Levothyroxine Sodium Tablets
DEFINITION
Levothyroxine Sodium Tablets contain NLT 95.0% and NMT 105.0% of the labeled amount of levothyroxine sodium (C15H10I4NNaO4).
IDENTIFICATION
• The retention time of the major peak of the Sample solution corresponds to the levothyroxine peak of the Standard solution, as obtained in the Assay.
ASSAY
• Procedure
[Note—Use Sample solution 2 for Tablets labeled to meet the requirements of Dissolution Test 3. For all other products, use the Sample solution. ]
Mobile phase:
Mixture of acetonitrile and water (4:6) containing 0.5 mL of phosphoric acid in each L of the mixture
Solution A:
Dissolve 400 mg of sodium hydroxide in 500 mL of water. Cool, and add 500 mL of methanol.
Diluent:
Mixture of methanol and water (6:4), containing 0.5 mL of phosphoric acid in each L of the mixture
Levothyroxine stock solution:
0.4 mg/mL of USP Levothyroxine RS in Solution A
Liothyronine stock solution:
0.4 mg/mL of USP Liothyronine RS in Solution A. Make a 1:100 dilution of this solution using Mobile phase.
Standard solution:
10 µg/mL of levothyroxine from Levothyroxine stock solution and 0.2 µg/mL of liothyronine from Liothyronine stock solution, in Mobile phase
Sample solution:
Weigh and finely powder NLT 20 Tablets. Transfer a portion of the powder, equivalent to about 100 µg of levothyroxine sodium, to a centrifuge tube, add 2 glass beads, pipet 10 mL of Mobile phase into the tube, and mix on a vortex mixer for 3 min. Centrifuge to obtain a clear supernatant, filtering if necessary.
Sample solution 2 (For Tablets labeled to meet the requirements of Dissolution Test 3):
Place the appropriate number of Tablets (see Table 1 below) into a suitable container, add 100.0 mL of Diluent, and shake by mechanical means for at least 30 min, or until the Tablets are fully disintegrated. Pass through a PTFE filter of 0.45-µm pore size.
Table 1
| Tablet Strength (µg/Tablet of Levothyroxine Sodium) |
Number of Tablets |
|---|---|
| Less than 100 | 20 |
| At least 100 but less than 200 | 15 |
| 200 or more | 10 |
Chromatographic system
Mode:
LC
Detector:
UV 225 nm
Column:
4.6-mm × 25-cm; packing L10
Flow rate:
1.5 mL/min
Injection size:
100 µL
System suitability
Sample:
Standard solution
Suitability requirements
Resolution:
NLT 5.0 between liothyronine and levothyroxine
Relative standard deviation:
NMT 2.0% for the levothyroxine peak
Analysis
Samples:
Standard solution and Sample solution
Calculate the percentage of C15H10I4NNaO4 in the portion of Tablets taken:
Result = (rU/rS) × (CS/CU) × (Mr1/Mr2) × 100
| rU | = | = peak response from the Sample solution |
| rS | = | = peak response from the Standard solution |
| CS | = | = concentration of USP Levothyroxine RS in the Standard solution (µg/mL) |
| CU | = | = nominal concentration of levothyroxine sodium in the Sample solution (µg/mL) |
| Mr1 | = | = molecular weight of levothyroxine sodium, 798.85 |
| Mr2 | = | = molecular weight of levothyroxine, 776.87 |
Acceptance criteria:
95.0%–105.0%
PERFORMANCE TESTS
• Dissolution 
711
711
[Note—All containers that are in contact with solutions containing levothyroxine sodium are to be made of glass. ]
Test 1
Medium:
0.01 N hydrochloric acid containing 0.2% sodium lauryl sulfate; 500 mL
Apparatus 2:
50 rpm
Time:
45 min
Determine the amount of C15H10I4NNaO4 dissolved by using the following method.
Mobile phase:
Methanol and 0.1% phosphoric acid (6:4)
Standard stock solution:
0.1 mg/mL of USP Levothyroxine RS in methanol
Standard solution:
Dilute the Standard stock solution with Medium to obtain a solution having a concentration similar to that expected in the Sample solution.
Sample solution:
Pass a portion of the solution under test through a suitable filter. [Note—Before use, check the filters for absorptive loss of drug. ]
Chromatographic system
Mode:
LC
Detector:
UV 225 nm
Column:
4.6-mm × 25-cm; packing L1
Flow rate:
2 mL/min
Injection size:
800 µL
System suitability
Sample:
Standard solution
Suitability requirements
Tailing factor:
NMT 1.5
Relative standard deviation:
NMT 4.0% of levothyroxine
Analysis
Samples:
Standard solution and Sample solution
Calculate the amount of C15H10I4NNaO4 dissolved.
Tolerances:
NLT 70% (Q) of the labeled amount of C15H10I4NNaO4 is dissolved.
Test 2:
If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 2.
Medium, Apparatus, Mobile phase, Standard solution, Sample solution, Chromatographic system, and System suitability:
Proceed as directed for Test 1.
Time:
15 min
Analysis
Samples:
Standard solution and Sample solution
Calculate the amount of C15H10I4NNaO4 dissolved.
Tolerances:
NLT 80% (Q) of the labeled amount of C15H10I4NNaO4 is dissolved.
Test 3:
If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 3.
Medium, Apparatus, Time, Standard solution, and Sample solution:
Proceed as directed in Test 1. [Note—Filter the Standard solution in a manner identical to the Sample solution. ]
Determine the amount of C15H10I4NNaO4 dissolved by employing the following method.
Mobile phase:
Acetonitrile and water (35:65) that contains 0.5 mL/L of phosphoric acid
Chromatographic system
Mode:
LC
Detector:
UV 225 nm
Column:
4.6-mm × 25-cm; 5-µm packing L10
Temperature:
30
Flow rate:
1.5 mL/min
Injection size:
100 µL
System suitability
Sample:
Standard solution
Suitability requirements
Tailing factor:
NMT 1.5
Relative standard deviation:
NMT 4.0%
Analysis
Samples:
Standard solution and Sample solution
Calculate the amount of C15H10I4NNaO4 dissolved.
Tolerances:
NLT 80% (Q) of the labeled amount of C15H10I4NNaO4 is dissolved.
Test 4:
If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 4.
[Note—Do not use paddle stirrers with synthetic coating. ]
Medium:
0.01 N hydrochloric acid; 500 mL for Tablets labeled to contain between 25 and 175 µg of levothyroxine sodium; and 900 mL for Tablets labeled to contain 200 or 300 µg of levothyroxine sodium
Apparatus 2:
75 rpm
Time:
45 min
Determine the amount of C15H10I4NNaO4 dissolved by using the following method.
Mobile phase:
Acetonitrile, water, and phosphoric acid, (500:700:2)
Standard stock solution:
Transfer about 100 mg of USP Levothyroxine RS to a 100-mL volumetric flask. Add 80 mL of alcohol and 1 mL of 1 N hydrochloric acid, sonicate for 2 min, dilute with alcohol to volume, and mix.
Standard solution:
Dilute the Standard stock solution with a mixture of alcohol and water (1:1) to obtain a solution having a concentration of 0.01 mg/mL of levothyroxine. Dilute the resulting solution with Medium to obtain a final concentration similar to that expected in the Sample solution.
Sample solution:
Sample per Dissolution 711. Centrifuge the solution under analysis.
711. Centrifuge the solution under analysis.
Chromatographic system
Mode:
LC
Detector:
UV 225 nm
Column:
4.0-mm × 12.5-cm; packing L7
Flow rate:
1.5 mL/min
Injection size:
500 µL
System suitability
Sample:
Standard solution
Suitability requirements
Tailing factor:
NMT 1.5
Relative standard deviation:
NMT 4.0% of levothyroxine
Analysis
Samples:
Standard solution and Sample solution
Calculate the amount of C15H10I4NNaO4 dissolved.
Tolerances:
NLT 80% (Q) of the labeled amount of C15H10I4NNaO4 is dissolved.
• Uniformity of Dosage Units 905:
Meet the requirements
905:
Meet the requirements
IMPURITIES
Change to read:
Organic Impurities
• Procedure: Limit of Liothyronine Sodium
[Note—Use Sample solution 2 for Tablets labeled to meet the requirements of Dissolution Test 3. For all other products, use the Sample solution. ]
Mobile phase, Standard solution, Sample solution, Chromatographic system, and System suitability:
Proceed as directed in the Assay.
Analysis:
Calculate the percentage of C15H11I3NNaO4 in the portion of Tablets taken:
Result = (rU/rS) × (CS/CU) × (Mr1/Mr2) × 100
| rU | = | = peak response of liothyronine from the Sample solution |
| rS | = | = peak response of liothyronine from the Standard solution |
| CS | = | = concentration of USP Liothyronine RS in the Standard solution (µg/mL) |
| CU | = | = nominal concentration of levothyroxine sodium in the Sample solution (µg/mL) |
| Mr1 | = | = molecular weight of liothyronine sodium, 672.96 |
| Mr2 | = | = molecular weight of liothyronine, 650.98 |
Acceptance criteria:
NMT 2.0% of liothyronine
(ERR 1-Aug-2014)
ADDITIONAL REQUIREMENTS
• Packaging and Storage:
Preserve in tight, light-resistant containers.
• Labeling:
When more than one Dissolution test is given, the labeling states the Dissolution test used only if Test 1 is not used.
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Auxiliary Information—
Please check for your question in the FAQs before contacting USP.
| Topic/Question | Contact | Expert Committee |
|---|---|---|
| Monograph | Elena Gonikberg, Ph.D.
Director - Chemical Medicines (301) 816-8251 |
(SM32010) Monographs - Small Molecules 3 |
| 711 |
Margareth R.C. Marques, Ph.D.
Senior Scientific Liaison (301) 816-8106 |
(GCDF2010) General Chapters - Dosage Forms |
| Reference Standards | RS Technical Services 1-301-816-8129 rstech@usp.org |
USP38–NF33 Page 4092
Pharmacopeial Forum: Volume No. 34(4) Page 954