This work describes the use of clavulanic acid (CA) precipitation as the final step in the process of purification of CA from fermentation broth as an alternative to conventional methods employed traditionally. The purpose of this study was to use a stable intermediate (t-octylamine) between the conversion of CA to its salt form (potassium clavulanate), thereby enabling the resulting intermediate (amine salt of clavulanic acid) to improve the purification process and maintain the stability of the resulting potassium clavulanate. To this end, response surface methodology was employed to optimize the precipitation step. For the first reaction, five temperatures (6.6 to 23.4 ºC), concentrations of clavulanic acid in organic solvent (6.6 to 23.4 mg/mL) and t-octylamine inflow rates (0.33 to 1.17 drop/min) were selected based on a central composite rotatable design (CCRD). For the second reaction, five temperatures (11.6 to 28.4 ºC), concentrations of clavulanic acid amine salt in organic solvent (8.2 to 41.8 mg/mL) and concentrations of potassium 2-ethylhexanoate (0.2 to 1.2 molar) were also selected using CCRD. From these results, precipitation conditions were selected and applied to the purification of CA from the fermentation broth, obtaining a yield of 72.37%.

Clavulanic acid (CA) is a potent inhibitor of beta-lactamases, enzymes that are responsible for the hydrolysis of beta-lactam antibiotics. It is a secondary metabolite produced by the filamentous aerobic bacterium Streptomyces clavuligerus in submerged cultivations. In the present work clavulanic acid production in batch, fed-batch and continuous bioreactors was studied with the objective of increasing productivity. The operating conditions: temperature, aeration and agitation, were the same in all cases, 28º C, 0.5 vvm and 800 rpm, respectively. The CA concentration obtained in the fed-batch culture, 404 mg L-1, was ca twice the value obtained in the batch culture, 194 mg L-1, while 293 mg L-1 was obtained in the continuous culture. The highest productivity was obtained in the continuous cultivation, 10.6 mg L-1 h-1, as compared with 8.8 mg L-1 h-1 in the fed-batch process and 3.5 mg L-1 h-1 in the batch process, suggesting that continuous culture of Streptomyces clavuligerus is a promising strategy for clavulanic acid production.

We have extended the Dirac-Hartree-Bogoliubov (DHB) approximation developed in a previous work [1] with the inclusion of blocking terms in order to study the pairing properties of both even and odd nuclei. We have concentrated our attention in the isotope chains of 12-26O, 34-56Ca, 48-78Ni and 100-132Sn as well as on the alpha-decay of the new superheavy element (277)112.