Penicillin annual production

The commercial production of penicillin and other antibiotics are the most dramatic in industrial microbiology. The annual production of bulk penicillin is about 33 thousand metric tonnes with annual sales market of more than US 400 million.8 The worldwide bulk sales of the four most important groups of antibiotics, penicillins, cephalosporins, tetracyclines and erythromycin, are US 4.2 billion per annum.10... 

Other immobilized enzyme product successes (where annual production of immobilized enzymes has surpassed 1 ton/year) comprise Aminoacylase (Amano), hydantoinase (Smith Kline Beecham), lactase (Valio), lipase (Novo Nordisk), penicillin G acylase (Gist-brocades, Smith Kline Beecham, Rohm) and penicillin V acylase (Novo Nordisk/Gist-brocades) (Poulsen, 1984). 

Chemferm is one of among several companies which apply penicillin acylase for the kinetically controlled industrial synthesis of semisynthetic antibiotics in aqueous environments (Scheme 37) [109-111]. Ampicillin (119) and amoxicillin (120) can be obtained by the enzyme-catalyzed condensation of 6-aminopenicillic acid (6-APA, 117) with the amide or ester of D-(-)-4-hydrox-yphenylglycine and D-(-)-phenylglycine, respectively. In a similar way, cephalexin (121) can be obtained by reaction of D-(-)-phenylglycine with 7-aminodesacetoxycephalosporanic acid (7-ADCA, 118). Penicillin acylase from diverse microbial strains such as E. colU Klyveromyces citrophiluy and Bacillus megabacterium was successfully applied for this transformation and was used in its immobilized form based on a gelatin carrier. The immobilization allows an easy separation from the reaction medium and the reuse of the enzyme for at least 50 cycles. Impressive characteristics of this transformation are yields >90%, a selectivity of >95%, and an optical purity of >99% ee. The industrial manufacture takes place in repetitive batch reactors at many locations worldwide with an annual production volume of 2,000 t. 

Chloroform was used chiefly as an anesthetic and in pharmaceutical preparations immediately prior to World War II. However, these uses have been banned. Annual output in both the United States and the United Kingdom was between 900 and 1350 metric tons. During the war, chloroform production in the United States tripled, largely to meet the requirement for penicillin manufacture. Demand for chloroform continued to increase in the postwar period as its technical appHcations were extended. Consumption continues to increase at a comparatively rapid rate. Chloroform is now used primarily in the manufacture of HCFC-22, monochlorodifluoromethane, a refrigerant, and as a raw material for polytetrafluoroethylene plastics. 

The discovery and production of antibiotics has been of tremendous importance to human and animal health care. Prior to their discovery about half a century ago, many bacterial infections caused debilitating diseases and fatalities were high. The discovery of antibiotics was a major step in the treatment of infectious diseases, especially those caused by bacteria. Today about 50,000 tonnes of antibiotics are produced annually. About a third of this consists of penicillins, whilst tetracyclines make up about a quarter of the market. 

Details of production methods and process flowsheets have been given by Shreve and Brink [3]. Despite the decreased cost of penicillin and of the related antibiotics such as streptomycin, neomycin, the tetracyclines, as their production methods were streamlined, the medical benefits of these drugs are so well established that the value of U.S. production of drugs in this class now exceeds a billion dollars annually [75]. 

The first commercial semi-synthetic antibiotic was ampicillin, which was introduced by Beecham in 1961,57L A few years later a new class of antibiotics, the cephalosporins, was marketed. Some of the semi-synthetic cephalosporins are prepared from 7-aminocephalosporanic acid (7-ACA), others from 7-aminodesace-toxycephalosporanic acid (7-ADCA). 7-ACA is an intermediate that can be obtained from the fermentation product cephalosporin C 7-ADCA is an intermediate that was discovered by Morin et al. 58 using chemical ring expansion of the penicillin nucleus (Fig. 12.2-4). The only difference between the two molecules is the absence of an acetoxy moiety in 7-ADCA. Today, the main intermediates for semi-synthetic cephalosporins (SSCs) and penicillins (SSPs), 7-ADCA and 6-APA, respectively, are produced in quantities of many thousands of tons annually in biocatalytic processes using penicillin amidases. 

Production of 6-amino penicillanic acid (6-APA) from penicillin G or V by the action of penicillin amidase from E. coli, Bacillus megaterium, or Bovista plumba (Toyo Jozo Inc., Asahi Chemical Industry Co., Ltd., Fujisawa Pharmaceutical Co., Gist-Brocades/DSM, Novo-Nordisk, Pfizer, and others). Annual world production of 6-APA 6000 tons, used for the manufacture of semisynthetic penicillins. 

A recombinant amidase from E. coli is also the most commonly employed enzyme for 6-APA production by deacylation of penicillin G [265], a process that has been established now for decades [266]. With an annual turnover of 30 tons, the E. coli penicillin amidase is one of the most widely used biocatalysts, despite... 

The advantages of the biocatalytic process are impressive if the conversion of 10001 penicillin is considered this yields ca. 5001 product or slightly less than one-eighth of annual world production (see below). 

Although the natural penicillins, G (32) and V (33), are useful antibiotics in their own right, their development as major pharmaceutical products was limited until a convenient method for the exchange of their 6-amido side chain was discovered. The new side chains increase the antibiotic activity of the jS-lactam and improve their resistance to the bacterial jS-lactamases, which will hydrolyse the jS-lactam ring. These two effects create some very valuable commercial products whose annual sales exceed 10 . 

Despite the nature of the process, penicillin is a cheap bulk intermediate for the pharmaceutical industry. The annual world production of penicillin G and V together is probably about 11 500 tonnes, although some estimates are closer to 20 000 tonnes. The cost is about 30 kg and it is far lower than it would be if it were the product of purely chemical processes. 

---