AAPS PharmSciTech

, 20:39 | Cite as

New Insights on Solid-State Changes in the Levothyroxine Sodium Pentahydrate during Dehydration and its Relationship to Chemical Instability

  • Harsh S. Shah
  • Kaushalendra Chaturvedi
  • Mazen Hamad
  • Simon Bates
  • Ajaz Hussain
  • Kenneth MorrisEmail author
Research Article Theme: Team Science and Education for Pharmaceuticals: the NIPTE Model
Part of the following topical collections:
  1. Theme: Team Science and Education for Pharmaceuticals: the NIPTE Model


Levothyroxine sodium pentahydrate (LEVO) tablets have been on the US market since the mid-twentieth century and remain the most highly prescribed product. Unfortunately, levothyroxine sodium tablets have also been one of the most highly recalled products due to potency and dissolution failures on stability. In 2008, the assay limits were tightened, yet the recalls did not decline, which highlights the serious quality concerns remaining to be elucidated. The aim of the present investigation was to test the hypothesis that the solid-state physical instability of LEVO precedes the chemical instability leading to product failure. The failure mode was hypothesized to be the dehydration of the crystal hydrate, when exposed to certain humidity and temperature conditions, followed by the oxidation of the API through vacated channels. It was previously reported by the authors that LEVO degradation occurred in the presence of oxygen at a low relative humidity (RH). Furthermore, powder X-ray diffractometry shows changes in the crystal lattice of LEVO initially and through the dehydration stages. Storage of LEVO at RT and 40 °C at 4–6% RH for 12 days shows a decrease in d-spacing of the (00 l) planes. Based on a structure solution from the powder data of the dehydrated material, the basic packing motif persists to varying degrees even when fully dehydrated along with disordering. Therefore, the crystal structure changes of LEVO depend on RH and temperature and are now explicable at the structural level for the first time. This exemplifies the dire need for “new prior knowledge” in generic product development.


crystal structure hydrate powder X-ray diffraction new prior knowledge levothyroxine 



We gratefully thank the Lachman Institute for Pharmaceutical Analysis at Long Island University, NY for the financial support. We would like to thank William Engen for his earlier contributions to the chemical stability studies.


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Copyright information

© American Association of Pharmaceutical Scientists 2019

Authors and Affiliations

  • Harsh S. Shah
    • 1
  • Kaushalendra Chaturvedi
    • 1
  • Mazen Hamad
    • 2
  • Simon Bates
    • 3
  • Ajaz Hussain
    • 4
  • Kenneth Morris
    • 5
    • 6
    Email author
  1. 1.Department of Pharmaceutical Sciences, Arnold and Marie Schwartz College of PharmacyLong Island UniversityBrooklynUSA
  2. 2.Department of Chemistry, College of Natural and Health SciencesUniversity of Hawai’i at HiloHiloUSA
  3. 3.Triclinic Labs Inc.LafayetteUSA
  4. 4.The National Institute of Pharmaceutical Technology and Education (NIPTE)MinneapolisUSA
  5. 5.Lachman Institute for Pharmaceutical AnalysisLong Island UniversityBrooklynUSA
  6. 6.Arnold and Marie Schwartz College of Pharmacy and Health SciencesLong Island University – Brooklyn CampusBrooklynUSA

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