Role of salt and excipient properties on disproportionation in the solid-state.
OBJECTIVE
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
It appears that both the solubility and pH(max) (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.
Guerrieri
Peter
P
Department of Industrial and Physical Pharmacy, School of Pharmacy, Purdue University, West Lafayette, Indiana 47907, USA.
Taylor
Lynne S
LS
D005079:Excipients; D006863:Hydrogen-Ion Concentration; D004364:Pharmaceutical Preparations; D012492:Salts; D012995:Solubility; D017550:Spectroscopy, Fourier Transform Infrared; D013059:Spectrum Analysis, Raman
D005079:Excipients; D004364:Pharmaceutical Preparations; D012492:Salts