Pharmaceutical Research

, Volume 32, Issue 2, pp 549–561 | Cite as

Salt Stability - Effect of Particle Size, Relative Humidity, Temperature and Composition on Salt to Free Base Conversion

  • Yi-Ling Hsieh
  • Lynne S. TaylorEmail author
Research Paper



The aim of this study was to investigate how factors such as temperature, relative humidity and particle size impact the extent of disproportionation (salt to free base conversion) in powder blends of miconazole, benzocaine or sertraline mesylate salts mixed with a basic additive.


Raman spectroscopy was used to quantitate the extent of disproportionation. The data was further analyzed by multivariate analysis with partial least squares (PLS) modeling.


It was found that salt disproportionation was significantly influenced by % weight gain due to moisture sorption both in terms of the kinetics and the conversion extent, suggesting a solution-mediated reaction. Temperature plays an important role in impacting the value of pHmax which in turn has a significant correlation to the amount of free base formed. The particle size and drug: additive ratio were also found to influence the extent of disproportionation.


This study shows that the extent of salt disproportionation is influenced by multiple factors and the application of PLS modeling demonstrated the feasibility of utilizing multivariate analysis to generate a predictive model for estimating the extent of conversion and thus may serve as a tool for risk assessment.


disproportionation multivariate analysis Raman spectroscopy salt storage conditions 


Acknowledgments and Disclosures

The Dane O’Kildsig Center for Pharmaceutical Processing Research is acknowledged for providing partial funding for this project. Pfizer Inc is thanked for providing a fellowship for Yi-Ling Hsieh. Kaho Kwok is thanked for assisting with the multivariate analysis.


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Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  1. 1.Department of Industrial and Physical PharmacyPurdue UniversityWest LafayetteUSA
  2. 2.IrvineUSA

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