Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1997-08-27
2001-01-09
Kight, John (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C540S346000, C540S349000
Reexamination Certificate
active
06172221
ABSTRACT:
This invention relates to liquid-liquid extraction processes. In particular the invention relates to processes in which a first liquid phase containing a dissolved solute is contacted with a second liquid phase which is also a solvent for the solute but is immiscible with the first liquid phase, and the solute is extracted into the second liquid phase.
In some known extraction processes, an organic solute in weak solution in an organic solvent is contacted with an aqueous medium to extract the solute into the aqueous medium and thereby form a relatively concentrated aqueous solution in the aqueous medium. This procedure is called “back extraction” or “stripping”. In some cases the solute is subjected to chemical treatment whilst in solution in the organic solvent to inter alia enhance the solubility of the solute in the aqueous medium, for example salt formation whilst in the organic solvent to enhance aqueous solubility of the solute as a salt.
In some processes the aqueous medium is in a circulating loop, in which a current of aqueous medium is allowed to contact a current of the solute dissolved in the organic solvent, thereby extracting a substantial proportion of the solute from the solvent, and then this aqueous medium containing extracted solute is circulated and allowed to contact fresh incoming solute dissolved in the organic solvent.
In one form of this circulating process, the aqueous medium is allowed to circulate several times so that the concentration of solute in the aqueous medium increases to an optimum. In some cases when the aqueous medium is in such a circulating loop, the organic solvent is itself in a circulating loop, for example resulting from a preliminary extraction into the organic solvent of the solute from an aqueous source of the solute, such as the product of a chemical reaction or fermentation, to pick up further solute and become more concentrated.
A general problem associated with such extraction processes, particularly when the aqueous medium is in a circulating loop, is that if only a limited degree of contact is achieved between the solute in the organic solvent and the aqueous medium, a relatively large volume ratio of aqueous medium:first organic solvent in the region of mixing is required. This can result in relatively bulky plant.
Moreover, some solutes are relatively unstable in both aqueous media and commonly used organic solvents, particularly if these are wet, and if only a limited degree of mixing is achieved between the solution in the organic solvent and the aqueous medium, particularly if the aqueous medium is circulated many times in the loop, the time for which the solute remains in the aqueous medium and the solvent is lengthened, to the detriment of the solute. This is particularly important in the case of pharmaceutical compounds, which are often sensitive to hydrolysis etc. in solution. Clavulanic acid is such a compound.
Clavulanic acid (Z)-(2R,5R)-3-(2-Hydroxyethylidene)-7-oxo-4-oxa-1-azabicyclo[3.2.0]heptane-2-carboxylic acid) is a &bgr;-lactamase inhibitor which is used commercially as a component of pharmaceutical formulations, usually in the form of its salts, especially potassium clavulanate. Clavulanic acid is produced commercially by culture of the microorganism
Streptomyces clavuligerus
, for example as described in GB 1508977.
Clavulanic acid or its salts may be extracted directly from the culture medium in various ways but normally the cells of the
S. clavuligerus
are first removed from the culture medium by such methods as filtration or centrifugation before such extraction procedures are commenced. Whole broth extraction may also be employed.
Clavulanic acid or its salts may be extracted from clarified culture medium by a variety of methods. Solvent extraction from cold clarified culture medium adjusted to acid pH values, and methods which utilize the anionic nature of clavulanic acid at neutral pH such as the use of anion exchange resins have been found to be particularly useful. A further useful method is to form an ester of clavulanic acid, purify the ester and regenerate the acid or its salt therefrom.
The extraction processes for obtaining clavulanic acid or its salts may notionally be divided into a primary isolation process followed by a further purification process.
Suitable primary isolation processes include solvent extraction of the free clavulanic acid. In the solvent extraction process the clavulanic acid is extracted into an organic solvent from cold clarified culture medium, which may be whole broth, adjusted to an acid pH value.
In one solvent extraction process for clavulanic free acid the clarified medium is chilled and the pH lowered into the region of pH 1-2 by the addition of acid while mixing with a substantially water-imiscible organic solvent. Suitable acids used to lower the pH include hydrochloric, sulphuric, nitric, phosphoric or the like mineral acids. Suitable organic solvents include n-butanol, ethyl acetate, n-butyl acetate and methyl isobutyl ketone, and other similar solvents. Methyl isobutyl ketone is a particularly suitable solvent for use in the extraction of the acidified culture filtrate. After separation of the phases clavulanic acid is found in solution in the organic phase.
The clavulanic acid may be back extracted from the organic phase into a new aqueous phase by making use of the greater water solubility of, for example, the alkali metal or alkaline earth metal salts of clavulanic acid in water than in organic solvents. Thus the clavulanic acid may be back extracted from the organic solvent into an aqueous solution or suspension of an alkali metal or alkaline earth metal base, such as sodium hydrogen carbonate, potassium hydrogen phosphate buffer or calcium carbonate, or water, while maintaining the pH at approximately neutrality, for example pH 7. This aqueous extract, after separation of the phases, may be concentrated under reduced pressure. Freeze-drying may also be employed to provide a solid crude preparation of the salt of clavulanic acid. Such solid preparations are stable when stored as a dry solid at −20° C. A similar process is described in GB 1563103. This process may be modified in known ways by for example additional purification steps applied to the organic solvent phase to remove high molecular weight impurities from the impure clavulanic acid.
A further secondary purification process for clavulanic acid is that described in for example EP 0026044, in which a solution of impure clavulanic acid in an organic solvent is contacted with t-butylamine to form the t-butylamine salt of clavulanic acid, which is then isolated, thereby separating the clavulanic acid from impurities remaining in the organic solvent, and the salt is then converted back to clavulanic acid or into a derivative of clavulanic acid such as an alkali metal salt or an ester. Other known secondary purification processes for clavulanic acid involve the use of other organic amines such as diethylamine, tri-(lower alkyl) amines, dimethylaniline and NN′-diisopropylethylenediamine to form salts and/or other derivatives thereof with the clavulanic acid. These purification process have the inherent disadvantage that they can introduce traces of the amine, or leave residual traces of salts of clavulanic acid with the amine, in the final product.
Such back extraction processes present a problem when clavulanic acid is prepared, as clavulanic acid is particularly water-sensitive. In conventional back extraction processes clavulanic acid can remain in contact with water for a long time, typically around an hour or more as the solution concentration of clavulanic acid builds up under the relatively gentle mixing and separating conditions generally used, and this can lead to extensive hydrolytic degradation.
The inventors have unexpectedly discovered that a known type of mixing device used in a novel way provides improved mixing conditions particularly suitable for such extraction processes.
Accordingly this invention provides an aqueous extraction process in which a stream
Covington Raymond
Kerekes Zoltan
Kight John
Kinzig Charles M.
SmithKline Beecham p.l.c.
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