Investigation of spatial heterogeneity of salt disproportionation in tablets by synchrotron X-ray diffractometry

Sampada Koranne, Ramprakash Govindarajan, Raj Suryanarayanan

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22 Scopus citations


Tablets which were binary mixtures of pioglitazone hydrochloride (PioHCl) with magnesium stearate (MgSt), croscarmellose sodium (CCS), microcrystalline cellulose, or lactose monohydrate were prepared. Two sets of experiments, using intact tablets, were performed. (i) Tablets containing PioHCl (90% w/w) and MgSt were exposed to 25 or 40°C and 75% RH in a custom-built temperature/humidity chamber. In situ spatiotemporal mapping of disproportionation was performed by transmission-mode synchrotron X-ray diffractometry (SXRD; Argonne National Laboratories). Tablets were scanned in radial direction starting from the top edge of the tablet and moving, in increments of 300 μm, toward the center. There was evidence of disproportionation after 10 min (at 40°C). The reaction was initiated on the tablet surface and progressed toward the core. (ii) SXRD of tablets stored for a longer time (up to 15 days) enabled the simultaneous quantification of the reactants and products of disproportionation and provided insight into the reaction progression. The influence of sorbed water and microenvironmental acidity on the disproportionation reaction was investigated. The most pronounced reaction was observed in the presence of MgSt followed by CCS. The transformation was solution-mediated, and the spatial heterogeneity in disproportionation could be explained by the migration of sorbed water. There was a good correlation between microenvironmental acidity (pHeq) and extent of PioHCl disproportionation. (Graph Presented).

Original languageEnglish (US)
Pages (from-to)1133-1144
Number of pages12
JournalMolecular pharmaceutics
Issue number4
StatePublished - Apr 3 2017

Bibliographical note

Funding Information:
S.K. was partially funded by the 3M Science and Technology Fellowship. The project was partially supported by the William and Mildred Peters endowment fund. This research used resources of the Advanced Photon Source, a U.S. Department of Energy (DOE) Office of Science User Facility operated for the DOE Office of Science by Argonne National Laboratory under Contract No. DE-AC02-06CH11357. The SEM studies in this work were carried out in the Characterization Facility, University of Minnesota, which receives partial support from NSF through the MRSEC program. We thank Dr. Wenqian Xu for his help during the in situ synchrotron XRD experiments conducted at the 17BM beamline. Dr. Abhishek Telang is acknowledged for his technical inputs in designing the temperature and humidity controlled chamber. Finally, we thank Dr. Seema Thakral for her insightful comments that helped to improve the manuscript.

Publisher Copyright:
© 2017 American Chemical Society.


  • Disproportionation
  • Excipients
  • In situ X-ray diffractometry
  • Magnesium stearate
  • Microenvironmental acidity
  • Salt stability
  • Synchrotron
  • Tablet mapping
  • pH indicators


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