Tetracyclines formulations

Acquired Lignac-De Toni-Fanconi syndrome, with polyuria, polydipsia, glycosuria, aminoaciduria, hyper-phosphaturia, and hypercalciuria, was described in a number of patients treated with outdated tetracycline formulations. The degeneration products responsible for the toxic action are probably epitetracycline, anhydro-4-epitetracycline, and anhydrotetracycline (117), as similar renal damage was produced in rats with anhydro-4-epite-tracycline (118). 

Several electrodes are used for the direct determination of pharmaceuticals. For example, an electrode is prepared using a polyvinyl chloride (PVC) membrane and bis(2-ethylhexyl)sebacate has been applied to tetracyclines in pharmaceutical formulations. The system has also been used to obtain the dissolution profile of some tetracycline formulations. A membrane for the determination of dopamine was synthesized using a CuS04-poly(ethylene-co-vinyl acetate) mixture in tetrahydrofuran, and the resulting solution was dropped into a tubular graphite-epoxy electrode. The drug was oxidized by Cu(II) immobilized on the membrane. 

Antacids also have clinically significant drug interactions with tetracycline, ferrous sulfate, isoniazid, quinidine, sul-fonylureas, and quinolone antibiotics. Antacid-drug interactions are influenced by antacid composition, dose, dosage schedule, and formulation. 

UV detection, diode-array detector (DAD) and fluorescence have been the detection techniques used, coupled to HPLC for the analysis of OTC. UV detection is set at 355 nm [49-51], 350 nm [40], or at 353 nm [52], Using the diode array detector [49] offers advantages that the target peak can be identified by its retention time and absorption spectrum. Compared to UV detection, fluorescence detection is generally more specific and is less interfered by other compounds in the sample matrix [51]. A HPLC method with electrochemical detection has also been suggested recently. Zhao et al. [53] described HPLC with a coulometric electrode array system for the analysis of OTC, TC, CTC, DC, and methacycline (MC) in ovine milk. An amper-ometric detection coupled with HPLC was developed by Kazemifard and Moore [54] for the determination of tetracyclines in pharmaceutical formulations. 

The current uses of tetracyclines in the poultry industry are almost entirely at the higher levels for the control of bacterial disease. This includes both feed additive and drinking water formulations. 

The first three of these agents to be discovered, tetracycline (1)chlortetracycline (2), and oxytetracycline (3), are subject to two major modes of degradation under conditions occurring during their isolation, purification, formulation, and administration. These are dehydration and epimerization. Each of these reactions leads to inactivation of the antibiotic thus, considerable effort has been expended in attempts to prevent or minimize these reactions. 

Buffering agents that are compounded with didanosine to counteract its degradation by gastric acid may interfere with the absorption of other drugs that require acidity (e.g., indinavir, delavirdine, ketoconazole, fluoroquinolones, tetracyclines, dapsone). An enteric-coated formulation Videx EC) that dissolves in the basic pH of the small intestine is not susceptible to these interactions. Ganciclovir and valganciclovir can increase blood levels of didanosine. The use of zalcitabine with didanosine is not recommended because that combination carries an additive risk of peripheral neuropathy. The combination of didanosine with stavudine increases the risk of pancreatitis, hepatotoxicity, and peripheral neuropa-... 

Bromine has also been suggested for an indirect detection process for the determination of tetracyclines in pharmaceutical formulations [155]. A bromine/hydrogen peroxide-based electrogenerated chemiluminescence reaction is shown to be enhanced by tetracycline derivatives and detection levels down to the pg dm level are reported on the basis of this enhancement effect. 

Two bismuth compounds are available bismuth subsalicylate, a nonprescription formulation containing bismuth and salicylate, and bismuth subcitrate potassium. In the USA, bismuth subcitrate is available only as a combination prescription product that also contains metronidazole and tetracycline for the treatment of H pylori. Bismuth subsalicylate undergoes rapid dissociation within the stomach, allowing absorption of salicylate. Over 99% of the bismuth appears in the stool. Although minimal (< 1%), bismuth is absorbed it is stored in many tissues and has slow renal excretion. Salicylate (like aspirin) is readily absorbed and excreted in the urine. 

Tetracyclines mainly differ in their absorption after oral administration and their elimination. Absorption after oral administration is approximately 30% for chiortetracycline 60-70% for tetracycline, oxytetracycline, demeclocycline, and methacycline and 95-100% for doxycycline and minocycline. A portion of an orally administered dose of tetracycline remains in the gut lumen, modifies intestinal flora, and is excreted in the feces. Absorption occurs mainly in the upper small intestine and is impaired by food (except doxycycline and minocycline) by divalent cations (Ca2+, Mg2+, Fe2+) or Al3+ by dairy products and antacids, which contain multivalent cations and by alkaline pH. Specially buffered tetracycline solutions are formulated for intravenous administration. 

Impurities of 4-epitetracycline, anhydro-tetracycline and 4-epianhydrotetracycline have been limited in tetracycline hydrochloride by european pharmacopoeia (15), british pharmacopoeia (80) to 4% (ETC) and 0.5% each for ATC and EATC. USP XX (81) allows the content of EATC up to 2%. The permissable content of EATC in various TC formulations such as capsules and injections has been even increased to 3.0% by USP XX. 

The microorganism used for tetracycline are Staphylococcus aureus NCTC 6751 and Staphylococcus aureus ATCC 6538 P. The buffer solution with a pH of 4.5 and the incubation temperature between 35 - 37 °C are used (90, 91). Additives in TC formulations can influence the results obtained by microbiological methods (92). Comparison of the microbiological results has been made with those obtained through other methods (93, 94). Effects of certain tablet-formula-tion-additives such as starch, bentonite, veegum F, talc, liquid paraffin, stearic acid etc. on the antimicrobial activity of TC-HC1 has been investigated (95). 

Paper partition chromatographic methods have been widely applied to the analysis of tetracyclines (128, 129). Pharmaceutical aqueous suspensions for oral use are acidified with HC1 and diluted with methanol. Crystalline formulations are dissolved only in methanol. A paper chromatographic method for TC determination in pharmaceutical preparations is based on the complexation of the antibiotic with a mixture of urea and disodium edetate on paper at pH 7.4. Urea helped in the separation of degradation products and led to the formation of well defined spots (130). Samples from fermentations must be acidified with oxalic acid to liberate TC from the mycelium. TC in filtrates may be precipitated in saturated solution of sodium tetraphenyl borate, precipitate dissolved in ethyl or butyl acetate and applied for paper chromatography. Various solvent systems and hRp values for paper chromatography are given in Table 4. 

Hydromorphone Hydrochloride Formulations containing hydromorphone with either minocycline hydrochloride or tetracycline hydrochloride were found incompatible and manifest as a color change from pale yellow to light green. Concentration-dependent incompatibilities are reported in formulations containing hydromorphone hydrochloride with dexamethasone sodium or phosphate,59 and fluorouracil.60 Visual incompatibility, such as haziness or precipitation, developed 4 hours after mixing thiopentone sodium and hydromorphone hydrochloride.61 Dependence, withdrawal, and interactions are similar to those of opioid analgesics. 

Diluents, although commonly presumed inert, do have the ability to influence the stability or bioavailability of the dosage form. For example, dibasic calcium phosphate (both anhydrous and dihydrate forms) is the most common inorganic salt used as a filler-binder for direct compression. It is particularly useful in vitamin products as a source of both calcium and phosphorous. Milled material is typically used in wet-granulated or roller-compacted formulations. The coarse-grade material is typically used in direct compression formulations. It is insoluble in water, but its surface is alkaline and it is therefore incompatible with drugs sensitive to alkaline pFI. Additionally, it may interfere with the absorption of tetracyclines [7]. 

Because there is such a wide selection available, rational choice of the necessary excipients and their concentration is required. Consideration must also be given to cost, reliability, availability, and international acceptability. Although generally considered inert, formulation incompatibility of excipients is also necessary. Lactose, for example, can react with primary and secondary amines via its aldehyde group by Maillaird condensation reaction [6], and calcium carbonate is incompatible with acids due to acid-base chemical reaction and with tetracyclines due to complexation. Additionally, excipients can contribute to the instability of the active substance through moisture distribution. 

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