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DOXYCYCLINE HYCLATE

Category Antibacterial; antiprotozoal.

      Doxycycline Hyclate contains not less than 800 μg and not more than 920 μg of C22H24N2O8 per mg.

Description Yellow, crystalline powder; hygroscopic.

Solubility Freely soluble in water and in methanol; sparingly soluble in ethanol. It dissolves in solutions of alkali hydroxides and carbonates. 

Contra-indication It is contra-indicated in patients with history of hypersensitivity reactions to any member of tetracyclines. 

Warning

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

      2. It should be used with caution in patients with impaired liver function or myasthenia gravis.

      3. It may cause discolouration of infants’ or children’s teeth, photosensitivity, benign intracranial hypertension, hepatotoxicity, and pancreatitis.

      4. Concomitant therapy with antacids, iron preparations, anticonvulsants including carbamazepine, phenobarbitone, and phenytoin; and rifampicin should be avoided. 

Precaution See under Tetracycline Hydrochloride, p. 157.

Additional information

      1. It may be taken with food, milk, or carbonated beverage if gastro-intestinal irritation occurs.

      2. Doxycycline has been reported to be relatively free of renal side effects, and is therefore preferred to other tetracyclines in case of renal dysfunction. 

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

      4. Gastro-intestinal disturbances are reported to be less frequent than with tetracycline, and doxycycline may also cause less tooth discolouration.

Packaging and storage Doxycycline Hyclate 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 Doxycycline Hyclate RS (Appendix 2.1) or with the reference spectrum of Doxycycline Hyclate.

      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 yellow colour is produced.

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

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

pH 2.0 to 3.0, in a 1.0 per cent w/v solution (Appendix 4.11).

Specific rotation –105º to –120º, calculated on the anhydrous basis, determined in a 1.0 per cent w/v solution of a mixture of 1 volume of 1 M hydrochloric acid and 99 volumes of methanol (Appendix 4.8).

Water Not less than 1.4 per cent w/w and not more than 2.8 per cent w/w (Karl Fischer Method, Appendix 4.12).

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

      Mobile, Diluent, and Chromatographic system Proceed as directed in the Assay.

      System suitability solution Prepare as directed for the Resolution solution in the Assay.​

      Methacycline standard stock solution Dissolve an accurately weighed quantity of Methacycline Hydrochloride RS in Diluent, and dilute quantitatively, and stepwise if necessary, to obtain a solution having a known concentration of about 1.2 mg per ml.

      Standard solution 1 Prepare as directed for the Standard preparation in the Assay.

      Standard solution 2 Transfer 2.0 ml of Standard solution 1 and 2.0 ml of Methacycline standard stock solution to a 100-ml volumetric flask, dilute with Diluent to volume, and mix. This solution contains about 0.024 mg each of Doxycycline Hyclate RS and Methacycline Hydrochloride RS per ml.

      Test solution Prepare as directed for the Assay preparation in the Assay.

      Procedure Separately inject equal volumes (about 20 μl) of Standard solution 2 and Test solution into the chromatograph, record the chromatograms for a period of time that is 1.7 times the retention time of doxycycline, and measure the peak areas.

      Calculation Calculate the percentage of methacycline in the portion of Doxycycline Hyclate taken by the expression: 

10,000(CM/W)(ru/rM)r

in which CM is the concentration, in mg per ml, of Methacycline Hydrochloride RS in Standard solution 2; W is the weight, in mg, of Doxycycline Hyclate taken to prepare Test solution; and ru and rM are the methacycline peak responses obtained from Test solution and Standard solution 2, respectively. Not more than 2 per cent of methacycline is found. Calculate the percentage of each related compound, other than methacycline, in the portion of Doxycycline Hyclate taken by the expression:

10,000(Cs/W)(ri /rs),

in which Cs is the concentration, in mg per ml, of Doxycycline Hyclate RS in Standard solution 2; W is the weight, in mg, of Doxycycline Hyclate taken to prepare the Test solution; ri is the peak response for each impurity obtained from Test solution; and rs is the doxycycline peak response obtained from Standard solution 2. Not more than 0.5 per cent of any impurity eluting before methacycline is found; not more than 2 per cent of 6- epidoxycycline is found; and not more than 0.5 per cent of any impurity eluting after the main doxycycline peak is found.

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

      Mobile phase Transfer 2.72 g of potassium dihydrogenphosphate, 740 mg of sodium hydroxide, 500 mg of tetrabutylammonium hydrogensulfate, and 400 mg of disodium edetate to a 1000-ml volumetric flask. Add about 850 ml of water, and stir to dissolve. Add 60 g of 2-methyl-2-propanol with the aid of water, dilute with water to volume, adjust with 1 M sodium hydroxide to a pH of 8.0±0.1 and filter. Make any necessary adjustments. Decreasing the proportion of 2-methyl-2-propanol results in a longer retention time of doxycycline and improved separation of doxycycline from the related substances.

      Diluent Prepare 0.01 M hydrochloric acid.

      Resolution solution Prepare a solution of Doxycycline Hyclate RS in Diluent containing about 6 mg of doxycycline per ml. Transfer 5.0 ml of this solution to a 25-ml volumetric flask, heat on a water-bath for 60 minutes, and evaporate to dryness on a hot plate, taking care not to char the residue. Dissolve the residue in Diluent, dilute with Diluent to volume, mix and filter. This solution contains a mixture of 4-epidoxycycline, methacycline, 6-epidoxycycline and doxycycline. When stored in a refrigerator, this solution may be used for 14 days. (Note Throughout the following sections, protect the Standard preparation and the Assay preparation from light.)

      Standard preparation Transfer about 12 mg of Doxycycline Hyclate RS, accurately weighed, to a 10-ml volumetric flask, add about 6 ml of Diluent, sonicate for about 5 minutes or until dissolved, dilute with Diluent to volume, and mix.

Assay preparation Transfer about 120 mg of Doxycycline Hyclate, accurately weighed, to a 100-ml volumetric flask, dissolve and dilute with Diluent to volume, mix, and filter.

      Chromatographic system The chromatographic procedure may be carried out using (a) a stainless steel column (25 cm × 4.6 mm) packed with rigid spherical styrene-divinylbenzene copolymer maintained at 60º±1º, (b) Mobile phase at a flow rate of about 1 ml per minute and (c) an ultraviolet photometer set at 270 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 0.4 for 4- epidoxycycline (the main degradation product), 0.6 for methacycline, 0.7 for 6-epidoxycycline, and 1.0 for doxycycline, the resolution factor between the 4- epidoxycycline and doxycycline peaks is not less than 3.0, and the symmetry factor for the doxycycline peak is not more than 2.0. 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 in the Doxycycline Hyclate taken, using the declared content of C22H24N2O8 in Doxycycline Hyclate RS. 

 

MONOGRAPHS • DOXYCYCLINE HYCLATE
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หมายเหตุ / Note : TP II 2011 PAGE 96-98