Edition: BP 2025 (Ph. Eur. 11.6 update)
Liothyronine Tablets
General Notices
Action and use
Thyroid hormone replacement.
DEFINITION
Liothyronine Tablets contain Liothyronine Sodium.
The tablets comply with the requirements stated under Tablets and with the following requirements.
Content of liothyronine sodium, C15H11I3NNaO4
90.0 to 110.0% of the stated amount.
IDENTIFICATION
In the test for Uniformity of content, record the UV spectrum of the principal peak in the chromatograms obtained with solutions (1) and (2) with a diode array detector in the range of 210 to 400 nm.
The UV spectrum of the principal peak in the chromatogram obtained with solution (1) is concordant with that of the peak in the chromatogram obtained with solution (2);
the retention time of the principal peak in the chromatogram obtained with solution (1) is similar to that of the peak in the chromatogram obtained with solution (2).
TESTS
Dissolution
Comply with the dissolution test for tablets and capsules, Appendix XII B1.
Plastic containers must not be used to prepare and store solutions.
TEST CONDITIONS
(a) Use Apparatus 2, rotating the paddle at 100 revolutions per minute.
(b) Use 500 mL of water, at a temperature of 37°, as the medium.
(c) Place a number of tablets containing 40 μg of Liothyronine Sodium in the dissolution vessel.
PROCEDURE
Carry out the method for liquid chromatography, Appendix III D, using the following solutions prepared immediately before use.
(1) After 45 minutes withdraw a sample of the medium and filter (a GMF filter is suitable), discarding the first 6 mL of the filtrate. To 10 volumes of the resulting solution, add 0.25 volume of a 2% v/v solution of diethylamine and 0.4 volume of 0.1 M sodium hydroxide.
(2) 0.004% w/v of liothyronine sodium EPCRS in 0.001M sodium hydroxide. Dilute with water to produce a solution containing 0.000008% w/v of liothyronine sodium EPCRS. To 10 volumes of the resulting solution, add 0.25 volume of a 2% v/v solution of diethylamine and 0.4 volume of 0.1M sodium hydroxide.
(3) 0.004% w/v of liothyronine sodium EPCRS in 0.001M sodium hydroxide and 0.004% w/v of levothyroxine sodium EPCRS in water. Dilute with water to produce a solution containing 0.000008% w/v of liothyronine sodium EPCRS. To 10 volumes of the resulting solution, add 0.25 volume of a 2% v/v solution of diethylamine and 0.4 volume of 0.1M sodium hydroxide.
CHROMATOGRAPHIC CONDITIONS
(a) Use a stainless steel column (15 cm × 4.6 mm) packed with cyanosilyl silica gel for chromatography (5 µm) (Spherisorb CN is suitable).
(b) Use isocratic elution and the mobile phase described below.
(c) Use a flow rate of 1.5 mL per minute.
(d) Use a column temperature of 40°.
(e) Use a detection wavelength of 225 nm.
(f) Inject 200 µL of each solution.
MOBILE PHASE
5 volumes of orthophosphoric acid, 100 volumes of acetonitrile R1 and 900 volumes of water.
When the chromatograms are recorded under the prescribed conditions, the retention time of liothyronine is about 6 minutes.
SYSTEM SUITABILITY
The test is not valid unless, in the chromatogram obtained with solution (3), the resolution between the peaks due to liothyronine and levothyroxine is at least 1.5.
DETERMINATION OF CONTENT
Calculate the total content of liothyronine sodium, C15H11I3NNaO4, in the medium from the chromatograms obtained and using the declared content of C15H11I3NNaO4 in liothyronine sodium EPCRS.
LIMITS
The amount of liothyronine sodium released is not less than 75% (Q) of the stated amount.
Related substances
Carry out the method for liquid chromatography, Appendix III D, using the following solutions prepared in solution A. Prepare the solutions immediately before use and protect from light.
Solution A 25 volumes of methanol and 75 volumes of 0.1M sodium hydroxide.
(1) To a quantity of powdered tablets containing 0.25 mg of Liothyronine Sodium add 20 mL of solution A. Shake for about 45 minutes and then mix with the aid of ultrasound. Dilute to 25 mL, centrifuge and use the supernatant liquid. (2) Dilute 1 volume of solution (1) to 100 volumes.
(3) 0.0002% w/v of liothyronine sodium impurity standard BPCRS.
(4) Dilute 1 volume of solution (2) to 10 volumes.
CHROMATOGRAPHIC CONDITIONS
(a) Use a stainless steel column (25 cm × 4.6 mm) packed with end-capped octadecylsilyl silica gel for chromatography (5 µm) (Phenomenex Gemini NX C18 is suitable).
(b) Use gradient elution and the mobile phase described below.
(c) Use a flow rate of 1.5 mL per minute.
(d) Use a column temperature of 45°.
(e) Use a detection wavelength of 225 nm.
(f) Inject 200 µL of each solution.
MOBILE PHASE
Mobile phase A 0.136% w/v of potassium dihydrogen orthophosphate in water, adjusted to pH 2.2 with orthophosphoric acid.
Mobile phase B 100 volumes of mobile phase A, 400 volumes of methanol and 500 volumes of acetonitrile R1.
| Time (Minutes) | Mobile phase A (% v/v) | Mobile phase B (% v/v) | Comment |
|---|---|---|---|
| 0–5 | 70 | 30 | isocratic |
| 5–30 | 70→35 | 30→65 | linear gradient |
| 30–42 | 35→25 | 65→75 | linear gradient |
| 42–47 | 25→5 | 75→95 | linear gradient |
| 47–52 | 5 | 95 | isocratic |
| 52–53 | 5→70 | 95→30 | linear gradient |
| 53–62 | 70 | 30 | re-equilibration |
When the chromatograms are recorded under the prescribed conditions, the relative retentions with reference to liothyronine (retention time about 21 minutes) are: impurity E, about 0.6; impurity 1, about 0.9; impurity A, about 1.2; impurity C, about 1.7 and impurity D, about 1.9.
SYSTEM SUITABILITY
The test is not valid unless, in the chromatogram obtained with solution (3):
the resolution between liothyronine and impurity A is at least 10.0;
the signal-to-noise ratio of the principal peak in the chromatogram obtained with solution (4) is at least 25.
LIMITS
Identify any peak corresponding to impurity 1 in the chromatogram obtained with solution (1), using the chromatogram obtained with solution (3), and multiply the area of this peak by a correction factor of 2.2.
In the chromatogram obtained with solution (1):
the area of any peak corresponding to impurity 1 is not greater than 6 times the area of the principal peak in the chromatogram obtained with solution (2) (6%);
the area of any other secondary peak is not greater than the area of the principal peak in the chromatogram obtained with solution (2) (1%);
the sum of the areas of any secondary peaks, excluding impurity 1, is not greater than 3.5 times the area of the principal peak in the chromatogram obtained with solution (2) (3.5%);
the sum of the areas of all secondary peaks, is not greater than 8 times the area of the principal peak in the chromatogram obtained with solution (2) (8%).
Disregard any peak with an area less than the area of the principal peak in the chromatogram obtained with solution (4) (0.1%).
Uniformity of content
Tablets containing less than 2 mg and/or less than 2% w/w of Liothyronine Sodium comply with the requirements stated under Tablets using the following method of analysis. Carry out the method for liquid chromatography, Appendix III D, using the following solutions in 0.05M sodium hydroxide. Carry out the test protected from light.
(1) To one tablet, add 1 mL of 0.05M sodium hydroxide and mix with the aid of ultrasound until the tablet is fully dispersed, cool and shake for 2 minutes. Add sufficient 0.05M sodium hydroxide to produce a solution containing 0.0005% w/v of Liothyronine Sodium, filter through a glass microfibre filter paper (Whatman GF/C is suitable) and use the filtrate. (2) 0.00055% w/v of liothyronine sodium EPCRS.
(3) 0.0005% w/v of liothyronine sodium EPCRS and 0.0005% w/v of levothyroxine sodium EPCRS.
CHROMATOGRAPHIC CONDITIONS
(a) Use a stainless steel column (25 cm × 4.6 mm) packed with cyanosilyl silica gel for chromatography (5 µm) (Nucleosil 5 CN is suitable).
(b) Use isocratic elution and the mobile phase described below.
(c) Use a flow rate of 1 mL per minute.
(d) Use an ambient column temperature.
(e) Use a detection wavelength of 225 nm.
(f) Inject 20 µL of each solution.
MOBILE PHASE
5 volumes of orthophosphoric acid, 300 volumes of acetonitrile R1 and 700 volumes of water.
When the chromatograms are recorded under the prescribed conditions, the retention time of liothyronine is about 7 minutes.
SYSTEM SUITABILITY
The test is not valid unless, in the chromatogram obtained with solution (3), the resolution between the peaks due to liothyronine and levothyroxine is at least 4.0.
DETERMINATION OF CONTENT
Calculate the content of C15H11I3NNaO4 in each tablet using the declared content of C15H11I3NNaO4 in liothyronine sodium EPCRS.
ASSAY
Use the average of the individual results determined in the test for Uniformity of content.
STORAGE
Liothyronine Tablets should be protected from light.
IMPURITIES
The impurities limited by the requirements of this monograph include those listed under Liothyronine Sodium and:
