title: Impact of counterion on the chemical stability of crystalline salts of procaine.
abstract: Pharmaceutical compounds may be formulated as the salt form for a variety of reasons, including to increase solubility and dissolution rate as well as to improve the chemical or physical stability. The choice of salt former will influence properties such as solubility and may also have consequences on the solid-state chemical stability of the salt, particularly in the presence of moisture. The purpose of this work is to investigate the role of the counterion in affecting chemical stability. A series of crystalline salts of the model hydrolyzable compound procaine, encompassing a large range in both solubility and saturated solution pH, were synthesized and subjected to conditions of elevated temperature and relative humidities. The counterion was found to have a profound effect on chemical stability with apparent rate constants varying by more than two orders of magnitude across the range of compounds studied. A model was developed to predict the chemical stability of the various salts, and good agreement was observed between the model predictions and experimental data. The most important factors affecting the solid-state stability were found to be a combination of the hygroscopicity of the salt, its aqueous solubility, and the pH of the saturated solution. Thus it can be concluded that for procaine salts, the nature of the counterion plays a significant role in influencing solid-state stability.
authors.affiliation: Department of Industrial and Physical Pharmacy, School of Pharmacy, Purdue University, West Lafayette, Indiana 47907, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Guerrieri
authors.forename: Kjell
authors.initials: K
authors.lastname: Jarring
authors.forename: Lynne S
authors.initials: LS
authors.lastname: Taylor
mesh_terms: D000779:Anesthetics, Local / Q000737:chemistry*; D002152:Calorimetry, Differential Scanning; D004355:Drug Stability; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D007477:Ions / Q000737:chemistry; D011343:Procaine / Q000737:chemistry*; D012492:Salts / Q000737:chemistry*; D012995:Solubility; D014867:Water / Q000737:chemistry
chemical_list: D000779:Anesthetics, Local; D007477:Ions; D012492:Salts; D014867:Water; D011343:Procaine