Medium To A Concentration That Is Similar To The Standard Solution. Identification Test D.)

Official Monographs / Levothyroxine 47
USP 32
Acceptance criteria:
93.0%107.0%
PERFORMANCE TESTS
DISSOLUTION 711
Medium: Water; 500 mL
Apparatus 2: 50 rpm
Time: 30 min
Detector: UV 279 nm
Standard solution: USP Levorphanol Tartrate RS in Medium
Sample solution: Sample per Dissolution 711. Dilute with
Medium to a concentration that is similar to the Standard
solution.
Tolerances: NLT 75% (Q) of the labeled amount of
C17H23NO C4H6O6 2H2O is dissolved.
UNIFORMITY OF DOSAGE UNITS 905: Meet the requirements
Standard solution: 80 g/mL of levorphanol tartrate from
USP Levorphanol Tartrate RS in 0.1 N hydrochloric acid
Sample solution: Transfer 1 Tablet to a glass-stoppered
flask, add 25.0 mL of 0.1 N hydrochloric acid, and allow the
Tablet to disintegrate. Shake well, and pass through a small
filter paper, discarding the first portion of the filtrate. Dilute
a portion of the filtrate quantitatively and stepwise to
provide a solution containing 80 g/mL of levorphanol
tartrate.
Blank: 0.1 N hydrochloric acid
Spectrometric conditions
Cell: 1 cm
Analytical wavelength: 279 nm
Analysis
Samples: Standard solution and Sample solution
Calculate the percentage of C17H23NO C4H6O6 2H2O in
the Tablet taken:
Result = (AU/AS) (CS/CU) (Mr1/Mr2) 100
AU
AS
CS
CU
Mr1
Mr2
= absorbance of the Sample solution

= absorbance of the Standard solution
= concentration of USP Levorphanol Tartrate RS,
on the anhydrous basis, in the Standard
solution (mg/mL)
= nominal concentration of levorphanol tartrate in
the Sample solution (mg/mL)
= molecular weight of hydrated levorphanol
tartrate, 443.49
= molecular weight of anhydrous levorphanol
tartrate, 407.47
ADDITIONAL REQUIREMENTS
PACKAGING AND STORAGE: Preserve in well-closed containers.
USP REFERENCE STANDARDS 11
USP Levorphanol Tartrate RS
Levothyroxine Sodium
(Comment on this Monograph)id=m45000=Levothyroxine
Sodium=L-Monos.pdf)
C15H10I4NNaO4 xH2O (anhydrous)

L-Tyrosine, O-(4-hydroxy-3,5-diiodophenyl)-3,5-diiodo-,
monosodium salt, hydrate;
Monosodium L-thyroxine hydrate [25416-65-3].
Anhydrous [55-03-8].
DEFINITION
Levothyroxine Sodium is the sodium salt of L-3,3,5,5tetraiodothyronine. It contains NLT 97.0% and NMT 103.0%
of C15H10I4NNaO4, calculated on the anhydrous basis.
IDENTIFICATION
A. PROCEDURE
Sample: 50 mg
Analysis: Ignite the Sample in a platinum dish over a flame.
Acceptance criteria: It decomposes and liberates iodine
vapors.
[NOTECool the residue obtained, and reserve it for use in
Identification test D.]
B. PROCEDURE
Acid sodium chloride solution: Alcohol, 1 N sodium
hydroxide, hydrochloric acid, and water (25:10:10:0.1:30)
Sample: 0.5 mg
Analysis: Add 7.5 mL of acid sodium chloride solution and
1 mL of sodium nitrite solution (1:100) to the Sample. Allow
to stand in the dark for 20 min, and add 1.25 mL of
ammonium hydroxide.
Acceptance criteria: A pink color is produced.
C. The retention time of the major peak of the Sample
solution corresponds to that of the Standard solution, as
obtained in the Assay.
D. IDENTIFICATION TESTSGENERAL, Sodium 191: The
solution meets the requirements of the flame test.
Sample solution: To the residue retained from Identification
test A, add a 1 N potassium hydroxide solution dropwise
until the residue is dissolved.
ASSAY
PROCEDURE
Mobile phase: Acetonitrile and water (4:6) that contains
0.5 mL of phosphoric acid in each 1000 mL
Solution A: 400 mg of sodium hydroxide in 500 mL of
water. Cool, and add 500 mL of methanol.
Levothyroxine stock solution: 0.4 mg/mL of USP
Levothyroxine RS in Solution A
Liothyronine stock solution: 0.4 mg/mL of liothyronine
from USP Liothyronine RS in Solution A. Make a 1:100
dilution of this solution using Mobile phase.
Standard solution: 10 g/mL of levothyroxine from
Levothyroxine stock solution and 0.2 g/mL of liothyronine
from Liothyronine stock solution, in Mobile phase
Sample solution: Prepare a solution of Levothyroxine
Sodium in Mobile phase having a known concentration of 10
g/mL.
[NOTEA small amount of 0.01 M methanolic sodium
hydroxide can be used to facilitate the dissolution of the
sample.]
Chromatographic system
(See Chromatography 621, System Suitability.)
Mode: LC
Detector: UV 225 nm
Column: 4.6-mm 25-cm; packing L10
Flow rate: 1.5 mL/min
Injection size: 100 L
System suitability
Sample: Standard solution
Suitability requirements
Resolution: NLT 5.0 between liothyronine and
levothyroxine
798.85
Copyright 2008 The United States Pharmacopeial Convention. All Rights Reserved.
For Discussion Purposes Only Not for Dissemination
48
Levothyroxine / Official Monographs
Relative standard deviation: NMT 2.0% of levothyroxine

Analysis
Calculate the percentage of C15H10I4NNaO4 in the
Levothyroxine Sodium:
Result = (rU/rS) (CS/CU) (Mr1/Mr2) 100
= peak response of the Sample solution
= peak response of the Standard solution
= concentration of USP Levothyroxine RS in the
Standard solution (g/mL)
= nominal concentration of levothyroxine in the
CU
Sample solution (g/mL)
= molecular weight of levothyroxine sodium,
Mr1
798.85
= molecular weight of levothyroxine, 776.87
Mr2
Acceptance criteria: 97.0%103.0%
rU
rS
CS
IMPURITIES
Inorganic Impurities
LIMIT OF INORGANIC IODIDES
Extracting solution: Sulfuric acid in water, 1 in 100
Reference solution: 0.131 mg/mL of potassium iodide in
water (equivalent to 0.100 mg/mL of iodide). Dilute with
Extracting solution to 0.06 g/mL of iodide.
[NOTEPrepare this solution on the day of use.]
Sample solution: 0.075 mg/mL of Levothyroxine Sodium
in the Extracting solution
[NOTESonicate for 5 min.]
Electrode system: Use an iodide-specific, ion-indicating
electrode and a silversilver chloride reference electrode
connected to a pH meter capable of measuring potentials
with a minimum reproducibility of 1 mV (see pH 791).
Analysis: Transfer the Reference solution to a beaker
containing a magnetic stirring bar. Rinse and dry the
electrodes, insert in the solution, stir for 5 min or until the
reading stabilizes, and read the potential, in mV. Repeat
this process using the Sample solution.
Acceptance criteria: The Sample solution has a higher
potential, in mV, than the Reference solution: the limit is
0.08%.
Organic Impurities
PROCEDURE 1: LIMIT OF LIOTHYRONINE SODIUM
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
Levothyroxine Sodium:
rU
rS
CS
= peak response from the Sample solution

= peak response from the Standard solution
= concentration of USP Liothyronine RS in the
Standard solution (mg/mL)
CU
= nominal concentration of liothyronine in the
Sample solution (mg/mL)
Mr1
= molecular weight of liothyronine sodium, 672.96
= molecular weight of liothyronine, 650.98
Mr2
Acceptance criteria: NMT 2.0%
PROCEDURE 2
Diluent: Acetonitrile and water (1:1)
Solution A: Dilute 5 mL of phosphoric acid with Diluent to
100.0 mL.
Mobile phase: Dissolve 1.0 g of sodium 1heptanesulfonate in 200 mL of water. Add 200 mL of
acetonitrile, 400 mL of methanol, and 1.0 mL of
phosphoric acid. Dilute with water to 1 L.
Standard stock solution 1: Transfer 25 mg of USP
Levothyroxine RS to a 100-mL volumetric flask. Add 50 mL
USP 32
of Diluent and 1 drop of 10 N sodium hydroxide, and
sonicate until dissolved. Add 7 mL of Solution A, and dilute
with Diluent to volume.
Standard stock solution 2: Transfer 25 mg of USP
Liothyronine RS to a 100-mL volumetric flask. Add 50 mL
of Diluent and 1 drop of 10 N sodium hydroxide, and
System suitability solution: 5.0 mL of the Standard stock
solution 1 and 5.0 mL of the Standard stock solution 2 to a
100-mL volumetric flask. Add 7 mL of Solution A, and dilute
Standard solution: Pipet 4.0 mL of the System suitability
solution to a 100-mL volumetric flask. Add 7 mL of Solution
A, and dilute with Diluent to volume.
Blank: Add 7 mL of Solution A to a 100-mL volumetric
flask, and dilute with Diluent to volume.
Sample solution: Transfer 25 mg of Levothyroxine Sodium
to a 100-mL volumetric flask. Add 50 mL of Diluent, and
Mode: LC
Detector: UV 225 nm
Column: 4.6-mm 15-cm; 5-m packing L1
Temperature: 35
System suitability
Samples: System suitability solution and Standard solution
Resolution: NLT 5.0 between levothyroxine and
liothyronine, System suitability solution
Relative standard deviation: NMT 2.0% for the
levothroxine peak in the Standard solution
Analysis
Samples: Standard solution, Blank, and Sample solution
[NOTERecord the chromatograms for at least six times
the retention time of the levothyroxine peak. Verify that
no peaks elute in the Blank solution at the expected
retention times for levothyroxine and related
compounds.]
Calculate the area percentage of each relative compound
in the portion of Levothyroxine taken:
Result = (rU/rS) (CS/CU) (Mr1/Mr2) 100/(1 0.01L)
rU
= peak area for each impurity from the Sample

solution
= peak area for levothyroxine from the Standard
rS
solution
= concentration of levothyroxine in the Standard
CS
solution (mg/ml)
= nominal concentration of levothyroxine sodium
CU
in the Sample solution (mg/ml)
Mr1
798.85
Mr2
L
= percentage of water in Levothyroxine Sodium,
as determined separately in the test for Water
Determination 921
[NOTEThe relative response factor for the impurities
listed in Impurity Table 1 is 1.00. Any unspecified
impurity peaks should be assigned a relative response
factor of 1.00.]
Disregard peaks corresponding to those of the Blank
solution, and disregard peaks corresponding to less than
0.03%.
Official Monographs / Levothyroxine 49
USP 32
Acceptance criteria
Individual impurities: See Impurity Table 1.
Total unknown impurities: NMT 1.5%
Impurity Table 1
Name
Relative
Retention
Time
Limit
(%)
Liothyronine
0.650.70
1.0
-Hydroxy-T4a
0.710.76
0.15
Levothyroxine
1.0
N/A
T4-Hydroxyacetic acidb
1.131.28
0.15
N-Formyl-T4c and T4Acetamided
1.471.53
0.15
N-Acetyl-T4e
1.501.86
0.20
T4-Acetic acidf
2.422.51
0.15
T4-Aldehydeg
3.173.45
0.15
T4-Benzoic acidh
3.463.70
0.15
Individual unspecified
impurity
N/A
Dilute with Solution A to volume, mix, and allow to stand for

4 h, with occasional mixing. Pass a portion of this mixture
through a filter that does not absorb levothyroxine.
Sample solution: Transfer 10.0 mL of the filtrate to a 50mL volumetric flask, and dilute with Solution A to volume.
Mode: LC
Detector: UV 225 nm
Flow rate: 1 mL/min
System suitability
Tailing factor: NMT 1.8
Analysis
Calculate the percentage of levothyroxine sodium
C15H10I4NNaO4 in the portion of Oral Powder taken:
0.10
O-(4-Hydroxy-3,5-diiodophenyl)-3,5-diiodo--hydroxy-L-tyrosine.
2-Hydroxy-2-(4-(4-hydroxy-3,5-diiodophenoxy)-3,5-diiodophenyl)acetic
acid.
c N-Formyl-O-(4-hydroxy-3,5-diiodophenyl)-3,5-diiodo-L-tyrosine.
d 2-(4-(4-Hydroxy-3,5-diiodophenoxy)-3,5-diiodophenyl) acetamide.
e N-Acetyl-O-(4-hydroxy-3,5-diiodophenyl)-3,5-diiodo-L-tyrosine.
f 2-(4-(4-Hydroxy-3,5-diiodophenoxy)-3,5-diiodophenyl)acetic acid.
g 4-(4-Hydroxy-3,5-diiodophenoxy)-3,5-diiodobenzaldehyde.
h 4-(4-Hydroxy-3,5-diiodophenoxy)-3,5-diiodobenzoic acid.
a
SPECIFIC TESTS
OPTICAL ROTATION, Specific Rotation 781S: 5 to 6
Sample solution: Equivalent to 30 mg/mL of anhydrous
Levothyroxine Sodium, in alcohol and 1 N sodium hydroxide
(2:1)
WATER DETERMINATION, Method I 921: NMT 11.0%
PACKAGING AND STORAGE: Preserve in tight containers,
protected from light.
USP Levothyroxine RS
USP Liothyronine RS
Levothyroxine Sodium Oral Powder

Sodium Oral Powder=L-Monos.pdf)
DEFINITION
Levothyroxine Sodium Oral Powder contains NLT 90.0% and
NMT 110.0% of the labeled amount of levothyroxine sodium
(C15H10I4NNaO4).
ASSAY
PROCEDURE
1 mL of phosphoric acid in each 1000 mL
Solution A: Dissolve 400 mg of sodium hydroxide in 500
mL of water. Cool, add 500 mL of methanol.
Standard solution: 4 g/mL of USP Levothyroxine RS in
Solution A
Sample stock solution: Transfer Oral Powder, equivalent to
5 mg of levothyroxine sodium, to a 250-mL volumetric flask.
rU
rS
CS
= peak response from the Sample solution

= peak response from the Standard solution
= concentration of USP Levothyroxine RS in
CU
in the Sample solution (mg/mL)
Mr1
798.85
Mr2
SPECIFIC TESTS
LOSS ON DRYING 731: Dry in vacuum at 60 for 3 h: it
loses NMT 2.0% of its weight.
PACKAGING AND STORAGE: Preserve in tight, light-resistant
containers.
LABELING: Label it to indicate that it is for veterinary use
only.
Levothyroxine Sodium Tablets

Sodium Tablets=L-Monos.pdf)
DEFINITION
Levothyroxine Sodium Tablets contain NLT 90.0% and NMT
110.0% of the labeled amount of levothyroxine sodium
(C15H10I4NNaO4).
(Official until October 3, 2009)
Change to read:
Levothyroxine Sodium Tablets contain NLT 95.0%USP32 and

NMT 105%USP32 of the labeled amount of levothyroxine
sodium (C15H10I4NNaO4).
(Official October 3, 2009)
50
Levothyroxine / Official Monographs
IDENTIFICATION
THIN-LAYER CHROMATOGRAPHIC IDENTIFICATION TEST 201
Adsorbent: 0.1-mm layer of cellulose
Diluent: Methanol and ammonium hydroxide (19:1)
Standard solution: 0.03 mg/mL of USP Levothyroxine RS in
Diluent
Sample solution: Shake an amount of powdered Tablets,
equivalent to 60 g of levothyroxine sodium with 2 mL of
Diluent in a centrifuge tube for 10 min, and centrifuge.
Application volume: 10 L
Developing solvent system: Tert-amyl alcohol, ammonium
hydroxide and water (5:1:4)
[NOTEShake and allow to stand. Transfer the upper phase
to a suitable chromatographic chamber arranged for thinlayer chromatography, pour it over the paper lining, cover
the chamber, and allow to stand for 1 h.]
Spray reagent: Add 65 mL of 2 N hydrochloric acid to 50
mL of a 1-in-10 solution of sodium arsenite in 1 N sodium
hydroxide, with vigorous stirring. Mix 1 volume of this
solution with 5 volumes of a 27-in-1000 solution of ferric
chloride in 2 N hydrochloric acid, and 5 volumes of a
freshly-prepared 35 mg/mL potassium ferricyanide solution.
Analysis: Develop the plate in the Developing solvent system
until the solvent front has moved NLT 10 cm beyond the
point of application of the Sample solution, air-dry, and spray
the plate with Spray reagent.
Acceptance criteria: The chromatogram of the Sample
solution shows a blue spot corresponding in RF value to that
of the Standard solution.
ASSAY
PROCEDURE
0.5 mL/L of phosphoric acid
Solution A: 400 mg of sodium hydroxide in 500 mL of
water. Cool, add 500 mL of methanol.
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 g/mL of levothyroxine from
Levothyroxine stock solution and 0.2 g/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 100 g of
levothyroxine sodium to a centrifuge tube, add two glass
beads, pipet 10 mL of Mobile phase into the tube, and mix
using a vortex mixer for 3 min. Centrifuge to obtain a clear
supernatant, filtering if necessary.
Mode: LC
Detector: UV 225 nm
System suitability
Resolution: NLT 5.0 between liothyronine and
levothyroxine
Analysis
Calculate the percentage of C15H10I4NNaO4 in the portion
Tablets taken:
rU
= peak response of levothyroxine from the Sample

solution
USP 32
rS
= peak response of levothyroxine from the

Standard solution
= concentration of USP Levothyroxine RS in the
CS
CU
Mr1
798.85
Mr2
PERFORMANCE TESTS
DISSOLUTION 711
[NOTEAll 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
employing 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: Sample per Dissolution 711. Dilute with
Medium to a concentration that is similar to the Standard
solution, and filter.
[NOTEBefore use, check the filters for absorptive loss of
drug.]
Mode: LC
Detector: UV 225 nm
Flow rate: 2 mL/min
System suitability
Relative standard deviation: NMT 4.0% of
levothyroxine
Analysis
Calculate the amount of C15H10I4NNaO4 dissolved.
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: Calculate the amount of C15H10I4NNaO4
dissolved.
Test 3
Medium, Apparatus, Time, Standard solution, and Sample
solution: Proceed as directed in Test 1.
[NOTEFilter the Standard solution in a manner identical to
the Sample solution.]
Official Monographs / Lidocaine 51
USP 32
0.5 mL/L of phosphoric acid
Mode: LC
Detector: UV 225 nm
Column: 4.6-mm 25-cm; 5-m packing L10
Temperature: 30
System suitability
levothyroxine
Analysis
Test 4
[NOTEDo not use paddle stirrers with synthetic coating.]
Medium: 0.01 N hydrochloric acid; 500 mL for Tablets
labeled to contain between 25 g and 175 g of
levothyroxine sodium; and 900 mL for Tablets labeled to
contain 200 g or 300 g of levothyroxine sodium
Apparatus 2: 75 rpm
Time: 45 min
Mobile phase: Acetonitrile, 85% orthophosphoric acid,
and water (500:2:700)
Standard stock solution: 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 this stock solution with a
mixture of alcohol and water (1:1) to obtain a solution
having a concentration of 0.01 mg/L of levothyroxine.
Dilute this intermediate solution with Medium to obtain a
solution having a concentration similar to that expected in
the Sample solution.
Sample solution: Sample per Dissolution 711. Centrifuge
the solution under analysis.
Mode: LC
Detector: UV 225 nm
Column: 4.0-mm 12.5-cm; packing L7
System suitability
levothyroxine
Analysis
UNIFORMITY OF DOSAGE UNITS 905:
Meet the requirements
IMPURITIES
Organic Impurities
PROCEDURE: LIMIT OF LIOTHYRONINE SODIUM
Mobile phase, Standard solution, Sample solution,
Chromatographic system, and System suitability:
Proceed as directed in the Assay.
Analysis: Calculate the percentage of liothyronine sodium
C15H11I3NNaO4 in the portion of Tablets taken:
= peak response of liothyronine from the Sample
solution
= peak response of liothyronine from the Standard
rS
solution
= concentration of USP Liothyronine RS in the
CS
CU
Mr1
= molecular weight of liothyronine sodium 672.96
= molecular weight of liothyronine, 650.98
Mr2
Acceptance criteria: NMT 2.0% of liothyronine
rU
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.
USP Liothyronine RS
Lidocaine
(Comment on this Monograph)id=m45070=Lidocaine=LMonos.pdf)
C14H22N2O
Acetamide, 2-(diethylamino)-N-(2,6-dimethylphenyl)-;
2-(Diethylamino)-2,6-acetoxylidide [137-58-6].
234.34
DEFINITION
Lidocaine contains NLT 97.5% and NMT 102.5% of C14H22N2O.
IDENTIFICATION
A. INFRARED ABSORPTION 197K: Previously dried in a
vacuum over silica gel for 24 h
B. PROCEDURE
Analysis: To 100 mg dissolved in 1 mL of alcohol, add 10
drops of cobaltous chloride TS, and shake the solution for 2
min.
Acceptance criteria: A bright green color develops, and a
fine precipitate is formed.

Medium To A Concentration That Is Similar To The Standard Solution. Identification Test D.)

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Official Monographs / Levothyroxine 47

= absorbance of the Sample solution

C15H10I4NNaO4 xH2O (anhydrous)

Levothyroxine / Official Monographs

Relative standard deviation: NMT 2.0% of levothyroxine

= peak response from the Sample solution

= peak area for each impurity from the Sample

Official Monographs / Levothyroxine 49

N-Formyl-T4c and T4Acetamided

Dilute with Solution A to volume, mix, and allow to stand for

Levothyroxine Sodium Oral Powder

= peak response from the Sample solution

Levothyroxine Sodium Tablets

Levothyroxine Sodium Tablets contain NLT 95.0%USP32 and

Levothyroxine / Official Monographs

= peak response of levothyroxine from the Sample

= peak response of levothyroxine from the

Official Monographs / Lidocaine 51

UNIFORMITY OF DOSAGE UNITS 905:

Meet the requirements

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