Investigating the influence of excipients on the stability of levothyroxine sodium pentahydrate
Abstract
O). LSP-excipient binary powder blends were stored under two conditions: (a) in hermetically sealed containers at 40 °C and (b) at 40 °C/75% RH. By use of synchrotron X-ray diffractometry, the disappearance of LSP could be quantified and the appearance of crystalline levothyroxine (free acid) could be identified. Under hermetically sealed conditions (40 °C) hygroscopic excipients such as povidone induced partial dehydration of LSP to form levothyroxine sodium monohydrate. When stored at 40 °C/75% RH, acidic excipients induced measurable disproportionation of LSP resulting in the formation of levothyroxine (free acid). HPLC analyses of drug-excipient mixtures revealed that lactose monohydrate, microcrystalline cellulose, and croscarmellose sodium caused pronounced chemical decomposition of LSP. On the other hand, magnesium stearate, sodium stearyl fumarate, and alkaline pH modifiers did not affect the physical and chemical stability of the API following storage at 40 °C/75% RH. HPLC, being a solution based technique, revealed chemical decomposition of the API, but the technique was insensitive to physical transformations. Excipient properties such as hygroscopicity and microenvironmental acidity were identified to be critical determinants of both physical and chemical stability of LSP in a drug product. For drugs exhibiting both physical and chemical transformations, simultaneous solid-state and solution based analyses will enable comprehensive stability evaluation.
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Acid excipients, such as lactose, mannitol, and sorbitol, can induce drug instability in tablets, while basic excipients can be added to improve the stability of LT4 tablets.
“Acid excipients, such as lactose, mannitol, and sorbitol, can induce drug instability in tablets (112, 113), while basic excipients can be added to improve the stability of LT4 tablets (114).”
From Levothyroxine: conventional and novel drug delivery formulations. (2023) · cites this paper as [112]
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“…of LT4 as a Class III drug (relatively high solubility and low permeability compounds) by Biopharmaceutics Classi fi cation System (BCS), several other factors markedly impact on the solubility and/or stability of the active ingredient, such as excipients in its pharmaceutic formulation (23, 24).”
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- Authors
- Kaur, N., & Suryanarayanan, R.
- Affiliations
- University of Minnesota (US)
- Corresponding author
- Suryanarayanan, Raj
- Venue
- Molecular Pharmaceutics
- Publisher
- American Chemical Society (ACS)
- Published
- 2021-06-01
- Volume
- 18
- Issue
- 7
- Pages
- 2683-2693
- ISSN
- 1543-8384 (ISSN-L)
- 1543-8392
- OpenAlex
- W3165501405
- Cited by
- 13
- References
- 52
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 2 · 2023: 1 · 2022: 2 · 2021: 2
- FWCI
- 0.88
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Molecular Pharmaceutics (publishedVersion)
- PubMed (publishedVersion)
- OSTI OAI (U.S. Department of Energy Office of Scientific and Technical Information) (submittedVersion)
- Funders
- National Science Foundation
- Argonne National Laboratory (DE-AC02-06CH11357)
- William and Mildred Peters Endowment Fund
- Topics
- Physical Sciences › Chemistry › Analytical Chemistry › Analytical Methods in Pharmaceuticals
- Physical Sciences › Materials Science › Materials Chemistry › Crystallization and Solubility Studies
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Drug Solubulity and Delivery Systems
- Keywords
- drug-excipient interaction, drug stability, polyvinylpyrrolidone, lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, magnesium stearate, sodium stearyl fumarate, pH modifiers, chemical decomposition, physical transformation, storage conditions
- MeSH terms
- Chemistry, Pharmaceutical, Drug Compounding, Drug Stability, Excipients, Powders, Tablets, Thyroxine, Water, Wettability
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