US3022286A - Process for preparing higher fatty acid salts of neomycin - Google Patents
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- US3022286A US3022286A US859160A US85916059A US3022286A US 3022286 A US3022286 A US 3022286A US 859160 A US859160 A US 859160A US 85916059 A US85916059 A US 85916059A US 3022286 A US3022286 A US 3022286A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/20—Carbocyclic rings
- C07H15/22—Cyclohexane rings, substituted by nitrogen atoms
- C07H15/222—Cyclohexane rings substituted by at least two nitrogen atoms
- C07H15/226—Cyclohexane rings substituted by at least two nitrogen atoms with at least two saccharide radicals directly attached to the cyclohexane rings
- C07H15/228—Cyclohexane rings substituted by at least two nitrogen atoms with at least two saccharide radicals directly attached to the cyclohexane rings attached to adjacent ring-carbon atoms of the cyclohexane rings
- C07H15/232—Cyclohexane rings substituted by at least two nitrogen atoms with at least two saccharide radicals directly attached to the cyclohexane rings attached to adjacent ring-carbon atoms of the cyclohexane rings with at least three saccharide radicals in the molecule, e.g. lividomycin, neomycin, paromomycin
Definitions
- the invention here is described as residing in the concept of dissolving approximately equivalent quantities of 3,iPZZ,Z$$ Patented Feb. 20, 1962 ice no apparent skin irritation.
- the higher fatty acid neomycin base with the appropriate higher fatty acid in a lower alkanol solvent and at a final pH between 6.5- 7.5 to form a chemical compound in which neomycin is, associated with a higherfatty acid in the form of a true salt.
- higher fatty acid means an aliphatic monocarboxylic acid containing 8 to 18 carbon atoms.
- the aliphatic portion of the acid may be straight chain or branched and saturated or unsaturated.
- the better known higher fatty acids are straight chain, saturated compounds containing 8 to 18 carbon atoms; the acids particularly useful in the practice of my invention can also be recognized as those whose alkali metal salts are generally known as soaps.
- My invention is not so limited and contemplates all aliphatic fatty acids having 8 to 18 carbon atoms and which produce waterinsoluble salts of neomycin.
- lower alkanol means saturated alcohols having less than 3 carbon atoms, i.e., methyl and ethyl alcohols.
- Neomycin also referred to as neomycin base
- neomycin base is a naturally occurring antibiotic elaborated by a soil organism of the Streptomyces genus when cultured on the appropriate nutrient media.
- the neomycinthus produced is a basic, water-soluble compound active against many gram positive and gram negative micro-organisms.
- the antibiotic is often isolated and incorporated into pharmaceutical preparations in the form of its mineral acid salts, most commonly neomycin sulfate and chloride. Because of the very high water solubility of neomycin mineral acid salts (one gram of neomycin sulfate dissolves in one milliliter of water), these salts are readily leached from preparations containing them. Hence, the beneficial effects of neomycin are not fully realized in such preparations when topically applied.
- the higher fatty acid salts of neomycin unlike neomyein base or neomycin mineral acid salts, are waxlike and practically insoluble in water and thus may be more effectively utilized in ointments, lotions, creams, soap bases and other preparations designed for topical use. Replacement of the mineral acid anion by a higher fatty acid anion does not materially detract from the germicidal properties of the neomycin moiety.
- neomycin sulfate and neomycin palmitate were compared in their anti-fungal and anti-bacterial properties against 34 representative micro-organisms including C. diphtheria, S. typhosa, St.
- the fatty acid salt was at least as effective as the sulfate; and in the case of 23 of the organisms tested, even smaller concentrations of the palmitate were sufiicient to produce equivalent inhibition in the growth of the test bacteria and fungi.
- salts of neomycin can be safely and effectively utilized in topical preparations for the treatment of dermatological conditions caused by neomycin susceptible organisms. These salts can also be incorporated into compositions su'ch as hand creams which are used to obtain substanunsuited for large scale production.
- the salts have the added advantage of producing their own emolient or demulcent effect.
- neomycin reacts in alcoholic solution and under carefully controlled conditions with the appropriate higher fatty acid to give excellent yields of the desired neomycin fatty acid salt.
- the pH and the ratio of reactants used must be carefully controlled in order to obtain good yields of high grade product. Deviation from the optimum conditions will still give the fatty acid salt of neomycin but in a lessened degree of purity.
- an object of the present invention to provide a convenient method for the preparation of higher fatty acid salts of neomycin free of inorganic and other contaminants.
- neomycin base with higher fatty acids is effected, according to my process, in a lower alkanol, preferably methanol or ethanol. Mixtures of those alcohols are also satisfactory. It is not necessary that the alcohol used be anhydrous; the usually available commercial grades of methyl or ethyl alcohol are most often employed.
- the order of mixing the reactants is not critical and all methods of mixing the reactants with each other and with the solvent are equivalent. Usually a solution of the acid is added to a solution of the neomycin base but the reverse order may be employed.
- the fatty acid can be added directly to the alcoholic solution of the neomycin base. Temperature control is not required and the process is carried out at ambient temperatures.
- a certain amount of warming results when the reactants are mixed raising the temperature of the reaction mixture from room temperature to about 40-45 degree Centigrade. Slight warming may be utilized to further solubility; this is especially the case when it is desired to clarify the solution with charcoal before recovery of the product.
- the final pH of the reaction mixture and the ratio of reactants fall within the limits stated below.
- the final pH of the reaction mixture must be about 6.5 to 7.5. If the final pH is allowed tovary from the suggested range, either the fatty acid will precipitate from solution or certain other salts of neomycin will be found in conjunction with the desired neomycin fatty acid salt. While it is not an object of the present invention to prepare such compositions, they can be made by varying the general procedure of my process.
- the best way to obtain the proper final pH and pure product is to titrate the neomycin base in alcohol solution with the fatty acid dissolved in the same solvent or to add the calculated approximate stoichiometric amount of acid (directly or in solution) to a solution of the base.
- the higher fatty acid salts of neomycin have a desirable waxy consistency.
- the palmitate and higher salts are sufiiciently insoluble in alcoholic solution so as to be capable of isolation directly by filtration, centrifugation, etc. Chilling, although not essential, may be utilized to diminish the solubility of the product.
- the presence of small amounts of water in the alcoholic solvent will accomplish the same result and may even be added for that purpose.
- the lower salts are too soluble to be isolated directly and are recovered by evaporation of the solvent, preferably by spray drying. This technique can be used successfully because of the absence of contaminating byproducts; the presence of small amounts of water will not interfere. In certain situations, the presence of up to about 20 percent of water in the alcoholic solvent used will not be detrimental and can be tolerated.
- novel neomycin higher fatty acid salts of my invention have been shown by X-ray analysis to be true salts and not mere mixtures of neomycin with the reactant fatty acid.
- Example I This example illustrates the preparation of neomycin palmitate from neomycin base and palmitic acid in alcohol solution.
- 80 grams of palmitic acid was added to methanolic solution containing 20 grams of neomycin base.
- Sufficient methanol was added to produce a clear solution at 50-55 degrees Centigrade.
- the final solution contained about 500 milliliters of methanol and had a pH of 6.8.
- 95 grams of neomycin palmitate having a potency of 205 mcg./ mg. was obtained on filtration.
- neomycin base in 22-24 gallons of methyl alcohol was used as the starting material. This solution was obtained by the methanol extraction of crude neomycin. Palmitic acid, amounting to about three times the weight of neomycin base solids present, was added to the neomycin the first agar plate 50 mcg./ml.
- Example 11 This example illustrates the preparation of neomycin pelargonate from neomycin base and pelargonic acid.
- the weight ratio of reactants was about 2.1 parts of acid to 1 part of neomycin base.
- the final solution had a pH of about 7 also but the product was too soluble to recover by filtration.
- a quantitative yield of neomycin pelargonate was obtained by spray drying the reaction mixture.
- the product was an off-white powder soluble in methyl alcohol but insoluble in water.
- Example III This example illustrates the preparation of neomycin undecylenate from neomycin base and undecylenic acid.
- a solution was prepared containing 277 grams of neomycin base in 7740 milliliters of methanol. After the addition of about 550 grams of undecylenic acid, the solution had a final pH of 7.1. Spray drying gave 640 grams of neomycin undecylenate having a potency of 250 meg/mg.
- the product was an off-white powder soluble in methyl alcohol, ethyl alcohol or propylene glycol and practically insoluble in glycerin or water.
- Example IV This example illustrates the preparation of neomycin caprylate from neomycin base and caprylic acid.
- caprylic acid was added to a solution of 323 grams of neomycin base in 9020 milliliters of methanol.
- the final reaction mixture (pH about 7.1) was spray dried to yield 610 grams of neomycin caprylate having a potency of 405 meg/kg.
- the product was an off-white powder soluble in methyl alcohol and insoluble in water.
- Neomycin sulfate was dissolved in pH 8.0 bufiier to a concentration of 1000 meg/mg. and neomycin palmitate was dissolved in absolute ethanol to the same activity. Each solution was sterilized by filtration through sterile glass filters. The anti-bacterial sensitivity tests were performed using a two-fold serial dilution tube technique for all cultures except Hemophilus influenza and pertussis which were done by the plate dilution method.
- the final concentration of the antibiotics were adjusted so that the first tube in the dilution series contained meg/ml. and For the bacterial tube sensitivities, trypticase soy broth was used for Strep. virz'dans and Cl. perfrigens where thioglycollate broth was employed. The antifungal activity of the drugs were determined using Sabourauds broth. Bordet-Gengou agar plus 15 percent rabbit blood was used for the plate sensitivities. All cultures were obtained from the American Type Culture Collection. The 24 hour broth cultures were diluted 1:1000 in broth prior to their addition to the serially diluted dings but those cultures which grew profusely were diluted l:10,000.
- test compounds All bacterial tube and plate sensitivities were incubated at 37 degrees centigrade for 18 hours while the antifungal sensitivities were incubated at 25 degrees centrigrade for 72 hours.
- the minimal inhibitory concentration of the test compounds were recorded as the lowest concentration in meg/ml. necessary to inhibit growth.
- salts are conveniently prepared by the reaction of neomycin base and the appropriate fatty 6 acid in lower alkanol solution.
- the process has the added advantage of being able to utilize alcoholic extracts of neomycin base directly as obtained from Streptomyces fermentation beers.
- the process for preparing higher fatty acid salts of neomycin which comprises: dissolving approximately stoichiornetrically equivalent quantities of neomyciu base and a higher fatty acid in a lower alkanol so that the final pH of the reaction mixture is between about 6.5 and about 7.5.
Description
3,022,286 PROCESS FOR PREPARING HIGHER FATTY ACID SALTS F NEOMYCIN Gerald H. van de Griendt, Summit, N.J., assignor to S. B. Penick and Company, New York, N.Y., a corporation of Delaware No Drawing. Filed Dec. 14, 1959, Ser. No. 859,160 8 Claims. (Cl. 260-210) This invention relates to compositions of matter known in the art of chemistry as organic salts of neomycin and more particularly to processes for making such compositions.
The invention here is described as residing in the concept of dissolving approximately equivalent quantities of 3,iPZZ,Z$$ Patented Feb. 20, 1962 ice no apparent skin irritation. Thus the higher fatty acid neomycin base with the appropriate higher fatty acid in a lower alkanol solvent and at a final pH between 6.5- 7.5 to form a chemical compound in which neomycin is, associated with a higherfatty acid in the form of a true salt.
As used herein the term higher fatty acid means an aliphatic monocarboxylic acid containing 8 to 18 carbon atoms. -The aliphatic portion of the acid may be straight chain or branched and saturated or unsaturated. The better known higher fatty acids are straight chain, saturated compounds containing 8 to 18 carbon atoms; the acids particularly useful in the practice of my invention can also be recognized as those whose alkali metal salts are generally known as soaps.- My invention, however, is not so limited and contemplates all aliphatic fatty acids having 8 to 18 carbon atoms and which produce waterinsoluble salts of neomycin. And as used herein the term lower alkanol means saturated alcohols having less than 3 carbon atoms, i.e., methyl and ethyl alcohols.
Neomycin, also referred to as neomycin base, is a naturally occurring antibiotic elaborated by a soil organism of the Streptomyces genus when cultured on the appropriate nutrient media. The neomycinthus produced is a basic, water-soluble compound active against many gram positive and gram negative micro-organisms. The antibiotic is often isolated and incorporated into pharmaceutical preparations in the form of its mineral acid salts, most commonly neomycin sulfate and chloride. Because of the very high water solubility of neomycin mineral acid salts (one gram of neomycin sulfate dissolves in one milliliter of water), these salts are readily leached from preparations containing them. Hence, the beneficial effects of neomycin are not fully realized in such preparations when topically applied.
The higher fatty acid salts of neomycin, unlike neomyein base or neomycin mineral acid salts, are waxlike and practically insoluble in water and thus may be more effectively utilized in ointments, lotions, creams, soap bases and other preparations designed for topical use. Replacement of the mineral acid anion by a higher fatty acid anion does not materially detract from the germicidal properties of the neomycin moiety. When neomycin sulfate and neomycin palmitate were compared in their anti-fungal and anti-bacterial properties against 34 representative micro-organisms including C. diphtheria, S. typhosa, St. faecolis, Candida albicans, Trichophytin tonsurans and Rizopus nigricans, the fatty acid salt was at least as effective as the sulfate; and in the case of 23 of the organisms tested, even smaller concentrations of the palmitate were sufiicient to produce equivalent inhibition in the growth of the test bacteria and fungi.
salts of neomycin can be safely and effectively utilized in topical preparations for the treatment of dermatological conditions caused by neomycin susceptible organisms. These salts can also be incorporated into compositions su'ch as hand creams which are used to obtain substanunsuited for large scale production.
tially antiseptic conditions. In many cases, the salts have the added advantage of producing their own emolient or demulcent effect.
' The mere mixing of higher fatty acids with neomycin base in aqueous solution has not proven to be a satisfactory method for the preparation of fatty acid salts of neomycin. The reaction is hampered by the poor solubility of both the reactant fatty acid and the resultant fatty acid salt. Particles of the poorly soluble acid became coated with the even more insoluble salt giving a system from which it is extremely difficult to isolate the low yields of product obtained. Such a process is grossly If it be desired to operate in an aqueous system, one must utilize the reaction of a mineral acid salt of neomycin with an alkali metal salt of the reactant fatty acid. This approach is not completely satisfactory because of the fact that one of the reactants is a soap and the product is soap-like and, hence difficult to handle, isolate cleanly or purify. Drying may also be a problem. Inorganic salts such as sodium sulfate, potassium chloride and potassium sulfate are; obtained as by-products and may contaminate the product.
I have discovered that neomycin reacts in alcoholic solution and under carefully controlled conditions with the appropriate higher fatty acid to give excellent yields of the desired neomycin fatty acid salt. As will be discussed below, the pH and the ratio of reactants used must be carefully controlled in order to obtain good yields of high grade product. Deviation from the optimum conditions will still give the fatty acid salt of neomycin but in a lessened degree of purity.
It is therefore; an object of the present invention to provide a convenient method for the preparation of higher fatty acid salts of neomycin free of inorganic and other contaminants.
The reaction of neomycin base with higher fatty acids is effected, according to my process, in a lower alkanol, preferably methanol or ethanol. Mixtures of those alcohols are also satisfactory. It is not necessary that the alcohol used be anhydrous; the usually available commercial grades of methyl or ethyl alcohol are most often employed. The order of mixing the reactants is not critical and all methods of mixing the reactants with each other and with the solvent are equivalent. Usually a solution of the acid is added to a solution of the neomycin base but the reverse order may be employed. The fatty acid can be added directly to the alcoholic solution of the neomycin base. Temperature control is not required and the process is carried out at ambient temperatures. A certain amount of warming results when the reactants are mixed raising the temperature of the reaction mixture from room temperature to about 40-45 degree Centigrade. Slight warming may be utilized to further solubility; this is especially the case when it is desired to clarify the solution with charcoal before recovery of the product.
In order to achieve consistently high yields of superior product, it is critical that the final pH of the reaction mixture and the ratio of reactants fall within the limits stated below. The final pH of the reaction mixture must be about 6.5 to 7.5. If the final pH is allowed tovary from the suggested range, either the fatty acid will precipitate from solution or certain other salts of neomycin will be found in conjunction with the desired neomycin fatty acid salt. While it is not an object of the present invention to prepare such compositions, they can be made by varying the general procedure of my process. However, the best way to obtain the proper final pH and pure product is to titrate the neomycin base in alcohol solution with the fatty acid dissolved in the same solvent or to add the calculated approximate stoichiometric amount of acid (directly or in solution) to a solution of the base.
A slight stoichiometric excess of acid is not harmful and in some cases may even be helpful; but the yield and quality of the product, as measured by its biological potency, fall off sharply at even slightly alkaline pI-Is in excess of 7.5. If necessary, the H of the reaction mixture may also be adjusted by the addition of small amounts of mineral acid or inorganic base. Other variations will be obvious to one skilled in the art.
The higher fatty acid salts of neomycin have a desirable waxy consistency. The palmitate and higher salts are sufiiciently insoluble in alcoholic solution so as to be capable of isolation directly by filtration, centrifugation, etc. Chilling, although not essential, may be utilized to diminish the solubility of the product. The presence of small amounts of water in the alcoholic solvent will accomplish the same result and may even be added for that purpose. The lower salts are too soluble to be isolated directly and are recovered by evaporation of the solvent, preferably by spray drying. This technique can be used successfully because of the absence of contaminating byproducts; the presence of small amounts of water will not interfere. In certain situations, the presence of up to about 20 percent of water in the alcoholic solvent used will not be detrimental and can be tolerated.
The novel neomycin higher fatty acid salts of my invention have been shown by X-ray analysis to be true salts and not mere mixtures of neomycin with the reactant fatty acid.
he scope and utility of my invention is further illustrated by the following examples:
Example I This example illustrates the preparation of neomycin palmitate from neomycin base and palmitic acid in alcohol solution. In a smaller scale run, 80 grams of palmitic acid was added to methanolic solution containing 20 grams of neomycin base. Sufficient methanol was added to produce a clear solution at 50-55 degrees Centigrade. The final solution contained about 500 milliliters of methanol and had a pH of 6.8. After chilling to ice temperature, 95 grams of neomycin palmitate having a potency of 205 mcg./ mg. was obtained on filtration.
In a larger scale run, a solution of 7-8 percent of neomycin base in 22-24 gallons of methyl alcohol was used as the starting material. This solution was obtained by the methanol extraction of crude neomycin. Palmitic acid, amounting to about three times the weight of neomycin base solids present, was added to the neomycin the first agar plate 50 mcg./ml.
extract, and the temperature raised to effect complete solution (about 45-50 degrees centrigrade). The clear solution (pH of about 7) was cooled to ice temperature and the resultant solid collected by filtration. There was obtained about 20 kilograms of neomycin palmitate having a potency of about 200 rncg./mg. The product was an off-white powder soluble in methanol, sparingly soluble in ethanol, slightly soluble in propylene glycol and insoluble in glycerin or water.
Example 11 This example illustrates the preparation of neomycin pelargonate from neomycin base and pelargonic acid. Using the general procedure of the first example, the weight ratio of reactants was about 2.1 parts of acid to 1 part of neomycin base. The final solution had a pH of about 7 also but the product was too soluble to recover by filtration. A quantitative yield of neomycin pelargonate was obtained by spray drying the reaction mixture. The product was an off-white powder soluble in methyl alcohol but insoluble in water.
Example III This example illustrates the preparation of neomycin undecylenate from neomycin base and undecylenic acid. A solution was prepared containing 277 grams of neomycin base in 7740 milliliters of methanol. After the addition of about 550 grams of undecylenic acid, the solution had a final pH of 7.1. Spray drying gave 640 grams of neomycin undecylenate having a potency of 250 meg/mg. The product was an off-white powder soluble in methyl alcohol, ethyl alcohol or propylene glycol and practically insoluble in glycerin or water.
Example IV This example illustrates the preparation of neomycin caprylate from neomycin base and caprylic acid. Using the general procedure of Example III, 446 grams of caprylic acid was added to a solution of 323 grams of neomycin base in 9020 milliliters of methanol. The final reaction mixture (pH about 7.1) was spray dried to yield 610 grams of neomycin caprylate having a potency of 405 meg/kg. The product was an off-white powder soluble in methyl alcohol and insoluble in water.
The germicidal properties of my novel neomycin fatty acid salts were illustrated by the comparison of a typical compound, neomycin palmitate, with neomycin sulfate. The general procedure is described as follows: Neomycin sulfate was dissolved in pH 8.0 bufiier to a concentration of 1000 meg/mg. and neomycin palmitate was dissolved in absolute ethanol to the same activity. Each solution was sterilized by filtration through sterile glass filters. The anti-bacterial sensitivity tests were performed using a two-fold serial dilution tube technique for all cultures except Hemophilus influenza and pertussis which were done by the plate dilution method. The final concentration of the antibiotics were adjusted so that the first tube in the dilution series contained meg/ml. and For the bacterial tube sensitivities, trypticase soy broth was used for Strep. virz'dans and Cl. perfrigens where thioglycollate broth was employed. The antifungal activity of the drugs were determined using Sabourauds broth. Bordet-Gengou agar plus 15 percent rabbit blood was used for the plate sensitivities. All cultures were obtained from the American Type Culture Collection. The 24 hour broth cultures were diluted 1:1000 in broth prior to their addition to the serially diluted dings but those cultures which grew profusely were diluted l:10,000. All bacterial tube and plate sensitivities were incubated at 37 degrees centigrade for 18 hours while the antifungal sensitivities were incubated at 25 degrees centrigrade for 72 hours. The minimal inhibitory concentration of the test compounds were recorded as the lowest concentration in meg/ml. necessary to inhibit growth.
Test Bacterial Organism Minimal Inhibitory Concentration Species Culture Palmi- Sulfate No. tate A. aerogenes 100 1. 56 3.12 C. diphtheriae. 311 0.10 0.10 S. ty hosa- 401 3.12 12. 5 E. 002' 536 6. 25 12. 5 H. influenzae. 554 25.0 6. 25 H. pertussis-.. 558 6. 25 1. 56 K. pneumoma 602 1. 56 3.12 Pr. vulgaris.-- 720 25.0 6. 25 Pr aeruginosa 813 12.5 12. 5 S. schott. (Para 010 6. 25 25.0 Sh. paradysenteriae 959 25.0 12. 5 M pz ogenes (albus) 1200 0.78 0.78 M pyogenes (aureus) 1209 1. 56 3.12 A l pyogenes (citreua)... 1206 3.12 6.25 M. pyagenes (epidermidzs) 1216 1. 56 0. 39 St. viridans 1300 3.12 100 St. hemlyt1cus- 1307-3 0. 78 6. 25 St. Pyoljenes. 13074 0.20 1. 56 St. faecalis 1341 50 100 D. pneumomue. 1900 1. 56 12. 5 Cl. perjringens 1054. 3 3.12 250 Test Fungal Organism Minimal Inhibitory Concentration Species Culture Palmi- Sulfate No. tate Candida albicans M63 500 500 C'ryptococcus neojormam. M260 500 500 Microsporum adom'ni- M80 15. 6 125 Microsporum gy scum. M82 15.6 500 Sporotrichum so enckii. 17161 62.5 500 Trz'chophyton mentagrop 17302 31.2 250 Trichophyto'n rubrum- 62. 5 500 500 500 15. 6 500 62.5 500 31. 2 500 62.5 500 62. 5 500 In summary, it can be said that the higher fatty acid salts of neomycin are white solids practically insoluble in water. They possess a waxy consistency and germicidal properties which render them useful in pharmaceutical compounding especially in preparations designed for topical application. These salts are conveniently prepared by the reaction of neomycin base and the appropriate fatty 6 acid in lower alkanol solution. In addition to giving high yields of good quality product, the process has the added advantage of being able to utilize alcoholic extracts of neomycin base directly as obtained from Streptomyces fermentation beers.
Having described my invention, I claim:
1. The process for preparing higher fatty acid salts of neomycin which comprises: dissolving approximately stoichiornetrically equivalent quantities of neomyciu base and a higher fatty acid in a lower alkanol so that the final pH of the reaction mixture is between about 6.5 and about 7.5.
2. The process for preparing higher fatty acid salts of neomycin which comprises dissolving approximately stoichiometrically equivalent qu'atities of neomycin base and a higher fatty acid in a lower alkanol so that the final pH of the reaction mixture is between about 6.5 and about 7.5 and recovering the higher fatty acid salt of ncomycin thus formed from the reaction mixture.
3. The process according to claim 2 wherein the fatty acid is undecylenic acid.
4. The process according to claim 2 wherein the fatty acid is pelargonic acid.
5. The process according to claim 2 wherein the fatty acid is caprylic acid.
6. The process according to claim 2 wherein the higher fatty acid is present in slight excess of the stoichiometric quantity.
7. The process according to claim 2 wherein the lower alcoholic solvent contains up to 20 percent of water.
8. The process for preparing IWOIHYClIl palmitate which comprises dissolving approximately stoichiornetrically equivalent quantities of neomycin base and palmitic acid in methyl alcohol at a final pH of about 7 and recovering the neomycin palmitate thus formed from the reaction mixture.
References Cited in the file of this patent UNITED STATES PATENTS 2,916,483 Dutcher Dec. 8, 1959 OTHER REFERENCES Baker-Drug and Cosmetic Ind., 80 (1957), 458 and 552-3, cited in C.A., vol. 51 (1957), 12438H.
Claims (1)
1. THE PROCESS FOR PREPARING HIGHER FATTY ACIDS SALTS OF NEOMYCIN WHICH COMPRISES: DISSOLVING APPROXIMATELY STOICHIOMETRICALLY EQUIVALENT QUANTITIES OF NEOMYCIN BASE AND A HIGHER FATTY ACID IN A LOWER ALKANOL SO THAT THE FINAL PH OF THE REACTION MIXTURE IS BETWEEN ABOUT 6.5 AND ABOUT 7.5.
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US859160A US3022286A (en) | 1959-12-14 | 1959-12-14 | Process for preparing higher fatty acid salts of neomycin |
GB42068/60A GB940243A (en) | 1959-12-14 | 1960-12-07 | Salts of neomycin |
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US859160A US3022286A (en) | 1959-12-14 | 1959-12-14 | Process for preparing higher fatty acid salts of neomycin |
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Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3226329A (en) * | 1961-09-14 | 1965-12-28 | Procter & Gamble | Germicidal cleansing composition |
US3311607A (en) * | 1963-12-23 | 1967-03-28 | Angeli Inst Spa | Neomycin pamoate |
US3546207A (en) * | 1968-01-26 | 1970-12-08 | Squibb & Sons Inc | Neomycin citrate |
EP1243255A2 (en) * | 2001-03-22 | 2002-09-25 | Heraeus Kulzer GmbH & Co.KG | Method of preparation of antibiotic compositions |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ES2151454B1 (en) * | 1999-05-06 | 2001-07-01 | Szlec Christopher Dura | POMADA FOR THE TREATMENT OF THE CHRONIC ANAL FISSURE AND OTHER INFLAMMATORY PROCESSES OF THE YEAR. |
CN107557413B (en) * | 2017-10-16 | 2019-12-17 | 河北圣雪大成制药有限责任公司 | Method for improving neomycin sulfate production quality |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2916483A (en) * | 1956-03-27 | 1959-12-08 | Olin Mathieson | Methymycin |
-
1959
- 1959-12-14 US US859160A patent/US3022286A/en not_active Expired - Lifetime
-
1960
- 1960-12-07 GB GB42068/60A patent/GB940243A/en not_active Expired
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2916483A (en) * | 1956-03-27 | 1959-12-08 | Olin Mathieson | Methymycin |
Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3226329A (en) * | 1961-09-14 | 1965-12-28 | Procter & Gamble | Germicidal cleansing composition |
US3311607A (en) * | 1963-12-23 | 1967-03-28 | Angeli Inst Spa | Neomycin pamoate |
US3546207A (en) * | 1968-01-26 | 1970-12-08 | Squibb & Sons Inc | Neomycin citrate |
EP1243255A2 (en) * | 2001-03-22 | 2002-09-25 | Heraeus Kulzer GmbH & Co.KG | Method of preparation of antibiotic compositions |
EP1243255A3 (en) * | 2001-03-22 | 2002-12-18 | Heraeus Kulzer GmbH & Co.KG | Method of preparation of antibiotic compositions |
US20020192279A1 (en) * | 2001-03-22 | 2002-12-19 | Heraeus Kulzer Gmbh & Co.Kg | Method for producing antibiotic composites |
US6942877B2 (en) | 2001-03-22 | 2005-09-13 | Heraeus Kulzer Gmbh & Co. Kg | Method for producing antibiotic composites |
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GB940243A (en) | 1963-10-30 |
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