An investigation into the influence of experimental conditions on in vitro drug release from immediate-release tablets of levothyroxine sodium and its relation to oral bioavailability
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The aim of this study was to investigate the influence of experimental conditions on levothyroxine sodium release from two immediate-release tablet formulations which narrowly passed the standard requirements for bioequivalence studies. The in vivo study was conducted as randomised, single-dose, two-way cross-over pharmacokinetic study in 24 healthy subjects. The in vitro study was performed using various dissolution media, and obtained dissolution profiles were compared using the similarity factor value. Drug solubility in different media was also determined. The in vivo results showed narrowly passing bioequivalence. Considering that levothyroxine sodium is classified as Class III drug according to the Biopharmaceutics Classification System, drug bioavailability will be less sensitive to the variation in its dissolution characteristics and it can be assumed that the differences observed in vitro in some of investigated media probably do not have significant influence on the absorption process, as long as rapid and complete dissolution exists. The study results indicate that the current regulatory criteria for the value of similarity factor in comparative dissolution testing, as well as request for very rapid dissolution (more than 85% of drug dissolved in 15 min), are very restricted for immediate-release dosage forms containing highly soluble drug substance and need further investigation. The obtained results also add to the existing debate on the appropriateness of the current bioequivalence standards for levothyroxine sodium products.
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The dissolution-pH profile of LT4 tablets is V-shaped: solubility at 30 minutes is approximately 100% at pH 1.2 and 2.4, decreases to less than 60% at pH 4.0, reaches a nadir at pH 5.0 where dissolution at 60 minutes is less than 40%, and increases to 80% to 85% at pH 8.0.
“As revealed in in vitro studies by Kocic et al and Pabla et al, the dissolution–pH profile is V-shaped (15, 16). The solubility of LT4 tablets at 30 minutes is approximately 100% at pH 1.2 and 2.4. Its solubility decreases substantially to less than 60% at pH 4.0, regardless of the brand. The nadir is reached at pH 5.0, where the percentage of dissolution at 60 minutes decreases to less than 40%.”
From Levothyroxine: conventional and novel drug delivery formulations. (2023) · cites this paper as [15]
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- Authors
- Kocic, I., Homsek, I., Dacevic, M., Parojcic, J., & Miljkovic, B.
- Corresponding author
- Kocic, Ivana
- Venue
- AAPS PharmSciTech
- Published
- 2011-07-12
- Volume
- 12
- Issue
- 3
- Pages
- 938-48
- ISSN
- 1530-9932 (ISSN-L)
- PMC
- PMC3167270
- OpenAlex
- W1972544999
- Cited by
- 19
- References
- 37
- Citations by year
- 2026: 1 · 2025: 2 · 2023: 2 · 2022: 1 · 2021: 2 · 2020: 1 · 2018: 3 · 2016: 1 · 2014: 1 · 2013: 3 · 2012: 2
- FWCI
- 1.18
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- AAPS PharmSciTech (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- FarFar - Pharmacy Repository (submittedVersion, other-oa)
- Topics
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Drug Solubulity and Delivery Systems
- Physical Sciences › Chemistry › Analytical Chemistry › Analytical Methods in Pharmaceuticals
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Advanced Drug Delivery Systems
- Keywords
- levothyroxine sodium, immediate release tablets, in vitro drug release, oral bioavailability, bioequivalence, dissolution media, similarity factor, dissolution testing, drug solubility, Biopharmaceutics Classification System, pharmacokinetics, thyroid hormone replacement
- MeSH terms
- Administration, Oral, Adult, Biological Availability, Biopharmaceutics, Female, Half-Life, Humans, Male, Middle Aged, Solubility, Tablets, Technology, Pharmaceutical, Therapeutic Equivalency, Thyroxine, Triiodothyronine, Cross-Over Studies, Area Under Curve
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