Penicillin manufacture

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. 

From this one ancestral fungus each penicillin manufacturer has evolved a particular production strain by a series of mutagenic treatments, each followed by the selection of improved variants. These selected variants have proved capable of producing amounts of penicillin far greater than those produced by the wild strain, especially when fermented on media under particular control conditions developed in parallel with the strains. These strain selection procedures have become a fundamental feature of industrial biotechnology. 

The medical success of these drugs gave new emphasis to the pharmaceutical industry, which was boosted further by the commencement of industrial-scale penicillin manufacture in the early 1940s. Around this time, many of the current leading pharmaceutical companies (or their forerunners) were founded. Examples include Ciba Geigy, Eli Lilly, Wellcome, Glaxo and Roche. Over the next two to three decades, these companies developed drugs such as tetracyclines, corticosteroids, oral contraceptives, antidepressants and many more. Most of these pharmaceutical substances are manufactured by direct chemical synthesis. 

DSM, through the acquisition of Gist-Brocades, has a strong position in enzymes for penicillin manufacture. 

One attempt to improve the situation has been successful for small to moderate scale operations where high purity is required—namely, the Podbielniak centrifugal counter-current contactor and separator, which dominates the solvent extraction phase of penicillin manufacture. 

Use Rubber accelerator, inhibitor in hydrogen peroxide, stabilizer for cellulose ester coatings, manufacture of intermediates (p-nitroaniline, p-nitroace-tanilide, p-phenylenediamine), synthetic camphor, pharmaceutical chemicals, dyestuffs, precursor in penicillin manufacture, medicine (antiseptic), ace-tanisole. 

Use Adhesives, thickening agent, sizing paper and textiles, substitute for natural gums, food industry, glass-silvering compositions, printing inks, felt manufacture, substitute for lactose in penicillin manufacture, fuel in pyrotechnic devices. 

Generic Recombinant Human Tissue Plasminogen Activator (tPA) Penicillin Manufacture Novobiocin Manufacture Polymers... 

Antibiotics. Solvent extraction is an important step in the recovery of many antibiotics (qv) such as penicillin [1406-05-9] streptomycin [57-92-17, novobiocin [303-81-1J, bacitracin [1405-87-4] erythromycin, and the cephalosporins. A good example is in the manufacture of penicillin (242) by a batchwise fermentation. Amyl acetate [628-63-7] or -butyl acetate [123-86-4] is used as the extraction solvent for the filtered fermentation broth. The penicillin is first extracted into the solvent from the broth at pH 2.0 to 2.5 and the extract treated with a buffet solution (pH 6) to obtain a penicillin-rich solution. Then the pH is again lowered and the penicillin is re-extracted into the solvent to yield a pure concentrated solution. Because penicillin degrades rapidly at low pH, it is necessary to perform the initial extraction as rapidly as possible for this reason centrifugal extractors are generally used. 

Other Reactions. The reaction of Thydioxybenzaldehyde with sodium cyanide and ammonium chloride, Strecker synthesis, yields /J-hydroxyphenylglycine [938-97-6] a key intermediate in the manufacture of semisynthetic penicillins and cephalosporins (see Antibiotics, p-LACTAMs). 

Pharmaceuticals. -Hydroxybenzaldehyde is often a convenient intermediate in the manufacture of pharmaceuticals (qv). For example, 2-(p-hydroxyphenyl)glycine can be prepared in a two-step synthesis starting with -hydroxybenzaldehyde (86). This amino acid is an important commercial intermediate in the preparation of the semisynthetic penicillin, amoxicillin (see ANTIBIOTICS, P-LACTAMs). Many cephalosporin-type antibiotics can be made by this route as well (87). The antiemetic trimethobenzamide [138-56-7] is convenientiy prepared from -hydroxybenzaldehyde (88) (see Gastrointestinal agents). 

Derivatiziag an organic compound for analysis may require only a few drops of reagent selected from silylatiag kits suppHed by laboratory supply houses. Commercial syathesis of penicillins requires silylatiag ageats purchased ia tank cars from the manufacturer (see Antibiotics, P-LACTAMS-penicillins AND others). 

At present all of the cephalosporins ate manufactured from one of four P-lactams, cephalosporin C (2), penicillin V [87-08-17, penicillin G [113-98-4] and cephamycin C (8), which ate all produced in commercial quantities by fermentation (87). The manufacturing process consists of three steps fermentation, isolation, and chemical modification. 

The second most important group of immobilized enzymes is stiU the penicillin G and V acylases. These are used in the pharmaceutical industry to make the intermediate 6-aminopenici11anic acid [551-16-6] (6-APA), which in turn is used to manufacture semisynthetic penicillins, in particular ampicilHn [69-53-4] and amoxicillin [26787-78-0]. This is a remarkable example of how a complex chemical synthesis can be replaced with a simple enzymatic one ... 

The manufacture of penicillin, for example, involves batch fermentation using... 

Fine chemicals There are many applications of the austenitic steels in the manufacture and storage of fine chemicals and pharmaceutical products. These include storage tanks, pipelines, valves, stills, steam-jacketed pans, mixing vessels, filters and tableting machinery. Considerable use has been made of these steels in penicillin production. 

The subsequent advance was rather fortuitous and rested more with serendipity than with scientific logic. A search was made for cheaper more effective replacements for casein hydrolysate. Amongst the tested materials was com steep liquor (CSL). CSL is a by-product of the manufacture of starch from maize kemals. Whole maize is incubated in warm water, at 50°C acidified with SO2. Thermophilic bacteria hydrolyse proteins and other components of the kemals, thereby loosening the starch granules. These are removed, leaving behind the steep liquor which is used to treat further maize kemals. Ultimately, the liquor is too viscous to re-use and the liquor is concentrated and used as cattle feed. It was this material that was used for penicillin fermentation. Surprisingly, the yield of penicillin increased by a further 5-10 fold giving yields of 50-100 ig ml. 

Before we leave our discussion of preparing 6-aminopenicillanic acid for use as a starting material in the manufacture of semi-synthetic penicillins, we should point out that similar processes are used in the manufacture of semi-synthetic cephalosporins. Here tire key intermediate is 7-aminodeacetoxycephalosporanic add (7-ADCA). We have drawn outline schemes comparing the production of semi-synthetic penicillins and cephalosporins in Figure 6.15. You will see that the two schemes are very similar. 

In section 6.6.1, we described how enzymatic methods have come to dominate the production of the important intermediates used in the manufacture of semi-synthetic -lactams. In principle, the hydrolytic penicillin acylases may be used in the reverse direction to add acyl groups to 6-APA. For example, a two-step enzymatic process has been described for the preparation of ampiciilin (D-(-)-a-aminobenzylpenidllin structure shown in Figure 6.17). 

There is only one choice for the antibiotic production process the synthesis of benzyl-penicillin (penicillin G, originally known as penicillin ). This, the most renowned antibiotic and the first one have been manufactured in bulk, is still universally prescribed.5 Although originally made by surface liquid culture, penicillin G is now produced by air-lift fermentation under aerated conditions. 

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