453 Hund Feb. 5, 1935 2,256,604 Auhagen Sept. 23, 1941 2,438,880 Furter Mar. 30, 1948