Tetracyclines solubility

In general, the tetracyclines are yellow crystalline compounds that have amphoteric properties (Fig. 2) (15). They are soluble in both aqueous acid and aqueous base. The acid salts tend to be soluble in organic solvents such as 1-butanol, dioxane, and 2-ethoxyethanol In fact, 1-butanol is used to extract the salts from aqueous solution. 

One hour after addition of the tetracycline, the clear reaction solution was poured into 1,500 ml of chloroform. A yellow product separated and was collected on a coarse sintered glass filter and air dried. The tetracycline-metaphosphoric acid complex weighed about 10 grams, contained 7.34% of phosphorus and had a bioassay of 634 gammas per milligram. Solubility in water is 750 mg/ml. 

There are problems as well in the absorption of certain drugs in the presence of specific food components. L-Dopa absorption may be inhibited in the presence of certain amino acids formed from the digestion of proteins [43], The absorption of tetracycline is reduced by calcium salts present in dairy foods and by several other cations, including magnesium and aluminum [115-117], which are often present in antacid preparations. In addition, iron and zinc have been shown to reduce tetracycline absorption [118], Figure 17 illustrates several of these interactions. These cations react with tetracycline to form a water-in-soluble and nonabsorbable complex. Obviously, these offending materials should not be co-administered with tetracycline antibiotics. 

As indicated, the ionized form of a drug will be more soluble than the nonionized form in the aqueous fluids of the GIT. The classic studies on the beneficial effects of changing nonionized drugs into salt forms were reported by Nelson for tetracycline [25], and Nelson et al. for tolbutamide [26]. Table 2 combines portions of the data from each study. Urinary excretion of the drug or its metabolite was taken as the in vivo measure of the relative absorption rate for the salt and the nonionized... 

Reduced absorption due to complex formation or other interactions between drugs and intestinal components leading to poor absorption has been described in a few cases. One example is the precipitation of cationic drugs as very poorly-soluble salts with bile acids, which has been reported for several compounds [62], Another well-known example is the complex formation between tetracycline together with calcium due to chelation after administration of the drug together... 

The tetracyclines are well known for their ability to form complexes with polyvalent cations. This property changes their solubility characteristics in the mobile solvents and often results in troublesome streaking. To overcome this difficulty, Selzer and Wright used paper dipped in Mcllvaine s buffer (pH 3.5) which contains citrate ions capable of binding the metallic ions. The chromatograms were developed with a mixture of nitromethane, chloroform, and pyridine (20 10 3) on paper still damp from the treatment with the buffer solution. 

Example 2 Chloramphenicol and Tetracycline—Sparingly soluble broad-spectrum antibiotics like chloramphenicol and tetracycline found to damage the gastrointestinal epithelium besides changing the normal micro-flora in the Gl-tract that are required for normal good health. 

Doxycycline (6-deoxy-5-hydroxytetracycline, Vibramycin, III) is, chemically, the most stable tetracycline in current use but its outstanding property is its high lipid solubility these features combine to make it the most reliably and completely absorbed tetracycline derivative, with the longest half-life. 

Drugs that may interact with laxatives include mineral oil, milk or antacids, H2 antagonists, proton pump inhibitors, lipid soluble vitamins (A, D, E, and K), and tetracycline. 

We have already met several of the important concepts in this topic, so now it is time to round them up and bring out the major principles. In the first place drug molecules clearly might interact with food molecules in the lumen of the gut. Perhaps the best-known example of this is the interaction between the tetracyclines and dietary calcium and iron. The binding, which occurs between them, produces a chelate, which is not particularly lipid-soluble, and therefore the overall absorption of tetracycline may be reduced to the point where plasma levels do not achieve effective antibiotic concentrations. The commonest dietary constituent to produce this binding is milk with its high calcium content. Tetracycline ingestion should be separated from food as far as possible. 

The tetracyclines are distributed throughout body tissues and fluids in concentrations that reflect the lipid solubility of each individual agent. Minocycline and doxycycline are the most lipid soluble, while oxytetracy-chne is the least hpid soluble. The tetracyclines penetrate (but somewhat unpredictably) the uninflamed meninges and cross the placental barrier. Peak serum levels are reached approximately 2 hours after oral administration cerebrospinal fluid (CSF) levels are only one-fourth those of plasma. 

By definition, the fraction that enters the circulatory system is eliminated by extrarenal mechanisms (usually metabolism by the liver and other tissues) and is derived by the difference from renal excretion that is, 1 — Fg. The excretory organs are able to eliminate polar compounds such as tetracycline and tylosin more efficiently than compounds that are highly soluble in lipids (i.e., lipophilic) such as metronidazole, erythromycin, clindamycin, and trimethoporin. Thus, the highly lipophilic compounds will not be eliminated until they are metabolized to more polar intermediates. 

Iron absorption occurs predominantly in the duodenum and upper jejunum. The physical state of iron entering the duodenum greatly influences its absorption. At physiological pH, ferrous iron is rapidly oxidized to the insoluble ferric form. Gastric acid lowers the pH in the proximal duodenum, enhancing the solubility and uptake of ferric iron. When gastric acid production is impaired, iron absorption is reduced substantially. Ascorbic acid enhances iron absorption. Ascorbic acid mobilizes iron from iron-binding proteins in vivo, which in turn could catalyze lipid peroxidation. Iron absorption is inhibited by antacids, phytates, phosphates and tetracyclines. 

Free tetracyclines are crystalline amphoteric substances of low solubility. They are available as hydrochlorides, which are more soluble. Such solutions are acid and, with the exception of chlortetracycline, fairly stable. Tetracyclines chelate divalent metal ions, which can interfere with their absorption and activity. A newly approved tetracycline analog, tigecycline, is a glycylcycline and a semisynthetic derivative of minocycline. 

CZE is the most widely used mode due to its simplicity of operation and its versatility. Selectivity can be most readily altered through changes in running buffer pH or by use of buffer additives such as surfactants or chiral selectors. The major drawback with CZE is that it deals with aqueous electrolytic systems, whereas components can only be separated if they are charged and soluble in water. CZE separation of various antibacterials including penicillins, tetracyclines, and macrolides has been reported (86). Determination of cefixime, an oral cephalosporin antibiotic, and its metabolites in human urine has been also successfully carried out with CZE (87). 

Tetracycline antibiotics are closely related derivatives of the polycyclic naphtha-cenecarboxamide. They are amphoteric compounds with characteristic dissociation constants corresponding to the acidic hydroxyl group at position 3 (pK about 3.3), die dimethylamino group at position 4 (pK, about 7.5), and the hydroxyl group at position 12 (pK about 9.4). In aqueous solutions of pH 4-7, tetracyclines exist as dipolar ions, but as the pH increases to 8-9 marked dissociation of the dimethylamine cation occurs. They are soluble in acids, bases, and alcohols but are quite insoluble in organic solvents such as chloroform. Their ultraviolet spectra show strong absorption at around 270 and 360 nm in neutral and acidic solutions. Tetracyclines are readily transformed into fluorescent products in the presence of metal ions or under alkaline conditions. 

In general, the tetracyclines are yellow crystalline compounds that have amphoteric properties (Fig. 2). They ate soluble in both aqueous acid and aqueous base. 

Tetracyclines (TCs) are chemically characterized by a partially conjugated octahydronaphtacene four-ring skeleton with a carboxyamide functional group. They are amphoteric compounds soluble in polar and moderately polar solvents, and they show the ability to form strong complexes... 

This increase in water solubility on conversion of an amine to its protonated salt has enormous practical consequences in drug delivery. Many important amine-containing drugs, such as morphine (a painkiller) and tetracycline (an antibiotic), are insoluble in aqueous body fluids and are thus difficult to deliver to the appropriate site within the body. Converting these drugs to their ammonium salts, however, increases their solubility to the point where delivery through the bloodstream becomes possible. 

MIP membranes were prepared for the recognition of water soluble L-glutamine [218], tetracycline [221], uric acid [223], theophylline [216, 222] and naringin... 

Miyazaki, S., M. Nakano, and T. Arita. 1975. A comparison of solubility characteristics of free bases and hydrochloride salts of tetracycline antibiotics in hydrochloric acid soluticSteem. Pharm. Bull. 23 1197-1204. 

Apart from being a diffusional barrier, mucin can also interact with drugs to decrease their bioavailability, as has been shown with tetracycline [106], phenylbutazone, and warfarin [107]. On the other hand, studies in rats showed that binding of some water-soluble drugs to intestinal mucus was essential for their absorption and that damage to the mucus significantly reduced absorption [108], The acidic mucus is essential for lipid absorption and could be important for the diffusion of lipophilic drugs (see below). 

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