Pharmaceutical Research

, Volume 26, Issue 8, pp 2015–2026

Role of Salt and Excipient Properties on Disproportionation in the Solid-State

Research Paper

DOI: 10.1007/s11095-009-9918-y

Cite this article as:
Guerrieri, P. & Taylor, L.S. Pharm Res (2009) 26: 2015. doi:10.1007/s11095-009-9918-y



Approximately 50% of active pharmaceutical ingredients (APIs) are manufactured and formulated as salts, due to their enhanced dissolution rates or improved solid state properties. It is essential to maintain the appropriate solid state form of the drug during processing and over the lifetime of the product. The aim of this study was to investigate the contributing factors in the process of disproportionation, whereby the salt converts back to the free form of the drug.


Infrared and Raman spectroscopy were used to detect and quantify the formation of free base in physical mixtures with excipients. The pH-solubility relationships were determined based on measured salt solubilities and properties of the free form.


The mesylate salts of two model pharmaceutical compounds were found to disproportionate to the free base form when physically mixed with certain common basic excipients and exposed to moderate relative humidities. In contrast, the napsylate salts were much more resistant to disproportionation. The napsylate salts had solubilities more than 3 orders of magnitude lower than the respective mesylate salts, and showed little to no detectable formation of free base. The mesylate salts with higher solubilities showed significant levels of conversion to the free base.


It appears that both the solubility and pHmax (the pH of a solution where there is saturation of both ionized and unionized species) of the salts, as well as the base solubility, play important roles in determining the susceptibility of salts to disproportionate. The extent of conversion was also affected by excipient properties, including basicity, solubility, physical state and surface area.


disproportionation pharmaceutical salts pH-solubility microenvironmental pH Raman spectroscopy 

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  1. 1.Department of Industrial and Physical Pharmacy, School of PharmacyPurdue UniversityWest LafayetteUSA

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