Impact of hydration state and molecular oxygen on the chemical stability of levothyroxine sodium
Abstract
Levothyroxine sodium is an important medication used primarily for treating patients with hypothyroidism. Levothyroxine sodium tablets have been recalled many times since their 1955 introduction to the US market. These recalls resulted from the failure of lots to meet their content uniformity and potency specifications. The purpose of this study is to test the hypothesis that the chemical stability of levothyroxine sodium pentahydrate is compromised upon exposing the dehydrated substance to molecular oxygen. The impact of temperature, oxygen and humidity storage conditions on the stability of solid-state levothyroxine sodium was examined. After exposure to these storage conditions for selected periods of time, high performance liquid chromatography (HPLC) was used to quantify the formation of impurities. The results showed that levothyroxine sodium samples degraded significantly over a 32-day test period when subjected to dry conditions in the presence of molecular oxygen. However, dehydrated samples remained stable when oxygen was removed from the storage chamber. Furthermore, hydrated samples were stable in the presence of oxygen and in the absence of oxygen. These results reveal conditions that will degrade levothyroxine sodium pentahydrate and elucidate measures that can be taken to stabilize the drug substance.
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Exposure to sunlight, high temperatures, humidity, and oxygen significantly accelerates the degradation of LT4 tablets.
“Exposure to sunlight, high temperatures, humidity, and oxygen significantly accelerates the degradation of LT4 tablets (121, 122).”
From Levothyroxine: conventional and novel drug delivery formulations. (2023) · cites this paper as [122]
Cites
Gaddum, J. H. (1955) · Nature · doi:10.1038/1761186b0 · Cited by 902 · see citing works
Roberts, C. G., & Ladenson, P. W. (2004) · The Lancet · doi:10.1016/s0140-6736(04)15696-1 · Cited by 567 · see citing works
Drug stability : principles and practices
Carstensen, J. T. (1995) · Medical Entomology and Zoology · Cited by 277 · see citing works
Hydrolysis in Pharmaceutical Formulations
Waterman, K. C., Adami, R. C., Alsante, K. M., Antipas, A. S., Arenson, D., Carrier, R. L., Hong, J., Landis, M. S., Lombardo, F., Shah, J. C., et al. (2002) · Pharmaceutical Development and Technology · doi:10.1081/pdt-120003494 · Cited by 162 · see citing works
Treatment of Hypothyroidism: A Reappraisal of Thyroxine Therapy
Evered, D., Young, E. T., Ormston, B. J., Menzies, R., Smith, P., & Hall, R. (1973) · BMJ · doi:10.1136/bmj.3.5872.131 · Cited by 104 · see citing works
Formulation and Analytical Development for Low‐Dose Oral Drug Products
(2008) · Wiley eBooks · doi:10.1002/9780470386361 · Cited by 82 · see citing works
Kinetics of degradation of levothyroxine in aqueous solution and in solid state
Won, C. M. (1992) · Pharmaceutical Research · doi:10.1023/a:1018952415732 · Cited by 69 · see citing works
Recent Advances in the Impurity Profiling of Drugs
Bartos, D., & Gǒrög, S. (2008) · Current Pharmaceutical Analysis · doi:10.2174/157341208786306199 · Cited by 66 · see citing works
Influence of Formulation and Processing Factors on Stability of Levothyroxine Sodium Pentahydrate
Collier, J. W., Shah, R. B., Gupta, A., Sayeed, V. A., Habib, M. J., & Khan, M. A. (2010) · AAPS PharmSciTech · doi:10.1208/s12249-010-9434-8 · Cited by 56 · see citing works
The effect of excipients on the stability of levothyroxine sodium pentahydrate tablets
Patel, H., Stalcup, A., Dansereau, R., & Sakr, A. (2003) · International Journal of Pharmaceutics · doi:10.1016/s0378-5173(03)00387-9 · Cited by 55 · see citing works
Gika, H., Samanidou, V., & Papadoyannis, I. N. (2004) · Journal of Chromatography B · doi:10.1016/j.jchromb.2004.10.025 · Cited by 53 · see citing works
The Stabilizing Effect of Moisture on the Solid-State Degradation of Gabapentin
Zong, Z., Desai, S. D., Kaushal, A. M., et al. (2011) · AAPS PharmSciTech · doi:10.1208/s12249-011-9652-8 · Cited by 44 · see citing works
Drug Stability: Principles and Practices
McGinity, J. W. (1991) · Journal of Pharmaceutical Sciences · doi:10.1002/jps.2600800127 · Cited by 42 · see citing works
Jian-ping, D., & Hoag, S. W. (2001) · Pharmaceutical Development and Technology · doi:10.1081/pdt-100000742 · Cited by 41 · see citing works
EFFECT OF EXCIPIENTS ON THE STABILITY OF LEVOTHYROXINE SODIUM TABLETS
Gupta, V. D., Odom, C., Bethea, C., & Plattenburg, J. (1990) · Journal of Clinical Pharmacy and Therapeutics · doi:10.1111/j.1365-2710.1990.tb00393.x · Cited by 18 · see citing works
Katrusiak, A., & Katrusiak, A. (2004) · Journal of Pharmaceutical Sciences · doi:10.1002/jps.20155 · Cited by 18 · see citing works
André, M., Domanig, R., Riemer, E., Moser, H.-P., & Groeppelin, A. (1996) · Journal of Chromatography A · doi:10.1016/0021-9673(95)01007-6 · Cited by 14 · see citing works
Interactions of Moisture with Solids
(2000) · Drugs and the pharmaceutical sciences · doi:10.1201/b14011-8 · Cited by 4 · see citing works
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Levothyroxine: conventional and novel drug delivery formulations.
Liu, H., Li, W., Zhang, W., Sun, S., & Chen, C. (2023) · Endocrine Reviews · doi:10.1210/endrev/bnac030 · Cited by 63 · see citing works
Poly(caprolactone)-based subcutaneous implant for sustained delivery of levothyroxine
Stewart, S. A., Domínguez-Robles, J., Utomo, E., Picco, C. J., Corduas, F., Mancuso, E., Amir, M. N., Bahar, M. A., Sumarheni, S., Donnelly, R. F., et al. (2021) · International Journal of Pharmaceutics · doi:10.1016/j.ijpharm.2021.121011 · Cited by 35 · see citing works
Ledeți, I., Romanescu, M., Cîrcioban, D., Ledeți, A., Vlase, G., Vlase, T., Suciu, O., Murariu, M., Olariu, S., Matusz, P., et al. (2020) · Pharmaceutics · doi:10.3390/pharmaceutics12010058 · Cited by 23 · see citing works
Levothyroxine sodium pentahydrate tablets – formulation considerations
Kaur, N., & Suryanarayanan, R. (2021) · Journal of Pharmaceutical Sciences · doi:10.1016/j.xphs.2021.08.006 · Cited by 19 · see citing works
Investigating the influence of excipients on the stability of levothyroxine sodium pentahydrate
Kaur, N., & Suryanarayanan, R. (2021) · Molecular Pharmaceutics · doi:10.1021/acs.molpharmaceut.1c00217 · Cited by 13 · see citing works
- Authors
- Hamad, M. L., Engen, W., & Morris, K. R.
- Affiliations
- University of Hawaii at Hilo (US)
- Corresponding author
- Hamad, Mazen Lee
- ORCID
- Morris, Kenneth R.
- Venue
- Pharmaceutical Development and Technology
- Publisher
- Informa UK Limited
- Published
- 2013-12-03
- Volume
- 20
- Issue
- 3
- Pages
- 314-319
- ISSN
- 1083-7450 (ISSN-L)
- 1097-9867
- OpenAlex
- W2046768387
- Cited by
- 14
- References
- 18
- Citations by year
- 2025: 1 · 2024: 1 · 2022: 2 · 2021: 4 · 2020: 2 · 2019: 2 · 2018: 1 · 2015: 1
- FWCI
- 0.32
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Pharmaceutical Development and Technology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- University of Hawai'i at Hilo
- National Center for Research Resources (P20RR016467)
- Topics
- Physical Sciences › Chemistry › Analytical Chemistry › Analytical Methods in Pharmaceuticals
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Pharmaceutical Quality and Counterfeiting
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein purification and stability
- Keywords
- levothyroxine sodium, chemical stability, drug degradation, molecular oxygen, hydration status, storage conditions, impurity formation, content uniformity
- MeSH terms
- Chromatography, High Pressure Liquid, Drug Stability, Drug Storage, Humidity, Oxygen, Tablets, Temperature, Thyroxine, Time Factors
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