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1.1. INTRODUCTION The cephalosporins, a subgroup of β-lactam antibiotics, consist of a 4-membered lactam ring fused through the nitrogen and the adjacent tetrahedral carbon atom to a second heterocycle forming a 6-membered dihydrothiazine ring. Other structural features common to all the cephalosporins are a carboxyl group on the dihydrothiazine ring on the carbon next to the ring nitrogen and a functionalized amino group on C-7, the carbon of the β-lactam ring opposite the nitrogen. These features are evidenced in 7-aminocephalosporanic acid [957-68-6] (7-ACA), C10H12N2O5S. Cephalosporins, like all β-lactam antibiotics, exert their antibacterial effect by interfering with the synthesis of the bacterial cell wall. These antibiotics tend to be “irreversible” inhibitors of cell wall biosynthesis and they are usually bactericidal at concentrations close to their bacteriostatic levels. Cephalosporins are widely used for treating bacterial infections. They are highly effective antibiotics and have low toxicity. 1.2. NATURAL OCCURENCES The first cephalosporin was extracted from sewage-contaminated water, and other naturally occurring ones have been isolated from moulds taken from soil samples. 1.3. BIOSYNTHESIS
1.4. HISTORY The first chemical compounds of the cephalosporin group were isolated from Cephalosporium acremonium, a cephalosporin-producing fungus first discovered by Brotzu in 1948 from a sewage outfall off the Sardinian coast.In 1953, during studies on the chemical nature of cephalosporin, Guy Newton and Edward Abraham found a second hydrophilic antibiotic in the culture broths of Acremonium that was named cephalosporin C (Newton and Abraham, 1954). The new antibiotic was easily obtained in its sodium salt form and showed antibiotic activity against Staphylococcus aureus, Salmonella typhi, and Escherichia coli. 1.5. CLASSIFICATION Cephalosporin antibiotics are divided in four subgroups called generations. The individual drugs are arranged into generations according their spectrum of antibacterial activity (including the susceptibility/resistance to betalactamases) – not according to their date of synthesis or introducing to the market. 1.5.1. FIRST GENERATION First-generation cephalosporins are characterized by good gram-positive activity and modest to weak gramnegative activity. Their spectrum further includes corynabacteria, meningococci, and some communityacquired stems of gram-negative rods like Escherichia coli or Proteus mirabilis. The drugs are active against anaerobes in the extent similar to penicillin.
Fig.1.5.1.Examples of 1st generation cephalosporins : A) Cephadrine B) Cefadroxil C) Cefalexin 1.5.2. SECOND GENERATION The second-generation cephalosporins have a broader spectrum and generally are more active against aerobic gram-negative organisms than the first-generation cephalosporins.Most second-generation cephalosporins have some activity against indole-positive Proteus, Enterobacter (except E. cloacae), and Haemophilus influenza.
Fig.1.5.2. Examples of 2nd generation cephalosporins : A) Loracarbef B) Cefuroxime C) Cefotiam 1.5.3. THIRD GENERATION Third-generation cephalosporins have an expanded gram-negative spectrum and are the most active against enteric gram-negative bacilli, including penicillinase-producing strains, as well as Serratia and Citrobacter. They are also highly active against Haemophilus influenzae and Neisseria gonorrhoeae, Streptococcus pneumoniae and pyogenes, moderately active against Pseudomonas aeruginosa and anaerobes, but somewhat less active against staphylococci than the first-generation cephalosporins.
Nevertheless.5.5. They can resist some potent beta-lactamases. Fig. Examples of 4th generation cephalosporins : A) Cefzopran B) Cefclidine C) Cefepime 184.108.40.206. Ceftobiprole and Ceftaroline.1.Fig. their activity against staphylococci is not better than with cephalotin and activity against P. 5th generation cephalosporins : A) Ceftaroline phosfamil (prodrug) and B) Ceftobiprole medocaril (prodrug) 3 .1. Fig. FIFTH GENERATION Currently there are only two drugs in this category.4.5.aeruginosa is not better than with ceftazidim.1. These new drugs are also the only β-lactam antibiotics that are effective against methicillin-resistant-Staphylococcusaureus (MRSA). Examples of 3rd generation cephalosporins : A) Cefdinir B) Cefixime C) Ceftibuten 1.4. FOURTH GENERATION st nd rd Antibiotics of this group have a broad spectrum summarizing the 1 .3.5. 2 and 3 generation.
Cefoxitin is used to treat mixed aerobic–anaerobic infections including pelvic infections. orthopedic. The third-generation cephalosporins are effective in the treatment of bacteremias. septic arthritis. Cefazolin. is the first-generation agent of choice for surgical prophylaxis. Single dose ceftriaxone has also been effectively used in the treatment of urinary tract infections. and infections of the skin and soft tissue. pneumonias. 4 . and nosocomial aspiration pneumonia. which has a longer half-life than the other first-generation compounds. osteomyelitis.CHAPTER-2 2. APPLICATIONS The cephalosporins are used for treating infectious diseases of bacterial origin in both humans and animals. Because of its long half-life. Cefuroxime is effective against community-acquired pneumonia in which ampicillin-resistant Haemophilus influenzae is the probable etiologic agent. cetriaxone has been used for outpatient treatment of skin and soft tissue infections. The first-generation cephalosporins have been widely used for prophylaxis in cardiovascular. They are especially useful for treating patients who are allergic to the pencillins or who have mixed infections from gram-positive and gramnegative bacteria. pelvic. biliary. and intra-abdominal surgery. Firstgeneration cephalosporins such as cephalothin and cephalexin are the most active against taphylococci and nonenterococcal streptococci and are effective alternatives to the penicillins in patients with endocarditis. intra-abdominal infections. and cellulitis. because of its long half-life has been used in a once-a-day regimen to treat a variety of mild to moderate infections including community-acquired pneumonias. intra-abdominal infections.1. urinary tract infections. urinary tract infections. Cefonicid. and skin and soft tissue infections. APPLICATIONS AND GRADES 2.
in 1988. were launched. This segment is more lucrative and not so price sensitive as 1st and 2nd generation. WORLD SCENARIO Cephalosporins first entered the marketplace in 1964.1. The third cephalosporin on the list was Claforan which had 1988 sales of $376. or 13% of the antibacterial market. By 1986 the worldwide antibiotic market was valued at around $11 billion and cephalosporins represented approximately 41% of the total. Indian Cephalosporin formulation market is valued at US$ 1. cephaloglycin [3577-01-3]. 3. On a worldwide basis. Antibiotic Cephalosporins Pencillin G and V Erythromycin Tetracyclines Vancomycin & Teichoplanin Semisynthetic cephalosporin World market($ million) 11.500 1. and cephalosporins accounted for $1. New and effective cephalosporins continue to be introduced and there is still a major need to find more effective cephalosporins for methicillin-resistant (MRSA) and other resistant pathogens. Cephalosporin sales are projected to reach 40% or $5. 4. which are both injectable.2 billion. With the advent of the more β-lactamase stable cephalosporins such as cefoxitin and cefuroxime .Table showing World Antibiotic market 2006 3. antibiotic sales totaled $9. It is estimated to be amongst top 10 markets by 2020. C18H19N3O6S. total pharmaceutical sales for 1983 were $71 billion. when cephalothin and cephaloridine.000 1. Cephalosporins are continuing to gain market share. The second best selling. INDIAN SCENARIO Indian pharmaceutical industry looks set for a solid long term growth. However this segment of market is too commoditized and thus is volume driven with relatively low realization both the top & bottom line. the top selling cephalosporin was the oral cephalosporin Ceclor which had 1988 sales of $605 million and projected 1989 sales of $696 million. and the more potent agents such as cefotaxime and other third-generation compounds. Japan and the United States. 6. 3rd & 4th generation Cephalosporin are derived from 7ACA & GCLE which are value added non commodised derivatives which accounts about US $ 700million and is mainly restricted to only 3 highly integrated players in markets. For years cephalexin was the leading oral cephalosporin on the market.144 million. 5. S. was launched only to be displaced by the end of the year by cephalexin.2.400 3.1 billion out of which 1st& 2nd generation Cephalosporin derived from Pen-G which contributes about US $ 400million.000 Table.8 million and projected sales of $597 million for 1989. cephalosporin was Rocephin which had 1988 sales of $475. and top parenteral. cephalosporins now dominate the antibiotic market worldwide. the injectable cephalosporins had become important therapeutic agents in the hospitals. currently it ranks 14th by value and 2nd in volume globally. and their final product cost still justifies continued development and manufacture in Europe. ECONOMIC SCENARIO 3. Marketing projections for antibiotics from 1986 to 1991 show an average annual growth rate of 3.400 1. 5 . 2.no 1. It has since been displaced by cefaclor.2.CHAPTER-3 3.2 billion. By the late 1970s.2 million and a projected decline in sales for 1989 to $353 million as it is displaced by the newer cephalosporins. As against this.000 4.7% to $13.234 million.3. Worldwide. Also in 1964 the first oral cephalosporin.
Quinoline Respiratory 23.5% Cephalosporin .2(a).3.3.1 10% 14.9 19% 0.Sales Anti-infectives Musculosketal Respiratory others Cardiovascular Alimentary and metabolism 25% 19% 10% 10% 28% 8% FIG.2.07 25% Anti-infectives 44.1 64.7 8% 28% 3.5% 6% Anti-rheumatics --- Table. Information related to the above chart.1% Cough preparations Cardiovascular 22. Chart showing market share of various segment of pharmaceutical sectors in India(2003).2% Calcium channel blockers Musculoskeletal Others 18.6 10% 6. 6 . Market segment Market size Rs Market share billion(2003) Market rate growth Top most selling category Alimentary metabolism and 58.
South Africa.Himachal pradesh 10.Mexico. Orchid Chemicals & Pharmaceuticals Ltd Alathur(Chennai). *13 China Brazil. Parabolic Drugs Punjab 4. Apex Pharma Mumbai 7.India 13 fast followers* Total fast followers comprise US$40 billion US$5-15 billion each US$1-5 billion each US$90 billion Venezuela. Maharashtra 6.Auranga bad Irungattukottai.no Company Location 1.Egypt.Poland.Gujarat Table.INDIAN COMPANIES MANUFACTURING CEPHALOSPORIN S. Wockhardt Limited Bharuch.Romania. Ltd.Thailand. 3. Aurobindo pharma Hyderabad.Andhra Pradesh 5. 7 . 4. 3. Chennai 9. Zota Pharmaceuticals Pvt.Russia. Phlox Pharmaceuticals Limited Vadodra.Indonesia. S. Gujarat 8.no Projected Growth Countries Additional in global sales by 2013 1.Argentina.Vietnam. Nectar Lifesciences Limited (NecLife) Chandigarh 2. Nootan Pharmaceuticals Baddi.Turkey. 3.Pakistan and Ukraine. 2.2: Projected growth by 2013. Lupin Pharmaceuticals Mumbai.
3.2(b): Chart depicting Table.Projected Sales by 2013 45 40 35 30 25 20 15 10 5 0 China India 13 fast followers Fig.3.2 8 .
One of the distinguishing physical characteristics of the cephalosporins is the infrared stretching frequency of the β-lactam carbonyl. 4. and serum and tissue inactivation. Rather. (a) path followed for nucleophiles. cephalosporinases) produced by bacteria.CHAPTER-4 4. For example. but can sometimes be obtained crystalline. serum binding.1. but rather decompose upon heating at elevated temperatures. are not obtained. The cephalosporins do not usually have sharp melting points.3. products equivalent to the penicilloic or penilloic acids derived from the penicillins under similar conditions.2.1. studies indicate involvement of the 3_-substituent as a leaving group (66). or pale yellow solids that are usually amorphous.PHYSICAL PROPERTIES Most cephalosporin antibiotics are white. BIOLOGICAL PROPERTIES The clinical effectiveness of Cephalosporins depends on the antibacterial and pharmacokinetic properties. tan. tan. tissue distribution. PROPERTIES 4. Cephalosporins are attacked by nucleophiles such as alkoxide or hydroxylamine.1. or pale yellow solids SAFETY INFORMATION: 9 . HANDLING AND STORAGE 4. PROPERTIES. although alcohols readily attack the penicillin β-lactam.1.1. New compounds are also tested for the ability to resist inactivation by β-lactamases (penicillinases.CHEMICAL PROPERTIES The cephalosporins are more resistant to ring opening than the penicillins.1. 4. off-white. but because of the nature of the dihydrothiazine ring. 4.2 Cephalosporin β-lactam reactivity where Nu is a nucleophile and X is a leaving group.2. Pharmacokinetic properties include the efficiency and rate of adsorption. off-white. (b) when Nu is the serine OH of an enzyme (ie. Nu=Enz−Ser−OH) deacylation may precede expulsion of the leaving group and both pathways (a) and (b) may be observed. the rate of metabolism and excretion. MATERIAL SAFETY DATA SHEET (MSDS) HAZARDS IDENTIFICATION APPEARANCE AND ODOUR White. This absorption occurs at higher frequencies (1770 − 1815 cm−1) than those of either normal secondary amides (1504 − 1695 cm−1) or ester carbonyl groups (1720 − 1780 cm−1). Fig.4. cephalosporins are sufficiently stable to permit the use of methanol as a recrystallization solvent. Thus 3deacetoxycephalosporins are found to be more stable than cephalosporins having 3-substituents that can be readily lost.
May cause blood. or charcoal hemoperfusion have not been established as beneficial for an overdose of cephalexin. Obtain medical attention If required. Obtain medical attention. INHALATION Physical form suggests that risk of inhalation exposure is negligible. Absorption of drugs from the gastrointestinal tract may be decreased by giving activated charcoal. blood gases. HEALTH HAZARD ACUTE AND CHRONIC This item may cause hypersensitivity (Rash. foam. Hives) or anaphylaxis. in many cases. Hazardous Combustion Products Hazardous combustion or decomposition products are expected when the product is exposed to fire. EYE CONTACT Wash immediately with clean and gently flowing water. within acceptable limits. liver or kidney dysfunction. SKIN CONTACT Using appropriate personal protective equipment. refer to the current prescribing information or to the local poison control information center. etc. ACCIDENTAL RELEASE MEASURES PERSONAL PROTECTION Wear protective clothing and equipment consistent with the degree of hazard. FIRST AID MEASURES INGESTION Never attempt to induce vomiting. FIRE FIGHTING MEASURES Fire and Explosion Hazards Assume that this product is capable of sustaining combustion. This may include immediate and/or delayed treatment of anaphylactic reactions. ingestion. inhalation. Obtain medical attention if skin reaction occurs. Special Firefighting Procedures Use a self contained breathing apparatus and full protective equipment. Repeated doses of charcoal over time may hasten elimination of some drugs that have been absorbed. which. eyes. it would be extremely unlikely that one of these procedures would be indicated. is more effective than emesis or lavage.HEALTH EFFECTS Exposure might occur via skin. serum electrolytes. In allergic individuals. Meticulously monitor and maintain. Wash out the mouth with water. Protect the patient’s airway and support ventilation and perfusion. For additional guidance. Forced diuresis. exposure to this material may require treatment for initial or delayed allergic symptoms and signs. May cause sensitisation by inhalation or skin contact. MEDICAL TREATMENT Treat according to locally accepted protocols. consider charcoal instead of or in addition to gastric emptying. hemodialysis. Extinguishing Media Water. Continue for atleast 15 minutes. Safeguard the patient’s airway when employing gastric emptying or charcoal. remove contaminated clothing and flush exposed area with large amounts of water. dry chemical. however. carbon dioxide. the patient’s vital signs. Do not attempt to give any solid or liquid by mouth if the exposed subject is unconscious or semi-conscious. peritoneal dialysis. 10 .
After mixing. In some of these reactions. Clean up puddle of Product immediately. erythema multiforme. 11 . and abdominal pain have also occurred. No studies during labor and delivery. supportive therapy may be necessary. Skin Effects Irritation might occur following direct contact. Dyspepsia. Wash hands and arms thoroughly after handling . No adequate and well-controlled studies in pregnant women. Normal room ventilation is expected to be adequate for routine handling of this product. Dilute the puddles with water & recover it.ENVIRONMENTAL PROTECTION For large spills. These reactions usually subsided upon discontinuation of the drug. METHODS FOR CLEANING UP RECOVERY Pump into an inert labelled emergency container. or surface drainage systems. Inhalation Toxicity Can produce respiratory irritation. and rarely. The most frequent side effect has been diarrhea. As with some penicillins and some other cephalosporins. HANDLING AND STORAGE SAFE HANDLING ADVICE No special control measures required for the normal handling of this product. EXPOSURE CONTROL / PERSONAL PROTECTION Wear appropriate clothing to avoid skin contact. angioedema. Should be used during pregnancy only if clearly needed. urticara. Keep tightly closed. store in a refrigerator. Stevens-Johnson syndrome. STORAGE Prior to mixing store at 20° to 25° C (68° to 77°F) [See USP Controlled Room Temperature]. gastritis. take precautions to prevent entry into waterways. Genetic Toxicity Not expected to be genotoxic based on animal studies. sewers . or toxic epidermal necrolysis have been observed. Reproductive Effects Not expected to produce adverse effects on fertility or development based on animal studies. transient hepatitis and chloestatic jaundice have been reported rarely. STABILITY AND REACTIVITY Stable under recommended storage conditions. Nausea and vomiting have been reported rarely. Eye Effects Irritation might occur following direct contact with eyes. Hypersensitivity Reactions Allergic reaction in the form of rash. TOXICOLOGICAL INFORMATION Oral Toxicity Not expected to be toxic following ingestion. It was very rarely severe enough to warrant cessation of therapy. Gastrointestinal Reactions Symptoms of pseudomembranous colitis may appear either during or after antibiotic treatment. Anaphylaxis has also been reported. Adverse effects might occur following Inhalation. Carcinogenicity Not expected to be carcinogenic based on animal studies.
Fig. a cephalosporin. Pharmacokinetic and adverse effects of Cephalosporins 12 .2.4. It is an agent intended for the treatment of bacterial infections.Pharmacological Effects This material is an antibiotic.
CHAPTER-5 5.Cephalosporin C is produced by the same fermentation process used for penicillns but utilizes diffewrnt growth media and producer organisms. MANUFACTURING PROCESS 5. Fig.1.ear.5. These drugs are broad-spectrum antibiotics. they act by inhibiting bacterial cell wall(peptidoglycan) synthesis and they kill growing cell .1(a): Production Flowchart 13 .Natural cephalosporin C is the main fermentation product but is not very therapeutically active and is converted to caphalexin or other active forms which are. However final fermentation broth concentrations are much lower and include many similar compounds resulting in a more difficult separation and purification process. In a maner similar to the penicillins.skin and bone infections caused y G+ and G.bacteria and they have low toxicity.active against respiratory. INTRODUCTION TO MANUFACTURING STRATEGIES Cephalosporins are economically and therapeutically as important as the pencillins.
Fig. 14 .pumps etc.agitators.Distillation columns are used for solvent recovery and purification.5.1(b). Highly specialized fermentation equipment is necessary including fermenters. whereas separation and purification include centrifuges and filters for separating microbes from broth and solvent extractors or membrane separators to separate antibiotic from fermentation broth . Block flow diagram for a general antibiotic production process. 5.airand fluid filters.2. GENERAL PRODUCTION TECHNIQUES: Antibiotic manufacturing plants contain two main processing segments : A highly specialized fermentation section A large energy intensive separation and purification section often termed as Downstream Processing While the fermentation section generally occupies about 50% of the space and acoounts for about 50% of the equipment cost .it accounts for a relatively small portion of the processing steps required for antibiotic production.heat exchangers.
2. A generalized. The antibiotic precursors are also important in order to produce the desired type of antibiotic.2.schematic representation of fermentation process.electricity and steam.2.oxygen transfer and temperature control in the fermenter.the growth medim is quite important and specific to the particular organism.5. Large amounts of cooling and chilled water are required to control the large amount of heat involved during aerobic fermtnation .Antibiotic fermentations are aerobic with optimum operating temperatures in the 20 to 30 C range. To prevent contamination a sterile environment must be maintained.1 RAW MATERIALS AND UTILITIES The yield and final fermentation broths are strongly dependent on the particular organism used.low temperature storage and freeze drying. Long term preservation of an efficient culture is vital to antibiotic manufacturing. 5. Fermentations require large volume of air which must be sterilized to remove bacteria which have particle size down to 0. cooling and chilled water . 15 . air and media sterilization .growth media. purified water. Utility requirements consist of sterilized air. 5. Three methods for culture preservation are subcultivation .5.Consumption of electricity is hifgh due to the large amount of agitation required for Oxygen transfer in the aerobic fermentations.Each production process is generally divided into the following key stages as shown in figure: Fig. Oxygen transfer in fermentation broth can be controlling variable with vigorous agitation required which often produces foaming problems so we use a standard antifoaming agent. FERMENTATION Operating an antibiotic fermentation unit requires special consideration be given to culture preservation .2.
sugar feeds are reduced are usually replaced by higher energy oils such as soyabean or peanut oil. QUALITY CONTROL Chromatography and fluorescence detection are standard methods of assaying antibitotics . penicillin Ndeacetylcephalosporin C and degraded cephalosporin C. Additives : Production scale fermentations are fed-batch with carbon supplied as simple or complex carbohydrate feeds during the growth phase. Besides fermenters other special reactors such as airlift. centrifugation . As the fermentation progresses . DL-Methionine addition which results in the onset of arthrospore formation is often added during the early growth phase of the fermentation.6.2. fed-batch fermentations.5.sedimentation.0 and the temperature range is controlled between 24 and 28 C. HPLC assays are particularly important for the B-lactum antibiotics in order to detect impurities. 5. membrane and immobilized cell reactors are also used.its quantity and the extent of purity required.4. PRODUCTION OF CEPHALOSPORIN ANTIBIOTICS High yielding strains of Acremonium chrysogenum are used in large scale. 16 .The choice of the separation methodology depends to a large extent on the nature of the product . Oil addition leads to multicellular arthropores stage which leads to greater oxygen availability to the organism increasing cephalosporin production.High performance liquid chromatography(HPLC) uses regular and reverse phase and ion exchange packing with ultraviolet light as the detector source. to analyze for penicillins and cephalosporins. The active broth contains not only the desired cephalosporin component but also small quantities of the biosynthetic precursors. The unit operations involved are filtration. The pH of the fermentation is maintained between 6.2. 5. the products are manufactured using variety of equipment.2 and 7. ammonia used to help control the pH throughout fermentation.3.2. purified and formulated for different en uses.2.5. The downstream processing steps are based on steady as well as unsteady state techniques. adsorption and liquid-liquid extraction . 5. the products formed are usually in low concentrations necessitating the handling of large volume and in some cases the broths are highly viscous. Organic nitrogen is often supplied as a combination of soybean and cottonseed meals supplemented with ammonium sulfate. CEPHALOPORIN C RECOVERY AND PURIFICATION: The purification and recovery of harvest cephalosporin C broth begins with the rapid chilling of the active broth to 3-5 c followed by removal of mycelia solids either by filtation or by centrifugation. DOWNSTREAM PROCESSING Downstream processing is an essential part of bioprocess technology in that the desired product needs to be isolated.
3. 2.0 --------0.575 6.45 0.0 2.2. 9.0 2.Thus two major strategies can be used for the recovery and purification of cephalosporin C STRATEGY ONE: This involves the use of activated carbon or the use of a non ionic resin . allowing a bulk filtration to be used to separate the solid matter from broth.About two third of the commercial cephalosporins are derive from 7-ACA by either using chemical or enzymatic deacylation.Two substituted derivatives .0 ----0. PRODUCT RECOVERY: Medium A% 4.3 0. 4.575 6.2 --3560 Medium C% 4.2 --4190 Medium D% 4. 6.0 2. Contacting the eluate with an anion exchange resin and eluting the resin with a salt solution at a pH of 5. Recent bulk market costs for 7-ACA ranges from $115 to $130/kg S. 17 .0 0.no 1. Removal of the adsorbed antibiotic by contacting the carbon with a mixture of water and polar organic solvent.2 --3240 Medium B% 4.0 3.45 0.Because of the high selectivity of the resin .45 0.4 ----0. An additional anion and cation exchange step usually results in high quality of cephalosporin C.0 220.127.116.11) followed by adsorption of filtrate on activated carbon . Enymatic processes are now used by the major producers of cephalosporis C.575 6. STRATEGY TWO: This strategy involves the substitution of the amine moiety on the α-aminoadipyl side chain at C-7.2. Recovery from the filtrate is difficult due to low concentration of product and the need to remove high molecular weight biological compounds which can lead to allergic and toxic manifestations when administerd. Table depicting growth medium for fermentation process 5. 10. Component Peanut meal Soybean meal Beet molasses Methyl oleate Lard oil Sodium sulfate Ammonium sulfate Methionine Calcium carbonate Calcim sulfate Yield:µg Cephalosporin /ml Table5.4-dichlorobenzoyl cephalosporin C and tetrabromocarboxybenzoyl cephalosporin C can be crystallized from the acidic aqueous solution N-Substituted cephalosporin C salts containing small amounts of contaminant can be easily converted to 7-ACA.4 3920 Cephalsporins are extracellular fermentation product.0 3.0 0. 8.0 3. 5.1 --0.4 0.cephalosporin C is preferentially adsorbed over penicillin N or the contaminating biosynthetic precursor molecules .Most of the penicillin is removed in the pH 2. 7.5-10.575 6.N-2.45 0.Thus many separation schemes are employed but most appropriate is to Filter the broth at acidic pH(5.0 3.0 acidification step.
BLOCK FLOW DIAGRAM 18 .2. PROCESS SELECTION The selected process strategy for the manufacture Cephalosporins C is Strategy One.4.33l or 33 Kilo Litre RESULT: After calculations we derived for a 50tonnes per annum plant capacity volume of the bioreactor required is 33kiloliters.94 kg/hr Concentration out in (kg/hr l):2.083e-4 kg/hr l Therefore volume required will be: total feed in / concentration out=33. CAPACITY SELECTION CHAPTER-6 PROCESS SELECTION MATERIAL BALANCE FOR CAPACITY SELECTION: Material balance for a capacity of= 50 tonnes/annum Amount of feed in : 50 tonnes/annum Outlet concentration of the fermentation broth : 25 g\l No of working days : 300 days Total time taken for the fermentation of the broth :120 hours.333. 6. 6. Total feed in (kg/hr ): =6.3.6. 6.
3.Permeate (Low dissolved solid) Fermentation MF 02µm 10000 MWCO UF Filtrate Permeate RO Concentrate cell harvest cell washing (CELL MASS) Concentrate protein .Pigment removal concentrate Adsorption Further downstream processing FiG. 19 .6. Figure depicting the block flow diagram for the process.
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