Effect of counterion on chemical stability of a model pharmaceutical salt

Effect of counterion on chemical stability of a model pharmaceutical salt

Purpose.
The goal of our research is to investigate the effect of counterion on the chemical stability in the presence of moisture for a
pharmaceutical compound exhibiting a pH-dependent hydrolysis. Despite the fact that water is a known promoter of
chemical degradation, fundamental understanding is still lacking about which compounds and formulations are likely to be
most sensitive to high relative humidities.
Methods.
Crystalline salts of procaine formed using a series of counterions from various classes of acids including sulfonic, inorganic
and carboxylic acids were subjected to stressed conditions of elevated temperature and relative humidities. The relative
humidities were chosen to be below the measured critical relative humidity of the deliquescent salts. The degradation was
quantified over time via HPLC and x-ray photoelectron spectroscopy (XPS). A separate study to investigate any effect of
particle size on degradation rate was conducted. The moisture sorption isotherms of the salts were measured using a
gravimetric water vapor sorption balance. The amorphous form of certain salts was prepared and the degradation studied in
the presence of moisture. Multivariate analysis was performed to determine the relationship between degradation rates and
properties such as solubility and pH.
Results.
The various procaine salts produced were all crystalline and had quite different hygroscopicities and pH values for the
saturated solutions. The hydrolysis rate varied between the procaine salts and was found to be influenced by both the
moisture uptake and pH of saturated solution of the crystalline salt form. The measured pH of saturated solutions could be
reasonably predicted from theoretical models.
Conclusion.
In the case of pH-dependent reactions, the pKa of the counterion is a useful predictor of chemical reactivity in the presence of
moisture, even at relative humidities below deliquescence at which theoretically no solution should be present. The
microenvironmental pH may be important for solid formulations where one or more of the components have acidic/basic
functionaliti