Pharmaceutical Research

, Volume 32, Issue 9, pp 3110–3118 | Cite as

Salt Stability – The Effect of pHmax on Salt to Free Base Conversion

  • Yi-Ling Hsieh
  • Jeremy M. Merritt
  • Weili Yu
  • Lynne S. TaylorEmail author
Research Paper



The aim of this study was to investigate how the disproportionation process can be impacted by the properties of the salt, specifically pHmax.


Five miconazole salts and four sertraline salts were selected for this study. The extent of conversion was quantified using Raman spectroscopy. A mathematical model was utilized to estimate the theoretical amount of conversion.


A trend was observed that for a given series of salts of a particular basic compound (both sertraline and miconazole are bases), the extent of disproportionation increases as pHmax decreases. Miconazole phosphate monohydrate and sertraline mesylate, although exhibiting significantly different pHmax values (more than 2 units apart), underwent a similar extent of disproportionation, which may be attributed to the lower buffering capacity of sertraline salts.


This work shows that the disproportionation tendency can be influenced by pHmax and buffering capacity and thus highlights the importance of selecting the appropriate salt form during the screening process in order to avoid salt-to-free form conversion.


buffering capacity mathematical modelling pHmax salt disproportionation 



Active pharmaceutical ingredient


Powder X-ray diffraction


Relative humidity


Thermogravimetric analysis


Tribasic sodium phosphate dodecahydrate



The Dane O’Kildsig Center for Pharmaceutical Processing Research is acknowledged for providing funding for this project. Pfizer Inc is thanked for providing a fellowship for Yi-Ling Hsieh. Sheri L. Shamblin, Kenneth C. Waterman, and Evgenyi Y. Shalaev, are thanked for the helpful discussions. Chris Seadeek is acknowledged for assisting in salt screens.


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Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Yi-Ling Hsieh
    • 1
    • 2
  • Jeremy M. Merritt
    • 3
  • Weili Yu
    • 4
  • Lynne S. Taylor
    • 1
    Email author
  1. 1.Department of Industrial and Physical PharmacyPurdue UniversityWest LafayetteUSA
  2. 2.Novartis Pharmaceutical CorporationSan CarlosUSA
  3. 3.Eli Lilly & CoIndianapolisUSA
  4. 4.Pfizer Global Research and DevelopmentGrotonUSA

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