Levothyroxine sodium pentahydrate tablets – formulation considerations
Abstract
Even though levothyroxine sodium pentahydrate tablets have been in the market since 1955, there continue to be recalls due to sub potency. We have comprehensively reviewed the factors affecting its stability in solid oral dosage forms. A compilation of marketed formulation compositions enabled the identification of the potential 'problem excipients'. Two excipient properties, hygroscopicity and microenvironmental acidity, appeared to be responsible for inducing drug instability. In drug products, depending on the formulation composition and storage conditions, the pentahydrate can dehydrate to highly reactive levothyroxine sodium monohydrate, or undergo salt disproportionation to the free acid form of the drug. The USP assay method (HPLC based) is insensitive to these different physical forms of the drug. The influence of physical form of levothyroxine on its chemical stability is incompletely understood. The USP has five product-specific dissolution tests reflecting the complexity in its evaluation.
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LT4 is one of the most frequently recalled products from the market in several countries, mostly for issues in maintaining potency during shelf life.
“LT4 is even one of the most frequently recalled products from the market in several countries, mostly for issues in maintaining potency during the shelf life (26).”
From ETA guidelines for the use of levothyroxine sodium preparations in monotherapy to optimize the treatment of hypothyroidism (2025) · cites this paper as [26]
Gradual loss of non-stoichiometric five crystal water molecules yielding LT4 monohydrate occurs under realistic storage conditions and, along with light exposure and high temperatures, may contribute to chemical decomposition of LT4.
“A further factor influencing stability and decomposition of LTSS is the gradual loss of the non-stoichiometric number of five crystal water molecules yielding LT4 monohydrate. This process already occurs under realistic storage conditions, and along with light exposure and high temperatures, may contribute to the chemical decomposition of LT4 (26).”
From ETA guidelines for the use of levothyroxine sodium preparations in monotherapy to optimize the treatment of hypothyroidism (2025) · cites this paper as [26]
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Thyroxine replacement therapy's effect on preserving hearing after total thyroidectomy
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- Authors
- Kaur, N., & Suryanarayanan, R.
- Affiliations
- University of Minnesota (US)
- Corresponding author
- Suryanarayanan, Raj
- Venue
- Journal of Pharmaceutical Sciences
- Publisher
- Elsevier BV
- Published
- 2021-12
- Volume
- 110
- Issue
- 12
- Pages
- 3743-3756
- ISSN
- 0022-3549 (ISSN-L)
- OpenAlex
- W3191883233
- Cited by
- 19
- References
- 237
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 5 · 2023: 6 · 2022: 3
- FWCI
- 0.42
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Pharmaceutical Sciences (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Physical Sciences › Chemistry › Analytical Chemistry › Analytical Methods in Pharmaceuticals
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Pharmaceutical Quality and Counterfeiting
- Physical Sciences › Materials Science › Materials Chemistry › Crystallization and Solubility Studies
- Keywords
- tablet formulation, drug stability, drug recall, pharmaceutical excipients, hygroscopicity, dehydration, dissolution testing, storage conditions
- MeSH terms
- Drug Compounding, Drug Stability, Excipients, Solubility, Tablets, Thyroxine
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