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Category Antibacterial; antiprotozoal.

      Tetracycline Hydrochloride contains not less than 900 μg of C₂₂H₂₄N₂O₈.HCl per mg.

Description Yellow, crystalline powder; odourless; moderately hygroscopic.

Solubility Soluble in water and in solutions of alkali hydroxides and carbonates; slightly soluble in ethanol; practically insoluble in chloroform and in ether.

Stability It is moderately hygroscopic. In solutions, it is destroyed when pH is less than 2 or more than 7.

Contra-indication It is contra-indicated in patients with history of hypersensitivity reactions to any member of tetracyclines, and in those with pre-existing renal dysfunction.

Warning

      1. It should not be used in children under 8 years of age, in pregnant women or in nursing mothers.

      2. It should be avoided in patients with systemic lupus erythematosus, impaired liver function and myasthenia gravis.

      3. The degradation products of tetracyclines (epianhydrotetracyclines and anhydrotetracyclines) cause “Fanconi syndrome” with nausea, vomiting, proteinuria, glycosuria and amino-aciduria, commencing within 2 or 3 days of treatment.

      4. It may cause discolouration of infants’ or children’s teeth, photosensitivity, nephrogenic diabetes insipidus (with demeclocycline), pigmentation of skin and mucous membranes (with minocycline), benign intracranial hypertension, hepatotoxicity, and pancreatitis.

      5. Concomitant therapy with penicillins; antacids containing aluminium, calcium, magnesium, or other divalent or trivalent cations; calcium or iron supplements; cholestyramine; colestipol; choline; estrogencontaining oral contraceptives; magnesium salicylate; and magnesium-containing laxatives should be avoided.

      6. High doses may cause nausea, vomiting, diarrhea, dry mouth, glossitis, stomatitis, and dysphagia.

Precaution

      1. Prolonged therapy may result in bacterial or fungal overgrowth of non-susceptible organisms some of which may be fatal (e.g., fulminating enteritis due to resistant staphylococci).

      2. Prolonged therapy requires periodic monitoring of organ system functions, including renal, hepatic and hematopoietic.

      3. Group A beta-hemolytic streptococcal infections should be treated for at least 10 days to help prevent the development of acute rheumatic fever or acute glomerulonephritis.

Additional information

      1. It should be taken on an empty stomach, or with food if irritation to stomach occurs, but avoid concurrent ingestion of milk or other dairy products.

      2. Darkened or discoloured tongue may be alarming to patients although medically insignificant.

Packaging and storage Tetracycline Hydrochloride shall be kept in tightly closed containers, protected from light.

Labelling The label on the container states (1) storage condition; (2) parenteral or non-parenteral grade.

Identification

      A. The infrared absorption spectrum is concordant with the spectrum obtained from Tetracycline Hydrochloride RS (Appendix 2.1) or with the reference spectrum of Tetracycline Hydrochloride.

      B. The retention time of the major peak in the chromatogram of the Assay preparation corresponds to that in the chromatogram of the Standard preparation, as obtained in the Assay.

      C. To 0.5 mg add 2 ml of sulfuric acid: a purplish red colour is produced. Add 1 ml of water: the colour becomes yellow.

      D. It yields the reactions characteristic of chlorides (Appendix 5.1).

Crystallinity It is crystalline (Method I, Appendix 4.14).

pH 1.8 to 2.8, in a 1.0 per cent w/v solution (Appendix 4.11).

Specific rotation –240º to –255º, calculated on the dried basis, determined in a 0.5 per cent w/v solution in 0.1 M hydrochloric acid (Appendix 4.8).

Loss on drying Not more than 2.0 per cent w/w after drying at 60º at a pressure not exceeding 0.7 kPa (about 5 Torr) for 3 hours (Appendix 4.15).

Heavy metals Not more than 50 ppm (Method II, Appendix 5.2). Use 500 mg; for the Standard Preparation, use 2.5 ml of lead standard solution (10 ppm Pb).

4-Epianhydrotetracycline Not more than 2.0 per cent w/w. Complies with the test as described under Assay, using Diluting solvent, Assay preparation, Chromatographic system and Procedure.

      Standard solution Dissolve an accurately weigh quantity of 4-Epianhydrotetracycline RS in Diluting solvent and dilute quantitatively with Diluting solvent to obtain a solution having a known concentration of about 10 μg per ml. 

      Calculation Calculate the percentage of 4- epianhydrotetracycline hydrochloride in the Tetracycline Hydrochloride taken, using the declared content of 4-epianhydrotetracycline in 4-Epianhydrotetracycline RS.

Assay Carry out the determination as described in the “High-pressure Liquid Chromatography” (Appendix 3.5).

      Diluting solvent Mix 680 ml of 0.1 M ammonium oxalate and 270 ml of dimethylformamide.

      Mobile phase Mix 68 volumes of 0.1 M ammonium oxalate, 27 volumes of dimethylformamide and 5 volumes of 0.2 M diammonium hydrogenphosphate. Adjust, if necessary, with 3 M ammonia or 3 M phosphoric acid to a pH of 7.6 to 7.7. Make any other necessary adjustments.

      Resolution solution Prepare a solution in Diluting solvent containing 100 g of tetracycline hydrochloride and 25 μg of 4-Epianhydrotetracycline Hydrochloride RS per ml.

      Standard preparation Dissolve an accurately weighed quantity of Tetracycline Hydrochloride RS, in Diluting solvent and dilute quantitatively with Diluting solvent to obtain a solution having a known concentration of about 500 μg per ml.

      Assay preparation Transfer about 50 mg of Tetracycline Hydrochloride, accurately weighed, to a 100-ml volumetric flask, dissolve in, dilute with Diluting solvent to volume, and mix.

      Chromatographic system The chromatographic procedure may be carried out using (a) a stainless steel guard column (3 cm × 4.6 mm) packed with octylsilane chemically bonded to totally porous silica particles (10 μm) and a stainless steel analytical column (25 cm × 4.6 mm) packed with octylsilane chemically bonded to totally porous silica particles (5 to 10 μm), (b) Mobile phase at a flow rate of about 2 ml per minute and (c) an ultraviolet photometer set at 280 nm.

      To determine the suitability of the chromatographic system, chromatograph Resolution solution, and record the peak responses as directed under Procedure: the relative retention times are about 0.9 for 4- epianhydrotetracycline and 1.0 for tetracycline and the resolution factor between the 4-epianhydrotetracycline and tetracycline peaks is not less than 1.2. Chromatograph Standard preparation, and  record the peak responses as directed under Procedure: the relative standard deviation for replicate injections is not more than 2.0 per cent.

      Procedure Separately inject equal volumes (about 20 μl) of Standard preparation and Assay preparation into the chromatograph, record the chromatograms and measure the responses for the major peaks.

      Calculation Calculate the content of C₂₂H₂₄N₂O₈.HCl in the Tetracycline Hydrochloride taken, using the declared content of C₂₂H₂₄N₂O₈.HCl in Tetracycline Hydrochloride RS.