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:
CAS No.: 51-48-9
Molecular Weight: 776.87 g/mol
Molecular Formula: C15H11I4NO4
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.
LIST OF LEVOTHYROXINE 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: 746.84 IUPAC Name: 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.
References:
- “Levothyroxine Sodium”. The American Society of Health-System Pharmacists. Archived from the original on 21 December 2016. Retrieved 8 December 2016.
- King, Tekoa L.; Brucker, Mary C. (2010). Pharmacology for Women’s Health. Jones & Bartlett Publishers. p. 544. ISBN 9781449658007. Archived from the original on 10 September 2017.
- Moore, Thomas. “Monitoring FDA MedWatch Reports Signals for Dabigatran and Metoclopramide” (PDF). QuarterWatch. Institute for Safe Medication Practices. Archived (PDF) from the original on 25 September 2013. Retrieved 20 April 2014
- World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl:10665/325771. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
- https://go.drugbank.com/drugs/DB00451
- https://www.fda.gov/drugs/news-events-human-drugs/real-world-case-study-levothyroxine-use-addresses-institutional-concerns-about-generic-product
