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WO2000063411A1 - Process of isolation of lovastatin from fermentation broth - Google Patents

Process of isolation of lovastatin from fermentation broth Download PDF

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Publication number
WO2000063411A1
WO2000063411A1 PCT/SK2000/000004 SK0000004W WO0063411A1 WO 2000063411 A1 WO2000063411 A1 WO 2000063411A1 SK 0000004 W SK0000004 W SK 0000004W WO 0063411 A1 WO0063411 A1 WO 0063411A1
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Prior art keywords
lovastatin
fermentation broth
isolation
lactone
filtrate
Prior art date
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Ceased
Application number
PCT/SK2000/000004
Other languages
French (fr)
Inventor
Mári JAKUBČOVÁ
Miloš BOŠANSKÝ
Dušan LUCINA
Gabriela BOROŠOVÁ
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Biotika AS
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Biotika AS
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Publication date
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Publication of WO2000063411A1 publication Critical patent/WO2000063411A1/en
Anticipated expiration legal-status Critical
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    • 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
    • C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
    • C12P17/02—Oxygen as only ring hetero atoms
    • C12P17/06—Oxygen as only ring hetero atoms containing a six-membered hetero ring, e.g. fluorescein
    • 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
    • C12P7/00—Preparation of oxygen-containing organic compounds
    • C12P7/62—Carboxylic acid esters

Definitions

  • the invention relates to a process of isolation of lovastatin from the harvested fermentation broth
  • Lovastatin is widely used as a highly active a ⁇ tihypercholesterolemic substance which acts by limiting cholesterol biosynthesis by inhibiting the enzyme HMG-CoA reductase
  • the isolation of lovastatin is based either on direct extraction of the active ingredient from the harvested fermentation broth into an organic solvent, or on its extraction from the filtrate of fermentation broth, the crude product is then concentrated and subsequently purified by chromatographic methods and recrystallization
  • the harvested fermentation broth of lovastatin contains a large number of ballast products (proteins nutrients that have not been metabolized, color polymer substances, by products) which should be removed during the isolation process for a final product to comply with the world pharmacopoeia specifications
  • ballast products proteins nutrients that have not been metabolized, color polymer substances, by products
  • the completed fermentation lovastatin is present in the broth mostly in the acid form, which is 3,5-d ⁇ hydroxy-7-[1 ,2 6 7,8 8a-hexahydro-2,6-d ⁇ methyl-8-(2- methylbutyryloxy) napthalene-1 -yl]- heptanoic acid and partially in the lactone form Because only the lactone form is of commercial interest, the acid form should be converted into lactone
  • Lacto ⁇ isation is effected by the reflux of rich extract in toluene at 106°C for 2 hours in accordance with the pat doc EP 0 033 536 A2 After the lactonisation is completed, the solution is concentrated, and pure substance is obtained by purification on a chromatographic column in the presence of solvents such as ethylacetate or ⁇ -hexane.
  • Lactonisation is effected in butylacetate during distillation without further addition of acids. It is a disadvantage of the above method that by using extraction in butylacetate, impurities of polar character proceed to the crude product, and these will also get into a recrystallised final product.
  • lovastatin precipitates from the filtrate in the region of acidic pH values, and it is removed by separation.
  • the crude product prepared as mentioned above does not require purification by chromatography any more, as only a small amount of accompanying ballast substances is isolated together with the product. It is just this amount of ballast substances that poses a problem. They make the extraction into an organic solvent or recrystallizatio ⁇ of such product difficult.
  • the pH value was adjusted to 10,5 by adding NaOH (20% by weight) and the fermentation broth was mixed for 5 hours at 15 °C Afterwards the filtrate and biomass were obtained by centnfugation, the latter was again mixed with water (600ml) and after adjusting a pH value to 10,5 with NaOH (20 wt %) it was again mixed for 2 hours and separated by centnfugation 1470 ml of filtrate were obtained having a pH of 10 5
  • the filtrate was acidified with H 2 S0 4 (20 wt %) to a pH of 2,5 and extracted for 2 hours with a 300 ml mixture of butylacetate n-octane (49 51 wt %) with an addition of 400 ppm of the Armogard 5445 demulsifier from the AK
  • the separation of the formed liquid layers was performed using a centrifuge.
  • the organic layer obtained was distilled under vacuum at 60°C with an addition of 1 ,5 ml of acetic acid to achieve a quantitative course of lactonisation.
  • the distillation residue was cooled to +5°C left to crystallize for 24 hours.
  • the crude crystal thus obtained was recrystallized in an organic solvent with an addition of activated carbon and gave 690 mg of lovastatin in the form of lactone having purity above 95%.
  • the fermentation broth 1000 g obtained by the fermentation of Aspergillus terreus (CCM 8236) had a pH value of 4,8 and a lovastatin content of 1150 mg/kg (both acid and lactone).
  • the pH value was adjusted to 11 by adding NaOH (20 wt %), and the fermentation broth was mixed for 3 hours at a temperature of 15 °C.
  • the filtrate and biomass were obtained by centrifugation, the latter was mixed with water (600ml) again and after adjusting a pH value to 11 with NaOH (20 wt %) it was again mixed for 2 hours and separated by centrifugation. 1470 ml of filtrate having a pH of 1 1 were obtained.
  • the filtrate was acidified with H 2 SO (20 wt %) to a pH of 3,0 and extracted for 2 hours with 300 ml of butylacetate with an addition of 600 ppm of Demulso 1 demulsifier from the PETROLITE Co., (GB).
  • the separation of the formed liquid layers was performed by a centrifuge.
  • the organic layer obtained was distilled under vacuum at 60°C with an addition of 2,5 ml of acetic acid to achieve a quantitative course of lactonisation.
  • the distillation residue was cooled to +5°C left to crystallize for 24 hours.
  • the crude crystal thus obtained was recrystallized with an addition of activated carbon and gave 665 mg of lovastatin in the form of lactone having purity above 95%.
  • the pH value was adjusted to 10,3 by adding NaOH (20 wt%), and the fermentation broth was mixed for 4 hours at a temperature of 15 °C Later, the filtrate and biomass were obtained by centrifugation the latter was mixed with water (600ml) again and after adjusting a pH value to 10,3 with NaOH (20 -wt %), it was again mixed for 2 hours and separated by centnfugation 1470 ml of filtrate were obtained having a pH of 10,3
  • the filtrate was acidified with H 2 SO 4 (20 wt %) to a pH of 2,1 and extracted for 2 hours with a 300 ml mixture of ethylacetate cyclohexane (65 35 wt %) with an addition of 800 ppm of the Armogard 5445 demuls
  • Lovastatin is industrially employed in pharmaceutical industry as a medicament for preparation of tablets which inhibit cholesterol biosynthesis in patients with hypercholesterolaemia and hyperlipaemia

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  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Zoology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Wood Science & Technology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Microbiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Biotechnology (AREA)
  • Health & Medical Sciences (AREA)
  • Biochemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pyrane Compounds (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)

Abstract

The solution relates to a process of isolation of lovastatin aimed at obtaining a product that complies with the pharmacopoeial criteria. This purpose is achieved by a process of isolation of lovastatin from the fermentation broth according to the invention the nature of which consists in that the harvested fermentation broth of lovastatin is adjusted to an alkaline pH value. The biomass is separated, and the filtrate containing the active component is extracted directly into the organic solvents of esters of carboxylic acids and alkanes in the presence of a cation-active or a non-ionic demulsifier in an acidic pH range. The rich organic extract of lovastatin obtained by using this process has high purity and no purification by chromatography is needed. The rich organic extract is subjected to vacuum distillation at a temperature above 40 °C in the presence of acetic acid whereby the lactone formed is concentrated. Crystallization takes place under cooling at 5 °C. The obtained crude product is recrystallized at an elevated temperature.

Description

PROCESS OF ISOLATION OF LOVASTATIN FROM FERMENTATION BROTH
Technical Field
The invention relates to a process of isolation of lovastatin from the harvested fermentation broth
Present Technical Status
Lovastatin is widely used as a highly active aπtihypercholesterolemic substance which acts by limiting cholesterol biosynthesis by inhibiting the enzyme HMG-CoA reductase The isolation of lovastatin is based either on direct extraction of the active ingredient from the harvested fermentation broth into an organic solvent, or on its extraction from the filtrate of fermentation broth, the crude product is then concentrated and subsequently purified by chromatographic methods and recrystallization
The harvested fermentation broth of lovastatin contains a large number of ballast products (proteins nutrients that have not been metabolized, color polymer substances, by products) which should be removed during the isolation process for a final product to comply with the world pharmacopoeia specifications After the completed fermentation lovastatin is present in the broth mostly in the acid form, which is 3,5-dιhydroxy-7-[1 ,2 6 7,8 8a-hexahydro-2,6-dιmethyl-8-(2- methylbutyryloxy) napthalene-1 -yl]- heptanoic acid and partially in the lactone form Because only the lactone form is of commercial interest, the acid form should be converted into lactone
Lactoπisation is effected by the reflux of rich extract in toluene at 106°C for 2 hours in accordance with the pat doc EP 0 033 536 A2 After the lactonisation is completed, the solution is concentrated, and pure substance is obtained by purification on a chromatographic column in the presence of solvents such as ethylacetate or π-hexane.
According to the US pat. doc. 4,916,239 it is possible to effect lactonisation at a lower temperature by shifting equilibrium to the lactone side by precipitating the lactone from a reaction medium. Removal of the lactone from the reaction medium causes a coπtinous shift of the equilibrium to the lactone side. Using this method of lactonisation a small amount of lovastatin dimers is formed which presents difficulties in isolating the pharmacopeial form. No purification of lovastatin by chromatography is needed when the procedure according to the pat. doc. PCT 94/29292 is followed. Extraction of the active substance from the acidified fermentation broth or filtrate thereof is carried out by using butylacetate. Lactonisation is effected in butylacetate during distillation without further addition of acids. It is a disadvantage of the above method that by using extraction in butylacetate, impurities of polar character proceed to the crude product, and these will also get into a recrystallised final product.
According to the the pat. doc. WO 94/10328 lovastatin precipitates from the filtrate in the region of acidic pH values, and it is removed by separation. The crude product prepared as mentioned above does not require purification by chromatography any more, as only a small amount of accompanying ballast substances is isolated together with the product. It is just this amount of ballast substances that poses a problem. They make the extraction into an organic solvent or recrystallizatioπ of such product difficult.
Background of the Invention
The above mentioned disadvantages are eliminated by a process of the isolation of lovastatin from the fermentation broth according to this invention, the nature of which consits in that the harvested lovastatin fermentation broth is adjusted to an alkaline pH value of 10 to 11 The biomass is separated, and the filtrate containing the active ingredient is directly extracted into a mixture of organic solvents which are esters of carboxylic acids and alkanes in a mutual proportion of 99 to 10% by weight of an ester to 1 to 90% by weight of an alkane in the presence of a cation- active or a non-ionic demulsifier in an amount of 100 to 1000 ppm within a range of pH values of 1 ,0 to 3,0 The rich organic extract of lovastatin obtained by this method has high purity, and there is no need for purification of the product by chromatography for a higher than 95% content to be obtained The rich organic extract is subjected to vacuum distillation at a temperature above 40°C in the presence of acetic acid in an amount of 0,1 to 1 ,0% whereby the lactone formed is concentrated Crystallization proceeds under cooling at a temperature of 5°C The crude product obtained is recrystal zed at an elevated temperature The procedure provides a product which complies with the pharmacopoeial criteria, and as there are no chlorinated solvents used, the procedure mentioned is friendly to the environment too
Examples of Embodiments of the Invention
EXAMPLE 1
After 120 hours of cultivation, the fermentation broth (1000 g) obtained by the fermentation of Aspergillus terreus (CCM 8236) had a pH value of 4,8 and a lovastatin content of 1200 mg/kg (both acid and lactone) The pH value was adjusted to 10,5 by adding NaOH (20% by weight) and the fermentation broth was mixed for 5 hours at 15 °C Afterwards the filtrate and biomass were obtained by centnfugation, the latter was again mixed with water (600ml) and after adjusting a pH value to 10,5 with NaOH (20 wt %) it was again mixed for 2 hours and separated by centnfugation 1470 ml of filtrate were obtained having a pH of 10 5 The filtrate was acidified with H2S04 (20 wt %) to a pH of 2,5 and extracted for 2 hours with a 300 ml mixture of butylacetate n-octane (49 51 wt %) with an addition of 400 ppm of the Armogard 5445 demulsifier from the AKZO NOBEL Co , (GB). The separation of the formed liquid layers was performed using a centrifuge. The organic layer obtained was distilled under vacuum at 60°C with an addition of 1 ,5 ml of acetic acid to achieve a quantitative course of lactonisation. The distillation residue was cooled to +5°C left to crystallize for 24 hours. The crude crystal thus obtained was recrystallized in an organic solvent with an addition of activated carbon and gave 690 mg of lovastatin in the form of lactone having purity above 95%.
EXAMPLE 2
After 120 hours of cultivation, the fermentation broth (1000 g) obtained by the fermentation of Aspergillus terreus (CCM 8236) had a pH value of 4,8 and a lovastatin content of 1150 mg/kg (both acid and lactone). The pH value was adjusted to 11 by adding NaOH (20 wt %), and the fermentation broth was mixed for 3 hours at a temperature of 15 °C. The filtrate and biomass were obtained by centrifugation, the latter was mixed with water (600ml) again and after adjusting a pH value to 11 with NaOH (20 wt %) it was again mixed for 2 hours and separated by centrifugation. 1470 ml of filtrate having a pH of 1 1 were obtained. The filtrate was acidified with H2SO (20 wt %) to a pH of 3,0 and extracted for 2 hours with 300 ml of butylacetate with an addition of 600 ppm of Demulso 1 demulsifier from the PETROLITE Co., (GB). The separation of the formed liquid layers was performed by a centrifuge. The organic layer obtained was distilled under vacuum at 60°C with an addition of 2,5 ml of acetic acid to achieve a quantitative course of lactonisation. The distillation residue was cooled to +5°C left to crystallize for 24 hours. The crude crystal thus obtained was recrystallized with an addition of activated carbon and gave 665 mg of lovastatin in the form of lactone having purity above 95%.
EXAMPLE 3
After 120 hours of cultivation, the fermentation broth (1000 g) obtained by the fermentation of Aspergillus terreus (CCM 8236) had a pH value of 4,8 and a lovastatin content of 1180 mg/kg (both acid and lactone) The pH value was adjusted to 10,3 by adding NaOH (20 wt%), and the fermentation broth was mixed for 4 hours at a temperature of 15 °C Later, the filtrate and biomass were obtained by centrifugation the latter was mixed with water (600ml) again and after adjusting a pH value to 10,3 with NaOH (20 -wt %), it was again mixed for 2 hours and separated by centnfugation 1470 ml of filtrate were obtained having a pH of 10,3 The filtrate was acidified with H2SO4 (20 wt %) to a pH of 2,1 and extracted for 2 hours with a 300 ml mixture of ethylacetate cyclohexane (65 35 wt %) with an addition of 800 ppm of the Armogard 5445 demulsifier from the AKZO NOBEL Co , (GB) The separation of the formed liquid layers was performed by a centrifuge The obtained organic layer was distilled under vacuum at 60°C with an addition of 2,0 ml of acetic acid to achieve a quantitative course of lactonisation The distillation residue was cooled to +5°C and left to crystallize for 24 hours The crude crystal thus obtained was recrystallized in an organic solvent with an addition of activated carbon and gave 680 mg of lovastatin in the form of lactone having purity above 95%
Industrial Applicability
Lovastatin is industrially employed in pharmaceutical industry as a medicament for preparation of tablets which inhibit cholesterol biosynthesis in patients with hypercholesterolaemia and hyperlipaemia

Claims

A process of isolation of lovastatin from the harvested fermentation broth characterized in that the harvested fermentation broth is adjusted to an alkaline pH value of 10 to 1 1 , it is separated to give biomass and filtrate, the latter being acidified to a pH of 1 to 3 and extracted with an ester of carboxylic acid in the presence of a cation-active or a non-ionic demulsifier in a concentration of 100- 1000 ppm; this organic extract is subjected to vacuum distillation at a temperature above 40°C in the presence of acetic acid in an amount of 0,1 to 1 ,0%, whereby the lactone is concentrated, it is left to crystallize by cooling and subsequently to recrystal ze.
A process of isolation according to Claim 1 characterized in that a mixture of organic solvents, which are esters of carboxylic acids and alkanes in a mutual ratio of 99 to 10 wt % of an ester to 1 to 90 wt % of an alkane is used to extract the active component
PCT/SK2000/000004 1999-04-16 2000-03-27 Process of isolation of lovastatin from fermentation broth Ceased WO2000063411A1 (en)

Applications Claiming Priority (2)

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SKPV0513-99 1999-04-16
SK513-99A SK282679B6 (en) 1999-04-16 1999-04-16 Process of isolation of lovastatin from fermentation broth

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6387258B1 (en) * 2000-02-24 2002-05-14 Biogal Gyogyszergyar Rt. Method of purifying statins from a fermentation broth
WO2004111255A1 (en) * 2003-06-09 2004-12-23 TEVA Gyógyszergyár Részvénytársaság Ion-exchange filtration of fermentation broth
CN102875505A (en) * 2012-08-02 2013-01-16 丽珠集团新北江制药股份有限公司 Process for extracting and refining Mevastatin
CN103012344A (en) * 2011-09-28 2013-04-03 北大方正集团有限公司 Method of recovering lovastatin from lovastatin crystal mother liquor
EP2597092A1 (en) 2011-11-24 2013-05-29 Sterling Biotech Limited A process for purification of lovastatin
CN106083789A (en) * 2016-06-07 2016-11-09 山东鲁抗医药股份有限公司 The method that precipitate and separate extracts lovastatin from fermentation liquid

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0033536A2 (en) * 1980-02-04 1981-08-12 Merck & Co. Inc. 6(R)-(2-(8'-etherified-hydroxy-2',6'-dimethylpolyhydro-naphthyl-1')-ethyl)-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-ones, the hydroxy acid form of said pyranones, the salts of said acid form, process for preparing the same and an antihypercholesterolemic pharmaceutical composition containing the same
EP0351918A1 (en) * 1988-07-19 1990-01-24 Merck & Co. Inc. Process for the lactonization of mevinic acids and analogs thereof
WO1994010328A1 (en) * 1992-11-04 1994-05-11 Biogal Gyógyszergyár Rt Process for the isolation and purification of mevinolin
WO1994029292A1 (en) * 1993-06-08 1994-12-22 Krka Tovarna Zdravil P.O. Process for the isolation of lovastatin
WO1997020834A1 (en) * 1995-12-06 1997-06-12 Antibiotic Co. Method of production of lovastatin

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0033536A2 (en) * 1980-02-04 1981-08-12 Merck & Co. Inc. 6(R)-(2-(8'-etherified-hydroxy-2',6'-dimethylpolyhydro-naphthyl-1')-ethyl)-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-ones, the hydroxy acid form of said pyranones, the salts of said acid form, process for preparing the same and an antihypercholesterolemic pharmaceutical composition containing the same
EP0351918A1 (en) * 1988-07-19 1990-01-24 Merck & Co. Inc. Process for the lactonization of mevinic acids and analogs thereof
WO1994010328A1 (en) * 1992-11-04 1994-05-11 Biogal Gyógyszergyár Rt Process for the isolation and purification of mevinolin
WO1994029292A1 (en) * 1993-06-08 1994-12-22 Krka Tovarna Zdravil P.O. Process for the isolation of lovastatin
WO1997020834A1 (en) * 1995-12-06 1997-06-12 Antibiotic Co. Method of production of lovastatin

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6387258B1 (en) * 2000-02-24 2002-05-14 Biogal Gyogyszergyar Rt. Method of purifying statins from a fermentation broth
WO2004111255A1 (en) * 2003-06-09 2004-12-23 TEVA Gyógyszergyár Részvénytársaság Ion-exchange filtration of fermentation broth
CN103012344A (en) * 2011-09-28 2013-04-03 北大方正集团有限公司 Method of recovering lovastatin from lovastatin crystal mother liquor
CN103012344B (en) * 2011-09-28 2014-11-12 北大方正集团有限公司 Method of recovering lovastatin from lovastatin crystal mother liquor
EP2597092A1 (en) 2011-11-24 2013-05-29 Sterling Biotech Limited A process for purification of lovastatin
CN102875505A (en) * 2012-08-02 2013-01-16 丽珠集团新北江制药股份有限公司 Process for extracting and refining Mevastatin
CN102875505B (en) * 2012-08-02 2015-08-05 丽珠集团新北江制药股份有限公司 A kind of extraction and purification process of mevastatin
CN106083789A (en) * 2016-06-07 2016-11-09 山东鲁抗医药股份有限公司 The method that precipitate and separate extracts lovastatin from fermentation liquid

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SK51399A3 (en) 2000-11-07
SK282679B6 (en) 2002-11-06

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