Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Patent
1996-08-28
1999-08-24
Peselev, Elli
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
536 65, 536 169, C07H 100
Patent
active
059426110
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
Natamycin, also known as pimaricin, was first isolated in 1955 from the fermentation broth of a culture of Streptomyces natalensis obtained from soil taken near the town of Pietermaritzburg In Natal, South Africa. (A. P. Struyk et al, Antibiotics Annual, 878 (1957-1958)). Pimaricin, designated natamycin by the WHO, is produced either from Streptomyces natalensis or Streptomyces gilvosporeus.
Early patents describe recovery processes requiring multiple purification steps and involving relatively expensive unit operations. British patent GB 846,933 discloses an adsorption/elution recovery of natamycin from fermentation broth using water miscible polar solvents such as methanol, butanol and acetone. U.S. Pat. No. 3,892,850 discloses recovery from fermentation broth by extraction into an organic solvent having limited water miscibility, followed by recovery from the solvent. U.S. Pat. No. 3,378,441 claims recovery of natamycin by salting it out of fermentation broth followed by solvent dissolution and evaporative precipitation. A later patent, GB 2,106,498, describes vacuum concentration or butanol extraction of filtered fermentation broth to obtain a raw antifungal complex from which natamycin can be isolated. WO 92/10580 discloses solubilization of natamycin with methanol at low pH, followed by removal of broth solids. Under these conditions, natamycin is susceptible to acid degradation, with potential for depressed recovery yield and reduced product purity. Thus, the prior art does not teach an efficient method for recovery of high quality natamycin.
SUMMARY OF THE INVENTION
The present invention concerns a new, simple and efficient process to recover high quality natamycin from fermentation broth using a substantially water-miscible solvent at alkaline pH. Specifically, natamycin is recovered from the fermentation broth via a process comprising the steps: amount of a substantially water-miscible solvent sufficient to dissolve the natamycin in the broth; natamycin from the broth; and
In its preferred embodiment, the pH of the broth is adjusted to between 10 and 11 in step a) and to between 5.5 and 7.5 in step c). Any of several methods may be used in steps b) and d), for example, centrifugation, depth filtration and crossflow filtration, with a preferred method being crossflow filtration. It is preferred that, prior to the recovery process, the fermentation broth is concentrated, for example, to a concentration of from 10 to 50% solids, on a weight/volume basis. For greater stability of the natamycin during the recovery process, an antioxidant such as BHA, BHT, ascorbic acid or sodium erythorbate can be added.
DETAILED DESCRIPTION OF THE INVENTION
The production of natamycin by fermentation is well known. The aforementioned British patent, GB 846,933, is representative and discloses the production of natamycin via fermentation using Streptomyces gilvosporeus. The fermentation method itself is not critical to the present invention.
Fermentation broth containing natamycin may be concentrated, if desired, through any suitable method such as evaporation, depth filtration, crossflow filtration or centrifugation, with a preferred method being crossflow filtration. Concentration to a range of about 10 to 50% solids on a weight/volume basis is preferred. During concentration, the broth may be heated to a range of 50 to 70.degree. C. to improve evaporation or filtration rate.
The broth is then adjusted to a pH greater than about 10, preferably between about 10 and about 11, using an appropriate basifying agent such as, for example, Na.sub.2 CO.sub.3, K.sub.2 CO.sub.3, KOH, NaOH, or a combination thereof. Depending on the degree of water removal in the concentration step, dilution of the concentrate with water or a water-miscible solvent may be necessary to facilitate agitation during the pH adjustment. Further, a substantially water-miscible solvent is added to the pH-adjusted concentrate in an amount sufficient to solubilize natamycin. Suitable water-miscible solvents include, for
REFERENCES:
patent: 3378441 (1968-04-01), Bridge
patent: 3892850 (1975-07-01), Struyk et al.
patent: 4568740 (1986-02-01), Oppici et al.
patent: 5231014 (1993-07-01), Eisenschink et al.
Borden George Wayne
Maher John Michael
Sklavounos Constantine
Cultor Ltd.
Peselev Elli
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