CA2116019A1 - Process for the fermentative production of cephalosporin c using acremonium chrysogenum - Google Patents
Process for the fermentative production of cephalosporin c using acremonium chrysogenumInfo
- Publication number
- CA2116019A1 CA2116019A1 CA002116019A CA2116019A CA2116019A1 CA 2116019 A1 CA2116019 A1 CA 2116019A1 CA 002116019 A CA002116019 A CA 002116019A CA 2116019 A CA2116019 A CA 2116019A CA 2116019 A1 CA2116019 A1 CA 2116019A1
- Authority
- CA
- Canada
- Prior art keywords
- fermentation
- fermenter
- cephalosporin
- cross
- solution
- Prior art date
- Legal status (The legal status 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 status listed.)
- Abandoned
Links
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
- C12P35/00—Preparation of compounds having a 5-thia-1-azabicyclo [4.2.0] octane ring system, e.g. cephalosporin
- C12P35/06—Cephalosporin C; Derivatives thereof
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Life Sciences & Earth Sciences (AREA)
- Zoology (AREA)
- Wood Science & Technology (AREA)
- Health & Medical Sciences (AREA)
- General Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Biotechnology (AREA)
- Biochemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Microbiology (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Cephalosporin Compounds (AREA)
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
- Immobilizing And Processing Of Enzymes And Microorganisms (AREA)
- Soy Sauces And Products Related Thereto (AREA)
Abstract
Abstract of the Disclosure Process for the fermentative production of cephalo-sporin C using Acremonium chrysogenum There is described a process for the fermentative produc-tion of cephalosporin C in which the fermentation solu-tion is filtered during the fermentation through a cross-flow filtration system. The amount of filtrate which has been drawn off from the fermenter can be replaced.
Description
~llfi~
HOE 91/F 262-Dr.T~/sch - 1 -De~criptlon Process for the f~rmontatlve production o~
cephalosporin C u~ing Acromonium chry~ogenum Antibiotic~-containing culturo liquid~ are genorally worked up a~ter the maxlmum contont ha~ b~on roachod. In most ca~e~, the first step i~ a separation of cells and solids by filtratlon or by contrifugation. Thi~ may be followed by concsntrating tho valuable con~tituents by extraction or by adsorption. As a rule, tho purifiod product is thon crystallized and can be proceosod to give ~emisynthotic antibiotics.
A disadvantage in thls step-by-~tep method ie the insta-bility of a large number oi antibiotic molecules such as, for example, cephalosporin C (CPC). CPC ie already degraded during the fermentation. This can be effected either purely chemically, by water attacking the ~-lactam ring, or onzymatically, for example by ostorasos ~Ronocny et al., 1973, J. of Antlb., 26, 3, 135-141). A series of aecondary products such a~ deacotoxycephaloeporin C
(DoCPC) and deacetylcephalosporin C (DCPC), which must bo removed from the CPC during the purification step, is also formed cluring the fermentation. Thl~ ro~ult~ ln considerable yleld losses. Cross-flow flltratlon ~ystoms using polymer or ceramics membranes have already been used for the worklng-up of culture ligulds which contain antibiotics (Harris et al., J. Chem. Techn. Biotechnol., 1988, 42, 19-30). A reduced decomposltlon of cephalosporin C ln thoso proco~sea has not boen demonstrated as yet. It 18 known to lsolate cephalosporln C after the fermentatlon u~lng cross-flow flltration (M.
Ralyanpur et al., Contrlbuted Paper, Chapter 32, pagos 455-470).
It is an ob~ect of the pro~ont invontion to flnd a proces~ in which the dogradation of cophalo~porin C and REPLACEMENT SHE~T
:. - , .
,:
.
J 1 ~
HOE 91/E~' 262-Dr.TI~/~ch the formation of ~econdary productl~ can be roduced and the yield relative to the amount of ~ub~trate e~ployed can be increa~ed.-" ' ' ~
~-~ .
HOE 91/F 262-Dr.T~/sch - 1 -De~criptlon Process for the f~rmontatlve production o~
cephalosporin C u~ing Acromonium chry~ogenum Antibiotic~-containing culturo liquid~ are genorally worked up a~ter the maxlmum contont ha~ b~on roachod. In most ca~e~, the first step i~ a separation of cells and solids by filtratlon or by contrifugation. Thi~ may be followed by concsntrating tho valuable con~tituents by extraction or by adsorption. As a rule, tho purifiod product is thon crystallized and can be proceosod to give ~emisynthotic antibiotics.
A disadvantage in thls step-by-~tep method ie the insta-bility of a large number oi antibiotic molecules such as, for example, cephalosporin C (CPC). CPC ie already degraded during the fermentation. This can be effected either purely chemically, by water attacking the ~-lactam ring, or onzymatically, for example by ostorasos ~Ronocny et al., 1973, J. of Antlb., 26, 3, 135-141). A series of aecondary products such a~ deacotoxycephaloeporin C
(DoCPC) and deacetylcephalosporin C (DCPC), which must bo removed from the CPC during the purification step, is also formed cluring the fermentation. Thl~ ro~ult~ ln considerable yleld losses. Cross-flow flltratlon ~ystoms using polymer or ceramics membranes have already been used for the worklng-up of culture ligulds which contain antibiotics (Harris et al., J. Chem. Techn. Biotechnol., 1988, 42, 19-30). A reduced decomposltlon of cephalosporin C ln thoso proco~sea has not boen demonstrated as yet. It 18 known to lsolate cephalosporln C after the fermentatlon u~lng cross-flow flltration (M.
Ralyanpur et al., Contrlbuted Paper, Chapter 32, pagos 455-470).
It is an ob~ect of the pro~ont invontion to flnd a proces~ in which the dogradation of cophalo~porin C and REPLACEMENT SHE~T
:. - , .
,:
.
J 1 ~
HOE 91/E~' 262-Dr.TI~/~ch the formation of ~econdary productl~ can be roduced and the yield relative to the amount of ~ub~trate e~ployed can be increa~ed.-" ' ' ~
~-~ .
- 2 - ~llfi~)l!) Surprisingly, it has now been found th~t th- u~ of a cross-flow filtration module during the f~rm-ntation of Acremonium chry~ogonum allowed the CPC ylold to be increasod, the formation of DCPC to bo roducod and the production time to be extendod. Tho filtration and the fact that small amounts of DCPC aro formod furthermoro simplify th0 working-up of cephalo~por~n C ~ubetantlally.
The invention therefors relatos to a procoss ~or the preparation of CPC wh~ch comprl~es fllterlng tho ferment-ation solut~on durlng the formont-tlon through a cross-flow filtratlon systam and the poselblllty of replaclng the withdrawn amount of flltrate ln the formenter.
Acremonium chry~ogenum (Cephalosporlum acremonlum) as well as mutants and eeloctant~, as long as thoy produco CPC derivatlves, aro suitable for u~o in tho procoss according to the lnventlon.
The nutrient ~olutlon contalns carbon sources auch as ~ucrose, corn 13tarch, doxtrose or molasses, and nitrogen sources 13uch a6 ~oyboan meal, groundnut meal, malt extract or ammonium acetate.
The nutrient modlum all30 contalns lnorganlc salts such as ~odium hydrogsn phosphate, sodium chloride, calcium chloride, calclum ~ulfato, calcium carbonate, magnesium sulfate or potassium hydrogen phosphate. Fat such as methyl oleate or soybean oil can also be added to the nutrient medium. Trace elements such a~ salts of iron, manganese, copper, zinc, cobalt or othor metals are also added.
, Acremonium chrysogenum ~Cephalosporium acremonium), i preferably DSM 6473, 18 cultured at temporaturee betwoon 20C and 30C, proforably ~t 25C, and at a p~ of betwoon and 8, preferably pH 7. It le flr~t cultured i REPLACEMENT S~EET
~ :
rJ~
i " ~. .
~v ' ,.
~ 3 aerobically in a ~haker fla~k and th~n in ~ fermont~r with s~irring and 4eratlon with air or pur~ oxygen. The microorgani~ms are culturod in the formontorn ovQr A
period of from 120 to 2~0 hour~, preferably b~tw~qn 130 and 170 hours.
The cross-flow filtration ~yst~m~ uoed can be plate module~, tube modules, cap~llary modules, wound moduleA
or hollow-fiber membrano module~ made of polymers, carbon or Gsramic~ and having ~eparation bordoro from the ultrafiltration to tho ~terile-filtration rango. Filtra-tion modules which are preferably employod are tho~e which have a pore size of 0.2 ~m or 4 nm. The membrane materials which can bo omployed are poly~ulfones, poly-amide~, cellulose acetate, aluminum oxide or zlrconium oxide. The filtration can be affected continuously or batchwise. It ~tarts approximately 2 - 3 day3 after inoculation of the fermenter and can be continued until the fermentation ha~ ended. The flow rate of the ferment-er ~olution over the filtration ~urface is between 0.5 and 20 m/~, preferably 1 to 10 m/s.
The filtrate which is drawn off from the fermenter during the fermantation can be replaced by a corresponding amount of li~lid or, alternatively, the filtrate can be recycled to the fermenter after the valuablo product has been ~eparated, for oxample by absorption. To this end, water, enriched with suitablo salts or other nutrient medium components, can be pumped in.
The liquid volume which has not permeated the membrane is recycled to the fermenter.
The fermenter and the cross-flow filtration ~ystem are connected to ~uitable pipes or tubes and sterilized before the fermentation. Approximatoly 0.2 m' of filtra-tion surface are required for a 100 1 fermenter. It is also possible to use greater and smaller filtration ~urfaces.
REPLAC~MENT SHEET
~r,:
~ s:
.~i 21 1.6~1..'3 Example 1:
Fermentation o$ Acr~monium chry~ogenum DgM 6473 The fermentation was cArried out u~lng th~ followlng nutrient aolution:
5 Preculture medium g/l Corn~teep 11.75 Ammonium acetate 4.5 Sucro~e 20.0 CaSO~.2H2O
10 MgSO~7.H2O o 5 p~ 7.0 (ad~usted using 15 % by wt. NaOH) Fermentation medium g/l Fat-free groundnut meal 100.0 Ammonium acetate 6.0 15 Glucoee monohydrate 5.0 Methyl oleate 5.0 D,L-Methionino 3.0 CaSO~-2H2O
MgSO47-~2O
20 CaCO3 5.0 A~tifoam o.5 Fed-batch solution:
Gluco~e monohydrate 500.0 D,L-Methionine 24.75 Agar slant~ are used for inoculating 100 ml of preculture medium (500 ml shakor flas~s eguipped with 4 baffles).
The flaeke are incubated for 48 hours at 150 rotations per minute (rpm) at 25 to 28C. These culturos are used for inoculating a furthor preculture (1000 ml of medium, 5000 ml flasks, 25 to 281:, 120 rpm, 58 to 60 hour~). The eecond preculture i~ ueed for inoculating 60 1 REP~ACEMENT S~T
, . . ,: , . . ..
.' "~ ' '' , 21 1 6~
fermentation medium in a ~tlrred formontor. The fermentation is aarried out at 25C. The gas flow i~
controlled in such a way that ~he pO, in th- ~erm-ntatlon nutrient ~olution is above 20 %.
After 74 hours f~rm~ntation, tho filtration 18 ~t-rtod usin~ a croes-flow coramics modulo (manufacturod by Membraflow, a-Al~O3) having a filtoring ~urface of 0.2 m' and a pore sizo of 0.2 ~m. Tho following procoss para-meters were adhered to:
10 Flow rate: 2 m/s Pumping rate: 1500 l/h Filtration capacity: 2 l/h Filtration tlme: 68 hours.
The table which follows shows the test rosults after15 142 hours of a fermentation without (A) and with (B) cross-flow filtration:
Table l:
CPC DCPC/ Productivity CPC Productivity CPC DCPC
t%] l%~ max. t%] after 6 after 6 days [%l days [~]
25 B ~ 44 200 400 53 Example 2 The fermentation is as in Exumple 1. Table 2 shows the results after 167 hours of a fermentation with cross-flow ~0 filtration (B) comparod with a parallol formontation without filtration, which was stopped aftor 142 hours:
REPLACEMENT SHEET
f r ~ ' ;~
~:- .. .. ..
~ ' ''""'' ' '' .
211~0 l !3 Table 2:
. ~ ~
CPC DCPC/CPC
- I ~%) (%) 1~ (142 hour~)100 100 B (167 hour~)129 69 .~ _ REPLACEM~JT SHEI :T
. .
The invention therefors relatos to a procoss ~or the preparation of CPC wh~ch comprl~es fllterlng tho ferment-ation solut~on durlng the formont-tlon through a cross-flow filtratlon systam and the poselblllty of replaclng the withdrawn amount of flltrate ln the formenter.
Acremonium chry~ogenum (Cephalosporlum acremonlum) as well as mutants and eeloctant~, as long as thoy produco CPC derivatlves, aro suitable for u~o in tho procoss according to the lnventlon.
The nutrient ~olutlon contalns carbon sources auch as ~ucrose, corn 13tarch, doxtrose or molasses, and nitrogen sources 13uch a6 ~oyboan meal, groundnut meal, malt extract or ammonium acetate.
The nutrient modlum all30 contalns lnorganlc salts such as ~odium hydrogsn phosphate, sodium chloride, calcium chloride, calclum ~ulfato, calcium carbonate, magnesium sulfate or potassium hydrogen phosphate. Fat such as methyl oleate or soybean oil can also be added to the nutrient medium. Trace elements such a~ salts of iron, manganese, copper, zinc, cobalt or othor metals are also added.
, Acremonium chrysogenum ~Cephalosporium acremonium), i preferably DSM 6473, 18 cultured at temporaturee betwoon 20C and 30C, proforably ~t 25C, and at a p~ of betwoon and 8, preferably pH 7. It le flr~t cultured i REPLACEMENT S~EET
~ :
rJ~
i " ~. .
~v ' ,.
~ 3 aerobically in a ~haker fla~k and th~n in ~ fermont~r with s~irring and 4eratlon with air or pur~ oxygen. The microorgani~ms are culturod in the formontorn ovQr A
period of from 120 to 2~0 hour~, preferably b~tw~qn 130 and 170 hours.
The cross-flow filtration ~yst~m~ uoed can be plate module~, tube modules, cap~llary modules, wound moduleA
or hollow-fiber membrano module~ made of polymers, carbon or Gsramic~ and having ~eparation bordoro from the ultrafiltration to tho ~terile-filtration rango. Filtra-tion modules which are preferably employod are tho~e which have a pore size of 0.2 ~m or 4 nm. The membrane materials which can bo omployed are poly~ulfones, poly-amide~, cellulose acetate, aluminum oxide or zlrconium oxide. The filtration can be affected continuously or batchwise. It ~tarts approximately 2 - 3 day3 after inoculation of the fermenter and can be continued until the fermentation ha~ ended. The flow rate of the ferment-er ~olution over the filtration ~urface is between 0.5 and 20 m/~, preferably 1 to 10 m/s.
The filtrate which is drawn off from the fermenter during the fermantation can be replaced by a corresponding amount of li~lid or, alternatively, the filtrate can be recycled to the fermenter after the valuablo product has been ~eparated, for oxample by absorption. To this end, water, enriched with suitablo salts or other nutrient medium components, can be pumped in.
The liquid volume which has not permeated the membrane is recycled to the fermenter.
The fermenter and the cross-flow filtration ~ystem are connected to ~uitable pipes or tubes and sterilized before the fermentation. Approximatoly 0.2 m' of filtra-tion surface are required for a 100 1 fermenter. It is also possible to use greater and smaller filtration ~urfaces.
REPLAC~MENT SHEET
~r,:
~ s:
.~i 21 1.6~1..'3 Example 1:
Fermentation o$ Acr~monium chry~ogenum DgM 6473 The fermentation was cArried out u~lng th~ followlng nutrient aolution:
5 Preculture medium g/l Corn~teep 11.75 Ammonium acetate 4.5 Sucro~e 20.0 CaSO~.2H2O
10 MgSO~7.H2O o 5 p~ 7.0 (ad~usted using 15 % by wt. NaOH) Fermentation medium g/l Fat-free groundnut meal 100.0 Ammonium acetate 6.0 15 Glucoee monohydrate 5.0 Methyl oleate 5.0 D,L-Methionino 3.0 CaSO~-2H2O
MgSO47-~2O
20 CaCO3 5.0 A~tifoam o.5 Fed-batch solution:
Gluco~e monohydrate 500.0 D,L-Methionine 24.75 Agar slant~ are used for inoculating 100 ml of preculture medium (500 ml shakor flas~s eguipped with 4 baffles).
The flaeke are incubated for 48 hours at 150 rotations per minute (rpm) at 25 to 28C. These culturos are used for inoculating a furthor preculture (1000 ml of medium, 5000 ml flasks, 25 to 281:, 120 rpm, 58 to 60 hour~). The eecond preculture i~ ueed for inoculating 60 1 REP~ACEMENT S~T
, . . ,: , . . ..
.' "~ ' '' , 21 1 6~
fermentation medium in a ~tlrred formontor. The fermentation is aarried out at 25C. The gas flow i~
controlled in such a way that ~he pO, in th- ~erm-ntatlon nutrient ~olution is above 20 %.
After 74 hours f~rm~ntation, tho filtration 18 ~t-rtod usin~ a croes-flow coramics modulo (manufacturod by Membraflow, a-Al~O3) having a filtoring ~urface of 0.2 m' and a pore sizo of 0.2 ~m. Tho following procoss para-meters were adhered to:
10 Flow rate: 2 m/s Pumping rate: 1500 l/h Filtration capacity: 2 l/h Filtration tlme: 68 hours.
The table which follows shows the test rosults after15 142 hours of a fermentation without (A) and with (B) cross-flow filtration:
Table l:
CPC DCPC/ Productivity CPC Productivity CPC DCPC
t%] l%~ max. t%] after 6 after 6 days [%l days [~]
25 B ~ 44 200 400 53 Example 2 The fermentation is as in Exumple 1. Table 2 shows the results after 167 hours of a fermentation with cross-flow ~0 filtration (B) comparod with a parallol formontation without filtration, which was stopped aftor 142 hours:
REPLACEMENT SHEET
f r ~ ' ;~
~:- .. .. ..
~ ' ''""'' ' '' .
211~0 l !3 Table 2:
. ~ ~
CPC DCPC/CPC
- I ~%) (%) 1~ (142 hour~)100 100 B (167 hour~)129 69 .~ _ REPLACEM~JT SHEI :T
. .
Claims (7)
1. A process for the fermentative production of cephalo-sporin C using Acremonium chrysgenum, which comprises filtering the fermentation solution during the fermentation through a cross-flow filtration system and the possibility of replacing the amount of filtrate in the fermenter.
2. The process as claimed in claim 1, wherein a polymer filter or ceramic filter is used as the cross-flow filtration system.
3. The process as claimed in claim 1 or 2, wherein the filter has a pore size of between 4 and 200 nm.
4. The process as claimed in one or more of claims 1 to 3, wherein the flow rate over the filter surface is 1 to 10 m/s.
5. The process as claimed in one or more of claims 1 to 4, wherein the filtrate solution in the fermenter can be replaced by water.
6. The process as claimed in claim 5, wherein the filtr-ate solution is replaced by a nutrient solution.
7. The process as claimed in claim 6, wherein the filtr-ate solution is recycled to the fermenter after the valuable product has been removed.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE4127648A DE4127648C1 (en) | 1991-08-21 | 1991-08-21 | |
| DEP4127648.5 | 1991-08-21 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2116019A1 true CA2116019A1 (en) | 1993-03-04 |
Family
ID=6438749
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002116019A Abandoned CA2116019A1 (en) | 1991-08-21 | 1992-08-08 | Process for the fermentative production of cephalosporin c using acremonium chrysogenum |
Country Status (19)
| Country | Link |
|---|---|
| EP (1) | EP0599891B1 (en) |
| JP (1) | JPH07501207A (en) |
| CN (1) | CN1045008C (en) |
| AT (1) | ATE130038T1 (en) |
| AU (1) | AU663519B2 (en) |
| CA (1) | CA2116019A1 (en) |
| CZ (1) | CZ281698B6 (en) |
| DE (2) | DE4127648C1 (en) |
| DK (1) | DK0599891T3 (en) |
| ES (1) | ES2079882T3 (en) |
| FI (1) | FI103988B1 (en) |
| HU (1) | HU213570B (en) |
| NO (1) | NO940565D0 (en) |
| PT (1) | PT100796B (en) |
| RU (1) | RU2094463C1 (en) |
| SK (1) | SK279794B6 (en) |
| TW (1) | TW317572B (en) |
| WO (1) | WO1993004188A1 (en) |
| ZA (1) | ZA926271B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR100446110B1 (en) * | 1997-10-24 | 2004-10-28 | 씨제이 주식회사 | Cephalosporin c-producing microorganism having tolerance against high concentration of glycerol |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS57106683A (en) * | 1980-12-24 | 1982-07-02 | Takeda Chem Ind Ltd | Method for concentrating beta-lactam antibiotic substance |
| DE3307095A1 (en) * | 1983-03-01 | 1984-09-06 | Degussa Ag, 6000 Frankfurt | MICROBIOLOGICALLY PRODUCED L-PHENYLALANINE DEHYDROGENASE, METHOD FOR THEIR DETERMINATION AND THEIR USE |
| CS244333B1 (en) * | 1984-11-02 | 1986-07-17 | Jan Rakyta | Method of c-cephalosporine fermentation production with utilization of fats as limitating carbonaceous substrate by means of acromonium chrysogenum strain |
-
1991
- 1991-08-21 DE DE4127648A patent/DE4127648C1/de not_active Expired - Fee Related
-
1992
- 1992-08-08 SK SK197-94A patent/SK279794B6/en unknown
- 1992-08-08 CA CA002116019A patent/CA2116019A1/en not_active Abandoned
- 1992-08-08 AU AU24024/92A patent/AU663519B2/en not_active Ceased
- 1992-08-08 AT AT92916796T patent/ATE130038T1/en not_active IP Right Cessation
- 1992-08-08 HU HU9400463A patent/HU213570B/en not_active IP Right Cessation
- 1992-08-08 RU RU9294015848A patent/RU2094463C1/en active
- 1992-08-08 ES ES92916796T patent/ES2079882T3/en not_active Expired - Lifetime
- 1992-08-08 DE DE59204277T patent/DE59204277D1/en not_active Expired - Fee Related
- 1992-08-08 JP JP5504067A patent/JPH07501207A/en not_active Withdrawn
- 1992-08-08 CZ CZ94366A patent/CZ281698B6/en not_active IP Right Cessation
- 1992-08-08 EP EP92916796A patent/EP0599891B1/en not_active Expired - Lifetime
- 1992-08-08 WO PCT/EP1992/001811 patent/WO1993004188A1/en active IP Right Grant
- 1992-08-08 DK DK92916796.3T patent/DK0599891T3/en active
- 1992-08-20 ZA ZA926271A patent/ZA926271B/en unknown
- 1992-08-20 PT PT100796A patent/PT100796B/en not_active IP Right Cessation
- 1992-08-21 CN CN92110651A patent/CN1045008C/en not_active Expired - Fee Related
- 1992-08-22 TW TW081106636A patent/TW317572B/zh active
-
1994
- 1994-02-18 NO NO940565A patent/NO940565D0/en not_active Application Discontinuation
- 1994-02-18 FI FI940778A patent/FI103988B1/en active
Also Published As
| Publication number | Publication date |
|---|---|
| CN1071953A (en) | 1993-05-12 |
| DK0599891T3 (en) | 1996-02-26 |
| FI103988B (en) | 1999-10-29 |
| CZ281698B6 (en) | 1996-12-11 |
| NO940565L (en) | 1994-02-18 |
| TW317572B (en) | 1997-10-11 |
| HU9400463D0 (en) | 1994-06-28 |
| ZA926271B (en) | 1993-04-28 |
| EP0599891A1 (en) | 1994-06-08 |
| RU2094463C1 (en) | 1997-10-27 |
| SK279794B6 (en) | 1999-03-12 |
| HU213570B (en) | 1997-08-28 |
| DE4127648C1 (en) | 1993-01-14 |
| NO940565D0 (en) | 1994-02-18 |
| WO1993004188A1 (en) | 1993-03-04 |
| FI103988B1 (en) | 1999-10-29 |
| SK19794A3 (en) | 1994-08-10 |
| PT100796B (en) | 1999-07-30 |
| JPH07501207A (en) | 1995-02-09 |
| EP0599891B1 (en) | 1995-11-08 |
| HUT69767A (en) | 1995-09-28 |
| ATE130038T1 (en) | 1995-11-15 |
| ES2079882T3 (en) | 1996-01-16 |
| AU2402492A (en) | 1993-03-16 |
| FI940778A (en) | 1994-03-16 |
| DE59204277D1 (en) | 1995-12-14 |
| CZ36694A3 (en) | 1994-07-13 |
| PT100796A (en) | 1993-09-30 |
| FI940778A0 (en) | 1994-02-18 |
| CN1045008C (en) | 1999-09-08 |
| AU663519B2 (en) | 1995-10-12 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| HUT74944A (en) | Novel process for the isolation of clavulanic acid and of pharmaceutically acceptable salts thereof from the fermentation broth of streptomyces sp. p 6621 ferm p 2804 | |
| CN1107070C (en) | Process for preparation of antibiotic | |
| US5994534A (en) | Process for the preparation of pharmaceutically acceptable salts of clavulanic acid | |
| CA2116019A1 (en) | Process for the fermentative production of cephalosporin c using acremonium chrysogenum | |
| US6274575B1 (en) | Isolation of clavulanic acid from fermentation broth by ultrafiltration | |
| EP0055137B1 (en) | Method for concentrating beta-lactam antibiotic solution | |
| US20030139595A1 (en) | Novel process for the fermentative production of cephalosporin | |
| RO133836A2 (en) | Process for separating 7-aminocephalosporanic acid | |
| US20050176115A1 (en) | Process for the production of methionine | |
| MXPA00009357A (en) | Novel process for the fermentative production of cephalosporin | |
| JPS6257179B2 (en) |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| FZDE | Discontinued |