## 7 Downstream Processing of CA  
Due to its low molecular weight and its instability in aqueous solution at room temperature diverse processes for CA separation and purification have been employed, e.g., filtration or centrifugation, liquid-liquid extraction, and ion exchange chromatography. In addition to the characteristic low productivity of the bioprocess, the product yield is also compromised by the degradation of CA in aqueous phases and the efficiency of the separation steps required for the obtention of potassium clavulanate (the stable commercial form). Several authors have confirmed the degradation of CA in fermentation broths [67; 69; 168; 169; 170], synthetic buffer [68; 171; 172], and pure water [173; 174; 175]. The CA secreted by _S. clavuligerus_ exhibits a high initial reaction rate (~5 h) in aqueous solution (e.g., fermentation broths) followed by a slower degradation rate in the next hours [168; 169]. Degradation of CA is considered consequence of susceptibility to nucleophilic attacks at specific points. This acts as a hydrolytic mechanism in two steps: an equilibrium reaction leading to an active intermediate and an irreversible reaction of this intermediate with another CA molecule, thus leading to the degradation product [67; 176; 177]. As consequence, CA increases its own degradation rate when increasing concentration in the fermentation broth [68; 176]. Usually, CA purification starts (after cultivation process) with the removal of the cells from cultivation broth either by centrifugation or filtration. Then, the antibiotic is separated through adsorption, liquid extraction, or both, followed by the clavulanate salt precipitation. Nevertheless, the observed instability of CA makes the efficient recovery necessary to improve the profitability of the CA production process at reduced operation costs. One of the most explored alternatives for CA recovery from fermentation broths is the adsorption with selective materials such as ion exchange resins, activated carbon, hydrolcalcites, zeolites, and double-layer hydroxides. This technique allows the biomolecules to be selectively adsorbed in solid materials while minimizing the degradation of the product. [PERSON] et al. [178; 179] studied the CA recovery from aqueous solutions by using natural and synthetic zeolites, namely, faujasite-type NaX zeolite (13X) and clinoptilolite-modenite zeolite (NZ) and their modified cationic forms (K\({}^{+}\), Na\({}^{+}\), Ca\({}^{2+}\), Ba\({}^{2+}\), Mg\({}^{2+}\), Sr\({}^{2+}\)), with aperture diameters ranging 0.062 and 0.150 mm. The 13X-Na zeolite showed the best CA retention (17.4%) in the equilibrium at a zeolite/liquid ratio of 0.5 mg.g\({}^{-1}\)[178]. Higher retention levels have been obtained in separations with quaternary ammonium anionic exchange resins, such as Amberlite IRA 400 and Q Sepharose XL. In this regard, [PERSON] et al. [180; 181] studied the temperature effect on CA adsorption and desorption in flask-scale experiments, showing that CA removal from aqueous solution is very favorable (retention values between 60 and 70%) at temperatures ranging from 5 to 10 \({}^{\circ}\)C given the exothermicity of the CA-resin bonding. The desorption process is facilitated by higher temperatures (up to 30 \({}^{\circ}\)C) than the adsorption, the equilibrium time is almost doubled and the desorption ratio is about 60% [180; 181]. [PERSON] et al. [182] proposed a simultaneous adsorption/desorption system of CA using sequential stirred tanks, allowing the recycling of the fermentation supernatants and hence, increasing the CA adsorption percentages. Absorption operations in packed columns with IRA 400 operating at a flow rate of 0.3 L h\({}^{-1}\) and 10 \({}^{\circ}\)C were used, followed by desorption with 2% NaCl at 30 \({}^{\circ}\)C. Even though the absorption in fixed beds have provided good results in terms of separation and concentration, CA degradation may occur within the sites of the ion-exchange resin, reducing the overall yield of the process [183].