Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1998-06-01
2000-10-03
Shah, Mukund J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
540348, A01N 4300, C07D48708
Patent
active
061273589
DESCRIPTION:
BRIEF SUMMARY
This invention relates to a process for purification and/or preparation of clavulanic acid and pharmaceutically acceptable salts and esters of clavulanic acid, particularly but not exclusively alkali salts especially potassium clavulanate.
Clavulanic acid is the common name for (2R,5R,Z)-30(2-hydroxyethylidene)-7-oxo-4-oxa-1-azabicyclo [3.2.0] heptane-2-carboxylic acid. Clavulanic acid and its alkali metal salts and esters are active as inhibitors of beta lactamase produced by some Gram positive as well as Gram negative micro-organisms. In addition to inhibition of beta lactamase, clavulanic acid and alkali metal salts thereof also have a synergistic action with penicillin and cephalosporin antibiotics. Clavulanic acid and its salts are used in pharmaceutical preparations to prevent the deactivation of beta lactam antibiotics. Commercial preparations contain potassium clavulanate in combination with amoxycillin trihydrate. Potassium clavulanate is more stable than the free acid or other salts.
Clavulanic acid is prepared by fermentation of a micro-organism such as strains of Streptomyces such as S.clavuligerus NRRL 3585, S.jumonjinensis NRRL 5741 and S.katsurahamanus IFO 13716 and Streptomyces sp.P6621 FERM P2804. The aqueous culture obtained after fermentation is purified and concentrated in accordance with conventional processes for example filtration and chromatographic purification as disclosed in GB 1508977, prior to extraction of the aqueous solution with an organic solvent to obtain a solution of impure clavulanic acid in the solvent.
GB 1508977 discloses preparation of clavulanate salts by filtration of the fermentation broth by passage through an anionic exchange resin. This process may achieve acceptable yields but sophisticated chromatographic purification methods are required and the use of resin columns involves substantial investment for manufacture on a commercial scale.
GB 1543563 discloses a fermentation process wherein the pH value of the medium is maintained in the range 6.3 to 6.7. Pharmaceutically acceptable salts such as potassium clavulanate are prepared by re-salting from lithium clavulanate.
EP-A-0026044 discloses use of the tertiary butylamine salt of clavulanic acid as an intermediate for purification of clavulanic acid. This salt was known from BE-862211 or DE 2733230 which disclosed that the salt was even more stable than the sodium or potassium clavulanate salts. Tertiary butylamine is a toxic compound and is also difficult to remove from waste water giving rise to serious pollution concerns.
EP-A-0562583 discloses use of salts of clavulanic acid with N,N'-monosubstituted symmetric ethylene diamines such as N,N'-diisopropylethylene diammonium diclavulanate as useful intermediates for isolation and preparation of pure clavulanic acid or alkaline metal clavulanate salts from ethyl acetate extract.
Conventionally filtered clavulanic acid containing fermentation broths may contain 10 to 20% of proteins calculated on the amount of clavulanic acid. These proteins hinder the subsequent isolation and purification of the clavulanic acid. Treatment of the filtered broth with ion exchange resins or flocculants is time consuming, expensive and can enhance the degradation of the unstable product.
According to the present invention a process for preparation and/or purification of clavulanic acid or a pharmaceutically acceptable salt or ester thereof comprises the steps of:
removing solids from a clavulanic acid containing fermentation broth by microfiltration to form a first filtrate,
further removing solids from the first filtrate by ultrafiltration to form a second filtrate,
concentrating the second filtrate by removal of water, and
treating the concentrated second filtrate to isolate clavulanic acid or a pharmaceutically acceptable salt or ester thereof
characterised in that the first filtrate is filtered using an ultrafiltration membrane having a molecular weight cut-off of 10 to 30 kD and a permeate flow rate of 10 to 30 lm.sup.-2 h.sup.-1.
Use of ultrafiltration in accordance with the
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Shah Mukund J.
Truong Tamthom N.
Urquhart-Dykes & Lord
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