Compression-Induced Polymorphic Transformation in Tablets: Role of Shear Stress and Development of Mitigation Strategies

Naveen K. Thakral, Seema Thakral, Gregory A. Stephenson, Robert Sedlock, Raj Suryanarayanan

Research output: Contribution to journalArticlepeer-review

12 Scopus citations


Our goals were to evaluate the effects of (i) hydrostatic pressure alone and (ii) its combined effect with shear stress during compaction, on the polymorphic transformation (form C → A) of a model drug, chlorpropamide. The powder was either subjected to hydrostatic pressure in a pressure vessel or compressed in a tablet press, at pressures ranging from 25 to 150 MPa. The overall extent of phase transformation was determined by powder X-ray diffractometry, whereas 2D-X-ray diffractometry enabled quantification of the spatial distribution of phase composition in tablets. Irrespective of the pressure, the extent of transformation following compaction was higher than that because of hydrostatic pressure alone, the difference attributed to the contribution of shear stress experienced during compaction. At a compression pressure of 25 MPa, there was a pronounced gradient in the extent of phase transformation when monitored from radial tablet surface to core. This gradient decreased with increase in compression pressure. Four approaches were attempted to minimize the effect of compression-induced phase transformation: (a) site-specific lubrication, (b) use of a viscoelastic excipient, (c) ceramic-lined die, and (d) use of cavity tablet. The ceramic-lined die coupled with site-specific lubrication was most effective in minimizing the extent of compression-induced phase transformation.

Original languageEnglish (US)
Pages (from-to)476-484
Number of pages9
JournalJournal of Pharmaceutical Sciences
Issue number1
StatePublished - Jan 2019

Bibliographical note

Funding Information:
The work was partially supported by the William and Mildred Peters Endowment Fund. NT was a recipient of the Lilly Innovation Fellowship Award. Dr. Mark E. Zimmerman, Department of Earth Sciences, is thanked for his help with the hydrostatic pressure experiments. Parts of this work were carried out in the Characterization Facility, University of Minnesota, which receives partial support from NSF through the MRSEC program.

Publisher Copyright:
© 2019 American Pharmacists Association®


  • hydrostatic pressure
  • phase transformation
  • shear stress
  • tablet
  • viscoelastic excipients


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