Partial Dehydration of Levothyroxine Sodium Pentahydrate in a Drug Product Environment: Structural Insights into Stability

Abstract

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.

Keywords: chemical stability; crystal structure; drug product; levothyroxine sodium; physical form.