Tetracycline Chemical Properties

Melting point:

175-177 °C(lit.)

alpha 

D25 -257.9° (0.1N HCl); D25 -239° (methanol)

Boiling point:

554.44°C (rough estimate)

Density 

1.3809 (rough estimate)

refractive index 

1.6500 (estimate)

storage temp. 

2-8°C

solubility 

95% ethanol: soluble12.5mg/mL

form 

powder

pka

pKa (50% aq DMF): 8.3, 10.2(at 25℃)

color 

yellow to yellow orange

optical activity

[α]25/D -239° in methanol (Specific rotation ) &_& [α]25/D -257.9°, c = 0.1 M HCl mol (Specific rotation )

Water Solubility 

Limited solubility in water. Soluble in 1M HCl with heating.

Merck 

13,9271

BRN 

2230417

BCS Class

3

Stability:

Hygroscopic

InChIKey

OFVLGDICTFRJMM-WESIUVDSSA-N

CAS DataBase Reference

60-54-8(CAS DataBase Reference)

NIST Chemistry Reference

Tetracycline(60-54-8)

EPA Substance Registry System

Tetracycline (60-54-8)

Safety Information

Hazard Codes 

Xn,Xi

Risk Statements 

22-36/37/38

Safety Statements 

22-36-26

WGK Germany 

3

RTECS 

QI8750000

F 

3-8-10

HS Code 

29413000

Hazardous Substances Data

60-54-8(Hazardous Substances Data)

Toxicity

LD50 in rats, mice (mg/kg): 807, 808 orally (Goldenthal)

MSDS

• Language:English Provider:SigmaAldrich

Tetracycline Usage And Synthesis

Description

Tetracycline is an antibiotic that has been utilized in disease management situations in which SmR strains of E. amylovora or P. syringae already exist. However, tetracycline does not appear to be as effective as streptomycin in reducing blossom populations of E. amylovora (17). Additionally, strains of P. syringae with resistance to tetracycline have been isolated from pear orchards in Oregon and Washington (18), suggesting that resistance to this antibiotic will probably develop in orchards where it is applied.

Chemical Properties

Crystalline Solid

Chemical Properties

Tetracycline trihydrate is a white crystalline substance.

Originator

Tetracyn,Pfizer,US,1953

Uses

Tetracycline is a linear, tetracyclic, broad spectrum antibiotic first prepared chemically by dechlorination of chlortetracycline and subsequently isolated from several Streptomyces species. Tetracycline has broad spectrum antibacterial and antiprotozoan activity, and acts by binding to the 30S and 50S ribosomal subunits blocking protein synthesis. Tetracycline is a pigment and, like many pigments, is degraded by light, oxygen, trace metal ions and pH variations. The purity of tetracycline is often variable, with significant levels of degradation products.

Uses

antibactierial

Uses

antibacterial, antiamebic, antirickettsial

Uses

Tetracycline is a broad spectrum polyketide antibiotic. It is used clinically to treat bacterial infections such as Rocky Mountain spotted fever, typhus fever, tick fevers, Q fever, and Brill-Zinsser disease. It is used to treat upper respiratory infections and acne. It is used to study multidrug resistance as well as potential side effects such as acute pancreatitis.

Uses

Antibiotic substance produced by Streptomyces spp. Antiamebic; antibacterial; antirickettsial

Indications

Tetracycline is often the first antibiotic prescribed. It is the least expensive, has few side effects, and is well tolerated for longer periods of time. Tetracycline is effective in low doses because high concentrations are achieved within sebaceous follicles, especially when inflammation is present.

Definition

ChEBI: Tetracycline is a broad-spectrum polyketide antibiotic produced by the Streptomyces genus of actinobacteria. It has a role as an antimicrobial agent, an antibacterial drug, an antiprotozoal drug, a protein synthesis inhibitor and an Escherichia coli metabolite. It is a tertiary alpha-hydroxy ketone and a member of tetracyclines. It is a conjugate acid of a tetracycline(1-) and a tetracycline zwitterion.

Manufacturing Process

Tetracycline is usually prepared by the catalytic dechlorination of chlortetracycline as described in US Patents 2,699,054 and 3,005,023, or obtained directly by fermentation of Streptomyces aureofaciens or Streptomyces viridifaciens according to US Patents 2,712,517, 2,734,018, 2,886,595 and 3,019,173. The purification of tetracycline produced by either route is described in US Patent 3,301,899.
The production of tetracycline by catalytic dechlorination is described in US Patent 2,699,054 as follows: Pure chlortetracycline (4.8 grams) was suspended in 100 ml of methanol and sufficient anhydrous dioxane was added to completely dissolve the product. To the solution was added 0.5 gram of 5% palladium-on-charcoal catalyst. The mixture was placed in a conventional hydrogenation apparatus and subjected to a pressure of 50 psi of hydrogen while being agitated.
After the initial drop in pressure due to the absorption of gas by the catalyst and the solvent, there was a steady drop in pressure due to the hydrogenation of the antibiotic. After approximately 1 mol of hydrogen had been absorbed, no further reaction was observed. This occurred after about 2 hours. The catalyst was filtered and washed with boiling methanol and boiling dioxane. The solution gave a positive test for chloride ion when treated with silver nitrate solution. It also possessed a strongly acidic reaction demonstrating the release of the nonionic chlorine in the form of hydrogen chloride. A bioassay of the crude product in solution indicated a potency of approximately 580 μg/mg with oxytetracycline as the standard at a potency of 1,000 μg/mg. The solution was concentrated under vacuum at room temperature and the residual liquid was dried from the frozen state under vacuum. 3.1 grams of bright yellow amorphous tetracycline hydrochloride was obtained.
This product may be converted to tetracycline per se by redissolving it in water, carefully neutralizing it to pH 4.5 with dilute sodium hydroxide, and recovering the product by drying the solution.

brand name

Achrocidin;Achromycin v;Achromycin y;Apo-tetra;Cyclopar;Decycline;Double-t;Gt-250;Hosta-500;Medicycline;Muracine;Mysteclin-f;Nasopomada;Neo-tetrine;Nor-tet;Novotetra;Retet;Robitet;Sk-tetracycline;Sumycin;Tepcycline;Teropicycline;Tetrabotic;Tetracaps;Tetracyn;Tetralan;Tetram;Tetrex;Tetrpsol;Wintracin.

Therapeutic Function

Antibacterial

World Health Organization (WHO)

The first tetracycline antibiotic, chlortetracycline, was introduced in 1948 and subsequently several semisynthetic derivatives have been used as antibacterial, antiamoebic and antirickettsial agents. All tetracyclines accumulate in the developing bones and teeth of the foetus and young children which can result in retarded bone growth and dental staining. Preparations intended specifically for children have been withdrawn in some countries, whereas in others warnings are required on the label advising against administration of tetracyclines to young children and pregnant women. Non-paediatric dosage forms of tetracycline remain in the WHO Model List of Essential Drugs.

Antimicrobial activity

It is also active against V. cholerae, chlamydiae, rickettsiae and spirochetes.

General Description

Chemical studies on chlortetracycline revealed that controlledcatalytic hydrogenolysis selectively removed the 7-chloro atom and so produced tetracycline (Achromycin,Cyclopar, Panmycin, Tetracyn). This process was patentedby Conover in 1955. Later, tetracycline was obtainedfrom fermentations of Streptomyces spp., but the commercialsupply still chiefly depends on hydrogenolysis of chlortetracycline.
Tetracycline is 4-dimethyl amino-1,4,4a,5,5a,6,11,12aoctahydro-3,6,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphthacenecarboxamide. It is a bright yellow, crystallinesalt that is stable in air but darkens on exposure tostrong sunlight. Tetracycline is stable in acid solutions witha pH above 2. It is somewhat more stable in alkaline solutionsthan chlortetracycline, but like those of the other tetracyclines,such solutions rapidly lose potency. One gram ofthe base requires 2,500 mL of water and 50 mL of alcohol todissolve it. The hydrochloride salt is used most commonly inmedicine, though the free base is absorbed from the GI tractabout equally well. One gram of the hydrochloride salt dissolvesin about 10 mL of water and in 100 mL of alcohol.Tetracycline has become the most popular antibiotic of itsgroup, largely because its plasma concentration appears to behigher and more enduring than that of either oxytetracyclineor chlortetracycline. Also, it is found in higher concentrationin the spinal fluid than the other two compounds.

Pharmaceutical Applications

A fermentation product of Streptomyces aureofaciens, also produced from chlortetracycline. Available as the hydrochloride for oral and topical use.

Pharmacokinetics

Oral absorption： c.75%
Cmax 500 mg oral： 2–4 g/L
Plasma half-life： 8.5 h
Volume of distribution： c.1.3 L/kg
Plasma protein binding： c.50–60%
Absorption
When taken with food, absorption is reduced by approximately 50%. Steady-state plasma concentrations of 4–5 mg/L occur after oral doses of 500 mg every 6 h. Women appear to produce higher concentrations than men. Divalent and trivalent cations such as calcium and aluminum present in antacids and milk interfere with absorption through chelation, as does ferrous sulfate. H2-receptor antagonists, by raising gastric pH, also interfere with absorption through impaired drug dissolution. Despite the effect of gastric pH, oral absorption is not affected in elderly patients with achlorhydria.
Distribution
Tetracycline is widely distributed in the body tissues. In particular, it penetrates well into the prostate, uterus, ovary and bladder, and also appears to be preferentially taken up by the gastrointestinal tract. It is also detectable within reticuloendothelial cells of the liver, spleen and bone marrow.
Protein binding is reduced in states of malnutrition. It is also bound to bone, dentine and tooth enamel of unerupted teeth. Sputum concentrations of 0.4–2.6 mg/L have been detected after 250 mg oral dosage every 8 h. Maxillary sinus secretions and bronchial mucosal tissue have concentrations comparable to those of serum.
CSF penetration is poor, but increases with meningeal inflammation. It crosses the placenta readily to enter the fetal circulation, where it achieves 25–75% of the maternal plasma concentration. It is also present in breast milk.
Metabolism
A small amount is metabolized to 4-epitetracycline.
Excretion
Tetracycline is largely eliminated unchanged by glomerular filtration, with more than 50% excreted within 24 h after oral administration. This rises to approximately 70% following parenteral administration. Urinary concentrations of 300 mg/L occur within the first 2 h and persist for up to 12 h. Urinary excretion is enhanced in alkaline urine. Renal clearance is reduced in severe protein calorie malnutrition, possibly through reduced glomerular filtration. It accumulates in the presence of renal failure and is only slowly removed by hemodialysis and minimally by peritoneal dialysis. The bile is an important route of excretion, accounting for about one-third of the dose. Biliary concentrations may be 10–25 times those found in serum. Impaired hepatic function or biliary obstruction leads to an increase in blood levels.

Clinical Use

Along with doxycycline it is one of the most commonly used tetracyclines.

Side effects

The gastrointestinal side effects common to the group are the most frequent cause of intolerance. Metallic taste and glossitis are less burdensome than diarrhea. Antibiotic-associated enterocolitis caused by Clostridium difficile toxin and staphylococcal enterocolitis have been reported. Steatorrhea and acute pancreatitis has also been described. Irritation and ulceration of the esophagus has occurred with local impaction of the drug. C. albicans overgrowth is common and may result in symptomatic oral or vaginal candidiasis and occasionally candida diarrhea.
Hypersensitivity reactions include contact dermatitis, urticaria, facial edema and asthma. Anaphylaxis is rare. A lupus syndrome has been reported, but its cause is uncertain. Photosensitivity can be severe and cause vesiculation, desquamation and onycholysis. The Jarisch–Herxheimer reaction has been observed in the treatment of syphilis, louse-borne relapsing fever, leptospirosis, brucellosis and tularemia. Deposition in deciduous teeth and bone (where it may temporarily inhibit growth) is of continuing concern. Between 3% and 44% of administered tetracycline is incorporated in the inorganic phase of bone, which may become visibly discolored and fluoresce. Concentrations as high as 290 mg/g have been recorded in bone in those on long-term tetracycline treatment for acne.
Existing renal insufficiency may be aggravated and is probably related to the antianabolic effect of this class of drugs; interference with protein synthesis places an additional burden on the kidney from amino acid metabolism. Acute renal failure may occur and can be aggravated by drug-induced diarrhea. Dehydration and salt loss from diuretic therapy may aggravate nephrotoxicity. Methoxyflurane and tetracycline in combination may be synergistically nephrotoxic.
An uncommon but serious adverse reaction is acute fatty liver, which may be complicated by renal insufficiency and electrolyte abnormalities. This is most likely to occur with highdose intravenous administration, especially during pregnancy. Hematological toxicity is uncommon. Leukopenia, thrombocytopenia and hemolytic anemia have been reported.
Altered coagulation may also occur with high intravenous dosage. Phagocyte function may be impaired as a result of the increased excretion of vitamin C.
Neurological toxicity is uncommon but includes benign intracranial hypertension . A transient myopathy has complicated long-term oral use for the treatment of acne, while intravenous administration has caused increased muscle weakness in those with myasthenia gravis and has also potentiated curare-induced neuromuscular blockade.
Metabolic effects include: precipitation of lactic acidosis in diabetic patients receiving phenformin; a reduction in vitamins B12, B6 and pantothenic acid with long-term therapy; interference with laboratory tests of urinary catecholamines and urinary tests for glucose (Clinitest and Benedict’s); and elevation of serum lithium concentrations. In addition, warfarin is potentiated and failure of oral Contraception occurs.

Synthesis

Tetracycline, 4-dimethylamino-1,4,4a,5,5a,6,11,12a-octahydro-3,6,10,12,12apentahydroxy-6-methyl-1,11-dioxo-2-naphthacencarboxamide (32.3.3), is synthesized by reducing chlorotetracycline with hydrogen using a palladium on carbon catalyst. However, it can be synthesized microbiologically using the actinomycete Streptomyces viridifaciens, as well as a certain mutant S. aureofaciens.

Potential Exposure

Tetracycline is an antibiotic medicine used as capsules, tablets, or intravenous injections against certain infections in humans and animals.

Veterinary Drugs and Treatments

The tetracyclines are most useful in cats for the treatment of Chlamydial and Mycoplasma conjunctivitis as well as nonspecific or symptomatic therapy for undiagnosed (causative organism not determined) conjunctivitis in cats. While its use in dogs and horses is questionable, it may be useful in goats for Chlamydial/ Mycoplasma keratoconjunctivitis. At the time of publication, there are no commercially available ophthalmic dosage forms of tetracycline. There are, however, Veterinary-Labeled forms of oxytetracycline and Polymyxin B ophthalmic ointments (Terramycin?). It is again, important to note, that severe anaphylaxis, sometimes fatal, has been associated with topical Polymyxin and neomycin in cats and caution is recommended when using this product in cats.

Drug interactions

Potentially hazardous interactions with other drugs
Anticoagulants: possibly enhance anticoagulant effect of coumarins and phenindione.
Oestrogens: possibly reduce contraceptive effects of oestrogens (risk probably small).
Retinoids: possible increased risk of benign intracranial hypertension with retinoids - avoid concomitant use.

Metabolism

Tetracycline is excreted in the urine and in the faeces. Renal clearance is by glomerular filtration. Up to 60
% of an intravenous dose of tetracycline, and up to 55
% of an oral dose, is eliminated unchanged in the urine. The tetracyclines are excreted in the bile, where concentrations 5-25 times those in plasma can occur. There is some enterohepatic reabsorption and considerable quantities occur in the faeces after oral doses.

Shipping

UN3249 Medicine, solid, toxic, n.o.s., Hazard Class: 6.1; Labels: 6.1-Poisonous materials.

Purification Methods

Tetracycline crystallises from toluene or aqueous MeOH as the trihydrate. [Stephen et al. J Am Chem Soc 76 3568 1954, Beilstein 14 IV 2625.]

Toxicity evaluation

Tetracycline is a potent inhibitor of bacterial protein biosynthesis, with less activity on mammalian cells. It binds to the 30S and 50S bacterial ribosomal subunits, and it inhibits the binding of aminoacyl–tRNA and the termination factors RF1 and RF2 to the A site of bacterial ribosomes (21). Acute oral LD₅₀ for mice >7 g/kg; for rats >10 g/kg, acute intravenous 100～200 mg/kg. Tlm for black bass: 250 ppm (24 h).

Incompatibilities

Although no dangerous incompatibilities are reported, the potency of this medicine is reduced by heat, sunlight, and solutions with pH <2; and destroyed by caustic hydroxide solutions.

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.

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