WO1992010580A1 - Natamycin recovery - Google Patents

Natamycin recovery Download PDF

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Publication number
WO1992010580A1
WO1992010580A1 PCT/US1991/008931 US9108931W WO9210580A1 WO 1992010580 A1 WO1992010580 A1 WO 1992010580A1 US 9108931 W US9108931 W US 9108931W WO 9210580 A1 WO9210580 A1 WO 9210580A1
Authority
WO
WIPO (PCT)
Prior art keywords
natamycin
methanol
water
solids
fermentation broth
Prior art date
Application number
PCT/US1991/008931
Other languages
French (fr)
Inventor
James R. Millis
Phillip Terry Olson
Michael Henry Reimer
Original Assignee
E.I. Du Pont De Nemours And Company
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by E.I. Du Pont De Nemours And Company filed Critical E.I. Du Pont De Nemours And Company
Priority to DE69104624T priority Critical patent/DE69104624T2/en
Priority to EP92903216A priority patent/EP0563269B1/en
Priority to CA002097840A priority patent/CA2097840C/en
Priority to BR919107207A priority patent/BR9107207A/en
Priority to JP50366992A priority patent/JP2908562B2/en
Publication of WO1992010580A1 publication Critical patent/WO1992010580A1/en

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P19/00—Preparation of compounds containing saccharide radicals
    • C12P19/44—Preparation of O-glycosides, e.g. glucosides
    • C12P19/60—Preparation of O-glycosides, e.g. glucosides having an oxygen of the saccharide radical directly bound to a non-saccharide heterocyclic ring or a condensed ring system containing a non-saccharide heterocyclic ring, e.g. coumermycin, novobiocin
    • C12P19/62—Preparation of O-glycosides, e.g. glucosides having an oxygen of the saccharide radical directly bound to a non-saccharide heterocyclic ring or a condensed ring system containing a non-saccharide heterocyclic ring, e.g. coumermycin, novobiocin the hetero ring having eight or more ring members and only oxygen as ring hetero atoms, e.g. erythromycin, spiramycin, nystatin
    • C12P19/626—Natamycin; Pimaricin; Tennecetin

Definitions

  • This invention relates to a process of recovery of natamycin from a fermentation broth containing natamycin by adding methanol and adjusting the pH to 1.0 to 4.5 to dissolve the precipitated natamycin; removing the remaining suspended solids; and raising the pH to 6.0 to 9.0 to precipitate high purity natamycin.
  • Natamycin is an antibiotic that has been known for decades (Florey, "Analytical Profiles of Drug Substances", Vol. 10, 1981; Merck Index,
  • natamycin has a well-defined specific chemical structure, melting point and ultraviolet spectrum. Its specific physic-chemical properties, particularly its solubility in various liquids, require processing techniques specific to this compound. Prior processes for natamycin have not been generally economically acceptable. Processes for recovery of other compounds having different properties give little insight into the recovery of natamycin.
  • Natamycin has been prepared by fermentation such as disclosed in British Patent 846,933 (American Cyanamid) using Streptomvces ⁇ ilvosporeus.
  • the natamycin . is recovered by methanol -2- extraction followed by tedious steps of adsorption and elution.
  • U.S. Patent 3,378,441 discloses recovering natamycin by salting it out of the fermentation broth, extracting with methanol, removing the solids, and then evaporating the liquid to recover the natamycin.
  • U.S. Patent 3,892,850 discloses recovery of pimaricin by extraction with acidified butanol followed by distillation and precipitation. It is noted that the pimaricin identification in this patent is inconsistent with those of natamycin as disclosed in Florey.
  • natamycin is mechanically removed from the liquid such as by filtration or centrifugation, then washed with water -3- an dried yielding natamycin of over 80% purity and usually over 90% purity.
  • steps 2 and 4 sufficient time is allowed to approach stable solubility conditions, usually 15-45 minutes being sufficient depending on the volume of the broth, solids concentration, vessel configura ⁇ tion and the like. Agitation may be helpful.
  • the process of the invention requires that the fermentation product plus the extracting liquid contain at least 2 g/1 natamycin. If the direct fermentation broth contains too little natamycin water must be removed. Since the fermentation product consists essentially of water and natamycin plus biomass solids, water can be removed by any convenient solid-liquid separation technique, such as filtering and/or centrifuging off water. Concentrations of up to 50% solids is achievable this way. If a higher solids content is desired in the recovery feed stream to minimize the required methanol, heat assisted vacuum evaporation may be used. Typically a temperature in the range 30*C to 80*C is used. Pro ⁇ longed use of temperatures above 95*C should be avoided to prevent possible product or biomass degra- dation.
  • the fermentation product used as the feed stock in the present process comprises solid suspended natamycin and biomass and water.
  • the solids content may be as low as 20% or less, for example, if no water is removed from the fermentation broth. If water must be removed to obtain a fermentation product plus extractant containing at least 2 g/1 natamycin, only the minimum water need be removed. Alternatively, depending on equipment availability, particularly for methanol recovery, it may be desirable to remove substantially all of the water before addition of the methanol extractant.
  • the concentration of natamycin can be as low as 2 g/1 natamycin.
  • the water content of the feed stream is decreased, higher concentrations of natamycin are desirable because of higher solubility of it in methanol containing lower amounts of water.
  • the natamycin content preferably is at least 6 g/1.
  • methanol is used as the extraction medium because natamycin has excellent solubility in this inexpensive solvent in comparison to higher alcohols, and because simple techniques for recovery of methanol are well known.
  • methanol is used in the range of 20 g to about 150 g natamycin per liter of methanol in the feed stream. Since natamycin tends to precipitate out of the acidified methanol/water extraction medium at high concentrations, lower concentration in the range of 20 g to 120 g natamycin per liter methanol is preferred.
  • the water content of the methanol extraction liquid increases greater quantities of methanol are needed to achieve the same recovery. For example, if the feed contains 70% water, about three times as much methanol is required than when starting with a substantially dry feed stream. If the feed contains 40% water, twice as much methanol is needed.
  • step 2 the pH is adjusted to 1.0-4.5 by the addition of an acidifying agent at any stage, such as directly to the methanol or simultaneously with or after the methanol addition directly to the fermentation product.
  • an acidifying agent such as directly to the methanol or simultaneously with or after the methanol addition directly to the fermentation product.
  • Hydrochloric acid is an excellent acidifying agent, although any conventional compatible acidic material is acceptable.
  • Typical salts that can be used are NaCl, CaCl2 and others such as disclosed in Penick U.S. Patent 3,378,441.
  • step 3 the remaining biomass suspended solids are removed by any convenient means such as filtration or centrifugation. These solids, which still contain a significant quantity of natamycin can be put to other valuable uses.
  • any compatible basic material can be used to raise the methanol/water/natamycin liquid pH to 6.0-9.0. This pH modification causes precipitation of high purity natamycin, which is removed and dried.
  • Typical useful inexpensive compatible basic materials are sodium and potassium hydroxides.
  • water may also be added in step 4 to assist in natamycin precipitation. This may be necessary where the water feed stream concentration is low and natamycin concentration is high. The remaining liquid by-product which contains valuable natamycin, fermentation residues, methanol, inorganic salts and water is sent to methanol recovery. Natamycin of about 80% purity can be recovered in the methanol recovery process.
  • Fermentation broth is concentrated to 98% solids (plus a small quantity of nutritive residues) by centrifuging followed by drying at 40°C under vacuum.
  • the clarified liquid consisting essentially of 61 g/1 natamycin, methanol and a small quantity of water is raised to pH 7.5 by the addition of potassium hydroxide, and let stand for 30 minutes. A thick white precipitate of natamycin forms. The solids are separated by filtration, washed with water and dried at 40°C under vacuum.
  • EXAMPLE 2 This example describes the use of fermentation product concentration solely by filtration.
  • Fermentation broth is concentrated by filtration to 50% solids. This feed stock containing about 13 g natamycin is slurried in 500 ml of methanol. Thereafter, the procedure of Example 1 is followed except acetic acid and NaOH are used as the acidic and basic pH adjusting additives.
  • EXAMPLE 3 This example describes the use of a low solids content fermentation product feed stock.
  • Fermentation broth is concentrated by simple mechanical filtration to 23% solids.
  • This fermenta ⁇ tion product containing about 2.9 g natamycin is slurried with 40 ml of methanol and the pH reduced to 2.2 by addition of hydrochloric acid. This slurry is agitated for 30 minutes and then the solids are removed by centrifugation followed by filtration.
  • the pH of the clarified liquid containing 38 g/1 natamycin is raised to 7.5 by addition of potas ⁇ sium hydroxide and let stand for 30 minutes. A thick white precipitate forms. The solids are separated out by filtration, washed with water, and dried under vacuum. The dry product is 92% pure natamycin.

Abstract

The invention relates to a process of recovery of natamycin from a fermentation broth containing at least 2 g/l natamycin by adding methanol and adjusting the pH to 1.0 to 4.5 to dissolve the precipitated natamycin; removing the remaining suspended solids; and raising the pH to 6.0 to 9.0 to precipitate high purity natamycin.

Description

NATAMYCIN RECOVERY
BACKGROUND OF THE INVENTION
This invention relates to a process of recovery of natamycin from a fermentation broth containing natamycin by adding methanol and adjusting the pH to 1.0 to 4.5 to dissolve the precipitated natamycin; removing the remaining suspended solids; and raising the pH to 6.0 to 9.0 to precipitate high purity natamycin.
Natamycin is an antibiotic that has been known for decades (Florey, "Analytical Profiles of Drug Substances", Vol. 10, 1981; Merck Index,
"Pimaricin", p 834). Despite its recognized valuable antibiotic properties, there has been little research or commercialization of natamycin because of the extremely high cost of its manufacture. This invention relates to an inexpensive, rapid process for recovering natamycin from a fermentation broth.
As is pointed out in Florey, natamycin has a well-defined specific chemical structure, melting point and ultraviolet spectrum. Its specific physic-chemical properties, particularly its solubility in various liquids, require processing techniques specific to this compound. Prior processes for natamycin have not been generally economically acceptable. Processes for recovery of other compounds having different properties give little insight into the recovery of natamycin.
Natamycin has been prepared by fermentation such as disclosed in British Patent 846,933 (American Cyanamid) using Streptomvces αilvosporeus. In this patent, the natamycin .is recovered by methanol -2- extraction followed by tedious steps of adsorption and elution.
U.S. Patent 3,378,441 (Penick) discloses recovering natamycin by salting it out of the fermentation broth, extracting with methanol, removing the solids, and then evaporating the liquid to recover the natamycin.
U.S. Patent 3,892,850 (Gist-Brocades) discloses recovery of pimaricin by extraction with acidified butanol followed by distillation and precipitation. It is noted that the pimaricin identification in this patent is inconsistent with those of natamycin as disclosed in Florey.
All of these processes require an expensive ultimate recovery step such as absorption and elution, distillation, or evaporation of liquids.
SUMMARY OF THE INVENTION It has been discovered that high purity natamycin can be recovered from fermentation broth containing natamycin by simple extraction with methanol extraction liquid under controlled pH conditions. The present process comprises the steps:
1. adding methanol to a natamycin fermentation product containing precipitated natamycin, the fermentation product plus extraction liquid containing at least 2 g/1 natamycin;
2. adjusting the pH to 1.0 to 4.5 to solubilize the natamycin; 3. removing the remaining suspended solids; and 4. raising the pH to 6.0-9.0 to precipitated natamycin. Following step 4, normally the natamycin is mechanically removed from the liquid such as by filtration or centrifugation, then washed with water -3- an dried yielding natamycin of over 80% purity and usually over 90% purity.
In steps 2 and 4, sufficient time is allowed to approach stable solubility conditions, usually 15-45 minutes being sufficient depending on the volume of the broth, solids concentration, vessel configura¬ tion and the like. Agitation may be helpful.
BRIEF DESCRIPTION OF THE DRAWING The Figure is a schematic representation of the process of the invention.
DETAILED DESCRIPTION OF THE INVENTION The process of the invention requires that the fermentation product plus the extracting liquid contain at least 2 g/1 natamycin. If the direct fermentation broth contains too little natamycin water must be removed. Since the fermentation product consists essentially of water and natamycin plus biomass solids, water can be removed by any convenient solid-liquid separation technique, such as filtering and/or centrifuging off water. Concentrations of up to 50% solids is achievable this way. If a higher solids content is desired in the recovery feed stream to minimize the required methanol, heat assisted vacuum evaporation may be used. Typically a temperature in the range 30*C to 80*C is used. Pro¬ longed use of temperatures above 95*C should be avoided to prevent possible product or biomass degra- dation.
The fermentation product used as the feed stock in the present process comprises solid suspended natamycin and biomass and water. The solids content may be as low as 20% or less, for example, if no water is removed from the fermentation broth. If water must be removed to obtain a fermentation product plus extractant containing at least 2 g/1 natamycin, only the minimum water need be removed. Alternatively, depending on equipment availability, particularly for methanol recovery, it may be desirable to remove substantially all of the water before addition of the methanol extractant.
For optimum natamycin recovery, the concentration of natamycin can be as low as 2 g/1 natamycin. However, as the water content of the feed stream is decreased, higher concentrations of natamycin are desirable because of higher solubility of it in methanol containing lower amounts of water. Thus, where the solids content of the feed stream is over about 50%, the natamycin content preferably is at least 6 g/1.
The Figure schematically shows the process of this invention as hereinafter described.
In step 1, methanol is used as the extraction medium because natamycin has excellent solubility in this inexpensive solvent in comparison to higher alcohols, and because simple techniques for recovery of methanol are well known. To assure optimum natamycin recovery, methanol is used in the range of 20 g to about 150 g natamycin per liter of methanol in the feed stream. Since natamycin tends to precipitate out of the acidified methanol/water extraction medium at high concentrations, lower concentration in the range of 20 g to 120 g natamycin per liter methanol is preferred. Again because of decreased solubility of natamycin, as the water content of the methanol extraction liquid increases greater quantities of methanol are needed to achieve the same recovery. For example, if the feed contains 70% water, about three times as much methanol is required than when starting with a substantially dry feed stream. If the feed contains 40% water, twice as much methanol is needed.
In step 2, the pH is adjusted to 1.0-4.5 by the addition of an acidifying agent at any stage, such as directly to the methanol or simultaneously with or after the methanol addition directly to the fermentation product. This renders the natamycin highly soluble in the methanol solvent. Hydrochloric acid is an excellent acidifying agent, although any conventional compatible acidic material is acceptable.
Under some circumstances it may be desired to also add an inorganic salt to assist solubilizing although this is normally not required. Typical salts that can be used are NaCl, CaCl2 and others such as disclosed in Penick U.S. Patent 3,378,441.
In step 3, the remaining biomass suspended solids are removed by any convenient means such as filtration or centrifugation. These solids, which still contain a significant quantity of natamycin can be put to other valuable uses.
In step 4, any compatible basic material can be used to raise the methanol/water/natamycin liquid pH to 6.0-9.0. This pH modification causes precipitation of high purity natamycin, which is removed and dried. Typical useful inexpensive compatible basic materials are sodium and potassium hydroxides. If desired, water may also be added in step 4 to assist in natamycin precipitation. This may be necessary where the water feed stream concentration is low and natamycin concentration is high. The remaining liquid by-product which contains valuable natamycin, fermentation residues, methanol, inorganic salts and water is sent to methanol recovery. Natamycin of about 80% purity can be recovered in the methanol recovery process. EXAMPLE 1
This example describes the use of substantially water free fermentation product as the feed stock of the present process. Fermentation broth is concentrated to 98% solids (plus a small quantity of nutritive residues) by centrifuging followed by drying at 40°C under vacuum.
Solids containing about 13 g natamycin are slurried in
240 ml of methanol and the pH is reduced to 3.8 by the addition of concentrated hydrochloric acid. The slurry is mixed for 30 minutes to assist in dissolving natamycin. The suspended solids (biomass and some natamycin) is removed by filtration.
The clarified liquid, consisting essentially of 61 g/1 natamycin, methanol and a small quantity of water is raised to pH 7.5 by the addition of potassium hydroxide, and let stand for 30 minutes. A thick white precipitate of natamycin forms. The solids are separated by filtration, washed with water and dried at 40°C under vacuum.
9.3 g of solids are obtained which is 93% purity natamycin (on an anhydrous basis) .
EXAMPLE 2 This example describes the use of fermentation product concentration solely by filtration.
Fermentation broth is concentrated by filtration to 50% solids. This feed stock containing about 13 g natamycin is slurried in 500 ml of methanol. Thereafter, the procedure of Example 1 is followed except acetic acid and NaOH are used as the acidic and basic pH adjusting additives.
About 9.5 g of natamycin of over 90% purity is obtained. EXAMPLE 3 This example describes the use of a low solids content fermentation product feed stock.
Fermentation broth is concentrated by simple mechanical filtration to 23% solids. This fermenta¬ tion product containing about 2.9 g natamycin is slurried with 40 ml of methanol and the pH reduced to 2.2 by addition of hydrochloric acid. This slurry is agitated for 30 minutes and then the solids are removed by centrifugation followed by filtration.
The pH of the clarified liquid containing 38 g/1 natamycin is raised to 7.5 by addition of potas¬ sium hydroxide and let stand for 30 minutes. A thick white precipitate forms. The solids are separated out by filtration, washed with water, and dried under vacuum. The dry product is 92% pure natamycin.
3.6 g/1 natamycin remains in the liquid, which liquid is sent to methanol recovery where the natamycin is recovered at about 80% purity.

Claims

WHAT IS CLAIMED:
1. The process for the recovery of natamycin from a fermentation broth product containing at least 2 g/1 natamycin comprising the following steps: a. adding to said broth product methanol; b. adjusting the pH to 1.0 to 4.5 to solubilize natamycin; c. removing the suspended solids; and d. raising the pH to 6.0-9.0 to precipitate natamycin.
2. The process of Claim 1 wherein the precipitated natamycin is recovered and dried.
3. The process of Claim 1 wherein the fermentation broth product contains 20 to 98% solids.
4. The process of Claim 1 wherein the fermentation product contains at least 50% solids.
5. The process of Claim 1 wherein the methanol is added in an amount of 1 liter methanol per 20 g to 150 g of natamycin in the fermentation broth product.
6. The process of Claim 1 wherein the methanol is added in an amount of 1 liter methanol per 20 g to 120 g of natamycin in the fermentation broth product.
7. The process of Claim 1 wherein water is added in step 4.
8. The process of Claim 1 wherein the fermentation broth product is prepared by removal of water from the direct fermentation broth.
9. The process of Claim 8 wherein said removal of water is done by mechanical means.
PCT/US1991/008931 1990-12-07 1991-12-05 Natamycin recovery WO1992010580A1 (en)

Priority Applications (5)

Application Number Priority Date Filing Date Title
DE69104624T DE69104624T2 (en) 1990-12-07 1991-12-05 NATAMYCING WINNING.
EP92903216A EP0563269B1 (en) 1990-12-07 1991-12-05 Natamycin recovery
CA002097840A CA2097840C (en) 1990-12-07 1991-12-05 Natamycin recovery
BR919107207A BR9107207A (en) 1990-12-07 1991-12-05 NATAMICINE RECOVERY
JP50366992A JP2908562B2 (en) 1990-12-07 1991-12-05 Recovery of natamycin

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US62358590A 1990-12-07 1990-12-07
US623,585 1990-12-07

Publications (1)

Publication Number Publication Date
WO1992010580A1 true WO1992010580A1 (en) 1992-06-25

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Family Applications (1)

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PCT/US1991/008931 WO1992010580A1 (en) 1990-12-07 1991-12-05 Natamycin recovery

Country Status (7)

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EP (1) EP0563269B1 (en)
JP (1) JP2908562B2 (en)
AU (1) AU9157091A (en)
BR (1) BR9107207A (en)
CA (1) CA2097840C (en)
DE (1) DE69104624T2 (en)
WO (1) WO1992010580A1 (en)

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995007998A1 (en) * 1993-09-17 1995-03-23 Bio-Technical Resources L.P. Natamycin recovery
WO1995011295A1 (en) * 1993-10-22 1995-04-27 Gist-Brocades N.V. An improved process to recover an aqueous fermentation broth
WO1995027073A1 (en) * 1994-03-31 1995-10-12 Pfizer Inc. Process for natamycin recovery
US5942611A (en) * 1995-01-19 1999-08-24 Cultor Ltd. Process for natamycin recovery
KR100461577B1 (en) * 2002-12-04 2004-12-17 주식회사 바이오알앤즈 Purification process of a natamycin
US6884611B2 (en) 1994-01-19 2005-04-26 Sudzucker Aktiengesellschaft Preparation of acariogenic sugar substitutes
KR100512331B1 (en) * 2002-12-04 2005-09-05 경상남도 Preparation of natamycin from Streptomyces natalensis
WO2006045831A1 (en) * 2004-10-28 2006-05-04 Dsm Ip Assets B.V. Stable needle-shaped crystals of natamycin
US7816332B2 (en) 2003-06-02 2010-10-19 Dsm Ip Assets B.V. Stable aqueous solution of natamycin fungicide
CN109321617A (en) * 2018-10-22 2019-02-12 淮北师范大学 A method of Natamycin is synthesized using industrial or agricultural by-product solid state fermentation

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101062934B (en) * 2007-05-31 2010-05-19 山东鲁抗医药股份有限公司 Method for extracting natamycin from fermentation technique culture

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR1188428A (en) * 1954-11-04 1959-09-22 Olin Mathieson Process for the recovery of nystatin
US3378441A (en) * 1963-10-17 1968-04-16 S B Penick & Company Tetraene antibiotic purification
US4006222A (en) * 1975-10-20 1977-02-01 E. R. Squibb & Sons, Inc. Purification of nystatin

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR1188428A (en) * 1954-11-04 1959-09-22 Olin Mathieson Process for the recovery of nystatin
US3378441A (en) * 1963-10-17 1968-04-16 S B Penick & Company Tetraene antibiotic purification
US4006222A (en) * 1975-10-20 1977-02-01 E. R. Squibb & Sons, Inc. Purification of nystatin

Cited By (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5591438A (en) * 1990-12-07 1997-01-07 Bio-Technical Resources L.P. Natamycin recovery
CN1056650C (en) * 1993-09-17 2000-09-20 生物技术资源两合公司 Natamycin recovery
WO1995007998A1 (en) * 1993-09-17 1995-03-23 Bio-Technical Resources L.P. Natamycin recovery
WO1995011295A1 (en) * 1993-10-22 1995-04-27 Gist-Brocades N.V. An improved process to recover an aqueous fermentation broth
US7208307B2 (en) 1994-01-19 2007-04-24 Sudzucker Aktiengesellschaft Preparation of acariogenic sugar substitutes
US6884611B2 (en) 1994-01-19 2005-04-26 Sudzucker Aktiengesellschaft Preparation of acariogenic sugar substitutes
WO1995027073A1 (en) * 1994-03-31 1995-10-12 Pfizer Inc. Process for natamycin recovery
US5942611A (en) * 1995-01-19 1999-08-24 Cultor Ltd. Process for natamycin recovery
KR100461577B1 (en) * 2002-12-04 2004-12-17 주식회사 바이오알앤즈 Purification process of a natamycin
KR100512331B1 (en) * 2002-12-04 2005-09-05 경상남도 Preparation of natamycin from Streptomyces natalensis
US7816332B2 (en) 2003-06-02 2010-10-19 Dsm Ip Assets B.V. Stable aqueous solution of natamycin fungicide
AU2005298640B2 (en) * 2004-10-28 2010-10-28 Dsm Ip Assets B.V. Stable needle-shaped crystals of natamycin
US7727966B2 (en) 2004-10-28 2010-06-01 Dsm Ip Assets B.V. Stable needle-shaped crystals of natamycin
WO2006045831A1 (en) * 2004-10-28 2006-05-04 Dsm Ip Assets B.V. Stable needle-shaped crystals of natamycin
EP2374897A1 (en) * 2004-10-28 2011-10-12 DSM IP Assets B.V. Stable needle-shaped crystals of natamycin
CN102964409A (en) * 2004-10-28 2013-03-13 帝斯曼知识产权资产管理有限公司 Stable needle-shaped crystals of natamycin
US8420609B2 (en) 2004-10-28 2013-04-16 Dsm Ip Assets, B.V. Stable needle-shaped crystals of natamycin
CN102964409B (en) * 2004-10-28 2015-05-13 帝斯曼知识产权资产管理有限公司 Stable needle-shaped crystals of natamycin
US9096633B2 (en) 2004-10-28 2015-08-04 Dsm Ip Assets B.V. Stable needle-shaped crystals of natamycin
US9615581B2 (en) 2004-10-28 2017-04-11 Dsm Ip Assets B.V. Stable needle-shaped crystals of natamycin
CN109321617A (en) * 2018-10-22 2019-02-12 淮北师范大学 A method of Natamycin is synthesized using industrial or agricultural by-product solid state fermentation

Also Published As

Publication number Publication date
CA2097840A1 (en) 1992-06-08
JPH06504908A (en) 1994-06-09
DE69104624D1 (en) 1994-11-17
EP0563269A1 (en) 1993-10-06
AU9157091A (en) 1992-07-08
JP2908562B2 (en) 1999-06-21
DE69104624T2 (en) 1995-05-04
EP0563269B1 (en) 1994-10-12
BR9107207A (en) 1994-02-08
CA2097840C (en) 2002-02-05

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