Chemical Structure Of Oxytetracycline

aValues taken from Brown, J. R., and Ireland, D. S.: Adv. Pharmacol. Chemother. 15:161, 1978. ^Values taken from Colazzi, J. L., and Klink, P. R.: J. Pharm. Sci. 58:158, 1969.

aValues taken from Brown, J. R., and Ireland, D. S.: Adv. Pharmacol. Chemother. 15:161, 1978. ^Values taken from Colazzi, J. L., and Klink, P. R.: J. Pharm. Sci. 58:158, 1969.

for example, 7-dimethylamino, 7-chloro, and 6-methyl, have the opposite effect. Accordingly, the partition coefficient of chlortetracycline is substantially greater than that of tetracycline and slightly greater than that of demeclocycline. Interestingly, minocycline (5-demethyl-6-deoxy-7-dimethy-laminotetracycline) has the highest partition coefficient of the commonly used tetracyclines.

The poorer oral absorption of the more water-soluble compounds tetracycline and oxytetracycline can be attributed to several factors. In addition to their comparative difficulty in penetrating lipid membranes, the polar tetracyclines probably experience more complexation with metal ions in the gut and undergo some acid-catalyzed destruction in the stomach. Poorer oral absorption coupled with biliary excretion of some tetracyclines is also thought to cause a higher incidence of superinfections from resistant microbial strains. The more polar tetracyclines, however, are excreted in higher concentrations in the urine (e.g., 60% for tetracycline and 70% for oxytetra-cycline) than the more lipid-soluble compounds (e.g., 33% for doxycycline and only 11% for minocycline). Significant passive renal tubular reabsorption coupled with higher fractions of protein binding contributes to the lower renal clearance and longer durations of action of doxycycline and minocycline compared with those of the other tetracyclines, especially tetracycline and oxytetracycline. Minocycline also experiences significant N-dealkylation catalyzed by cy-tochrome P450 oxygenases in the liver, which contributes to its comparatively low renal clearance. Although all tetracyclines are distributed widely into tissues, the more polar ones have larger volumes of distribution than the nonpolar compounds. The more lipid-soluble tetracyclines, however, distribute better to poorly vascularized tissue. It is also claimed that the distribution of doxycycline and minocycline into bone is less than that of other tetracyclines.175



Chemical studies on chlortetracycline revealed that controlled catalytic hydrogenolysis selectively removed the 7-chloro atom and so produced tetracycline (Achromycin, Cyclopar, Panmycin, Tetracyn). This process was patented by Conover176 in 1955. Later, tetracycline was obtained from fermentations of Streptomyces spp., but the commercial supply still chiefly depends on hydrogenolysis of chlor-tetracycline.

Tetracycline is 4-dimethyl amino-1,4,4a,5,5a,6,11,12a-octahydro-3,6,10,12,12a-pentahydroxy-6-methyl-1,11-

dioxo-2-naphthacenecarboxamide. It is a bright yellow, crystalline salt that is stable in air but darkens on exposure to strong sunlight. Tetracycline is stable in acid solutions with a pH above 2. It is somewhat more stable in alkaline solutions than chlortetracycline, but like those of the other tetracyclines, such solutions rapidly lose potency. One gram of the base requires 2,500 mL of water and 50 mL of alcohol to dissolve it. The hydrochloride salt is used most commonly in medicine, though the free base is absorbed from the GI tract about equally well. One gram of the hydrochloride salt dissolves in about 10 mL of water and in 100 mL of alcohol. Tetracycline has become the most popular antibiotic of its group, largely because its plasma concentration appears to be higher and more enduring than that of either oxytetracycline or chlortetracycline. Also, it is found in higher concentration in the spinal fluid than the other two compounds.

Several combinations of tetracycline with agents that increase the rate and the height of plasma concentrations are on the market. One such adjuvant is magnesium chloride hexahydrate (Panmycin). Also, an insoluble tetracycline phosphate complex (Tetrex) is made by mixing a solution of tetracycline, usually as the hydrochloride, with a solution of sodium metaphosphate. There are various claims concerning the efficacy of these adjuvants. The mechanisms of their actions are not clear, but reportedly177,178 these agents enhance plasma concentrations over those obtained when tetracycline hydrochloride alone is administered orally. Remmers et al.179,180 reported on the effects that selected aluminum-calcium gluconates complexed with some tetra-cyclines have on plasma concentrations when administered orally, intramuscularly, or intravenously. Such complexes enhanced plasma levels in dogs when injected but not when given orally. They also observed enhanced plasma levels in experimental animals when complexes of tetracyclines with aluminum metaphosphate, aluminum pyrophosphate, or aluminum-calcium phosphinicodilactates were administered orally. As noted previously, the tetracyclines can form stable chelate complexes with metal ions such as calcium and magnesium, which retard absorption from the GI tract. The complexity of the systems involved has not permitted unequivocal substantiation of the idea that these adjuvants compete with the tetracyclines for substances in the alimentary tract that would otherwise be free to complex with these antibiotics and thereby retard their absorption. Certainly, there is no evidence that the metal ions per se act as buffers, an idea alluded to sometimes in the literature.

Tetracycline hydrochloride is also available in ointments for topical and ophthalmic administration. A topical solution is used for the management of acne vulgaris.


Rolitetracycline, N-(pyrrolidinomethyl)tetracycline (Syntetrin), was introduced for use by intramuscular or intravenous injection. This derivative is made by condensing tetracycline with pyrrolidine and formaldehyde in the presence of tert-butyl alcohol. It is very soluble in water (1 g dissolves in about 1 mL) and provides a means of injecting the antibiotic in a small volume of solution. It has been recommended for cases when the oral dosage forms are not suitable, but it is no longer widely used.

Oxytetracycline Molecule

Chlortetracycline Hydrochloride

Chlortetracycline (Aureomycin hydrochloride) was isolated by Duggar181 in 1948 from S. aureofaciens. This compound, which was produced in an extensive search for new antibiotics, was the first of the group of highly successful tetracyclines. It soon became established as a valuable antibiotic with broad-spectrum activities.

Components Pharmaceutical Chemistry

It is used in medicine chiefly as the acid salt of the compound whose systematic chemical designation is 7-chloro-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,6,10, 12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naph-thacenecarboxamide. The hydrochloride salt is a crystalline powder with a bright yellow color, which suggested its brand name, Aureomycin. It is stable in air but slightly photosensitive and should be protected from light. It is odorless and bitter. One gram of the hydrochloride salt will dissolve in about 75 mL of water, producing a pH of about 3. It is only slightly soluble in alcohol and practically insoluble in other organic solvents.

Oral and parenteral forms of chlortetracycline are no longer used because of the poor bioavailability and inferior pharmacokinetic properties of the drug. It is still marketed in ointment forms for topical and ophthalmic use.

Oxytetracycline Hydrochloride

Early in 1950, Finlay et al.182 reported the isolation of oxy-tetracycline (Terramycin) from S. rimosus. This compound was soon identified as a chemical analog of chlortetracy-

cline that showed similar antibiotic properties. The structure of oxytetracycline was elucidated by Hochstein et al.183 and this work provided the basis for the confirmation of the structure of the other tetracyclines.

Oxytetracycline hydrochloride is a pale yellow, bitter, crystalline compound. The amphoteric base is only slightly soluble in water and slightly soluble in alcohol. It is odorless and stable in air but darkens on exposure to strong sunlight. The hydrochloride salt is a stable yellow powder that is more bitter than the free base. It is much more soluble in water, 1 g dissolving in 2 mL, and more soluble in alcohol than the free base. Both compounds are inactivated rapidly by alkali hydroxides and by acid solutions below pH 2. Both forms of oxytetracycline are absorbed rapidly and equally well from the digestive tract, so the only real advantage the free base offers over the hydrochloride salt is that it is less bitter. Oxytetracycline hydrochloride is also used for par-enteral administration (intravenously and intramuscularly).

Methacycline Hydrochloride

The synthesis of methacycline, 6-deoxy-6-demethyl-6-meth-ylene-5-oxytetracycline hydrochloride (Rondomycin), reported by Blackwood et al.184 in 1961, was accomplished by chemical modification of oxytetracycline. It has an antibiotic spectrum like that of the other tetracyclines but greater potency; about 600 mg of methacycline is equivalent to 1 g of tetracycline. Its particular value lies in its longer serum halflife; doses of 300 mg produce continuous serum antibacterial activity for 12 hours. Its toxic manifestations and contraindications are similar to those of the other tetracyclines.

The greater stability of methacycline, both in vivo and in vitro, results from modification at C-6. Removal of the 6-hydroxy group markedly increases the stability of ring C to both acids and bases, preventing the formation of isotetracy-clines by bases. Anhydrotetracyclines still can form, however, by acid-catalyzed isomerization under strongly acidic conditions. Methacycline hydrochloride is a yellow to dark yellow, crystalline powder that is slightly soluble in water and insoluble in nonpolar solvents. It should be stored in tight, light-resistant containers in a cool place.


Demeclocycline, 7-chloro-6-demethyltetracycline (Declo-mycin), was isolated in 1957 by McCormick et al.171 from a mutant strain of S. aureofaciens. Chemically, it is 7-chloro-4-(dimethylamino)1,4,4a,5,5a,6, 11, 12a-octahydro-3, 6, 10, 12, 12a-pentahydroxy 1, 11-dioxo2-naphthacenecarboxamide. Thus, it differs from chlortetracycline only in the absence of the methyl group on C-6.

Demeclocycline is a yellow, crystalline powder that is odorless and bitter. It is sparingly soluble in water. A 1% solution has a pH of about 4.8. It has an antibiotic spectrum like that of other tetracyclines, but it is slightly more active than the others against most of the microorganisms for which they are used. This, together with its slower rate of elimination through the kidneys, makes demeclocycline as effective as the other tetracyclines, at about three fifths of the dose. Like the other tetracyclines, it may cause infrequent photosensitivity reactions that produce erythema after exposure to sunlight. Demeclocycline may produce this reaction somewhat more frequently than the other tetracy-clines. The incidence of discoloration and mottling of the teeth in youths from demeclocycline appears to be as low as that from other tetracyclines.

Meclocycline Sulfosalicylate

Meclocycline, 7-chloro-6-deoxy-6-demethyl-6-methylene-5-oxy tetracycline sulfosalicylate (Meclan), is a semisynthetic derivative prepared from oxy tetracycline.184 Although meclocycline has been used in Europe for many years, it became available only relatively recently in the United States for a single therapeutic indication, the treatment of acne. It is available as the sulfosalicylate salt in a 1% cream.

Meclocycline sulfosalicylate is a bright yellow, crystalline powder that is slightly soluble in water and insoluble in organic solvents. It is light sensitive and should be stored in light-resistant containers.


A more recent addition to the tetracycline group of antibiotics available for antibacterial therapy is doxycycline, a-6-deoxy-5-oxytetracycline (Vibramycin), first reported by Stephens et al.185 in 1958. It was obtained first in small yields by a chemical transformation of oxytetracycline, but it is now produced by catalytic hydrogenation of methacy-cline or by reduction of a benzyl mercaptan derivative of methacycline with Raney nickel. The latter process produces a nearly pure form of the 6a-methyl epimer. The 6a-methyl epimer is more than 3 times as active as its jS-epimer.169 Apparently, the difference in orientation of the methyl groups, which slightly affects the shapes of the molecules, causes a substantial difference in biological effect. Also, absence of the 6-hydroxyl group produces a compound that is very stable in acids and bases and that has a long biological half-life. In addition, it is absorbed very well from the GI tract, thus allowing a smaller dose to be administered. High tissue levels are obtained with it, and unlike other tetracyclines, doxycycline apparently does not accumulate in patients with impaired renal function. Therefore, it is preferred for uremic patients with infections outside the urinary tract. Its low renal clearance may limit its effectiveness, however, in urinary tract infections.

Doxycycline is available as a hydrate salt, a hydrochloride salt solvated as the hemiethanolate hemihydrate, and a monohydrate. The hydrate form is sparingly soluble in water and is used in a capsule; the monohydrate is water insoluble and is used for aqueous suspensions, which are stable for up to 2 weeks when kept in a cool place.

Minocycline Hydrochloride

Minocycline, 7-dimethylamino-6-demethyl-6-deoxytetracy-cline (Minocin, Vectrin), the most potent tetracycline currently used in therapy, is obtained by reductive methylation of 7-nitro-6-demethyl-6-deoxytetracycline.172 It was released for use in the United States in 1971. Because minocycline, like doxycycline, lacks the 6-hydroxyl group, it is stable in acids and does not dehydrate or rearrange to anhydro or lactone forms. Minocycline is well absorbed orally to give high plasma and tissue levels. It has a very long serum half-life, resulting from slow urinary excretion and moderate protein binding. Doxycycline and minocycline, along with oxytetracycline, show the least in vitro calcium binding of the clinically available tetracyclines. The improved distribution properties of the 6-deoxytetracyclines have been attributed to greater lipid solubility.

Perhaps the most outstanding property of minocycline is its activity toward Gram-positive bacteria, especially staphylococci and streptococci. In fact, minocycline has been effective against staphylococcal strains that are resistant to methicillin and all other tetracyclines, including doxycycline.186 Although it is doubtful that minocycline will replace bactericidal agents for the treatment of life-threatening staphylococcal infections, it may become a useful alternative for the treatment of less serious tissue infections. Minocycline has been recommended for the treatment of chronic bronchitis and other upper respiratory tract infections. Despite its relatively low renal clearance, partially compensated for by high serum and tissue levels, it has been recommended for the treatment of urinary tract infections. It has been effective in the eradication of N. meningitidis in asymptomatic carriers.

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  • Hope
    Why should oxytetracycline be stored under dry condition medicinal chemistry?
    11 months ago

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