Commercialization penicillin

Whereas the carboxylic acid is shown for many of these compounds, the majority of the commercial penicillins are sodium salts. Penicillin G is available as the calcium salt [973-53-5] C gH N20 S d/s Ca, and as the potassium salt [113-98-4] C2gH2yN20 S K. 

The degradation of several commercial penicillin antibiotics has been reported.110 113 Thus the kinetics and mechanism of decomposition of cefazolin ester (136) in phosphate buffers110 and the effect of hexadecyltrimefhylammonium bromide-based microemulsions on the decomposition of the antibiotic cephalosporin, cephaclor (137)111 have been reported. Reaction of the latter can occur intramolecularly or intermolecularly by hydroxide attack. Degradation in the solid state of cephaclor (137) has also been reported.112 The same group has looked at the decomposition under aqueous acidic conditions.113 The degradation pathways that have been recognized are... 

Ref 19, pp. 1065-1085, summarizes the pharmacological properties of the more important commercial penicillins. 

The early commercial penicillin was a yellow to brown amorphous powder that was so unstable that refrigeration was required to maintain a reasonable level of activity for a short time. Improved purification procedures provided the white crystalline material in use today. Crystalline penicillin must be protected from moisture, but when kept dry, the salts will remain stable for years without refrigeration. Many penicillins have an unpleasant taste, which must be overcome in the formation of pediatric dosage forms. All of the... 

Thadani et al.22 studied the purity of commercial penicillin V by countercurrent distribution in different solvent systems. They found 95.0% penicillin V and 2.9% penicillin J. 

The behavior of drops in the centrifugal field has been studied (211) and the residence times and mass-transfer rates have been measured (212). PodbieHiiak extractors have been widely used in the pharmaceutical industry, eg, for the extraction of penicillin, and are increasingly used in other fields as weU. Commercial units having throughputs of up to 98 m /h (26,000 gal/h) have been reported. 

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). 

P-Lactams. AH 3-lactams are chemically characterized by having a 3-lactam ring. Substmcture groups are the penicillins, cephalosporias, carbapenems, monobactams, nocardicias, and clavulanic acid. Commercially this family is the most important group of antibiotics used to control bacterial infections. The 3-lactams act by inhibition of bacterial cell wall biosynthesis. 

Most of the new commercial antibiotics have resulted from semisynthetic studies. New cephalosporkis, a number of which are synthesized by acylation of fermentation-derived 7-amkiocephalosporanic acid, are an example. Two orally active cephalosporkis called cefroxadine and cephalexin are produced by a synthetic ring-expansion of penicillin V. 

The development of new antibiotics to combat resistance, and to provide easier oral administration and improved pharmacokinetics has been successful through synthetic modifications. This approach has been particularly rewarding in the area of P-lactams. The commercial importance of the P-lactams is evident from Table 3 which gives the market share of antibacterials. Fully 62% of the 1989 world antibacterial market belonged to the cephalosporin and penicillin P-lactams (20). 

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. 

Fermentation. The commercial P-lactam antibiotics which act as starting material for all of the cephalosporins ate produced by submerged fermentation. The organisms used for the commercial production of the penicillins and cephalosporins ate mutants of PenicU/in chTysogenum and Cephalosporium acremonium respectively (3,153,154). Both ate tme fungi (eucaryotes). In contrast, the cephamycins ate produced by certain species of procaryotic Streptomyces including Streptomyces clavuligerus and Streptomyces lipmanii (21,103). 

Chemical Modification. The chemistry and synthetic strategies used in the commercial synthesis of cephalosporins have been reviewed (87) and can be broadly divided into ( /) Selection of starting material penicillin precursors must be rearranged to the cephalosporin nucleus (2) cleavage of the acyl side chain of the precursor (2) synthesis of the C-7 and C-3 side-chain precursors (4) acylation of the C-7 amino function to introduce the desked acylamino side chain (5) kitroduction of the C-3 substituent and 6) protection and/or activation of functional groups that may be requked. 

Most methods used for the production of the commercially important a-amino penicillins, such as ampicillin and amoxicillin, are based on modifications of an enamine process employing the appropriate phenylglycine and methylacetoacetate followed by coupling with 6-APA (64). Other aspects of the fermentation, strain maintenance, equipment, inoculum development, media, and procedures used in the production of penicillin are well covered in previous editions of the Enyclopedia. Developments in these areas have been reviewed (65). 

En2yme techniques are primarily developed for commercial reasons, and so information about immobilisation and process conditions is usually Limited. A commercially available immobilised penicillin V acylase is made by glutaraldehyde cross-linking of a cell homogenate. It can be used ia batch stirred tank or recycled packed-bed reactors with typical operating parameters as iadicated ia Table 2 (38). Further development may lead to the creation of acylases and processes that can also be used for attaching side chains by ensymatic synthesis. 

Aerobic Fermentation The classic example of large-scale aerobic fermentation is the production of penicillin by the growth of a specific mold. Commercial vessel sizes are 40,000 to 200,000 L (1,400 to 7,000 ft ). The operation is semibatch in that the lactose or glucose nutrient and air are charged at controlled rates to a precharged batch of liquid nutrients and cell mass. Reaction time is 5 to 6 days. 

Despite these advantages, deep (submerged) cultures were still deemed to be the most viable route to satisfying the market demand for penicillin. It was estimated that a surface culture equivalent to 2 hectares would be required to produce the same amount of penicillin as a deep culture equivalent to 5 x 104 litres. The desire to switch to deep cultures was thus driven by commercial consideration. 

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... 

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