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| | Ampicillin Chemical Properties |
| Melting point | 208 °C (dec.)(lit.) | | Boiling point | 684℃ | | refractive index | 265 ° (C=0.1, H2O) | | Fp | 87 °C | | storage temp. | Sealed in dry,2-8°C | | solubility | NH4OH 1 M: 50 mg/mL, clear, colorless | | form | solid | | color | white to off-white | | pka | 2.5 (COOH)(at 25℃) | | Water Solubility | 0.1-1 g/100 mL at 21 ºC | | Merck | 14,586 | | BRN | 5399534 | | Stability: | Hygroscopic | | InChIKey | RXDALBZNGVATNY-CWLIKTDRSA-N | | CAS DataBase Reference | 7177-48-2(CAS DataBase Reference) | | EPA Substance Registry System | Ampicillin trihydrate (7177-48-2) |
| | Ampicillin Usage And Synthesis |
| Description | As a penicillin group of beta-lactam antibiotics, Ampicillin is the first broad-spectrum penicillin, which has in vitro activity against Gram-positive and Gram-negative aerobic and anaerobic bacteria, commonly used for preventing and treating bacterial infections of respiratory tract, urinary tract, middle ear, sinuses, stomach and intestines, bladder, and kidney, etc. caused by susceptible bacteria. It is also used to treat uncomplicated gonorrhea, meningitis, endocarditis salmonellosis, and other serious infections through administered by mouth, intramuscular injection or by intravenous infusion. Like all antibiotics, it is not effective for the treatment of viral infections.
Ampicillin functions by killing the bacteria or preventing their growth. After penetrating Gram-positive and Gram-negative bacteria, it acts as an irreversible inhibitor of the enzyme transpeptidase needed by bacteria to make the cell wall, which results to the inhibition of cell wall synthesis and eventually leads to cell lysis. | | References | https://en.wikipedia.org/wiki/Ampicillin
https://www.drugbank.ca/drugs/DB00415
http://www.medicinenet.com/ampicillin/article.htm | | Chemical Properties | Ampicillin in anhydrous form occurs as
crystals. | | Chemical Properties | White or almost white, crystalline powder. | | Originator | Polycillin,Bristol,US,1963 | | Uses | Penicillin antibacterial. | | Uses | Commonly used to select for ampicillin resistance in mutated and transformed cells | | Indications | Ampicillin may also be helpful in certain patients, particularly pregnant
women with acne, for whom the use of tetracycline, erythromycin, and
minocycline should be avoided. In resistant acne patients, culture may reveal
a gram-negative bacteria responsive to ampicillin. | | Definition | ChEBI: Ampicillin trihydrate is a hydrate. It contains an ampicillin. | | Manufacturing Process | The known methods for the preparation of D-(-)-α-aminobenzylpenicillin by
the acylation of 6-aminopenicillanic acid result in the preparation of aqueous
mixtures which contain, in addition to the desired penicillin, unreacted 6-
aminopenicillanic acid, hydrolyzed acylating agent, and products of side
reactions such as the products of the acylating agent reacted with itself
and/or with the desired penicillin, as well as other impurities.
The D-(-)-α-aminobenzylpenicitlin may then be recovered from the aqueous
reaction mixture by concentration to small volume and recovering the product
by filtration. However, due to the fact that anhydrous D-(-)-α-
aminobenzylpenicillinis soluble in water to the extent of about 20-25 mg/ml at
20°-25°C, it is very difficult to recover the product in high yields.
Furthermore, the recovered D-(-)-α-aminobenzylpenicillin may be obtained in
the form of a monohydrate. The monohydrates (as well as the dihydrates) of
D-(-)-α-aminobenzylpenicillin possess poor biological stability.
The trihydrate which is obtained in high yields, is relatively insoluble in water,
possesses high biological stability and can be obtained by contacting, at a
temperature not above 60°C, an acid addition salt of D-(-)-α-
aminobenzylpenicillin with an amine in a water immiscible solvent containing
at least 3 mols of water per mol of such penicillin.
The following is an example of the conduct of such a process. To a vigorously
agitated mixture of 100 ml of methyl isobutyl ketone there are added at 25°
to 30°C 15 ml of water and 10 ml of a mixture of secondary amines.
To this mixture there is then added slowly over a period of 30 minutes 10
grams of D-(-)-α-aminobenzylpenicillin α-naphthalenesulfonate. The mixture is
agitated for 3 hours at 25-30°C. The product, D-(-)-α-aminobenzylpenicillin
trihydrate precipitates and is collected by filtration. The filter cake of the
product is washed several times with methyl isobutyl ketone and is dried at
40°C. The product is obtained in about a 90% yield and has a potency of 865
mcg/mg. It is determined by Karl Fischer analysis to have a moisture content
of 13.4% by weight. | | Brand name | Amcill (Parke-Davis); Omnipen (Wyeth-Ayerst);
Polycillin (Apothecon); Principen (Apothecon). | | Therapeutic Function | Antibacterial | | Antimicrobial activity | Ampicillin is slightly less active than benzylpenicillin
against most Gram-positive bacteria but is more
active against E. faecalis. MRSA and strains of Str. pneumoniae
with reduced susceptibility to benzylpenicillin are resistant.
Most group D streptococci, anaerobic Gram-positive cocci
and bacilli, including L. monocytogenes, Actinomyces spp. and
Arachnia spp., are susceptible. Mycobacteria and nocardia are
resistant.
Ampicillin has similar activity to benzylpenicillin against
N. gonorrhoeae, N. meningitidis and Mor. catarrhalis. It is 2–8
times more active than benzylpenicillin against H. influenzae
and many Enterobacteriaceae, but β-lactamase-producing
strains are resistant. Pseudomonas spp. are resistant, but
Bordetella, Brucella, Legionella and Campylobacter spp. are
often susceptible. Certain Gram-negative anaerobes such
as Prevotella melaninogenica and Fusobacterium spp. are susceptible,
but B. fragilis is resistant, as are mycoplasmas and
rickettsiae.
Activity against molecular class A β-lactamase-producing
strains of staphylococci, gonococci, H. influenzae, Mor. catarrhalis,
certain Enterobacteriaceae and B. fragilis is enhanced by
the presence of β-lactamase inhibitors, specifically clavulanic
acid.
Its bactericidal activity resembles that of benzylpenicillin.
Bactericidal synergy occurs with aminoglycosides against
E. faecalis and many enterobacteria, and with mecillinam
against a number of ampicillin-resistant enterobacteria. | | Acquired resistance | β-Lactamase-producing pathogens, including most clinical
isolates of Staph. aureus, are resistant. Strains of pneumococci,
enterococci, gonococci and H. influenzae with altered
PBPs have reduced susceptibility to ampicillin. Isolates
of N. gonorrhoeae and H. influenzae with a TEM plasmid-
mediated
β-lactamase (which are more common) are fully
resistant. Resistance among H. influenzae is often linked with
resistance to chloramphenicol, erythromycin or tetracycline,
due to plasmid-encoded resistance markers that are co-transferred
with the gene for the TEM enzyme. However, at
least 70% of current H. influenzae isolates remain susceptible
to ampicillin worldwide.
The widespread use of ampicillin and other aminopenicillins
has led to resistance becoming common in formerly
susceptible species of enteric pathogens as a result of the
widespread dissemination of plasmid-mediated β-lactamases.
Surveillance data from North America and Europe indicate
less than 50% susceptibility to ampicillin in Esch. coli. At least
90% of current isolates of Mor. catarrhalis are β-lactamaseproducing
strains. Ampicillin-resistant strains of salmonellae,
notably S. enterica serotypes Typhi and Typhimurium (many of which are also resistant to chloramphenicol, sulfonamides
and tetracyclines) present a serious problem in Africa, Asia
and South America. Multiresistant strains of shigellae also
predominate in many parts of the world. | | General Description | Odorless white microcrystalline powder with a bitter taste. A 0.25% solution in water has a pH of 3.5 to 5.5. | | Air & Water Reactions | Slightly soluble in water. | | Reactivity Profile | Ampicillin absorbs insignificant amounts of moisture at 77° F and relative humidities up to approximately 80%, but under damper conditions Ampicillin absorbs significant amounts. A pH-rate profile reveals specific-acid- and specific-base- catalyzed hydrolysis. The pH of maximum stability is 5.8. | | Fire Hazard | Flash point data for Ampicillin are not available; however, Ampicillin is probably combustible. | | Contact allergens | Ampicillin caused contact dermatitis in a nurse also
sensitized to amoxicillin (with tolerance to oral phenoxymethylpenicillin)
and in a pharmaceutical factory
worker. Systemic drug reactions are common. Crossreactivity
is regular with ampicillin and can occur with
other penicillins. | | Biochem/physiol Actions | A β-lactam antibiotic with an amino group side chain attached to the penicillin structure. Penicillin derivative that inhibits bacterial cell-wall synthesis (peptidoglycan cross-linking) by inactivating transpeptidases on the inner surface of the bacterial cell membrane. Bactericidal only to growing Escherichia coli . Mode of resistance: Cleavage of β-lactam ring of ampicillin by β-lactamase. Antimicrobial spectrum: Gram-negative and Gram-positive bacteria. | | Pharmacokinetics | Oral absorption: 30–40%
Cmax 500 mg oral: 3.2 mg/L after c. 2 h
500 mg intramuscular: 5–15 mg/L after 1 h
500 mg intravenous infusion: 12–29 mg/L
Plasma half-life: 1–1.5 h
Volume of distribution: 0.38 L/kg
Plasma protein binding: 20%
Absorption and distribution
Ampicillin is highly stable to acid: in 2 h at pH 2 and 37°C, only 5% of activity is lost. Absorption is impaired when it is given with meals. It is distributed in the extracellular fluid. Adequate concentrations are obtained in serous effusions. Effective CSF levels are obtained only in the presence of inflammation, variable peak concentrations around 3 mg/L being found in the first 3 days of treatment in patients receiving 150 mg/kg per day. It accumulates and persists in the amniotic fluid. Metabolism and excretion
A small proportion is converted to penicilloic acid. About 34% of an oral dose and 60–80% of parenteral doses are recoverable from the urine, where concentrations around 250–1000 mg/L appear. Excretion is partly in the glomerular filtrate and partly by tubular secretion, which can be blocked by probenecid. Impairment of renal function reduces the rate of excretion, the plasma half-life rising to 8–9 h in anuric patients.
Although excretion is mainly renal, up to 50 times the corresponding serum level may be attained in the bile. There is a degree of enterohepatic recirculation and significant quantities appear in the feces. Bioavailability may be affected in severe liver disease. | | Clinical Use | Ampicillin, 6-[D-α-aminophenylacetamido]penicillanic acid,D-α-aminobenzylpenicillin (Penbritn, Polycillin, Omnipen,Amcill, Principen), meets another goal of the research onsemisynthetic penicillins—an antibacterial spectrum broaderthan that of penicillin G. This product is active against thesame Gram-positive organisms that are susceptible to otherpenicillins, and it is more active against some Gram-negativebacteria and enterococci than are other penicillins.Obviously, the α-amino group plays an important role in thebroader activity, but the mechanism for its action isunknown. It has been suggested that the amino group confersan ability to cross cell wall barriers that are impenetrableto other penicillins. D-(－)-Ampicillin, prepared from D-(－)-α-aminophenylacetic acid, is significantly more active thanL-(＋)-ampicillin.
Ampicillin is water soluble and stable in acid. Theprotonated α-amino group of ampicillin has a pKa of 7.3,46and thus it is protonated extensively in acidic media, whichexplains ampicillin’s stability to acid hydrolysis and instabilityto alkaline hydrolysis. It is administered orally andis absorbed from the intestinal tract to produce peak plasmaconcentrations in about 2 hours. Oral doses must be repeatedabout every 6 hours because it is excreted rapidly andunchanged through the kidneys. It is available as a white, crystalline, anhydrous powder that is sparingly soluble inwater or as the colorless or slightly buff-colored crystallinetrihydrate that is soluble in water. Either form may be usedfor oral administration, in capsules or as a suspension.Earlier claims of higher plasma levels for the anhydrousform than for the trihydrate following oral administrationhave been disputed. The white, crystalline sodium salt isvery soluble in water, and solutions for injections should beadministered within 1 hour after being made. | | Clinical Use | Isolates should be tested for susceptibility before use, especially
for serious infections. For oral therapy, amoxicillin is
preferable to ampicillin.
Urinary tract infections
Bacterial meningitis
Respiratory tract infections
Gastrointestinal infections, including typhoid fever and bacillary dysentery
Enterococcal endocarditis and septicemia (in combination with an
aminoglycoside)
Listeriosis (in combination with an aminoglycoside) | | Side effects | Ampicillin is generally free from severe toxicity and, apart
from gastrointestinal intolerance, the only significant side
effects seen have been rashes. In common with other semisynthetic
penicillins, it appears to be less likely than benzylpenicillin
to elicit true allergic reactions. However, it is more
likely to cause rashes, which are found in approximately 9% of
treated patients and which occur more frequently in patients
receiving large doses or in renal failure. Rashes occur in 95% of patients with infectious mononucleosis or other lymphoid
disorders. This unusual susceptibility disappears when the
disease resolves. In keeping with a toxic rather than an allergic
origin, skin tests to ampicillin and to mixed-allergen moieties
of benzylpenicillin are negative. Since the typical maculopapular
rash of ampicillin does not have an allergic origin, its
development does not indicate penicillin allergy and is not a
contraindication to the use of other penicillins.
Gastrointestinal side effects are relatively common (around
10%) in patients treated with oral ampicillin, and occur in
2–3% of patients given the drug parenterally, presumably as
a result of drug entering the gut through the bile. The very
young and the old are most likely to suffer. Diarrhea can be
sufficiently severe to require withdrawal of treatment and
pseudomembranous colitis may occur. Interference with the
bowel flora, which is presumably implicated in diarrhea, can
also affect enterohepatic recirculation of steroids, and the
derangement can be sufficient to impair the absorption of oral
contraceptives and affect the interpretation of estriol levels. | | Safety Profile | Mildly toxic by
ingestion. An experimental teratogen. Other
experimental reproductive effects. When
heated to decomposition it emits toxic
fumes of SO,xand NOx. | | Synthesis | Ampicillin, [2S-[2α,5α,6β(S)]]-3,3-dimethyl-7-oxo-6-(2-amino-2-phenylacetamido)-4-thia-azabicylco[3.2.0]-heptan-2-carboxylic acid (32.1.1.16), is synthesized in various ways using different methods of protection of amino group in the starting phenylglycine. One of the most widely used methods uses the benzyl chloroformate. Reacting this with phenylglycine initially forms benzyloxycarbonylphenylglycine (32.1.1.13). Treating this with ethyl chloroformate in the presence of triethylamine gives a mixed anhydride (32.1.1.14) with a protected amino group that easily reacts with 6-APA in the presence of sodium bicarbonate, to form the sodium salt of the N-benzyloxycarbonyl-protected ampicillin (32.1.1.15). Removing the protecting group by hyrogenolysis using a palladium on barium carbonate catalyst gives the desired ampicillin (32.1.1.16).
Another method of making ampicillin is analogous to the method described above, and it differs in the method of protecting the α-amino group in the initial phenylglycine. In order to do this, acetoacetic ester is reacted with the sodium salt of phenylglycine, which forms an intermediate—aminocrontonic ester (32.1.1.17). Subsequent transformation of this product to the mixed anhydride (32.1.1.18) followed by a reaction with 6-APA in the presence of sodium bicarbonate gives ampicillin (32.1.1.16) in the form of a sodium
salt.
A method of directly acylating 6-APA with phenylglycine chloride hydrochloride also has been proposed.
| | Potential Exposure | Used as an antibiotic. | | Drug interactions | Potentially hazardous interactions with other drugs
Ciclosporin: may increase ciclosporin levels.
Reduces excretion of methotrexate (increased risk of
toxicity). | | Metabolism | Ampicillin is metabolised to some extent to penicilloic
acid which is excreted in the urine.
Renal clearance of ampicillin occurs partly by glomerular
filtration and partly by tubular secretion; it is reduced by
probenecid. About 20-40% of an oral dose and 60-80%
of an IV dose may be excreted unchanged in the urine
in 6 hours. High concentrations are reached in bile; it
undergoes enterohepatic recycling and some is excreted in
the faeces. | | Shipping | UN3077 Environmentally hazardous substances,
solid, n.o.s., Hazard class: 9; Labels: 9-Miscellaneous hazardous
material, Technical Name Required. | | Incompatibilities | May be incompatible with oxidizers
(chlorates, nitrates, peroxides, permanganates, perchlorates,
chlorine, bromine, fluorine, etc.); contact may cause fires
or explosions. Keep away from alkaline materials, strong
bases, strong acids, oxoacids, epoxides. | | Waste Disposal | It is inappropriate and possibly
dangerous to the environment to dispose of expired or waste
pharmaceuticals by flushing them down the toilet
or discarding them to the trash. Household quantities of
expired or waste pharmaceuticals may be mixed with wet cat
litter or coffee grounds, double-bagged in plastic, discard in
trash. Larger quantities shall carefully take into consideration
applicable DEA, EPA, and FDA regulations. If possible return
the pharmaceutical to the manufacturer for proper disposal
being careful to properly label and securely package the material.
Alternatively, the waste pharmaceutical shall be labeled,
securely packaged and transported by a state licensed medical
waste contractor to dispose by burial in a licensed hazardous
or toxic waste landfill or incinerator. |
| | Ampicillin Preparation Products And Raw materials |
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