Penicillin Distributed Development

The development of penicillin into one of the most infiuential antibiotics of the twentieth century followed an entirely different and accidental path from that of Freon, which was a purposeful search with a definite goal in mind (the need for a nonflammable and nontoxic refrigerant), and developed within a single organization. In his Nobel Lecture in December 1945, Alexander Fleming said (Nobel e-museum 2002)  

It began as an accidental discovery and observation that lay dormant for many years, as the discoverer lacked the means and connection to develop a product with sufficient quantity and purity to be used in clinical use. It laid dormant until another team appeared on the horizon, and it took World War II to provide the motivation and the resources critical to its development before penicillin became the life saver for millions. 

The fermentation broth typically contains 20-30 mg/L of antibiotics, which is to say 30 parts per billion, and must be extracted into concentrated form using solvent extraction. The solvent extraction method was developed by Shell Oil and by Podbielniack and is based on the principle that penicillin is hydrolyzed in aqueous medium to H+ and RCOO ions. Thus, equilibrium in an acidic medium (i.e., one with low pH or high H+ concentration) is favored by the neutral RCOOH form, whereas equilibrium in an alkaline medium (i.e., one with high pH or low H+ concentration) is favored by the RCOO ionic form. The neutral form is more soluble in an organic medium, and the ionic form is more soluble in an aqueous medium. Thus, with amyl acetate as the organic solvent the partition coefficient of penicillin between solvent and water is about 100 at pH 3 and about 1 at pH 6. In the industrial process, the aqueous broth was acidified to pH 3 for the extraction into the organic solvent, and alkalized to a pH 6 for reverse extraction back into an aqueous medium. 

Natural penicillin is fragile and breaks down in the presence of impurities and enzymes, having a half-life of just 2.5 h even when cooled to 0 °C. The method of choice for stabilizing penicillin for storage and shipment turned out to be the freeze-drying method. Penicillin is frozen in trays at —30 °C it is then placed in a chamber at a pressure of 0.1-0.6 Torr to sublimate the ice crystals into water vapor and removed. 

A glimpse of the progress in production can be seen with the following figures  

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Schugerl 115] has recently furnished a detail analysis of the reactive extraction of penicdlin-G and V and precursors like phenyl and phenoxy acetic acids. Thirty different amines have been studied for reactive extraction of penicillins 116] in various solvents such as butyl acetate, chloroform, di-isopropyl ether, kerosene, dioctyl ether, etc. Tertiary amines in n-butyl acetate were found to be advantageous because of their low reactivity with solvent but the distribution coefficients of their complexes are significantly lower than those of secondary amines. While using quaternary ammonium salts for ion-exchange extraction, re-extraction is difficult and very large amounts of anion (e.g.. Cl ) are needed to recover penicillins. The basic relationship for distribution coefficient and extraction kinetics have now been fairly developed for amine-penicillin systems. 

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