A comparative pH-dissolution profile study of selected commercial levothyroxine products using inductively coupled plasma mass spectrometry

Pabla, Dimple; Akhlaghi, Fatemeh; Zia, Hossein

doi:10.1016/j.ejpb.2008.10.008

Cited by 124Drug Solubulity and Delivery SystemsAnalytical Methods in PharmaceuticalsThyroid Disorders and Treatments

A comparative pH-dissolution profile study of selected commercial levothyroxine products using inductively coupled plasma mass spectrometry

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Pabla, Dimple, Akhlaghi, Fatemeh, Zia, Hossein·2009·European Journal of Pharmaceutics and Biopharmaceutics

DOI 10.1016/j.ejpb.2008.10.008

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Abstract

Levothyroxine (T4) is a narrow therapeutic index drug with classic bioequivalence problem between various available products. Dissolution of a drug is a crucial step in its oral absorption and bioavailability. The dissolution of T4 from three commercial solid oral dosage forms: Synthroid (SYN), generic levothyroxine sodium by Sandoz Inc. (GEN) and Tirosint (TIR) was studied using a sensitive ICP-MS assay. All the three products showed variable and pH-dependent dissolution behaviors. The absence of surfactant from the dissolution media decreased the percent T4 dissolved for all the three products by 26-95% (at 30 min). SYN dissolution showed the most pH dependency, whereas GEN and TIR showed the fastest and highest dissolution, respectively. TIR was the most consistent one, and was minimally affected by pH and/or by the presence of surfactant. Furthermore, dissolution of T4 decreased considerably with increase in the pH, which suggests a possible physical interaction in patients concurrently on T4 and gastric pH altering drugs, such as proton pump inhibitors. Variable dissolution of T4 products can, therefore, impact the oral absorption and bioavailability of T4 and may result in bioequivalence problems between various available products.

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Pabla et al. noted rapid and efficient in vitro dissolution of gel capsules at low pH concentrations.
“Pabla et al. (110) studied in vitro dissolution of gel capsules and noted rapid and efficient dissolution at low pH concentrations.”
From Guidelines for the Treatment of Hypothyroidism: Prepared by the American Thyroid Association Task Force on Thyroid Hormone Replacement (2014) · cites this paper as [110]
In vitro evidence shows pH variations of the medium interfere with T4 dissolution.
“Evidence has been provided in vitro that pH variations of the medium interfere with T4 dissolution (48).”
From ETA guidelines for the use of levothyroxine sodium preparations in monotherapy to optimize the treatment of hypothyroidism (2025) · cites this paper as [48]
Novel formulations, such as liquid solutions and soft gel capsules, do not require dissolution, and are thus more efficient for hypothyroidism therapy.
“Novel formulations, such as liquid solutions and soft gel capsules, do not require dissolution, and are thus more efficient for hypothyroidism therapy (16).”
From Levothyroxine: conventional and novel drug delivery formulations. (2023) · cites this paper as [16]
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 [16]

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Authors: Pabla, D., Akhlaghi, F., & Zia, H.
Affiliations: University of Rhode Island (US)
Corresponding author: Zia, Hossein
ORCID: Akhlaghi, Fatemeh
Venue: European Journal of Pharmaceutics and Biopharmaceutics
Publisher: Elsevier BV
Published: 2009-05
Volume: 72
Issue: 1
Pages: 105-110
ISSN: 0939-6411 (ISSN-L)
DOI: 10.1016/j.ejpb.2008.10.008
OpenAlex: W1985550170
Cited by: 124
References: 26
Citations by year: 2026: 1 · 2025: 4 · 2024: 9 · 2023: 5 · 2022: 9 · 2021: 10 · 2020: 5 · 2019: 6 · 2018: 8 · 2017: 11 · 2016: 9 · 2015: 6 · 2014: 13 · 2013: 10 · 2012: 9
FWCI: 1.87
Type: journal article
Language: en
Open access: green
digitalcommons.uri.edu
Licence: cc-by
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations: European Journal of Pharmaceutics and Biopharmaceutics (publishedVersion)
PubMed (publishedVersion)
Journal of Media Literacy Education (submittedVersion, cc-by)
Funders: Sandoz
National Center for Research Resources (P20 RR 16457, P20RR016457)
Topics: Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Drug Solubulity and Delivery Systems
Physical Sciences › Chemistry › Analytical Chemistry › Analytical Methods in Pharmaceuticals
Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
Keywords: levothyroxine, dissolution profile, pH-dependent dissolution, bioequivalence, generic drugs, surfactant effects, proton pump inhibitors, oral absorption, thyroid hormones
MeSH terms: Administration, Oral, Biological Availability, Chemistry, Pharmaceutical, Hydrogen-Ion Concentration, Models, Chemical, Sodium Dodecyl Sulfate, Solubility, Mass Spectrometry, Surface-Active Agents, Therapeutic Equivalency, Thyroxine, Time Factors, Drug Design, Models, Statistical

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A comparative pH-dissolution profile study of selected commercial levothyroxine products using inductively coupled plasma mass spectrometry

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