Levothyroxine sodium pentahydrate (LSP; C15H10I4NNaO4·5H2O) gradually loses one molecule of water of crystallization as the water vapor pressure is decreased from 90% to 15% RH (40 °C), a behavior characteristic of nonstoichiometric hydrates. LSP loses four molecules of water of crystallization to form levothyroxine sodium monohydrate (LSM; C15H10I4NNaO4·H2O) under realistic storage conditions (40 °C/0% RH for 3 h). The crystal structure of LSP was determined following which the specimen was partially dehydrated in situ to form LSM. The crystal structure of LSM provided insight into its potential for high reactivity. Thus, its presence in a drug product is undesirable. In LSP-oxalic acid mixtures stored in a hermetic container at 40 °C, there was moisture transfer from drug to excipient. Synchrotron X-ray diffractometry revealed dehydration of LSP resulting in LSM, while anhydrous oxalic acid transformed to its dihydrate. In formulations of LSP, chemical degradation of levothyroxine sodium may be preceded by its partial dehydration.
Bibliographical noteFunding Information:
The project was partially funded by the William and Mildred Peters Endowment Fund. This research used resources of the Advanced Photon Source, a U.S. Department of Energy (DOC) Office of Science User Facility operated for the DOE Office of Science by Argonne National Laboratory under Contract DE-AC02-06CH11357. Parts of this work were carried out in the Characterization Facility, University of Minnesota, which receives partial support from NSF through the MRSEC program. The Bruker-AXS D8 Venture diffractometer was purchased through a grant from NSF/MRI ( Grant 1229400) and the University of Minnesota. We thank Andrew Goode and Dr. Vadim Gurvich for their help with the HPLC work. We acknowledge Dr. John Ellis, Dr. Kenneth Morris, Dr. Paroma Chakravarty, and Dr. Naga Duggirala for helpful discussions.
- chemical stability
- crystal structure
- drug product
- levothyroxine sodium
- physical form
PubMed: MeSH publication types
- Journal Article
- Research Support, U.S. Gov't, Non-P.H.S.
- Research Support, Non-U.S. Gov't