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Abstract

Clavulanic acid (CA) is a beta-lactamase inhibitor produced by strains of Streptomyces clavuligerus. Nowadays, the combination of CA with amoxycillin is the most successful example of the use of a beta-lactam antibiotic sensitive to beta-lactamases together with an inhibitor of these enzymes. Clavulanic acid is purified from fermentation broth by a series of steps consisting mainly of two-phase separation processes such as liquid-liquid extraction, adsorption or ion-exchange chromatography, among others. Amberlite IRA 400, a strong anion-exchange resin, has a very high adsorption capacity for CA (Mayer et al. 1997). This resin can be pre-treated with NaCl (chloride cycle), to remove selectively only those anions, which are able to displace chloride from the resin or with NaOH (hydroxyl cycle), to remove all species of anions. In order to decide the best operating conditions for CA recovery by ion-exchange resins and then to construct a model of this separation process, batch experiments were conducted using Amberlite IRA 400 in the chloride cycle. These runs were carried out in a 200 ml stirred tank, at two different initial solution pH, 6.2 and 4.0; the temperature was maintained at 10 degrees C and 20 degrees C during adsorption and 30 degrees C during the desorption step. It was possible, on the basis of these batch results, to model the separation process, including the adsorption kinetics, equilibrium data and mass transfer limitations.

Purification of clavulanic acid produced by Streptomyces clavuligerus via submerged fermentation using polyethylene glycol/cholinium chloride aqueous two-phase systems

“…Unfortunately, these previous studies do not provide any further details about the CA purification [4,43,53]. Others have applied ionic exchange adsorption processes with CA recoveries from 60 to 100% and PF around 1.5 [5,60]. Recoveries of CA between 49 and 99% and a PF of 1.5-fold were obtained when ATPS-based in phosphate/PEG systems were adopted [45].…”

“…Thus, to keep its stability this compound is mostly maintained in the form of sodium, potassium or lithium salts. Even so the extraction yields achieved nowadays are generally quite low making CA production cost-intensive [2,5,8,9]. All these limitations have been pushing the development or improvement of alternative, cheaper and more environmental friendly purification methods to improve the efficiency of CA recovery and to decrease the process costs.…”

Dextran sulfate/Triton X two-phase micellar systems as an alternative first purification step for clavulanic acid

“…As a consequence, this drug shows high degradation rates at both basic (pH > 7.5) and acidic (pH < 4.5) medium [9]. Clavulanic acid presents a relatively complex downstream process, including successive liquid-liquid extraction steps with organic solvents and a final chromatographic step, resulting in low purification yields [10,11]. Therefore, the search for new environmentally friendly (less organic solvents) purification strategies presenting better yields and lower costs is important.…”

Extraction of clavulanic acid using aqueous two‐phase micellar system

“…Primary extraction includes successive liquid–liquid extraction steps employing organic solvents, and usually, the last step refers to adsorption chromatography techniques 7. However, this drug does not present any particular hydrophobic group and is chemically unstable, due to susceptibility of the carbonyl group linked to the β‐lactam ring to suffer attacks by protons or hydroxide ions and water molecules, resulting in low purification yields 8,9. Therefore, new environmentally friendly (less organic solvents) purification strategies presenting better yields and lower costs are highly desirable.…”