An Outline on Levothyroxine and It’s Related Impurities 

Levothyroxine is a medicine used for the treatment of thyroid hormone deficiency (hypothyroidism), to treat goiter, and also used to prevent some types of thyroid tumors.  

Levothyroxine is also known as?

Levothyroxine is a levo-isomer of the thyroid hormone thyroxine (T4) prepared synthetically and is also known as L-thyroxine. Levothyroxine is available in the form of tablets, intramuscular injections, and also as a solution for intravenous infusion. Levothyroxine was first produced in 1927 and it is on the World Health Organization’s list of Essential Medicines. Levothyroxine in the year 2019 was the second most commonly prescribed medication in the United States. 

Levothyroxine an overview:

Levothyroxine is available both as generic versions and as brands like Eltroxin, Euthyrox, Levaxin, etc. Levothyroxine is also sold as Levothyroxine sodium an active salt under the different names as Levothroid, Unithroid, Levoxyl, etc.  Levothyroxine was the most commonly prescribed medicine in the U.S. in the years 2011 and 2016.

Further continual process improvement in the synthesis of Levothyroxine, Research and development has taken place which leads to feasible process at a commercial level, to control the impurities as per the regulatory guidelines ICH (International Conference on Harmonization), yield improvement and various methods are available for synthesis as reported in the literature. Levothyroxine is chemically known as (2S)-2-amino-3-[4-(4-hydroxy-3,5-diiodophenoxy)-3,5-diiodophenyl]propanoic acid.

The structure of Levothyroxine is represented as:

Levothyroxine Impurity and Related compound

CAS No.: 51-48-9

Molecular Weight: 776.87 g/mol   

Molecular Formula: C15H11I4NO                               

IUPAC Name: 3-[4-(4-Hydroxy-3,5-diiodophenoxy)-3,5-diiodophenyl]-L-alanine

As per the FDA Levothyroxine is the most broadly prescribed drug in the United States. The manufacturing process of the active substance ingredient (API) and the impurities are always considered critical as it depends on the manufacturing process and its process parameters. There are different available analytical techniques that are being used to control the impurities at different stages during the manufacturing process and can be analyzed by column chromatography to get the product purity as per pharmacopeia. The specification and the critical intermediates have limits for the specified and unspecified impurities and also the impurity profile for the final active pharmaceutical ingredient (API).

 Which are the Levothyroxine related Impurities?

Several impurities of Levothyroxine have been isolated and purified by synthetic chemical methods and analytical techniques and are reported in pharmacopeia and also Levothyroxine is available at Veeprho as EP and USP Pharmacopeial and nonpharmacopeial impurities.


Levothyroxine EP Impurity A / Liothyronine Acid
CAS No.: 6893-02-03 
Molecular Weight: 650.97
IUPAC Name: (2S)-2-amino-3-[4-(4-hydroxy-3-iodophenoxy)-3, 5-diiodophenyl]propanoic acid
Levothyroxine EP Impurity A (Na salt) / Levothyroxine Sodium (Na salt)
CAS No.: 55-06-1
Molecular Weight: 672.96 g/mol
IUPAC Name: Sodium (2S)-2-amino-3-[4-(4-hydroxy-3-iodophenoxy)-3, 5-diiodophenyl]propanoate
Levothyroxine EP Impurity B / Levothyroxine Chloro Impurity / 3-Chloro Thyroxine
CAS No.: 1628720-66-0
Molecular Weight: 685.42
IUPAC Name: (2S)-2-Amino-3-[4-(3-chloro-4-hydroxy-5-iodophenoxy)-3, 5-diiodophenyl]propanoic acid  
Levothyroxine EP Impurity C / T3-Acetic Acid / Liothyronine EP Impurity C
CAS No.: 51-24-1
Molecular Weight: 621.93
IUPAC Name: [4-(4-Hydroxy-3-iodophenoxy)-3, 5-diiodophenyl]acetic acid 
Levothyroxine EP Impurity D / Levothyroxine Tetraiodothyrolactic Acid / Liothyronine EP Impurity D
CAS No.: N/A
Molecular Weight: 747.83
IUPAC Name: 4-(4-Hydroxy-3, 5-diiodophenoxy)-3, 5-diiodobenzeneacetic Acid
Levothyroxine EP Impurity E / Diiodothyronine
CAS No.: 1041-01-06
Molecular Weight: 525.08
IUPAC Name: (2S)-2-Amino-3-[4-(4-hydroxyphenoxy)-3, 5-diiodophenyl]- propanoic acid.  
Levothyroxine EP Impurity F / Levothyroxine T6 Impurity (USP)
CAS No.:911661-90-0
Molecular Weight: 1120.76
IUPAC Name:(2S)-2-Amino-3-[4-[4-(4-hydroxy-3, 5-diiodophenoxy)-3, 5-diiodophenoxy]-3, 5-diiodophenyl]propanoic acid  
Levothyroxine EP Impurity H / T4-Benzonic Acid
CAS No.: 2055-97-2
Molecular Weight: 733.8
IUPAC Name: 4-(4-hydroxy-3, 5-diiodophenoxy)-3, 5-diiodobenzoic acid
Levothyroxine EP Impurity I / Levothyroxine T4 Aldehyde
CAS No.: 2016-06-0
Molecular Weight: 717.8
IUPAC Name: 4-(4-Hydroxy-3, 5-diiodophenoxy)-3, 5-diiodobenzaldehyde
Levothyroxine EP Impurity J / O-(4-Hydroxy3-Iodophenyl)-Levothyroxine
CAS No.: 4604-41-5
Molecular Weight: 525.08
IUPAC Name: (2S)-2-Amino-3-[4-(4-hydroxy-3-iodophenoxy)-3-iodophenyl] propanoic acid  
Levothyroxine EP Impurity K / 3, 3’, 5’-Triiodo-L-Thyronine
CAS No.: 5817-39-0
Molecular Weight: 650.97
IUPAC Name: (2S)-2-Amino-3-[4-(4-hydroxy-3, 5-diiodophenoxy)-3-iodophenyl] propanoic acid   
Levothyroxine Impurity 10
CAS No.: 909279-46-5
Molecular Weight: 685.43
IUPAC Name: 3-[3-Chloro-4(4-hydroxy-3, 5-diodophenoxy)-5-iodopheyl]-L-Alanine  
Levothyroxine Impurity 30 sodium salt
CAS No.: N/A
Molecular Weight: 812.88 g/mol
IUPAC Name: sodium (S)-2-amino-3-(4-(3, 5-diiodo-4-methoxyphenoxy)-3, 5-diiodophenyl)propanoate
Levothyroxine Acetamide Impurity / Levothyroxine T4-Acetamide (USP)
CAS No.: 176258-88-1
Molecular Weight:
2-(4-(4-Hydroxy-3, 5-diiodophenoxy)-3, 5-diiodophenyl)acetamide
Levothyroxine Ethyl Ester
CAS No.: 76353-71-4
Molecular Weight: 804.92
IUPAC Name: O-(4-Hydroxy-3, 5-diiodophenyl)-3, 5-diiodo-L-tyrosine Ethyl Ester  
Levothyroxine Beta Hydroxy / Levothyroxine Impurity 21 / b-Hydroxy-T4
CAS No.: 107849-54-7 
Molecular Weight: 792.87 
IUPAC Name: O-(4-Hydroxy-3, 5-diiodophenyl)-3, 5-diiodo-beta-hydroxy-L- Tyrosine 
Levothyroxine Lactose Adduct
CAS No.: N/A 
Molecular Weight: 1101.15
IUPAC Name: (S)-2-(((2R, 3R, 4R, 5S, 6R)-3, 4-Dihydroxy-6-(hydoxymethyl)-5-(((2S, 3R, 4S, 5R, 6R)-3, 4, 5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)tetrahydro-2H-pyran-2-yl)amino)-3-(4-(4-hydroxy-3, 5-diiodophenoxy)-3, 5-diiodophenyl)propanoic Acid
Levothyroxine N-Methylamide
CAS No.: 2088032-52-2
Molecular Weight: 789.91
IUPAC Name: (S)-2-Amino-3-[4-(4-hydroxy-3, 5-diiodophenoxy)-3, 5-diiodophenyl]-Nmethylpropanamide  
Levothyroxine N-Formyl Impurity / N-Formyl-T4 (USP)
CAS No.: 671235-41-9
Molecular Weight: 804.88
IUPAC Name: N-Formyl-O-(4-hydroxy-3, 5-diiodophenyl)-3, 5-diiodo-L-tyrosine  
Levothyroxine N-Acetyl Impurity / N-Acetyl-T4 (USP)
CAS No.: 26041-51-0
Molecular Weight: 818.91
IUPAC Name: N-Acetyl-O-(4-hydroxy-3, 5-diiodophenyl)-3, 5-diiodo-L-tyrosine
Levothyroxine O-Methyl Impurity
CAS No.: N/A
Molecular Weight: 790.17
IUPAC Name: 2-amino-3-(4-(3, 5-diiodo-4-methoxyphenoxy)-3, 5-diiodophenyl) propanoic acid
Levothyroxine T4-Amine O-Methyl / Levothyroxine O-Methyl-Tetraiodothyroethylamine
CAS No.: N/A
Molecular Weight: 746.84
IUPAC Name: 2-[4-(3, 5-Diiodo-4-methoxyphenoxy)-3, 5-diiodophenyl]ethanamine
Levothyroxine T4-Hydroxyacetic Acid Impurity
CAS No.: 93647-48-4
Molecular Weight: 763.89
IUPAC Name: 2-hydroxy-2-(4-(4-hydroxy-3, 5-diiodophenoxy)-3, 5-diiodophenyl) acetic acid 
Levothyroxine T4-Formic Acid N-Methyl Amide
CAS No.: N/A
Molecular Weight: 746.84
IUPAC Name: 4-(4-Hydroxy-3, 5-diiodophenoxy)-3, 5-diiodo-N-methylbenzamide  
3,5,3’,5’-Tetraiodo Thyrolactic Acid
CAS No.: 7069-47-8
Molecular Weight: 777.9
IUPAC Name: 3-[4-(4-Hydroxy-3, 5-diiodophenoxy)-3, 5-diiodophenyl]lactic Acid
4-(4-hydroxy-3-iodophenoxy)-3, 5-diiodobenzoic acid
CAS No.: 607.90 g/mol
Molecular Weight: 607.90 g/mol
IUPAC Name: 4-(4-hydroxy-3-iodophenoxy)-3, 5-diiodobenzoic acid    

Levothyroxine is available both as a generic version and as a brand. As per the FDA Levothyroxine is the most broadly prescribed drug in the United States. Levothyroxine is also known as L-thyroxine and is a synthetic form of the thyroid hormone thyroxine (T4). Levothyroxine is available in the form of tablets, intramuscular injections, and also as a solution for intravenous infusion. Several impurities of Levothyroxine have been isolated and reported.


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