Salt Disproportionation in the Solid State: Role of Solubility and Counterion Volatility

Naveen K. Thakral, Robert J. Behme, Aktham Aburub, Jeffrey A. Peterson, Timothy A. Woods, Benjamin A. Diseroad, Raj Suryanarayanan, Gregory A. Stephenson

Research output: Contribution to journalArticlepeer-review

23 Scopus citations


Disproportionation propensity of salts (HCl, HBr, heminapadisylate) and adipic acid cocrystal of corticotropin releasing hormone receptor-1 antagonist was studied using model free kinetics. Using thermogravimetic weight loss profile or heat flow curves from differential scanning calorimetry, an activation energy plot for salts and cocrystal was generated based on model free kinetics. This activation energy of disproportionation provided qualitative information about the solid state salt stability. To ensure the stability throughout the shelf life, “prototype” formulations of salts and cocrystal in tablet form were stored at 40 °C and several water vapor pressures. Disproportionation kinetics were studied in these prototype tablet formulations using two-dimensional X-ray diffractometry. Formulations containing the adipic acid cocrystal or heminapadisylate salt did not show disproportionation of API when stored at 40 °C/75% RH for 300 days. On the other hand, formulations containing HCl or HBr salt disproportionated. Though isostructural, the disproportionation propensity of HBr and HCl salts was quite different. The HCl salt highlighted the important role that volatility of the counterion plays in the physical stability of the formulations. Solution state stability (i.e., in dissolution medium) of salts and cocrystal was also assessed and compared with solid state stability, by determining their solubility at different pH’s, and intrinsic dissolution rate.

Original languageEnglish (US)
Pages (from-to)4141-4151
Number of pages11
JournalMolecular pharmaceutics
Issue number12
StatePublished - Dec 5 2016

Bibliographical note

Funding Information:
N.K.T. was sponsored by the Lilly Innovation Fellowship Award. The work was partially supported by the William and Mildred Peters Endowment Fund. The authors thank Jeremy Merritt for the consultations and enlightening discussion. Use of the Advanced Photon Source was supported by the U.S. Department of Energy, Office of Science, Office of Basic Energy Science, under Contract No. 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.

Publisher Copyright:
© 2016 American Chemical Society.


  • X-ray diffractometry
  • cocrystal
  • counterion
  • disproportionation
  • intrinsic dissolution
  • model free kinetics
  • salt
  • solubility
  • volatilization


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