Solid-state properties of warfarin sodium 2-propanol solvate

Agam R. Sheth, William W. Brennessel, Victor G. Young, Francis X. Muller, David J.W. Grant

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18 Scopus citations


The goal of the present work was to understand the effect of relative humidity (RH) and temperature on the molecular structure, crystal structure, and physical properties of warfarin sodium 2-propanol solvate (W). After previous determination of the crystal structure of W, which corresponds to a 1:1 2-propanol solvate, the present work shows that W has a critical RH (60% ≤ RH0 ≤ 68%), below which minimal uptake of water occurs, due to surface adsorption, but above which gradual and continuous uptake of water occurs, due to deliquescence. Deliquescence begins at the surface and proceeds inward into the bulk of the crystal. Single crystal X-ray diffractometry indicates no change in the crystal and molecular structure of W during the initial stages of deliquescence. Studies of the unit cell and volume computations of W show that water can neither find space to enter the crystal lattice, nor can replace 2-propanol. Thus, water does not exchange with 2-propanol within the lattice, contrary to previous reports. Storage of single crystals of W at 120°C for 23 h produces shrinkage cracks along the needle (b) axis, which are interpreted as a reduction in d-spacing of the 00l planes. Thus, under thermal stress, W crystals undergo amorphization with concurrent loss of 2-propanol, which may proceed via an intermediate crystalline phase. The phase changes of W, which depend on RH and temperature, are explained at the molecular level.

Original languageEnglish (US)
Pages (from-to)2669-2680
Number of pages12
JournalJournal of Pharmaceutical Sciences
Issue number11
StatePublished - Nov 2004

Bibliographical note

Funding Information:
The authors thank Dr. Stuart McKernan and Dr. John Nelson, Characterization Facility, Institute of Technology, University of Minnesota, for assistance with microscopic studies and for helpful discussions. We also thank GlaxoSmithKline for partial financial support. In addition, we thank the University of Minnesota Supercomputing Institute for financially supporting their use of the Medicinal Chemistry/Supercomputing Institute Visualization Workstation Laboratory.


  • Amorphous
  • Crystal structure
  • Deliquescence
  • Solvate
  • X-ray diffractometry


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